Abstract
Objective: We investigated relapse rates after anti-tumor necrosis factor (anti-TNF) withdrawal in inflammatory bowel disease (IBD) patients, response to restart of anti-TNF treatment and predictors for relapse.
Methods: IBD patients in remission receiving infliximab or adalimumab treatment for ≥1 year who discontinued treatment were included. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis.
Results: In total, 101 patients were included (77 CD, 24 UC). A total of 56 patients (55%) experienced a relapse (CD 38, UC 18) with a median time to relapse of 32 and 18 months in CD and UC, respectively. Of patients that were retreated with the same anti-TNF agent, 84% responded. A trough serum concentration ≥2 µg/ml within 1 year prior to anti-TNF discontinuation was associated with a higher relapse rate in CD patients (HR 2.89; p = .018), which was more evident in patients requiring retreatment with biologicals, bowel-related surgery or experimental medication (HR: 4.18; p = .009). A young age (<17 years) at diagnosis was associated with a higher relapse rate (HR: 2.29; p = .040) and fecal calprotectin levels <25 µg/g with a lower relapse rate in CD patients (HR: 0.34; p = .041). Relapse rates, requiring treatment with biologicals or experimental medication, was lower in UC patients who continued immunosuppressive treatment (HR: 0.26; p = .042).
Conclusions: Approximately 55% of patients relapsed after anti-TNF withdrawal with a median time to relapse of 32 and 18 months in CD and UC, respectively. Retreatment with the same anti-TNF was successful in 84% of patients.
Introduction
The introduction of anti-tumor necrosis factor (anti-TNF) agents has revolutionized the treatment of inflammatory bowel disease (IBD) and has resulted in better long-term outcomes [Citation1–7]. Anti-TNF agents are able to induce mucosal healing and decrease the risk of hospitalization and surgery [Citation6–9]. Patients that achieve remission with anti-TNF agents are often treated for many years if they tolerate the treatment [Citation10,Citation11]. Long-term treatment with anti-TNF agents is considered to be safe [Citation12–16], although side effects include infusion/injection site reactions, infections, skin problems and a small increase in risk for some malignancies in combination with immunosuppressive agents [Citation13,Citation15,Citation17]. As a result, the proportion of patients treated with anti-TNF agents is steadily increasing which is associated with high costs [Citation8,Citation18] in spite of the introduction of biosimilars [Citation19].
Due to the increasing number of IBD patients treated with anti-TNF agents, elective discontinuation of these agents is of particular interest. Common reasons for anti-TNF discontinuation are loss of efficacy, anti-drug-antibody formation, side-effects, pregnancy, patient preference, disease remission and costs. The decision to stop anti-TNF treatment in patients with primary non-response, secondary loss of response or severe side effects is usually simple. However, the decision to stop treatment in patients in remission or in patients with mild side effects is more difficult and is influenced by factors such as doctor and patient preference, treatment duration, treatment adherence and costs. It is known that adherence to long-term treatment is generally low, which is associated with suboptimal treatment outcomes and this also might be a reason to stop treatment [Citation20,Citation21].
Several studies have been conducted to investigate the effect of anti-TNF withdrawal and retreatment [Citation22–30]. These studies showed that retreatment with the same anti-TNF agent was effective in the majority of patients. Nevertheless, it still remains uncertain when and how to stop anti-TNF treatment in IBD patients who are in remission and which patients are likely to have successful retreatment. Therefore, guidelines on elective anti-TNF discontinuation in IBD patients are still lacking.
In this study, we aimed to evaluate the frequency of relapse, predictive factors associated with relapse and effect of retreatment after discontinuation of anti-TNF treatment in a tertiary cohort of IBD patients in corticosteroid-free clinical remission. These real-life findings might be useful for the development of future prediction models and guidelines.
Methods
Study design and patient population
This was a single-center observational cohort study performed at the Department of Gastroenterology and Hepatology of the Amsterdam UMC. Consecutive adult CD and UC patients that discontinued infliximab (IFX) or adalimumab (ADL) treatment between November 2012 and February 2018 were included. Patients were in corticosteroid-free clinical remission and treated with IFX or ADL for at least 1 year. All patients were prospectively followed on the outpatient clinic by IBD experts with regular appointments. Clinical, biochemical, endoscopic and radiological evaluation were performed during follow-up at physician’s discretion. All patients were followed until the end of the observation period (September 2018) or until relapse. Patients with a relapse, who were retreated with an anti-TNF agent, were followed until the end of the observation period or when retreatment failed.
Definitions
Remission was determined by physician’s global assessment and was based on absence of clinical symptoms and/or normal biochemistry [i.e., fecal calprotectin <250 µg/g and C-reactive protein (CRP) <5 mg/l] and/or endoscopic/radiologic remission (no signs of active inflammation) in the year prior to discontinuation. The cutoff for fecal calprotectin of 250 µg/g was based on data showing that it correlates well with endoscopic lesions [Citation31]. In case endoscopic, radiological or biochemical evaluations were not available in the year prior to discontinuation, inclusion was based on the absence of clinical symptoms alone. Relapse was defined as the requirement for (re)treatment with IBD medication (i.e., corticosteroids, immunosuppressives, biologicals or experimental medication), dose increase of IBD medication in follow-up period or IBD-related surgical interventions (i.e., bowel resections, deviating ileo/colostomy). In case of a relapse, treatment decisions were made at physician’s discretion. Response to retreatment with the same anti-TNF agent was determined by physician’s global assessment based on clinical, biochemical, endoscopic and/or radiological assessments. Intensified IFX schedules were defined as treatment intervals <7 weeks or a dose of 10 mg/kg and intensified ADL schedule were defined as doses of 40 mg every week.
Data collection
Data were collected from medical records. The following data were collected: gender, diagnosis, date of diagnosis, Montreal classification, smoking habits, IBD-related surgical history, previous and current medical treatment, anti-TNF start and stop date, anti-TNF treatment schedule and reasons for anti-TNF discontinuation. At the time of anti-TNF discontinuation, we reviewed age, duration of anti-TNF treatment, continued IBD medication, laboratory results (CRP, albumin, hemoglobin, leukocytes, thrombocytes and fecal calprotectin), endoscopic and radiologic results in the year prior to discontinuation of TNF inhibitors. Duration of follow-up and occurrence of relapse was documented. At the time of relapse and after anti-TNF retreatment, clinical, biochemical, endoscopic and radiological data were collected.
Statistical analysis
Descriptive statistics were used to characterize the patient population. Results were provided as numbers (percentages) for discrete variables and median (range) for continuous variables and as frequencies and percentages for categorical variables. Differences in not normally distributed paired parameter were tested with the Wilcoxon signed rank test. Time to relapse and relapse rates were assessed using Kaplan–Meier analysis. Univariable Cox regression analysis was used to study potential predictors for relapse. Multivariable Cox proportional hazard analysis was not performed since data was collected retrospectively resulting in occasionally missing data. The proportional hazards assumption was tested by testing the product of time to relapse and each variable for interaction within the model with the same variable alone. A p-value of <.05 was considered to be statistically significant. All statistical analyses were performed using SPSS 24.0 software (IBM Corporation, Armonk, NY).
Ethical approval and patient consent
This study was approved by the ethical committee of the Amsterdam UMC. Since this was a retrospective study, included patients provided consent with an opt-out procedure.
Results
Patient population
In total, 101 patients who discontinued anti-TNF treatment were included (77 CD, 24 UC). Patient characteristics are shown in . The median follow-up time of all patients was 47 months (IQR 33–51). The median treatment duration prior to anti-TNF discontinuation was 53 months (IQR 24.5–86.5). At the time of anti-TNF discontinuation, 51% of patients did not continue any medical treatment and 37% continued treatment with immunosuppressive agents ().
Table 1. Patient characteristics in CD and UC patients.
Table 2. Continued treatment at time of anti-TNF discontinuation in CD and UC patients.
Anti-TNF discontinuation
IFX and ADL treatment was discontinued in 57/101 (56%) and in 44/101 (44%) of patients, respectively. Endoscopy results showing quiescent disease within 1 year from anti-TNF discontinuation were available in 60/101 patients. Fecal calprotectin levels <250 µg/g in the year prior to discontinuation were available in 66/101 and CRP concentrations <5mg/l were available in 94/101. Thirty-three patients had both normal endoscopy and fecal calprotectin levels within 1 year prior to anti-TNF discontinuation and 7/101 had normal radiological findings in combination with normal fecal calprotectin levels. In 8/101 patients, remission was based on clinical symptoms alone. Out of these eight patients, one patient had a normal endoscopy (performed 21 months prior to discontinuation) and two patients had normal fecal calprotectin levels (measured at 13 months and 23 months prior to discontinuation) during anti-TNF treatment. Six patients had measurable anti-drug antibodies prior to anti-TNF discontinuation. shows additional reasons besides disease remission why it was decided to discontinue anti-TNF treatment.
Table 3. Reasons for discontinuing anti-TNF treatment.
Relapse rates
In total, 56/101 (55%) patients relapsed during the observation period. The relapse rate for CD patients was 49% (38/77) and 75% (18/24) for UC patients (). The median time to relapse was 28 months for all patients (). The median time to relapse was 32 months in CD and 18 months in UC patients (). Time to relapse was not significantly different between CD and UC patients (p = .143). Within 1 year after anti-TNF discontinuation, 22/77 (29%) CD and 8/24 (33%) UC patients relapsed and corresponding numbers within 2 years were 32/77 (42%) and 12/24 (50%). In 45/101 (45%) patients (33 CD, 12 UC), treatment with biologicals (i.e., anti-TNF, vedolizumab), IBD-related surgery or experimental medication (clinical trials) was required at the time of relapse. The median time to relapse for this subgroup was 41 months for all patients (44 months for CD and 38 months for UC patients ().
Figure 1. Flowchart of included patients.
Figure 2. Time to relapse in all patients (a), CD patients (b) and UC patients (c).
Figures 3. Time to relapse requiring treatment with biologicals, surgery or experimental medication in all patients (a), CD patients (b) and UC patients (c).
Efficacy of anti-TNF retreatment
Treatments started at the time of relapse are shown in . Anti-TNF treatment was re-started in 37 patients (20 IFX, 15 ADL, 2 golimumab). Thirty-three patients were re-treated with the same anti-TNF agent that was discontinued earlier (19 IFX, 14 ADL). The median follow-up time for patients retreated with the same anti-TNF agent was 38 months (IQR 29–26). Retreatment with any anti-TNF agent was successful in 30/37 (81%) patients (22 CD, 8 UC). Retreatment with the same anti-TNF agent was successful in 28/33 (84%) of which 21 were CD and 7 were UC patients. In 21/33 patients fecal calprotectin levels were available and improved significantly after a median of 4 (IQR 2–11) months (mean 1384 µg/ml vs. 196 µg/ml; p < .001). CRP levels were available in 24 patients showing a significant decrease after a median of 11 months (IQR 8-21) (mean 13.6 mg/ml vs. 2.5 mg/ml; p = .001). Insufficient endoscopic and radiological data were available to reliably assess retreatment effects.
Table 4. Treatment started at relapse in CD and UC patients.
Three patients did not respond to retreatment with the same anti-TNF. One patient had side effects (allergic reaction and skin rash) and in one patient the follow-up time after retreatment was only 1 month. One patient lost response to retreatment after an initial response after 17 months, one patient stopped the anti-TNF agent at 18 months after retreatment because of achieving clinical and biochemical remission after 8 months and one patient stopped the anti-TNF agent after retreatment because of anti-TNF induced lupus after a favorable initial response.
Predictors for relapse in patients requiring IBD treatment
Variables included in the univariable cox proportional hazards analysis are shown in . The assumption of proportionality was met for all tested variables. A trough serum drug concentration >2 µg/ml, irrespective of the anti-TNF agent in the year prior to discontinuation, was associated with a higher relapse risk in CD patients (HR: 2.89; p = .018), but not in UC patients (HR: 1.14; p = .829) with serum drug concentrations >2 µg/ml. Fecal calprotectin values <50 µg/g were not associated with a lower relapse risk in CD and UC patients (HR: 0.53; p = .114 and HR: 1.06; p = .93). However, fecal calprotectin values <25 µg/g before discontinuation were associated with a lower relapse risk in CD (HR: 0.34; p = .041), but not in UC patients (HR: 0.79; p = .697). Continuation of immunosuppressive agents was not associated with a lower relapse risk in all IBD patients, but a trend towards a lower relapse rate was observed in UC patients (HR: 0.37; p = .071). Younger age at diagnosis in CD patients (<17 years) was associated with a higher relapse risk (HR: 2.29; p = .040). A trend towards a higher relapse risk was seen in CD patients that received prior intensified anti-TNF treatment (HR: 1.96; p = .081). Due to incomplete data in several variables, multivariable analysis was not performed using variables p < .1.
Table 5. Univariable Cox proportional hazard analysis of potential predictors for relapse.
Predictors for relapse in patients requiring biologicals, surgery or experimental medication
Subgroup analysis was performed in patients who relapsed requiring treatment with biologicals (n = 40), IBD-related surgery (n = 1) or experimental medication in the setting of a clinical trial (n = 4). In this group, continuing treatment with immunosuppressive agents was associated with a lower relapse risk in UC (HR: 0.60; p = .042), but not in CD patients (HR: 0.83; p = .405). A trough level >2 µg/ml was associated with a higher relapse rate in all patients (HR: 3.31; p = .008) and in CD (HR: 4.18; p = .009), but not in UC patients (HR: 1.14; p = .829). Younger age at diagnosis in CD patients (<17 years) was associated with a higher relapse risk (HR: 2.68; p = .017). A trend towards a higher relapse risk was observed in CD patients requiring prior intensified anti-TNF treatment (HR: 2.00; p = .089) and a trend towards a lower relapse risk was seen in patients with fecal calprotectin values <25 µg/g (HR:0.45; p = .069). Due to incomplete data in several variables, multivariable analysis was not performed with variables p < .1.
Discussion
In this observational cohort study, we observed an overall relapse rate after anti-TNF discontinuation of 55% out of 101 consecutive IBD patients, with a median follow-up of 47 months. Of CD patients, 49% and of UC patients 75% relapsed. Retreatment with anti-TNF therapy was effective in 84% of patients. The relatively long follow-up period before and after relapse (median 47 and 38 months, respectively) in our cohort, allows for good estimations of relapse rate and retreatment success.
The outcomes in our study are comparable with relapse rates reported previously [Citation22,Citation23,Citation26–28,Citation30,Citation32]. However, follow-up periods vary considerably between the different studies and most of them lack long-term outcomes. Long-term data from the STORI trial in CD patients after IFX withdrawal showed that approximately 20% of patients remained without biological treatment, surgery or perianal disease with a 7 year follow-up period [Citation30]. In our study, half of CD patients remained relapse-free with a median follow-up of 32 months. The success percentage of retreatment of 84% in our cohort is in line with other studies ranging between 71% and 94% [Citation22,Citation23,Citation27–30,Citation32–35]. An exception was the study performed by Fiorino et al. [Citation33] In their cohort of 193 UC patients, only 51% achieved remission after anti-TNF retreatment. In the STORI trial, anti-TNF retreatment was safe and effective in 88% of patients [Citation30]. The small differences in reported relapse rates after anti-TNF cessation as well as in efficacy outcomes after retreatment between these studies could be explained by heterogeneity in study populations, different definitions of response and remission and variable follow-up periods after discontinuation and retreatment. Overall, it seems evident that a substantial proportion of IBD patients that discontinue anti-TNF treatment are prone to experience a relapse within several years and that retreatment with the same anti-TNF agent is effective and safe in the majority of patients.
Predicting which patients have an increased relapse risk is of great value for the decision-making process when considering elective anti-TNF discontinuation. We identified several potential predictors for relapse in our cohort. Low trough levels at the time of anti-TNF discontinuation were associated with a lower relapse risk in CD patients, but not in UC patients. This predictor has also been identified by Ben Horin et al. and by the STORI investigators [Citation26,Citation30]. Thus, a significant proportion of patients that remain in remission with low anti-TNF serum concentrations probably do not need the drug, hence they might be over-treated. Only six patients had measurable anti-drug antibodies prior to anti-TNF discontinuation. Therefore, we were unable to assess the effect of anti-drug antibody formation on relapse risk. Continuation of immunosuppressive agents was associated with a lower relapse risk in UC patients, but not in CD patients in our study. This was also shown in a cohort of UC patients by Fiorino et al. [Citation33]. Casanova et al. [Citation22] showed a minor advantage of continuation of immunosuppressive agents in CD patients after anti-TNF discontinuation. In addition, disease onset at a younger age in CD patients was associated with an increased relapse risk in our cohort, which has also been reported in three other studies [Citation22,Citation23,Citation36]. Low fecal calprotectin levels (<25 µg/ml) before anti-TNF discontinuation were associated with a lower relapse rate, which was mainly observed in CD patients. The frequently used cutoff of 50 μg/g was not associated with a lower relapse rate in this study. Therefore, we decided to investigate the 25 μg/g cutoff as potential predictor for relapse since unpublished data from our group suggest that lower fecal calprotectin values could predict histological remission more accurately. Other studies have also shown that normal biochemistry (i.e., CRP <5mg/ml and fecal calprotectin <250 µg/g) at the time of anti-TNF discontinuation is associated with a lower relapse risk [Citation32]. Therefore, it seems appropriate to at least confirm that fecal calprotectin levels are within the normal range before electively stopping anti-TNF treatment. Finally, we observed a trend towards a higher relapse risk in CD patients who received prior intensified anti-TNF treatment. To our knowledge this association, although not statistically significant, has not yet been observed in other studies.
Several other predictors for an increased relapse risk have been identified by others, including treatment with ADL, anti-TNF discontinuation because of adverse events, stricturing disease, perianal disease, gender, disease duration, ileocolonic or colonic disease, previous anti-TNF use and previous failure to immunosuppressives [Citation22,Citation28,Citation30,Citation32,Citation35–37]. However, in our study, none of these factors were identified as potential risk factors. Variability in relapse predictors between different studies could be explained by heterogeneity in study populations, study design, follow-up time and statistical methods. Nevertheless, several risk factors and protective factors have been identified in various independent cohorts which should be confirmed in larger prospective studies.
Identification of patients that are likely to have a favorable response to retreatment is also important for elective discontinuation of anti-TNF therapy. To our knowledge, only one study by Baert et al. [Citation34] has addressed this issue so far. They showed that the absence of anti-drug antibodies and re-initiation with immunosuppressive agents were predictive for safe and effective IFX retreatment. These findings are not surprising since it is well known that combination therapy and absence of anti-drug antibodies are important factors for successful anti-TNF treatment [Citation38,Citation39]. In our cohort, we were unable to assess predictors for successful retreatment due to the relative low number of patients that were retreated with anti-TNF agents. Larger cohorts are needed to identify additional predictors for successful retreatment.
Our study has several limitations. Firstly, this was not a controlled study and evaluations were performed at physician’s discretion. However, patients were followed up with regular appointments on the outpatient clinic, hence the occurrence of relapses could be accurately estimated. Additionally, data from real-life experience could be considered a strength, since it reflects the normal clinical setting. Secondly, patient data were collected retrospectively. Therefore, biochemical, endoscopic and/or radiological data were not always available. Results from the univariable Cox regression analysis for the identification of potential relapse predictors should thus be interpreted with caution and should be considered as an explorative analysis. For this reason, we decided not to perform a multivariable Cox regression analysis. To our opinion, predictive models using multiple variables should be based on large prospective datasets. Finally, our cohort consists of 77 CD and 24 UC patients. Especially the UC patient number might be too small for analyzing relapse predictors. Despite this, we identified several predictors that could be associated with a lower or higher relapse risk, confirming earlier work. These predictors might be used in future algorithms in order to discontinue anti-TNF treatment in patients with a low relapse risk.
In conclusion, this real-life IBD cohort shows a relapse rate of 55% and retreatment success of 84% confirming previous studies. The most important predictors for an increased relapse risk after stopping anti-TNF therapy in our cohort were young age (<17 years), trough levels >2µg/ml and elevated fecal calprotectin levels in CD patients. Continuation of immunosuppressive agents was associated with a decreased relapse risk in UC patients. Prospective studies are needed to confirm these predictors for relapse and to identify factors that could predict successful retreatment with anti-TNF agents.
| Abbreviations | ||
| IBD | = | inflammatory bowel disease |
| CD | = | Crohn’s disease |
| UC | = | ulcerative colitis |
| IFX | = | infliximab |
| ADL | = | adalimumab |
Disclosure statement
S. Bots has served as speaker for Abbvie, Merck, Sharp & Dome, Takeda, Jansen Cilag, Pfizer and Tillotts. S. Kuin has no potential conflicts of interest to declare. M. Löwenberg has served as speaker and/or principal investigator for: Abbvie, Celgene, Covidien, Dr. Falk, Ferring Pharmaceuticals, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Takeda, Tillotts, Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Achmea healthcare and ZonMW. C. Ponsioen has served as advisor to Takeda and Pliant, has received speaker’s fees from Takeda, Tillotts, Abbvie, and received research grants form Takeda. M. Duijvestein has served as advisor for Echo pharma and Robarts Clinical Trials, reports nonfinancial support from Dr. Falk Pharma, and received speaker fees from Janssen, Merck & Co., Inc., Pfizer, Takeda and Tillotts Pharma. K. Gecse has served as speaker and/or advisor for Amgen, AbbVie, Biogen, Boehringer Ingelheim, Ferring, Hospira, Immunic AG, Janssen, MSD, Pfizer, Samsung Bioepis, Sandoz, Takeda, Tigenix and Tillotts. G. D’Haens has served as advisor for Abbvie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts and Vifor. No external funding was obtained for this study.
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