Alimentary Pharmacology and Therapeutics

Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy J. P. Gisbert, A. C. Marın & M. Chaparro

Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigaci on Sanitaria Princesa (IIS-IP), Centro de Investigaci on Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Spain.

Correspondence to: Dr J.P. Gisbert, Playa de Mojacar 29. Urb. Bonanza, 28669 Boadilla del Monte. Madrid. Spain. E-mail: [email protected]

Publication data Submitted 1 April 2015 First decision 20 April 2015 Resubmitted 13 May 2015 Resubmitted 14 May 2015 Resubmitted 22 May 2015 Resubmitted 24 May 2015 Accepted 25 May 2015 EV Pub Online 15 June 2015 This uncommissioned review article was subject to full peer-review.

SUMMARY Background The discontinuation of anti-tumour necrosis factor (anti-TNF) treatment in inflammatory bowel disease (IBD) patients in remission could be considered. Aim To evaluate the factors associated with relapse of IBD after discontinuation of anti-TNF therapy. Methods Electronic (PubMed/Embase) and manual search up to January 2015. Results The overall risk of relapse after discontinuation of anti-TNFs (27 studies) was 44% for Crohn’s disease (CD; follow-up range: 6–125 months) and 38% for ulcerative colitis (follow-up range: 6–24 months). Several factors were investigated to identify patients who are more likely to achieve long-lasting remission after anti-TNF discontinuation. The factors associated with a higher risk of relapse are younger age, smoking, longer disease duration, and fistulising perianal CD. Laboratory markers such as low haemoglobin levels, high C-reactive protein levels and high faecal calprotectin seem to increase the risk of relapse. On the other hand, low serum antiTNF levels seem to be associated with a lower risk of flare-up. Mucosal healing seems to decrease the risk of relapse after anti-TNF discontinuation (overall, this risk is 26% at 1 year with mucosal healing and 42% without), although this observation has not been confirmed by some authors. In patients receiving escalated anti-TNF doses or receiving anti-TNFs for the prevention of post-operative CD recurrence, the risk of relapse after discontinuation is high (>75%). Re-administration of the drug in those who relapsed after stopping treatment is effective and safe. Conclusions A high proportion of patients with IBD relapse after discontinuation of antiTNF treatment. As available data are insufficient to make strong recommendations on when anti-TNF therapy could be stopped, decisions should be taken on an individual basis. Aliment Pharmacol Ther 2015; 42: 391–405

ª 2015 John Wiley & Sons Ltd doi:10.1111/apt.13276

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J. P. Gisbert et al. INTRODUCTION The cytokine tumour necrosis factor (TNF) a is a key mediator of inflammation in inflammatory bowel disease (IBD). The use of anti-TNF-a drugs has greatly advanced the armamentarium for the treatment of both Crohn’s disease (CD) and ulcerative colitis (UC). Infliximab (IFX), adalimumab (ADA) and certolizumab pegol (CZP) have shown significant efficacy in IBD refractory to conventional treatments, including immunosuppressive drugs.1 The use of anti-TNF therapy is also associated with clinical benefits in IBD, such as higher mucosal healing, fewer hospitalisations and surgical procedures, and improved quality of life.2–5 However, anti-TNF agents are expensive and can cause severe side effects, such as infection6 and malignancy.7 Remission could, theoretically, last when the patient is off-treatment8; in fact, although some decision analysis models have established that anti-TNF agents are cost-effective,9 it is not so certain that they remain so in the long run. Moreover, patients in remission may still withhold anti-TNF treatment owing to treatment, pregnancy or reimbursement problems. However, the concerns related to discontinuation of anti-TNF in IBD patients include the risk of relapse, the possible loss of efficacy when the drug has to be restarted, the risk of infusion reactions or other adverse events at re-treatment and, finally, the worries over losing future – and limited – medical treatment options.10 Therefore, although patients who are likely to maintain remission could theoretically be considered for discontinuation, in clinical practice anti-TNF therapy should be continued in patients in remission. It remains unknown when, and if, anti-TNF agents can ever be stopped. In most countries, the decision to discontinue anti-TNF drugs is made on an individual basis by weighing up benefits against risks and cost-effectiveness.11 Cost of therapy is becoming a major issue in the decision on whether or not to prescribe biological drugs, and it is important to identify patients who will remain in long-term remission after discontinuation of anti-TNF therapy. Before making recommendations on when to stop anti-TNF therapy in patients with IBD, we first need to understand the factors influencing the duration of sustained clinical benefit after discontinuation. The aim of the present review was to systematically evaluate the factors associated with the risk of relapse after anti-TNF discontinuation in IBD patients to help the clinician to decide whether and when these drugs can be stopped.

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SEARCH STRATEGY A systematic bibliographic search was designed to identify studies investigating the risk of relapse in IBD patients (CD or UC) who discontinued anti-TNF therapy (IFX, ADA or CZP) while in remission. An electronic search was performed in PubMed and Embase up to January 2015 using the following algorithm: (infliximab OR adalimumab OR certolizumab) AND (inflammatory bowel disease OR crohn’s disease OR ulcerative colitis) AND (stop OR stopped OR discontinuation OR discontinue OR withdrawal OR withdrawn). International conference abstracts were inspected by means of a manual search of American Digestive Disease Week, United European Gastroenterology Week and the conferences of the European Crohn’s and Colitis Organisation (ECCO). In addition, the reference lists from the selected articles were reviewed to identify additional studies of potential interest. Articles published in any language were included. WHAT IS THE RISK OF RELAPSE OF IBD AFTER DISCONTINUATION OF ANTI-TNF THERAPY? A meta-analysis by our group on the risk of relapse after discontinuation of anti-TNF therapy in patients with IBD12 included 27 studies.10, 13–38 We found the overall risk of relapse after discontinuation to be 44% for CD (follow-up range: 6–125 months) and 38% for UC patients (follow-up range: 6–24 months). In CD, the relapse rate was 38% at 6 months after discontinuation, 40% at 12 months and 49% in the long term (>24 months). In UC, 28% relapsed at 12 months. Therefore, it was concluded that approximately one-third of IBD patients in remission under anti-TNF treatment relapsed 1 year after discontinuation.12 Accordingly, in the pioneering STORI study (The study of infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors), Louis et al. prospectively assessed the risk of relapse in 115 CD patients when IFX therapy was stopped after a 6-month corticosteroid-free remission period and found the 1-year relapse rate to be 44%.20 Experience with longer (>1 year) follow-ups is very limited. The risk of relapse >24 months after discontinuing anti-TNF agents in the previously mentioned metaanalysis was approximately 50%.12 In one long-term study, Steenholdt et al. followed a group of CD patients in clinical remission after discontinuation of IFX for up to 10 years and showed that 61% of patients remained in remission at 1 year, the percentage dropping to 50%

Aliment Pharmacol Ther 2015; 42: 391–405 ª 2015 John Wiley & Sons Ltd

Systematic review: anti-TNF discontinuation in IBD and 12%, respectively, at 2 and 10 years.10 More recently, Papamichael et al.39 reported a relapse rate of 48% in a group of CD patients followed up for a median of almost 10 years after discontinuation of IFX.39 These results are in agreement with the conclusion of two recent reviews, where the average 1-year relapse rate in CD patients who stop IFX was 40–45% and the 5-year rate 75%.8, 40 Similar results have been reported in rheumatoid arthritis, with an average remission rate after stopping IFX of 65% at 1 year and 50% at 5 years.8, 41–44 The aforementioned experiences imply that, if followed up for long enough, most IBD patients who discontinue antiTNF therapy will relapse. Anti-TNF therapy has the potential to completely interrupt the inflammatory process and theoretically induce long-term remission even after anti-TNF maintenance therapy is discontinued. One could hope that antiTNF therapy allows us to ‘put the counter back to zero’.18 However, the natural relapsing–remitting behaviour of IBD over time could explain why some patients experience long-term remission after stopping anti-TNF agents and why in the vast majority of these patients the disease eventually flares up again.45 Thus, it has been suggested that patients who discontinue anti-TNF treatment while in remission follow the natural disease course of CD46 and that prior effective anti-TNF therapy does not impose a subsequent disease-modifying effect.10 We need more studies, ideally randomised controlled trials, to compare the anti-TNF discontinuation strategy with a control group where the anti-TNF is maintained and the natural disease course with standard anti-TNF treatment (including the well-known loss of response to these drugs) is ascertained. A subgroup of IBD patients can achieve ‘indefinite’ or at least very long-term remission after discontinuation of anti-TNF therapy. Thus, below we review whether patients with a low risk of relapse can be identified using genetic, clinical, serologic, faecal, endoscopic or radiological markers. We will also review experience with discontinuation of anti-TNF in special circumstances, such as in patients whose dose of anti-TNF therapy was escalated, patients receiving anti-TNF therapy for prevention of post-operative recurrence of CD and pregnant patients. Finally, we investigate both the efficacy and safety of re-treating a relapse of IBD with the same antiTNF.

GENETIC MARKERS Genetic differences between CD patients with sustained remission and patients who relapse after discontinuing Aliment Pharmacol Ther 2015; 42: 391–405 ª 2015 John Wiley & Sons Ltd

IFX while in corticosteroid-free remission have been investigated.21 Genetic analyses were performed on samples from 14 patients (six with sustained long-term remission after stopping IFX and eight who relapsed rapidly after stopping the drug). Nearly a third of patients in full clinical remission who stopped IFX for reasons other than loss of response remained in sustained clinical remission. The authors concluded that the presence of IBD5 or NOD2/CARD15 mutations could not predict which patients might have sustained remission and which would relapse rapidly after stopping IFX. The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to IFX in patients with CD. Thus, another study evaluated its influence on risk of relapse after IFX discontinuation in 111 CD patients in remission, and demonstrated that this risk was higher for V/V patients than for F carriers.47

CLINICAL MARKERS Age Age ≥25 years at diagnosis was shown to be independently associated with sustained clinical remission.39 The novel finding that patients diagnosed with CD at a younger age have a higher cumulative probability of relapse after discontinuation of IFX could be explained by the fact that the more aggressive and complicated disease commonly seen in these patients probably requires continuous anti-TNF therapy.48 Sex Some authors have found that males have a higher risk of relapse after discontinuation,20 while others report opposite results.27 Smoking Smoking has been reported to be a risk factor for relapse after anti-TNF discontinuation.22, 27 These findings seem to be in accordance with the well-known negative effect of smoking in CD patients, namely, more severe disease course, increased therapeutic requirements, a poor response to medical therapy and a higher recurrence rate after surgery.49, 50 Disease duration The finding that a shorter time from diagnosis until the start of IFX favours sustained clinical remission after discontinuation has been attributed to the observation that early introduction of anti-TNF therapy is associated with 393

J. P. Gisbert et al. normalisation of dysregulated immunity, less severe intestinal tissue impairment and restored mucosal immune homoeostasis.45 If long-lasting and deep antiTNF–free remission can be achieved in IBD, it seems that such a state could be more likely reached in disease of short duration and with marked suppression of inflammation before irreversible immunological damage has taken place.45 However, most of the studies that have evaluated the effect of discontinuing anti-TNF treatment have included patients whose disease course lasted several years. For example, in the STORI trial, median disease duration was almost 8 years20; therefore, it is uncertain whether its conclusions apply to patients with early CD.

Type of IBD In our meta-analysis on the risk of relapse after antiTNF discontinuation in CD patients, the overall relapse rate was 44% (including studies with a follow-up ranging from 6 to 125 months). The corresponding figure for UC patients was slightly lower (38%), although the analysis included studies with shorter follow-ups (6–24 months).12 Some studies included both CD and UC patients and revealed a nonsignificant trend towards longer persistence of remission after discontinuation of IFX in patients with UC.10 These differences should be confirmed in adequately controlled studies. Disease location and phenotype Some authors have reported that CD patients with ileocolonic disease have a higher risk of relapse after discontinuation than those with isolated ileal disease.15 However, these findings have not been confirmed by other authors.22 With respect to disease progression when anti-TNF treatment is started, the diagnosis of complicated disease (stenosis and/or fistula in patients with CD) has been associated with a higher risk of flare after discontinuation.40 However, the influence of previous surgery for CD on the risk of relapse remains unclear, as some studies have found a higher risk,8, 24 while others reported a protective effect.20 Several authors found no differences in the duration of remission between patients with fistulising CD and patients with luminal CD,10, 15, 22 and no clear differences between luminal and fistulising CD were found in terms of risk of relapse after discontinuation.12 However, in most studies, perianal and other intestinal fistulas were grouped together. Furthermore, Domenech et al. showed that in luminal CD, discontinuation of IFX was 394

relatively successful, with a cumulative probability of being free of relapse of approximately 70% at 12 months17; in contrast, in perianal disease, early relapse was the rule after stopping IFX treatment, with only one-third of patients maintaining remission at 1 year.17 A major drawback of this study was that the response to IFX was only measured in terms of the physical examination because of its retrospective design, and imaging techniques were not systematically performed.51 It is well known that perianal disease is often active despite external closure of fistulas52; in fact, patients with complex fistulas often need long-term treatment, and it has been suggested that response to anti-TNF treatment in perianal disease should be evaluated by imaging techniques rather than by physical examination alone.51, 53 In a similar study, 58% of patients with luminal CD remained in corticosteroid-free complete remission after discontinuation of IFX, while the fistulas remained closed in only 35% of patients.54 Again, adequately controlled studies should be performed to conclude whether perianal and luminal disease are to be managed differently when anti-TNF therapy is discontinued. Taking into account that fistulising perianal CD is a very disabling condition, discontinuation of anti-TNF therapy in patients with perianal disease should be considered with caution; it cannot be generally recommended, unless careful evidence of healing is observed using adequate imaging techniques.

Pouchitis In recent years, anti-TNF therapy administered for the medical management of chronic refractory pouchitis has yielded encouraging results.55 However, data regarding the long-term efficacy of these agents and optimal duration of their administration are lacking in the literature.56 The first and only study to report on the longterm outcome of patients with chronic refractory pouchitis after discontinuation of successful anti-TNF therapy indicates that IFX could be discontinued in those who maintain complete clinical response after 1 year of therapy.56 These results need to be confirmed in future studies. ANALYTICAL AND SEROLOGICAL MARKERS Haemoglobin, leucocytes and platelets A low haemoglobin level (6 9 109/L) was found to be a risk factor for relapse after withdrawal of anti-TNF therapy.20

C-reactive protein Several studies have shown a correlation between intestinal inflammation and serum C-reactive protein (CRP).57 However, few data have been reported on the usefulness of close monitoring of this biomarker to predict relapse of IBD. Elevated CRP at discontinuation of anti-TNF therapy has been associated with a higher risk of relapse.8, 20, 22, 27 Some authors have evaluated in detail the usefulness of close monitoring of CRP levels to predict relapse of CD after discontinuation of IFX58: luminal CD patients treated for at least 1 year with IFX and in clinical remission for at least 6 months were prospectively recruited into the STORI trial, and their levels were monitored every 2 months until 18 months of follow-up or clinical relapse. During follow-up, CRP levels were found to be highly variable, regardless of the occurrence of relapse. However, median concentrations of CRP per patient were statistically higher in relapsers than in nonrelapsers (3.9 vs. 2.8 mg/L). In relapsers, a slight and progressive increase was followed by a sudden and more pronounced increase in CRP levels during the 4 months preceding clinical relapse. Thus, CRP values >5 mg/L were associated with relapse in the short term with a hazard risk of relapse of approximately 4. In summary, elevated levels of CRP are associated with an increased risk of short-term relapse after discontinuation of anti-TNF therapy in IBD patients, even if levels varied widely during follow-up. Nevertheless, it is well known that some patients do not synthesise CRP despite having severe mucosal inflammation, thus limiting the accuracy of this serum marker.57 Anti-Saccharomyces cerevisiae antibodies High concentrations of anti-Saccharomyces cerevisiae antibodies have been associated with a higher risk of relapse after discontinuation of anti-TNF.24 FAECAL MARKERS Faecal calprotectin Faecal calprotectin has been proposed as a non-invasive surrogate marker of intestinal inflammation in IBD.59 It correlates significantly with endoscopic lesions and with response to therapy.60 Furthermore, faecal calprotectin can also predict clinical relapse of IBD.61 Not surprisingly, it has been reported that elevated calprotectin is Aliment Pharmacol Ther 2015; 42: 391–405 ª 2015 John Wiley & Sons Ltd

associated with a higher risk of relapse once anti-TNF therapy is discontinued.15, 20, 24, 58, 62 The rationale for this correlation is that calprotectin may indicate the risk of relapse before the actual clinical relapse occurs. Many of the patients in whom anti-TNF therapy is interrupted seem to experience – in a relatively short period of time – endoscopic relapse, which can in turn lead to clinical relapse.45 Indeed, it seems that even patients who do not experience short-term clinical relapse on stopping therapy may experience low-degree inflammation in the intestinal mucosa.45 In a subanalysis of the STORI study, de Suray et al. assessed in detail the value of monitoring calprotectin levels to predict relapse after discontinuation of IFX in patients with CD.58 Patients with luminal CD treated for at least 1 year with IFX and in clinical remission for at least 6 months were recruited prospectively. During follow-up, the authors found a high variability in calprotectin, regardless of the occurrence of relapse. However, the evolution of this faecal marker was significantly different between relapsers and nonrelapsers. Thus, in nonrelapsers, a slight but significant increase in calprotectin levels was observed throughout follow-up. However, a sudden increase in calprotectin levels predicted the occurrence of a relapse during the following 4 months. Calprotectin values >250 lg/g were associated with relapse in the short term (hazard ratio >6). In a more recent study, Molander et al. prospectively enrolled IBD patients who were in clinical, endoscopic and calprotectin-based (3 lg/mL in 1 study14 or >6 lg/mL in another one39) were associated with relapse.8 The fact that patients with higher IFX trough levels at discontinuation are more prone to relapse suggests that these patients probably require continued administration and an adequate drug concentration to maintain clinical remission; therefore, they are more likely to relapse once therapy is discontinued.39 From another perspective, low anti-TNF trough levels (6 9 109/L)20 HR 3.2 (1.6–6.4) (hsCRP level ≥5 mg/L)20 OR 2.38 (0.92–6.19)22 HR 4.2 (1.9–9.2) (CRP > 5 mg/L)58 PPV for relapse 67% (FC > 50 lg/g)15 HR 2.5 (1.1–5.8) (FC 300 lg/g)20 HR 6.5 (2.7–15.6) (FC > 250 lg/g)58 HR 2.5 (1.1–5.4) (infliximab trough levels ≥2 lg/mL)20 Higher relapse risk if trough levels >3 lg/mL14 or >6 lg/mL39

Evidence based on few studies Evidence based on few studies False-negative results limit clinical application

When anti-TNFs were stopped based on achievement of clinical remission, 42% of CD patients relapsed during the following year.12 However, if patients discontinued anti-TNFs after achieving also endoscopic remission, this figure decreased to 26%.12 Similar differences were observed for UC at 12–24 months: relapse rates were 50% and 33% after therapy withdrawal based on clinical and endoscopic remission, respectively12

Lower risk not confirmed by some studies Degree of mucosal healing necessary unclear

Lack of validated cut-off point limits clinical application Lack of validated cut-off point limits clinical application

CD, Crohn’s disease; UC, ulcerative colitis; HR, hazard ratio (95% confidence interval); OR, odds ratio (95% confidence interval); CRP, C-reactive protein; faecal calprotectin; PPV, positive predictive value.

reactions.27, 95 Thus, a recent study evaluated a group of patients who required re-treatment with IFX because of a clinical relapse after at least 6 months of discontinuation of the first treatment.95 Infusion Aliment Pharmacol Ther 2015; 42: 391–405 ª 2015 John Wiley & Sons Ltd

reactions with the new administration of IFX were recorded in 24% of patients, of whom 17% discontinued treatment owing to severe reactions. Patients who maintained immunomodulators during the holiday 401

J. P. Gisbert et al. between the two IFX treatments had significantly fewer reinfusion reactions than those who did not receive immunomodulators.

CONCLUSIONS AND REMARKS FOR CLINICAL PRACTICE For reasons of cost and safety, discontinuation of antiTNF treatment could be considered in IBD patients who achieve remission. However, approximately one-third of IBD patients in remission will relapse 1 year after discontinuation, and this figure can reach >50% in the long term. Therefore, it seems clear that discontinuation of anti-TNF cannot be considered a universally advisable strategy in routine clinical practice. However, it is increasingly recognised that some patients can safely stop anti-TNF therapy and remain in remission for long periods off the drug. The factors associated with risk of relapse after antiTNF discontinuation are summarised in Table 1. To date, no genetic markers have been clearly associated with the risk of relapse after discontinuation. The only clinical markers associated with a higher cumulative probability of relapse after discontinuation of IFX are diagnosis with CD at a younger age, longer disease duration from diagnosis until initiation of anti-TNF therapy, and smoking; however, this evidence is based on few studies. As for CD phenotype, several authors found no differences in duration of remission between patients with fistulising and luminal CD, while others found opposite results, namely, a higher risk of relapse in perianal disease. Taking into account that perianal CD is a very disabling condition, discontinuation in this phenotype should be considered with caution and is probably not recommended unless evidence of cure has been confirmed using adequate imaging techniques. As for laboratory markers, low haemoglobin level and high leucocyte count have been associated with a higher risk of relapse after discontinuation. However, once again, this evidence is from few studies. Elevated CRP is associated with an increased risk of relapse shortly after discontinuation of anti-TNF therapy, although the falsenegative results with this marker limit its clinical application. Elevated levels of faecal calprotectin are associated with an increased risk of relapse shortly after discontinuation; however, again, the lack of a validated cutoff point for this marker limits its use in clinical practice.

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High IFX trough concentrations at discontinuation have been associated with relapse, suggesting that patients probably require continued anti-TNF therapy and an adequate drug concentration to maintain clinical remission. Mucosal healing is probably a major factor that should be evaluated when considering withdrawal of anti-TNF agents. It seems that patients in deep remission (clinical, biological and endoscopic remission) have a lower risk of relapse, although some studies report a high frequency of relapse, even after mucosal healing was confirmed. Therefore, in routine clinical practice, withdrawal should probably be considered only in patients in long-standing stable remission (clinical, biological and endoscopic). Nevertheless, the degree of mucosal healing that is necessary is unclear. In patients who require anti-TNF dose optimisation and in patients for whom anti-TNF therapy was prescribed to prevent post-operative recurrence, discontinuation of treatment cannot be recommended. Discontinuation of anti-TNF treatment in the second trimester of pregnancy is safe for the mother in terms of disease control and risks related to resumption of treatment. In conclusion, available data are insufficient to make strong recommendations on when anti-TNF therapy could be stopped. We feel that no definitive recommendation should be made until data from controlled studies are available. In the meantime, the decision to discontinue anti-TNF therapy should be individualised, and the benefits and risks should always be discussed extensively with the patient. An argument in favour of discontinuation is that response to re-treatment with the same antiTNF drug is generally effective and safe in patients who relapse.

AUTHORSHIP Guarantor of the article: None. Author contributions: JP Gisbert had the original idea for the study and designed the protocol. All the authors contributed to data extraction, the interpretation of the results, and the redaction of the manuscript. ACKNOWLEDGEMENTS Declaration of personal interests: JP Gisbert and M Chaparro have served as speakers, consultants and advisory members for and have received research funding from MSD and Abbvie. AC Marın: none. Declaration of funding interests: None.

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Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy.

The discontinuation of anti-tumour necrosis factor (anti-TNF) treatment in inflammatory bowel disease (IBD) patients in remission could be considered...
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