What Is Known/What Is New
What Is Known
- Combination therapy of an immunomodulator with an antitumor necrosis factor biologic in children and adults with inflammatory bowel disease may help in optimizing biologic pharmacokinetics, minimizing immunogenicity, and improving treatment outcomes such as corticosteroid-free clinical remission and mucosal healing.
- The optimal duration of combination therapy and long-term benefits and risks of this treatment strategy are yet to be defined especially in children with inflammatory bowel disease.
What Is New
- Over a median follow-up of 1 year, the majority of children with inflammatory bowel disease in clinical remission on combination therapy for over 6 months remain in clinical remission after discontinuation of immunomodulator.
- Children presenting with clinically severe Crohn disease are more likely to relapse while on antitumor necrosis factor treatment as monotherapy after discontinuation of immunomodulator.
Inflammatory bowel diseases (IBDs), primarily Crohn disease (CD) and ulcerative colitis (UC), are chronic, noncurable immune-related diseases with remissions and relapses (1,2). Several medications are used for the management of IBD, including immunomodulators (IMs) and biologics including antitumor necrosis factor (anti-TNF) agents (3). The introduction of biologics has revolutionized the management of IBD. We recently demonstrated that utilization of anti-TNF agents has increased from <10% in 2004 to approximately 60% in patients with CD and 40% in patients with UC by 2016 (4). Early studies suggested that combination therapy of infliximab (IFX) and IM may help to optimize biologic pharmacokinetics, minimize immunogenicity, and improve outcomes such as corticosteroid-free clinical remission and mucosal healing (5,6). The reported risks associated with using IM are, however, concerning. In particular, cancer and infection risks associated with IM, especially azathioprine (AZA) challenge the concept of prolonged periods of combination therapy (7,8). In addition, clear evidence on long-term benefits of combination therapy is lacking. Consequently, discontinuation of IM with continuation of an anti-TNF agent as monotherapy in patients who are in clinical remission appear to be a logical and safe approach, although at this time no evidence exists to prove the efficacy of this strategy in pediatric IBD. The aim of this work was to determine the frequency and factors associated with the first clinical relapse after discontinuation of IM in a cohort of children with IBD on combination therapy.
METHODS
Study Design and Patients
We conducted a retrospective analysis of all children and adolescents (<17 years) diagnosed with IBD in 4 tertiary care pediatric IBD centers in Western Canada who were receiving combination therapy of IM and an anti-TNF agent for at least 6 months followed by discontinuation of IM after the establishment of clinical remission, between January 2014 and December 2018. Patients who received non-anti-TNF biologics were excluded. The diagnosis of IBD was based on the combination of the clinical picture and investigations including laboratory markers, radiological, endoscopic, and histopathological evidence.
Study Measures and Definitions
Baseline data included the following variables age at IBD diagnosis, sex, family history of IBD, IBD phenotype at diagnosis, clinical severity of IBD at diagnosis, and physician global assessment (PGA) at diagnosis. We also collected, data concerning patient's pharmacotherapy including IM, anti-TNF biologics, and therapeutic drug monitoring, mainly last IFX trough level before IM discontinuation, and fecal calprotectin if available.
Clinical remission was defined using Pediatric Crohn Disease Activity Index (PCDAI) for CD and Pediatric Ulcerative Colitis Activity Index for UC as <10. Relapse was defined as clinical activity indices >10 for CD and UC, respectively (9–11). The primary endpoint was the first clinical relapse after discontinuation of IM while on an anti-TNF agent as a monotherapy. Factors associated with the first relapse such as diagnosis, age at diagnosis, sex, disease severity at diagnosis, IM type and duration, and therapeutic drug monitoring and fecal calprotectin before stopping of IM if available were collected.
Statistical Analysis
Continuous data with normal distribution were presented as mean ± standard deviation, and nonnormally distributed data were presented as median with interquartile range (IQR). We used Shapiro-Wilk test to examine the normality of all continuous variables included in our analyses. Categorical variables were described as frequency distributions and crosstabulations. Chi square or Fisher exact test was used where appropriate to test the relationship between categorical variables. For continuous variables with normal distribution, Levene test was used to determine the equality of variance between groups. Independent sample t test was used to determine the differences between the means of 2 groups. For ordinal variables or continuous variables without normal distribution, Mann-Whitney U test was used to estimate the difference in distribution between 2 independent groups. Logistic regression was used to model the clinical relapse with other explanatory variables. Cox-regression model was used to estimate the hazard ratio with 95% confidence interval for the risk of having a clinical relapse on a monotherapy during follow-up. All tests were 2 tailed with the level of significance set as P < 0.05. We used SPSS (IBM Corp; Released 2013. IBM SPSS Statistics for Windows, Version 21.0. IBM Corp, Armonk, NY) to perform the statistical analysis.
Ethical Considerations
The study protocol was approved by the local research ethics boards of all collaborating centers.
RESULTS
A total of 105 patients (54 boys; 89 with CD; mean age at diagnosis of 11.6 ± 2.9 years) were included. The median duration of follow-up since the diagnosis of IBD was 3.4 years (IQR 2.5–4.6 years). Ninety-one (86.7%) patients were receiving IFX (median dose: 6.3 mg/kg [IQR 5.00–8.23]), 9 patients were on adalimumab (ADA), and 5 received both IFX and ADA sequentially. In addition to the anti-TNF agent, 53 (50.5%) were on Methotrexate (MTX) and 52 were on AZA. The median duration of combination therapy before IM discontinuation was 2.1 (IQR 1.3–2.8) years. All participants were in clinical remission at the time of IM discontinuation. IM was discontinued as patients were doing well, and it was felt that IM were not needed. The median duration of follow-up after IM withdrawal was 12.0 (IQR 5.0–19.0) months. Only 11 (10.5%) patients (9 with CD) relapsed over that period of follow-up. Table 1 summarizes the demographic and disease characteristics in those who relapsed compared with those who did not.
TABLE 1 -
Baseline demographics and disease characteristics in children with inflammatory bowel disease who relapsed versus nonrelapsed ones after immunomodulator withdrawal
|
Relapse (n = 11) |
No relapse (n = 94) |
OR (95% CI) |
| Sex |
| Male |
6 |
48 |
0.87 (0.25–3.05) |
| Female |
5 |
46 |
Ref |
| Diagnosis |
| CD |
9 |
80 |
Ref |
| UC |
2 |
14 |
8.89 (0.15–4.04) |
| Family history |
| Positive |
5 |
32 |
0.62 (0.18–2.19) |
| Negative |
6 |
62 |
Ref |
| Age classification (Paris classification) (12) |
| A1a |
5 |
22 |
0.37 (0.10–1.32) |
| A1b |
6 |
72 |
Ref |
| Growth impairment (Paris classification) (12) |
| G0 |
6 |
68 |
Ref |
| G1 |
4 |
22 |
0.49 (0.13–1.88) |
| Perianal disease |
|
|
|
| Present |
2 |
23 |
1.46 (0.30–7.24) |
| Absent |
9 |
71 |
Ref |
| Physician global assessment |
| Mild |
0 |
15 |
– |
| Moderate |
7 |
56 |
1.46 (0.39–5.47) |
| Severe |
4 |
22 |
Ref |
| Fulminant |
0 |
1 |
– |
| Immunomodulator (IM) |
| Azathioprine |
5 |
47 |
Ref |
| Methotrexate |
6 |
47 |
0.85 (0.15–2.79) |
| Infliximab (IFX) trough level at IM discontinuation |
| IFX level<5 μg/mL |
4 |
26 |
0.39 (0.08–1.88) |
| IFX level ≥5 μg/mL |
3 |
50 |
Ref |
| Fecal calprotectin (FCal) at IM discontinuation |
| FCal <250 μg/mg |
6 |
53 |
Ref |
| FCal ≥250 μg/mg |
2 |
14 |
0.79 (0.14–4.36) |
CD = Crohn disease; CI = confidence interval; IFX = infliximab; IM = immunomodulator; UC = ulcerative colitis.
No differences were found among all examined variables, although median trough IFX level before discontinuing IM was numerically higher in those who did not relapse (6.2 μg/mL) versus those who relapsed (3.8 μg/mL), but the difference was not significant (P = 0.4).
For the 11 patients who relapsed, 9 were on IFX, and 2 were on ADA. Following relapse, 3 patients were switched to a different biologic, 1 had an additional dose of IFX and reduction in future infusion interval, and 1 was restarted on MTX. The remaining patients continued on the same anti-TNF agent monotherapy and received no additional treatment with close clinical follow-up as their clinical relapse was perceived by their physicians as mild.
In the follow-up period, 60 of those who remained in clinical remission had proactive fecal calprotectin measured; the median value was 83 μg/mg (IQR 34–188).
For patients with CD, the mean PCDAI at diagnosis was 37.5 ± 20. Twenty-five (28.1%) of them had perianal disease, as defined by Paris classification, and 25 (28.1%) were classified as having growth retardation (G1) at diagnosis (12). Forty-seven (52.8%) received MTX, and 43 had AZA. IM was initiated after a median duration of 0.1 year (IQR 0–0.4) from diagnosis and continued for a median duration of 2 years (IQR 1.3–2.8 years). The median baseline PCDAI of patients who relapsed after IM discontinuation was 47.5 (IQR 35.0–55.0), which was significantly higher than those who did not relapse (median 35.0, IQR 20.0–52.5; P = 0.04) (Table 2).
TABLE 2 -
Investigated potential predictive factors of a clinical relapse in children with Crohn disease after discontinuation of immunomodulators
| Variable (median) |
Relapse (n = 9) |
No relapse (n = 80) |
P
|
HR (95% CI) |
| Age at diagnosis |
11.0 (IQR: 7.4–12.5) |
11.7 (IQR: 10.0–13.9) |
0.16 |
0.84 (0.65–1.07) |
| PCDAI at diagnosis |
47.5 (IQR: 35.0–55.0) |
35.0 (IQR: 20.0–52.5) |
0.04
|
1.02 (0.98–1.06) |
| Immunomodulator duration, y |
2.3 (IQR: 0.5–3.0) |
1.96 (IQR: 1.3–2.8) |
0.72 |
0.92 (0.42–2.02) |
| Duration of follow-up (mo) from stopping IM |
25.0 (IQR: 11.0–30.5) |
12.0 (IQR: 5.3–18.0) |
0.25 |
1.00 (0.93–1.08) |
| FCal (μg/mg) at stopping of IM |
123.0 (IQR: 50.0–145.0) |
75.0 (IQR: 33.8–192.8) |
0.48 |
1.00 (0.99–1.00) |
| TDM IFX (μg/mL) at stopping of IM |
3.6 (IQR: 2.6–10.3) |
6.1 (IQR: 4.0–10.0) |
0.19 |
0.93 (0.77–1.13) |
CI = confidence interval; FCal = fecal calprotectin; HR = hazard ratio; IFX = infliximab; IM = immunomodulator; IQR = interquartile range; PCDAI = Pediatric Crohn Disease Activity Index; TDM = therapeutic drug monitoring.Significant of P values in the table.
Anti-TNF agents were initiated after a median duration of 1 month (IQR 0–2 months) from diagnosis. Seventy-five (84.3%) received IFX, 9 (10.1%) had ADA, and the rest received 1 anti-TNF, then switched to the other. No patients had previous surgery.
Age of diagnosis, sex, disease phenotype at diagnosis, the presence of perianal disease in patients with CD, type, or duration of immunotherapy did not predict disease relapse after withdrawal of IM.
All patients with UC (15 patients, 10 girls) received IFX with 9 receiving AZA.
DISCUSSION
The benefits of combining immunosuppressive agents and anti-TNF biologics have been demonstrated in adult and pediatric IBD with several landmark studies such as the SONIC study in adults with CD and SUCCESS study in adults with UC showing the superiority of combination therapy over monotherapy (5,6,13–15). Because of risks associated with prolonged IM exposure, we conducted a multicenter retrospective study to examine discontinuation of IM in children with IBD in clinical remission. Our pilot data demonstrate that almost 90% of children who established clinical remission on combination therapy of an IM and an anti-TNF agent for over 6 months could be switched to anti-TNF monotherapy provided they have good anti-TNF drug level and remain in a clinical remission. In patients with CD, clinical disease severity at presentation may predict relapse following IM discontinuation. Moreover, patients with higher trough IFX levels at IM discontinuation may be able to continue on anti-TNF monotherapy for longer durations without experiencing a clinical relapse compared with those with lower IFX trough levels, although the difference did not reach statistical significance. De-escalation of treatment in IBD was recommended in several recently published algorithms and reviews, suggesting that the majority of patients in remission will continue to be in remission after de-escalation with monitoring trough levels of anti-TNF agents (16,17). Definitive data on discontinuation of immunosuppression in patients in remission, however, do not exist, especially in pediatric IBD. Our results, however, are concordant with those that examined the withdrawal of IM in adult patients with IBD on combination therapy. Van Assche et al (18) performed an open, randomized, controlled study to compare the clinical outcome of continuing or discontinuing IM therapy in adults with IBD in remission after 6 months of IFX combination therapy (16). Consistent with our findings, after 2 years of follow-up, no significant differences were reported in the presence of mucosal healing, the need for an increased IFX dose, or IFX discontinuation. Patients remaining on combination therapy, however, had higher median IFX trough levels. The same group published their retrospective experience in 223 adults with CD (65 receiving IFX as monotherapy and the rest on combination therapy) who were followed for a longer duration of follow-up of 34 months. The combination therapy group had higher trough IFX levels and fewer patients developing anti-IFX antibodies as compared to those on IFX monotherapy. The IFX trough levels, however, remained stable after IM discontinuation, but 38% required IFX dose to be increased over the follow-up period (19). In our cohort, only 1 (9%) of the 11 patients who relapsed was managed by shortening IFX infusion intervals.
Conversely, in another open, randomized, controlled study, Roblin et al (20) recruited adult patients with IBD in clinical remission on combination therapy of IFX and AZA. They were randomized to 3 groups; 1 maintained on the same dose of AZA (2–2.5 mg · kg−1 · day−1) that they have been receiving, 1 on a reduced dose of AZA (1–1.25 mg · kg−1 · day−1), and 1 without AZA and only on IFX as a monotherapy. The 3 groups were followed-up for 1 year and were assessed for the primary endpoint that was occurrence of a clinical relapse. No difference was found between low and normal dose AZA groups, but both of these groups did better (14%–15% relapsed) compared with the group on IFX monotherapy (42.3% relapsed).
Moreover, IFX trough levels in the IFX monotherapy group significantly decreased compared with the other 2 groups (20).
Although our study provides novel data in children with IBD as it is the first pediatric study to assess the strategy of discontinuing IM in stable children with IBD on combination therapy, our results are limited by the nonrandomized retrospective design, lack of a control group, small sample size (especially for those with UC), lack of endoscopic assessment at the end of follow-up, and the small number of the outcome event (clinical relapse). Our results, however, serve to provide pilot data for a properly designed, adequately powered randomized controlled study to examine this question.
CONCLUSIONS
We demonstrate that the majority of children with IBD in clinical remission on combination therapy of an IM agent and an anti-TNF medication for more than 6 months remain in clinical remission after discontinuation of the IM provided they have adequate anti-TNF drug levels. Clinicians, however, should be cautious discontinuing IM in those presenting with clinically severe CD and low trough IFX levels.
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