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Inflammatory Bowel Diseases:
doi: 10.1097/01.MIB.0000442680.47427.bf
Clinical Review Articles

Stopping Anti-TNF Agents in Patients with Crohn's Disease in Remission: Is It a Feasible Long-term Strategy?

Sorrentino, Dario MD*,†,‡; Nash, Peter MD§; Viladomiu, Monica MS; Hontecillas, Raquel PhD; Bassaganya-Riera, Josep PhD

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*IBD Center, Division of Gastroenterology, Virginia Tech-Carilion School of Medicine, Roanoke, Virginia;

Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia;

Department of Clinical and Experimental Medical Sciences, University of Udine Medical School, Udine, Italy; and

§Department of Medicine, University of Queensland-Brisbane, Brisbane, Australia.

Reprints: Dario Sorrentino, MD, IBD Center, Division of Gastroenterology, Virginia-Tech Carilion School of Medicine, 3 Riverside Circle, Roanoke, VA 24016 (e-mail: drsorrentino@carilionclinic.org).

D. Sorrentino has been a consultant for and received honoraria from Janssen, Centocor, AbbVie, MSD, Hoffmann-LaRoche, Giuliani, Schering-Plough, and Ferring. P. Nash has been a consultant for and received honoraria from Pfizer, AbbVie, Bristol-Mayer Squibb and Janssen. The other authors have no conflicts of interest to disclose.

Received November 08, 2013

Accepted December 19, 2013

Crohn's disease (CD) is a chronic inflammatory disorder whose incidence is on the rise. Its relentless course often leads to surgery if the disease is left untreated. CD etiology is unknown and as such, it cannot be cured. As it is often the case with such conditions, the next best option to keep the disease under control is to suppress inflammation.1 Today's therapeutic armamentarium for CD includes steroids, antibiotics, immunomodulators (IM) and biologics. The latter, in most countries, only include tumor necrosis factor (TNF) neutralizing agents (infliximab, adalimumab, and certolizumab), by far the most effective agents. As in other chronic diseases, medical treatment must be life long to keep inflammation under control. Stopping therapy, by definition, is expected to cause quick relapse of inflammation. Yet, recent clinical data have partly challenged this basic assumption in the management of CD. Here, we will first review the original data suggesting that medical therapy with anti-TNF agents must be continuous to be effective in the long term. We will then review more recent data that indicate that anti-TNF agents may be stopped in a proportion of patients in remission without a major impact on disease control; the risk factors associated with relapse on stopping therapy and the likelihood of reinducing remission with the same medication in relapsing patients. Next, we will focus on the potential biological and clinical implications of these observations and discuss possible alternative long-term options in CD management.

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TRADITIONAL APPROACHES

Since their introduction in the late 1990s,2 anti-TNF agents have been proven extremely effective in treating luminal and perianal CD.3 Anti-TNF antibodies have also been successfully used in ulcerative colitis (UC) as well as rheumatologic, dermatologic, and other diseases.4,5 Over the years, it has become clear that to maximize their efficacy, anti-TNF agents must be given early in the course of the disease, before irreversible bowel damage (e.g., scarring) has taken place, and on a maintenance basis.3,6 As a consequence, recommended guidelines for their use include relatively early, severe inflammatory disease.7

As for the long-term strategy, it was shown long ago by Rutgeerts et al8 that after successfull induction of remission, patients given placebo rapidly relapse compared with those continued on infliximab who seem to maintain the clinical benefit over the long term. In addition, proposed long-term strategies in rheumatology and gastroenterology patients on infliximab included combination therapy with IM to reduce immunization phenomena, which could lead to antibody to infliximab (ATI) formation, possible loss of response, or infusion reactions.9 Such consequence was later attributed to the practice of treating patients on demand (i.e., stop and restart), rather than continuously.10 Hence, the available evidence suggested that patients should be optimally treated on a maintenance basis and that the medication, once initiated, should not be interrupted.

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NOVEL APPROACHES

Maintaining Remission After Stopping Infliximab

In recent years, data have been published indicating that a proportion of patients with CD in remission while on anti-TNF agents may be kept in remission even after stopping the medication (Table 1). One of the most recent and well-designed studies by Louis et al11 recruited 115 patients who received at least 1 year of therapy with scheduled infliximab and an IM such as azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) for active luminal CD. For enrollment, the patients had to be in corticosteroid-free remission over the past 6 months before inclusion with a Crohn's Disease Activity Index (CDAI) ≤150. Infliximab was then stopped, and the IM continued. Relapse was defined by a CDAI above 250 points or between 150 points and 250 points with a 70-point increase from baseline over 2 consecutive weeks. In case of relapse, the patients were retreated with infliximab, resuming the treatment as previously scheduled. In these patients, clinical response was defined by a decrease in CDAI of at least 70 points and 25% from CDAI at relapse. Remission was defined by a CDAI ≤150. Follow-up ended after the third retreatment infusion. The primary endpoint was time to relapse after withdrawal of infliximab and identification of risk factors associated with relapse. Secondary endpoints were tolerance, safety, and efficacy of retreatment with infliximab in patients who experienced a relapse. The median follow-up time was 28.2 months. This study showed that patients with CD stopping infliximab while on combination therapy with IM leads to clinical recurrence in approximately 50% of cases within 1 or 2 years with a median time to relapse of 16.2 months.

TABLE 1
TABLE 1
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In a different longitudinal cohort study, Waugh et al12 enrolled 48 patients with CD in full steroid-free clinical remission for at least 6 months who discontinued infliximab for reasons other than loss of response (and which included adverse events in 16% of cases). IM were concomitantly administered to 67% of these patients. They were monitored for up to 7 years, and relapse was defined as an intervention with CD medications or surgery. Kaplan–Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year period. In a third observational single center retrospective study, 53 patients with CD and 28 patients with UC stopped infliximab while in steroid-free remission and were monitored for up to 10 years.13 On anti-TNF interruption, 87% of patients with CD and 86% of patients with UC were on IM as well. Relapse was defined as an intervention with biologics or steroids or surgery (not with IM). After infliximab discontinuation, 61% of patients with CD remained in remission at 1 year, the percentage dropping to 50% and 12%, respectively at 2 and 10 years. Of the patients with UC, 75% were still in remission at 1 year and 40% after 4.5 years. Thus, with the limitations due to its retrospective nature, this study shows that, if followed long enough, virtually all patients in whom therapy has been stopped will relapse.

Rismo et al14 treated 37 patients with anti-TNF agents (infliximab or adalimumab) until complete mucosal healing, documented by colonoscopy, at which point treatment was stopped and the patients followed-up. During follow-up, 86% of patients were on IM (either MTX or AZA). Median time to clinical relapse was 26 weeks with 7 of 27 evaluated patients (26%) still in remission by week 52.14

Molnár et al15 stopped anti-TNF agents in 121 patients treated either with infliximab (72%) or adalimumab (28%) after 1 year of therapy, with the patients in clinical remission (defined as a CDAI < 150). One third of these patients accepted to undergo colonoscopy, which showed mucosal healing in only 35% of them. Eighty-five percent of these patients were on IM (thiopurines) as well, although 9% stopped them on initiation of anti-TNF agents. During follow-up, which lasted up to 1 year, 45% of patients had clinical relapse and restarted biologics. In a similar study,16 the same authors stopped infliximab in 51 patients with UC who had achieved clinical remission after 1 year of therapy. Thirty-five percent of the patients needed to be retreated with infliximab within 1 year after treatment cessation.

Other studies, aimed at different outcomes, provide additional useful data. Schnitzler et al17 conducted an observational cohort study to assess the long-term clinical benefit of infliximab in 614 consecutive patients with CD. Median follow-up time was 55 months. Five hundred forty-seven patients had an initial response to infliximab. Of these, during follow-up, approximately 1 of 3 had to stop the medication because of side effects, loss of response, or other reasons; whereas 2 of 3 had a sustained clinical benefit. Of the latter group, 110 patients stopped infliximab while on remission after a median of 6.2 months of therapy and a median of 4 infusions. Treatment had been episodic in 74% of patients, scheduled in 17% while the remaining had switched from episodic to scheduled. The majority of these patients (84%) were treated concomitantly with IM (80% with AZA, 20% with MTX), whereas 16% were only on infliximab. After stopping infliximab, remission was maintained for a median of 47.3 months.

In the follow-up of the “step-up versus top-down” study,18 Baert et al19 report a representative subset of 49 patients from the initially randomized cohort who underwent ileocolonoscopy after 2 years of therapy. Patients had initially been given either a combination of AZA and 3 infusions of infliximab (top-down) or treatment with conventional corticosteroids (step-up). Patients given AZA were given repeated doses of infliximab for relapses, whereas patients given corticosteroids were given AZA in cases of corticosteroid dependency and infliximab only if AZA failed. After colonoscopy, patients were followed for 2 additional years. In patients with complete mucosal healing, 17/24 patients (70.8%) were maintained in remission without steroids (as opposed to 6/22 without mucosal healing). Of these 17 patients, 15 were maintained in remission without infliximab. Three of these patients were in remission without even IM.

Few studies (vide supra) have checked the intestinal mucosal status in patients in whom anti-TNF agents were interrupted. In a prospective cohort study by our group,20 12 patients were treated immediately after surgery with induction and maintenance infliximab (5 mg/kg every 8 wk) monotherapy for a total of 3 years by which time none of them had developed clinical or endoscopic recurrence. Infliximab was then stopped for 4 months, and patients subjected to colonoscopy. The latter showed recurrence in 10/12 (83%) of patients.20 It could be argued that all these 10 patients were bound to develop disease recurrence if left untreated after surgery. Hence, the de facto endoscopic relapse rate after stopping infliximab was 100%. In a follow-up study from the RCT for infliximab for prevention of postoperative CD, Regueiro et al21 stopped infliximab in 5 out of 10 patients in complete clinical and endoscopic remission after 1 year of therapy. Four of these patients were on AZA, 1 on 5-ASA. Within 4 years, 100% of patients had endoscopic recurrence and 60% had clinical recurrence.

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Risk Factors for Recurrence After Stopping Infliximab

Only some of the studies described above were designed for and have attempted to identify the factors responsible for recurrence after stopping infliximab. Louis et al11 have identified an incomplete disease control before drug discontinuation as the major risk factor for relapse. Incomplete disease control included recent corticosteroid use, low hemoglobin levels, elevated WBC, mucosal damage (Crohn's Disease Endoscopic Index of Severity >0), C-reactive protein (CRP) ≥5 mg/L, and elevated fecal calprotectin. In addition, the authors found that male gender, infliximab trough levels >2 μg/mL and the absence of previous surgical resection also exposed the patients to a greater risk of recurrence. Interestingly, the last 2 factors seem to run counter current knowledge because both higher infliximab trough levels and lack of previous surgery are considered favorable prognostic factors in CD.22 In addition, elevated inflammatory indices as risk factors for relapse in this study indicate that at least some of the patients were not in profound remission (see below).

In their study, Waugh et al12 could not identify any risk factor for relapse. They report that multivariate analysis of concomitant drug therapy, number of infliximab doses, age, gender, disease location, and number of years from diagnosis to the start of infliximab therapy did not statistically impact the survival curve.12 Steenholdt et al13 report that patients with CD who relapsed had longer disease duration at the time of first infliximab infusion. No risk factors for relapse could be identified for patients with UC and, for both groups, there were no variables associated with prolonged remission.13 In the study by Rismo et al,14 univariate analysis showed that the median time to relapse differed according to mucosal cytokine levels. Patients with elevated and normal IL-17A and TNF-α expression levels had a median time of relapse of 20 and 68 weeks, respectively, after anti-TNF agents were stopped. No other factors were significantly associated with risk of relapse.14 Molnar et al15 showed that biological therapy in the past, elevated CRP levels at 52 weeks and dose intensification during the 1 year course of therapy with anti-TNF agents were associated with risk of relapse on stopping therapy. In a Cox-regression analysis, smoking was only borderline significant as a risk factor. In patients with UC, only previous use of biological agents was associated with the need of restarting infliximab on stopping therapy.16

Schnitzler et al17 studied the factors associated with poor long-term clinical benefit in all the patients who initiated infliximab therapy (not only in those in whom the medication was stopped). They found that luminal CD (as opposed to fistulising CD) and the lack of an initial drop of CRP to normal levels (on initiating treatment) were associated with poorer long-term response.17 Finally, Baert et al19 report that the conventional step-up therapeutic strategy (as opposed to the top-down strategy) and the presence of mucosal damage at the end of the 2-year study period were associated with relapse/need for therapy in years 3 and 4.

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Reinduction of Remission in Patients with Relapse

In the study by Louis et al,11 52 patients were retreated after a mean holiday of 6.6 months. After 2 infusions, as judged by a CDAI <150 and by a decrease in CDAI of at least 70 points and 25% from the CDAI at relapse, respectively, 88% of patients were in clinical remission and 98% had a clinical response. Importantly, none of the patients were positive for ATI before retreatment while after the second infusion, ATI were negative or inconclusive in all patients.11 Steenholdt et al13 also report an excellent outcome after retreatment: 24 out of 25 (96%) patients with CD and 5 out of 7 (71%) patients with UC experienced complete clinical remission. Finally, Molnár et al report that retreatment with biologics was effective in 55% of patients with CD and 94% of patients with UC after discontinuation of anti-TNF agents and clinical relapse.15,16 In the postoperative setting, endoscopic remission in all patients after anti-TNF interruption and retreatment has been shown since 2010.20

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Summary

Current evidence suggests that a group of CD patients, possibly 30% to 40%, in clinical remission while on IM and infliximab can stop the latter and maintain clinical remission for a relatively long interval.11–17,19 It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.13,14 Few of these studies have systematically included the mucosal status as a study outcome. When the latter is considered, majority of patients in whom therapy was interrupted seem to develop, in a relative short period of time, endoscopic relapse;14,20,21 which often leads to clinical relapse.21 Indeed, it seems that even patients who do not develop short-term clinical relapse on stopping therapy may experience a state of low-degree inflammation in the intestinal mucosa. A follow-up study by Louis' group only published in preliminary form so far23 shows that patients bound to develop clinical relapse have a sudden and predictable increase in CRP and fecal calprotectin levels on stopping infliximab. However, even those who are not bound to develop clinical relapse in the short term have a moderate, although significant, increase in these inflammatory indices compared with their own levels at baseline, before stopping therapy.

All studies show that infliximab can be restarted after a relatively long “drug holiday” without risking loss of response or adverse events in a large proportion of patients. This runs counter the long acquired notion that such strategy carries a negative prognostic outcome.8 A possible explanation for this finding may be related to the fact that in most of these studies, anti-TNF agents were given, before interruption, on a maintenance basis rather than on demand, which was customary in the past.

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How to Explain the Data

How can we explain the clinical observation that remission-inducing anti-TNF agents may be stopped in a proportion of patients with CD without a major impact on disease control?

The question raised by these observations comes to what is the immunological nature of true remission in CD, and whether the induction of remission with therapy requires a reset of the immune system and the re-establishment of immunological tolerance.

Alternatively, persistence of remission in some of these patients after stopping anti-TNF agents may be the result of the specific timing of initiation/cessation of therapy relatively to the individual natural course of CD.

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Are Anti-TNF Agents Resetting the Immune System in CD?

Helpful hints to answer the question may come from earlier studies in rheumatoid arthritis (RA), a chronic disease that shares a number of features with CD including the unknown etiology, a genetic predisposition, features of autoimmunity, aberrant T-cell immunity, and response to a variety of targeted biological therapies.5 In RA, remission and drug-free remission are now realistic therapeutic targets24 as is durability of remission over time.

In RA, remission has been defined in terms of clinical remission—using the clinical American College of Rheumatology and the European League Against Rheumatism criteria,25,26imaging remission—absence of significant synovitis on sensitive imaging studies such as power doppler ultrasound, or true remission—a state of no detectable disease either clinically or on imaging with no progression of structural damage.25,26

Studies of remission, both in patients with RA and animal models of inflammatory arthritis, have shown that regulatory T cells (CD4 + CD25 + FoxP3 + [Tregs]) seem to play a crucial role. They regulate the transition from acute inflammation to chronic inflammation and are essential in the maintenance of peripheral tolerance. The odds of sustained remission in RA are significantly increased in patients with short symptom duration, low inflammation-related cells frequency, high Treg cell frequency and high proportions of naive CD4+ T cells.27,28 Once remission has been induced, recurrence of disease activity occurs with the re-emergence of effector T-cell infiltration of synovium.29 The T-cell recruitment in the joint is dictated by local homeostatic forces, selective homing, or antigenic stimulation. Complete eradication of the synovial T-cell compartment seems to be needed to induce robust remissions.29 Globally, these data support the theory that early treatment may be effective in inducing profound and long-term remission because it may be associated with normalization of the immune system. By the same token, these data might imply that successful cessation of treatment can only be achieved when immunological abnormalities are not yet observed. This may only happen within the first few months of disease. Afterwards, it seems that the thymus looses its ability to control immunological homeostasis either as a consequence of inflammation or indirectly because of another unknown event that profoundly affects the immune system. The immunological status of the patients may then switch from reversible to controllable.30 This model is also supported by the clinical data related to remission induced by stem cell transplantation after immunological ablation.31 These data show that patients reaching long-term stabilization have a peak in CD25 FoxP3 expression in CD4+ cells, which are now anergic to nonspecific stimulation and have regained potent suppressive capacity in vitro. This clinical stabilization seems long lasting, which suggests the establishment of a renewed immune balance.31

Thus, durable and drug-free remission in RA, “the Holy Grail,” involves 2 critical immunologic features. First, an important temporal component: once the “window of opportunity” has passed, disease control but not disease reversibility is the best achievable target. The second component is the development of a degree of mucosal immune dysregulation that once achieved makes the process controllable with therapy but irreversible. These factors, rather than the resetting of the immune system or the re-establishment of immune tolerance, probably determine the likelihood of achieving long-term drug-free remission in RA.

As for CD, intestinal inflammation may predominantly result from an innate dysregulated expression of type 1 T-helper lymphocyte [Th1] and Th17-related cytokines, activated by triggering luminal antigens and followed by a dominant Th1 and Th17 adaptive response.32–34 Resistance to effector T-cell apoptosis (which leads to an expanded population of Th1 and Th17 cells) and continuous exposure to luminal antigens and adjuvants contribute to the chronic maintenance of this inflammatory response.33,34

The therapeutic efficacy of anti-TNF agents in CD can be in part explained by their ability to induce apoptosis of activated cells expressing TNF-α in their membrane, which, together with induction of cytotoxicity, results in a reduced number of inflammatory cells relatively to Tregs.35–39 Moreover, TNF-blocking agents largely restore gut barrier function in CD40 and affect many other inflammation-related aspects.38,41,42

As in RA, use of anti-TNF treatment in early CD is more effective and associated with better outcomes.6,18,19,43–45 This is likely the result of a re-established balance of the regulatory versus effector immune response, with mucosal healing and induction of remission, a state characterized by tolerance or controlled inflammation.39,46 Thus, as in RA, once early treatment has effectively downregulated inflammatory tissue-damaging responses and restored mucosal immune homeostasis, discontinuation of therapy may result in maintenance of remission during longer periods of time.13,14 By contrast, stopping treatment in patients with CD in clinical remission but in whom immunoregulatory networks remain defective and have not been completely restored by therapy is likely to result in fast relapse of the disease. This may be more likely in advanced disease (Fig. 1).

FIGURE 1
FIGURE 1
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Regardless of these considerations, it is unclear whether a true drug free and long-lasting remission can be achieved in CD because in most patients clinical remission, on interruption of anti-TNF therapy, seems to be maintained by concomitant IM. More importantly, the absence of symptoms does not rule out mucosal inflammation, the forerunner of clinical recurrence.21,47 Proper testing of this model should be conducted in very early CD, a condition rarely if ever seen in clinical practice since diagnosis probably follows the biological onset by years.48 Additionally, proper endpoints should include objective evidence of profound remission (i.e., the equivalent of true remission in RA) such as mucosal healing, normal CRP, and fecal calprotectin levels,14,20 which is missing from most published studies.

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Are We Piggyback Riding a Natural Remission Phase?

A landmark study by Munkholm et al,49 dating back almost 20 years, has shown that the best predictor of course behavior in CD is the disease activity within the initial 3 years after diagnosis. Although after the first presentation approximately 13% of patients experience an essentially relapse-free disease course and another 20% have continuously active disease, the majority (2/3) fluctuate between years in relapse and years in remission with waves of at least 2 years duration. Importantly, such disease course, as described in that study, seems truly natural, i.e., independent of treatment.49 More recent data seem consistent with this observation.50 Hence, in most patients with CD, the disease seems to proceed with a course a poussées51 (Fig. 2A), just as in other immune-mediated diseases (e.g., multiple sclerosis).52 By definition, the typical relapsing–remitting patient with CD is treated with anti-TNF agents during a phase of flare. This will result, in most cases, in reduced inflammation, improvement of clinical symptoms, and induction of remission. If drug-induced remission is profound and maintained for a long enough time, it is possible that the patient, on stopping the medication, will remain in remission because interruption of therapy may now coincide with the naturally occurring phase of quiescence (Fig. 2B). However, if after induction of remission the medication is stopped too early or before profound remission is reached, it is likely that the disease will soon relapse because the patient will still be in the naturally occurring phase of flare (Fig. 2C).

FIGURE 2
FIGURE 2
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Thus, the natural relapsing–remitting behavior of CD over time can potentially explain why some patients may experience a long remission after stopping anti-TNF agents while others may relapse immediately afterwards. Such model can also explain why the lack of full disease control (i.e., elevated CRP or fecal calprotectin) is a risk factor for disease relapse on stopping anti-TNF therapy11; why even in patients in continuous remission after drug withdrawal, there is a state of low inflammation23; and why in the large majority of these patients the disease may eventually flare again.13,14,50 Finally, if such explanation is correct, it would imply that a limited course of medications (even if very effective such as anti-TNF agents) may not be capable of altering the natural history of the disease.

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Any Other Long-term Option?

Uninterrupted treatment of CD with biologics seems to most unsustainable in the long term because of costs and potential side effects. Hence, some advocate a drug holiday strategy based on the data discussed above. However, dose optimization could represent an alternative and efficient approach to reduce costs and potentially adverse events in patients on long-term anti-TNF agents.

Although dose increase (or shortening of the therapeutic interval) is an accepted strategy for patients who have lost response to anti-TNF agents,53,54 no study has questioned whether the minimal effective dose of these medications in all patients with CD is truly the one recommended by the manufacturer (i.e., 5 mg/kg body weight [bw] for infliximab)55 or whether a lower dose could be equally effective. It is possible that early dose finding studies, conducted in advanced longstanding disease,56 only showed efficacy for infliximab doses ≥5 mg/kg bw. However, we now know that in longstanding disease, any medical therapy may be only marginally effective.57 Today, we tend to treat CD with anti-TNF agents at an earlier time, when patients are more responsive because of low disease burden. Hence, doses lower than 5 mg/kg bw might indeed be effective. Such a concept has been already explored in RA and other rheumatologic diseases.58,59

We have tested this hypothesis in postoperative CD, a setting where, by definition, the disease burden must be low. After a 4-month interruption of infliximab therapy, initiated immediately after surgery at standard doses of 5 mg/kg bw and continued for 3 years with all patients in endoscopic and clinical remission, endoscopic relapse was observed in 83% of patients.20 In all those with recurrence, anti-TNF therapy was restarted at lower doses with the endpoints being reinduction of endoscopic remission (i.e., a Rutgeerts score <2) and maintenance of endoscopic and clinical remission for at least 1 year. Infliximab was restarted at 1 mg/kg bw and the dose progressively increased until the primary outcome was reached. Colonoscopy was performed after 6 months of treatment with any given dose. While the doses of 1 and 2 mg/kg bw were largely ineffective in reaching the primary endpoint, the dose of 3 mg/kg bw restored and maintained mucosal remission in all patients and the benefit was long lasting (1 yr) (Fig. 3). Importantly, fecal calprotectin, a surrogate marker of mucosal inflammation, showed a significant correlation with the endoscopic scores at different infliximab doses.20 Hence, in a dose optimization study, noninvasive markers of intestinal inflammation such as fecal calprotectin, highly sensitive CRP and possibly others60 could replace endoscopy.

FIGURE 3
FIGURE 3
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It has been argued by many authors that the likelihood of clinical response to anti-TNF agents in patients with CD is a function of therapeutic drug trough concentrations, which, according to many, should be ≥3 μg/mL (reviewed in 54). Drug trough levels, in turn, are the result of several factors54 including drug doses. Hence, low drug doses may be expected to be associated with low drug trough levels, which may, in turn, cause formation of ATI, a factor which may also affect drug efficacy and cause adverse reactions.61 To examine this issue, we have conducted a long-term follow-up study in a subgroup of the postoperative, low infliximab dose-treated patients20 and measured drug trough levels and ATI.62 The data showed that while infliximab trough levels were well below 3 μg/mL in 60% of patients and low levels ATI’s were present in 40% of them, all patients maintained full endoscopic and clinical remission after an average of 2.5 years at the dose of 3 mg/kg.

Thus, it is possible that the threshold therapeutic infliximab trough level may vary depending on the clinical scenario and the disease burden, while the clinical meaning of low levels ATI may need further studies.61,63,64 Most importantly, this study shows that low dose infliximab is effective and safe in the long term to prevent postoperative recurrence in CD.62,65 Because of its small size, this study clearly needs confirmation. In addition, it was limited to postoperative patients. However, these findings may well pave the way to test a dose titration strategy in nonsurgical patients and eventually to compare such approach to the drug holiday strategy.

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CONCLUSIONS

A few recent studies have indicated that a substantial proportion of patients with CD kept in clinical remission by anti-TNF agents may maintain such remission for several months after stopping the medication. In most cases, patients were also treated with IM, which were not stopped. Some aspects limit the interpretation of these findings. For example, it is unclear whether patients were in true, profound remission at the time anti-TNF agents were stopped and whether such remission was maintained throughout, since objective biological parameters of disease activity (e.g., the intestinal mucosa status) are often missing from these studies both at enrollment and during follow-up. Yet, complete remission when stopping therapy seems to be the most reliable predictor of successful cessation.66 As mucosa examination and healing is rapidly becoming the standard endpoint when starting therapy, normal colonoscopy (and/or normal surrogate markers of disease activity) should also be adopted as a criterion when stopping therapy and during follow-up.

If a long lasting and profound drug (anti-TNF)-free remission can be achieved in CD as in RA, it seems that such state could be more likely reached in disease of short duration and on profound suppression of inflammation, before irreversible immunological aberrations have taken place.

Current data, showing maintenance of remission in patients with CD stopping anti-TNF therapy, might be explained by its typical relapsing–remitting course with the outcome essentially dependent on the individual disease course and timing of therapy interruption.

Finally, initial studies in postoperative CD indicate that optimizing anti-TNF agents dose may be effective in the long term and afford advantages both in terms of costs and potentially long-term side effects. Whether such strategy could also be proposed in nonsurgical CD must await dedicated studies.

As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.67–69 Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented.70 If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (≥1 yr) remission and continuing the IM. Such patients should be closely followed-up by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.

More studies may be needed to decide whether starting and stopping anti-TNF therapy will become a routine strategy in the long-term management of patients with CD. They should include biological disease activity among the endpoints and should focus on early disease.

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REFERENCES

1. Nathan C. Points of control in inflammation. Nature. 2002; 420:846–852.

2. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997; 337:1029–1035.

3. Danese S, Colombel JF, Reinisch W, et al. Review article: infliximab for Crohn's disease treatment—shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther. 2011; 33:857–869.

4. Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Therap Adv Gastroenterol. 2013; 6:269–293.

5. Nash PT, Florin TH. Tumour necrosis factor inhibitors. Med J Aust. 2005; 183:205–208.

6. Colombel JF, Sandborn WJ, Reinisch W, et al.; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362:1383–1395.

7. D'Haens GR, Panaccione R, Higgins PD, et al. The London position statement of the World Congress of Gastroenterology on biological therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011; 106:199–212.

8. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology. 1999; 117:761–769.

9. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003; 348:601–608.

10. Hanauer SB. Risks and benefits of combining immunosuppressives and biological agents in inflammatory bowel disease: is the synergy worth the risk? Gut. 2007; 56:1181–1183.

11. Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012; 142:63–70.

12. Waugh AW, Garg S, Matic K, et al. Maintenance of clinical benefit in Crohn's disease patients after discontinuation of infliximab: long-term follow-up of a single centre cohort. Aliment Pharmacol Ther. 2010; 32:1129–1134.

13. Steenholdt C, Molazahi A, Ainsworth MA, et al. Outcome after discontinuation of infliximab in patients with inflammatory bowel disease in clinical remission: an observational Danish single center study. Scand J Gastroenterol. 2012; 47:518–527.

14. Rismo R, Olsen T, Cui G, et al. Normalization of mucosal cytokine gene expression levels predicts long-term remission after discontinuation of anti-TNF therapy in Crohn's disease. Scand J Gastroenterol. 2013; 48:311–319.

15. Molnár T, Lakatos PL, Farkas K, et al. Predictors of relapse in patients with Crohn's disease in remission after 1 year of biological therapy. Aliment Pharmacol Ther. 2013; 37:225–233.

16. Farkas K, Lakatos PL, Nagy F, et al. Predictors of relapse in patients with ulcerative colitis in remission after one-year of infliximab therapy. Scand J Gastroenterol. 2013; 48:1394–1398.

17. Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort. Gut. 2009; 58:492–500.

18. D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet. 2008; 371:660–667.

19. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology. 2010; 138:463–468.

20. Sorrentino D, Paviotti A, Terrosu G, et al. Low dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn's disease. Clin Gastroenterol Hepatol. 2010; 8:591–599.

21. Regueiro M, Kip KE, Schraut WH, et al. 4.5 Yr follow-up of patients enrolled in the randomized controlled trial (RCT) of infliximab (Inf) for prevention of postoperative Crohn's Disease (CD). Gastroenterology. 2010; 138:S694

22. Sorrentino D, Radford-Smith G. Maintenance of remission after stopping infliximab in Crohn's disease. Is all that glitters true gold? Gastroenterology. 2012; 142:17–19.

23. De Suray N, Salleron J, Vernier-Massouille G, et al. Close monitoring of CRP and fecal calprotectin is able to predict clinical relapse in patients with Crohn's disease in remission after infliximab withdrawal. A sub-analysis of the Stori study. Gastroenterology. 2012; 142:S-149

24. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2008; 58:S126–S135.

25. Felson DT, Smolen JS, Wells G, et al.; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011; 63:573–586.

26. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011; 70:404–413.

27. Frey O, Reichel A, Bonhagen K, et al. Regulatory T cells control the transition from acute into chronic inflammation in glucose-6-phosphate isomerase-induced arthritis. Ann Rheum Dis. 2010; 69:1511–1518.

28. Saleem B, Keen H, Goeb V, et al. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis. 2010; 69:1636–1642.

29. Harry RA, Anderson AE, Isaacs JD, et al. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann Rheum Dis. 2010; 69:2042–2050.

30. Roord ST, de Jager W, Boon L, et al. Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4+CD25+Foxp3+ regulatory T cells. Blood. 2008; 111:5233–5241.

31. Radbruch A, Thiel A. Cell therapy for autoimmune diseases: does it have a future? Ann Rheum Dis. 2004; 63:(suppl 2):ii96–ii101.

32. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003; 3:521–533.

33. Barnes MJ, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity. 2009; 31:401–411.

34. Sartor RB. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006; 3:390–407.

35. Itoh J, de La Motte C, Strong SA, et al. Decreased Bax expression by mucosal T cells favours resistance to apoptosis in Crohn's disease. Gut. 2001; 49:35–39.

36. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology. 2003; 124:1774–1785.

37. Peake ST, Bernardo D, Peake ST, et al. Mechanisms of action of anti-tumor necrosis factor α agents in Crohn's disease. Inflamm Bowel Dis. 2013; 19:1546–1555.

38. Danese S. Mechanisms of action of infliximab in inflammatory bowel disease: an anti-inflammatory multitasker. Dig Liver Dis. 2008; 40:S225–S228.

39. Hölttä V, Sipponen T, Westerholm-Ormio M, et al. In Crohn's disease, anti-TNF-α treatment changes the balance between mucosal IL-17, FOXP3, and CD4 Cells. ISRN Gastroenterol. 2012; 2012:505432

40. Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease. Am J Gastroenterol. 2002; 97:2000–2004.

41. Di Sabatino A, Pender SL, Jackson CL, et al. Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology. 2007; 133:137–149.

42. Di Sabatino A, Biancheri P, Piconese S, et al. Peripheral regulatory T cells and serum transforming growth factor-β: relationship with clinical response to infliximab in Crohn's disease. Inflamm Bowel Dis. 2010; 16:1891–1897.

43. Frøslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007; 133:412–422.

44. Ha C, Kornbluth A. Mucosal healing in inflammatory bowel disease: where do we stand? Curr Gastroenterol Rep. 2010; 12:471–478.

45. Rubin DT, Uluscu O, Sederman R. Response to biologic therapy in Crohn's disease is improved with early treatment: an analysis of health claims data. Inflamm Bowel Dis. 2012; 18:2225–2231.

46. Liu C, Xia X, Wu W, et al. Anti-tumour necrosis factor therapy enhances mucosal healing through down-regulation of interleukin-21 expression and T helper type 17 cell infiltration in Crohn's disease. Clin Exp Immunol. 2013; 173:102–111.

47. McLeod RS, Wolff BG, Steinhart AH, et al. Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease. Gastroenterology. 1997; 113:1823–1827.

48. Benevento G, Avellini C, Terrosu G, et al. Diagnosis and assessment of Crohn's disease: the present and the future. Expert Rev Gastroenterol Hepatol. 2010; 4:757–766.

49. Munkholm P, Langholz E, Davidsen M, et al. Disease activity courses in a regional cohort of Crohn's disease patients. Scand J Gastroenterol. 1995; 30:699–706.

50. Solberg IC, Vatn MH, Høie O, et al. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol. 2007; 5:1430–1438.

51. Pariente B, Cosnes J, Danese S, et al. Development of the Crohn's disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011; 17:1415–1422.

52. Andersen O. Disease mechanisms in multiple sclerosis: phases of disease improvement unrelated to relapses. Nat Rev Neurol. 2012; 8:596–598.

53. Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn's disease: a review. Am J Gastroenterol. 2009; 104:760–767.

54. Ordás I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2012; 10:1079–1087.

55. REMICADE® (infliximab) Prescribing Information 2012. www.remicade.com

Available at: www.remicade.com. Accessed November 5, 2013


56. Hanauer SB, Feagan BG, Lichtenstein GR, et al.; ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002; 359:1541–1549.

57. Peyrin-Biroulet L, Bigard MA, Malesci A, et al. Step-up and top-down approaches to the treatment of Crohn's disease: early may already be too late. Gastroenterology. 2008; 135:1420–1422.

58. Jois RN, Leeder J, Gibb A, et al. Low-dose infliximab treatment for ankylosing spondylitis—clinically- and cost-effective. Rheumatology. 2006; 45:1566–1569.

59. van den Bemt BJF, den Broeder AA, Snijders GF, et al. Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study. Ann Rheum Dis. 2008; 67:1697–1701.

60. Beniwal P, Harrell L. The status of diagnostic markers for inflammatory bowel disease. Curr Gastroenterol Rep. 2010; 12:479–484.

61. Ordás I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012; 91:635–646.

62. Sorrentino D, Hauenstein S, Marino M, et al. Low dose infliximab for prevention of postoperative recurrence of Crohn's disease: long term follow-up and impact of infliximab trough levels and antibodies to infliximab. Gastroenterology. 2013; 144:S-777

63. Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease. Scand J Gastroenterol. 2011; 46:310–318.

64. Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn's disease: a critical systematic review. Inflamm Bowel Dis. 2009; 15:1264–1275.

65. Sorrentino D. State of the art medical prevention of post-operative Crohn's disease. Nat Rev Gastroenterol Hepatol. 2013; 10:413–422.

66. Andrews JM. Commentary: predicting relapse in Crohn's disease patients in remission with biologics. Aliment Pharmacol Ther. 2013; 37:497–498.

67. Peyrin-Biroulet L, Danese S. Stopping infliximab in Crohn's disease: still an ongoing STORI. Inflamm Bowel Dis. 2012; 18:2201–2202.

68. Clarke K, Regueiro M. Stopping immunomodulators and biologics in inflammatory bowel disease patients in remission. Inflamm Bowel Dis. 2012; 18:174–179.

69. Hashash JG, Regueiro MD. The great debate: stopping immunomodulators and biologics in Crohn's disease patients in remission. Expert Rev Gastroenterol Hepatol. 2013; 7:501–503.

70. Pittet V, Froehlich F, Maillard MH, et al. When do we dare to stop biological or immunomodulatory therapy for Crohn's disease? Results of a multidisciplinary European expert panel. J Crohns Colitis. 2013; 7:820–826.

Keywords:

anti-TNF agents; Crohn's disease; long term therapy; stopping biologics; immunomodulators

Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

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