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  • Review
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14 May 2021

28 Pages

Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis

,
,
and
1
Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
J. Clin. Med.2021, 10(10), 2132;https://doi.org/10.3390/jcm10102132
This article belongs to the Special Issue Novel Insight into the Diagnosis and Management of Crohn’s Disease
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Abstract

Loss of response to antitumor necrosis factor (anti-TNF) therapies in inflammatory bowel disease occurs in a high proportion of patients. Our aim was to evaluate the loss of response to anti-TNF therapy, considered as the need for dose intensification (DI), DI effectiveness and the possible variables influencing its requirements. Bibliographical searches were performed. Selection: prospective and retrospective studies assessing DI in Crohn’s disease and ulcerative colitis patients treated for at least 12 weeks with an anti-TNF drug. Exclusion criteria: studies using anti-TNF as a prophylaxis for the postoperative recurrence in Crohn’s disease or those where DI was based on therapeutic drug monitoring. Data synthesis: effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (ulcerative colitis vs. Crohn’s disease), anti-TNF drug and follow-up. Results: One hundred and seventy-three studies (33,241 patients) were included. Overall rate of the DI requirement after 12 months was 28% (95% CI 24–32, I2 = 96%, 41 studies) in naïve patients and 39% (95% CI 31–47, I2 = 86%, 18 studies) in non-naïve patients. The DI requirement rate was higher both in those with prior anti-TNF exposure (p = 0.01) and with ulcerative colitis (p = 0.02). The DI requirement rate in naïve patients after 36 months was 35% (95% CI 28–43%; I2 = 98%; 18 studies). The overall short-term response and remission rates of empirical DI in naïve patients were 63% (95% CI 48–78%; I2 = 99%; 32 studies) and 48% (95% CI: 39–58%; I2 = 92%; 25 studies), respectively. The loss of response to anti-TNF agents―and, consequently, DI―occurred frequently in inflammatory bowel disease (approximately in one-fourth at one year and in one-third at 3 years). Empirical DI was a relatively effective therapeutic option.

1. Introduction

Biologic therapies have become the mainstay of treatment in inflammatory bowel disease (IBD). Antibodies targeting tumor necrosis factor-alpha (anti-TNF) have become essential in the armamentarium for the treatment of both ulcerative colitis (UC) and Crohn’s disease (CD). TNF is a key proinflammatory cytokine that plays an important role in several autoimmune disorders, including IBD. Elevated stool and mucosal TNF concentrations in UC and CD patients have been shown to correlate with the disease activity [1]. Anti-TNF drugs operate via a multitude of mechanisms: they bind and clear soluble TNF but, also, cell-bound TNF, inducing cytotoxicity on immune cells, like T-cell apoptosis [2]. They are effective at inducing symptom relief, disease remission and mucosal healing and reducing the need for surgery and hospitalizations among patients with moderate-to-severe IBD. The current clinical guidelines recommend anti-TNF agents for patients who are refractory to other treatments [3,4,5,6].
However, a considerable proportion of these patients does not respond to induction therapy (primary nonresponse) or lose response over time (secondary nonresponse or loss of response, LOR). In patients who experience LOR to a particular anti-TNF agent, dose escalation or intensification (DI), either by increasing the dose or decreasing the dosing intervals, is commonly used as a rescue strategy to regain the therapeutic effect. Nevertheless, the exact incidence and chronology of this intensification, and its efficacy, are still not well-known.
The aim of this systematic review was to evaluate the incidence of LOR (defined as the need for DI) over time and DI efficacy in regaining both the response and remission in inflammatory bowel disease. The secondary objectives were to identify the possible variables (baseline medical condition, anti-TNF therapy and time of follow-up) influencing the DI requirement and its efficacy.

2. Materials and Methods

2.1. Literature Search and Study Selection

Bibliographic searches were performed in four electronic databases (Medline, Embase, Cochrane Library CENTRAL and CINAHL) from inception up to January 2020. The search strategy (with corresponding keywords in all fields) was: “(inflammatory bowel disease OR Crohn’s disease OR ulcerative colitis) AND (infliximab OR adalimumab OR certolizumab OR golimumab OR antiTNF OR anti-TNF) AND (intensification OR escalation OR optimization OR optimisation)”. Additional hand searches were performed by the cross-referencing of eligible studies in order to identify further relevant publications. Abstracts were screened to discard duplicates. When the literature search yielded two or more studies by the same author assessing the same populations, only the most recent one was chosen, irrespective of the time interval, as it was assumed the latter published would include the most comprehensive and complete data.
The process of study selection is depicted in a flow diagram following the PRISMA statement [7]. The present systematic review was registered in PROSPERO (CRD42017073757). The selection process, data extraction and analyses were performed by two authors (LG and OPN) independently. If discrepancies occurred, consensus was reached by a third reviewer (JPG). The corresponding authors of the studies without sufficient data were contacted for additional information.

2.2. Selection Criteria

Prospective and retrospective studies assessing the LOR to anti-TNF therapy, considered as the need for DI in patients with CD and UC treated for at least 12 weeks with an anti-TNF drug, were selected for inclusion. There were no language restrictions.
Articles in which an anti-TNF was used as the prophylaxis for postoperative recurrence in CD and those where DI was based during therapeutic drug monitoring were excluded. Systematic or narrative reviews, case studies and congress abstracts were excluded from this systematic review.

2.3. Data Extraction and Quality Assessment

A predefined, pre-piloted data extraction form was used to collect the data. The variables recorded were: year of publication; study design (prospective or retrospective); age of the study population (adults ≥ 18 years and children < 18 years); type of inflammatory bowel disease (UC or CD); therapeutic regimens (infliximab (IFX), adalimumab (ADA), certolizumab-pegol, and golimumab); previous anti-TNF treatments (naïve or non-naïve); length of follow-up in months; sample size; and outcome measures (DI requirement and DI efficacy).
The Cochrane risk of bias tool [8] was used to assess the quality of the randomized controlled trials, as they were considered the most reliable method of outcome assessment. The decision was reached post-hoc after performing an exploratory mapping review and confirming the wide range of observational studies in terms of the number and design available in the literature responding to our topic of interest.

2.4. Data Synthesis and Statistical Analysis

All analyses were preplanned a priori. The primary outcomes were the DI requirement measured as the number of patients receiving a DI out of the total of patients studied and DI efficacy in the short term as the number of patients responding out of the total of patients receiving a DI, expressed as the response rate with its standard error. These outcomes were thereafter combined using the inverse variance method, providing 95% confidence intervals (CIs). The statistical significance threshold was set at p-value < 0.05. A random effects model was used.
The study heterogeneity was analyzed using the I2 statistic: according to the I2 values, the heterogeneity was considered as: not important (I2 < 40%), moderate (40–75%) and considerable (>75%). Such interpretations also adjusted for the magnitude of the effect and/or the strength of the evidence given (i.e., p-value < 0.1 of the χ2 test). Begg’s funnel plot [9] was used to estimate the possibility of publication bias.
Post-hoc sensitivity analyses were performed for each meta-analysis subgroup by excluding those studies that were identified as potentially introducing a critical risk of bias that could likely modify the outcome.
Data were analyzed using the Review Manager program (version 5.2).

3. Results

A total of 173 studies (including 33,241 patients) met the inclusion criteria and were finally included in the systematic review and meta-analysis (Figure 1).
Figure 1. PRISMA flowchart of the screening and selection.
The description of each included study is summarized in Table 1.
Table 1. Studies included in the meta-analysis.
There were six randomized, placebo-controlled trials (RCTs) [10,11,12,13,14,15], 48 prospective open-label observational trials and 119 retrospective studies.
A total of 157 studies assessed the need for DI; the response rate was evaluated in 52 studies, and the remission rate was reported in 33 studies.
One hundred and one studies focused on naïve patients, and 29 evaluated non-naïve patients, while 50 studies included both naïve and non-naïve patients in their assessments. In six studies, prior anti-TNF exposure was not reported. One hundred and seven studies reported the data from IFX users and 92 from ADA users. Only five studies included patients receiving golimumab [16,17,18,19,20], and four studies evaluated patients receiving certolizumab [21,22,23,24]; thus, a meta-analysis was not performed.

3.1. Dose Intensification Requirements

3.1.1. Twelve-Month Follow-Up

Anti-TNF Use by Medical Condition in Naïve Patients
The DI requirement rate after the 12-month follow-up with all the anti-TNF agent data was statistically higher in UC than in CD patients (test for subgroup differences: χ2 = 5.29, p = 0.02, I2 = 81.1%). No other subgroup differences were reported by the medical condition or anti-TNF used (Table 2).
Table 2. Dose intensification rate after the 12-month follow-up by the anti-TNF agent and medical condition.

3.1.2. Thirty-Six Month Follow-Up

A total of 25 studies with a median follow-up of 36 months were analyzed. There was only one study reporting the DI rate in non-naïve patients, and therefore, no subgroup analysis was performed.
The DI rates in naïve patients ranged from 0% (113) to 70% (183), with an overall rate of 35% (95% CI 28–43%, I2 = 98%, 18 studies) (Figure 3).
Figure 3. Dose intensification requirements after the 36-month follow-up in anti-TNF naïve patients.
Anti-TNF Use by Medical Condition in Naïve Patients
No statistical differences (p > 0.05) in the medical conditions or the anti-TNF drug used were found between the subgroups (Table 3).
Table 3. The DI rate after 36-month follow-up by the anti-TNF agent and medical condition.

3.1.3. Short-Term Follow up

A total of 17 studies with a median of three to nine months of follow-up were included. The DI rates in naïve patients ranged from 14% (130) to 71% (79) with an overall pooled rate of 29% (95% CI 31–37, I2 = 96%, five studies).
A subgroup analysis evaluating the follow-up time (short-term vs. 12 months vs. 36 months) showed no statistical differences (p > 0.05) in terms of the DI requirements in naïve patients.

3.2. Dose Intensification Efficacy

3.2.1. Response Rate

The response rates ranged from 0% (147) to 96% (48) in naïve patients and from 41% (60) to 75% (181) in non-naïve patients.
The overall rate of the short-term response to the empirical DI was 63% (95% CI: 48–78%, I2 = 99%, 32 studies) and 58% (95% CI: 47–70%, I2 = 68%, nine studies) in the naïve and non-naïve patients, respectively (Figure 4). No statistical differences were found between the groups (p > 0.05).
Figure 4. Response rate after the empirical dose intensification in anti-TNF naïve vs. non-naïve patients.
No statistical differences were found when comparing CD vs. UC patients or the anti-TNF drugs used (Table 4). Neither were found (p > 0.05) between different intensification regimens (i.e., intensification of dosing vs. reduction of the interval of administration).
Table 4. Response rate by the anti-TNF agent and medical condition.

3.2.2. Remission Rate

The remission rates ranged from 17% (168) to 94% (183) in naïve patients and from 17% (60) to 85% (124) in non-naïve patients. The overall remission rate to empirical DI was 48% (95% CI: 39–58%, I2 = 92%, 25 studies) and 44% (95% CI: 17–71%, I2 = 95%, six studies) in naïve and non-naïve patients, respectively (Figure 5). No significant differences were found between the subgroups (p > 0.05).
Figure 5. Remission rates after the empirical dose intensification in anti-TNF naïve vs. non-naïve patients.
No statistical differences were found when comparing CD vs. UC patients or the anti-TNF drugs used (Table 5). Neither were found between the different intensification regimens.
Table 5. Remission rate by the anti-TNF agent and medical condition in naïve patients.

3.3. Pediatric Population

A total of 24 studies reported data on children (<18 years) (Table 1). When compared to the adult population, no statistical differences were found in terms of the DI required or its efficacy. The random-effects pooled DI rate in naïve patients after a 12-month follow-up was 29% (95% CI 21–37%, I2 = 81%, n = 9).

3.4. Randomized Controlled Trials

A total of five randomized controlled trials (Table 1) assessed the DI requirements after a 12-month follow-up in naïve patients. The random-effects pooled DI rate was 29% (95% CI 18–41%. I2 = 88%, five studies). No statistical differences were found when this subgroup was compared to the group of observational studies.

3.5. Sensitivity Analyses and Risk of Bias

We further investigated potential sources of heterogeneity by excluding studies that included extreme or diverging values in certain subgroups, such as the DI requirements after 12 months [34,100,123,127,147,165] and 36 months [85,113] of follow-up or the response [147] and remission [61,145,168,183] rates. The effects of including different follow-up periods in the same subgroup [34,147,149] or the use of different induction dosing regimens [13,126,138] were also explored. In all cases, the results were stable, with no significant variations after the sensitivity analysis, although the heterogeneity remained considerable.
Among the six RCTs evaluated for a potential risk of bias, five had a low risk of bias for randomization, and four of them reported on the implementation of the random allocation sequence preserving concealment. Four studies also reported the adequate blinding of participants and personnel. Three studies showed low risks of attrition bias; in two of them, the number of excluded patients was not specified, and in the remaining one, there was a difference in the proportion of the outcome data. Finally, none of the studies was considered to show reporting biases. In conclusion, for most of the RCT items assessed, there was a low potential risk of bias detected.

4. Discussion

A LOR to the anti-TNF agents represents a therapeutic challenge to gastroenterologists, as these drugs are usually indicated in severe forms of the disease, and the remaining treatment options in such situations are limited. However, there is no unanimous definition of LOR in the literature [185,186]; it has been defined as an increase in clinical activity (which can be assessed by numerous activity indices) or, alternatively, as the need to modify or discontinue the current treatment. Thus, several authors have proposed that the DI requirement, which has been shown to recapture the response in multiple studies [187], would be a more objective and reliable measure [188] and, therefore, a useful surrogate for the LOR. Several reviews have previously assessed the incidence of a LOR, mainly in CD [185,186,187,188,189,190,191]. When compared to previous reviews, our study includes a considerably higher number of studies, up to January 2020, assessing both UC and CD patients and, therefore, conferring more robustness and reliability to our work.

4.1. Prior Anti-TNF Exposure

Several studies have estimated that approximately one-third of inflammatory bowel disease patients experience LOR and require DI, and that occurs more frequently in patients with prior anti-TNF exposure [188,189,190,191].
In our study, the overall rate of the DI requirements at a one-year follow-up was 28% in naïve and 39% in non-naïve patients, respectively. This shows no relevant differences with the previous data and constitutes one main finding of our study: dose escalation was needed more often in patients with prior anti-TNF use. In fact, the vast majority of the included studies evaluating both naïve and non-naïve patients showed a greater incidence in the loss of response in those non-naïve [30,34,35,60,81,84,111,121,132,161,163,168,192,193].

4.2. Time of Follow-Up

Additionally, the time course of LOR remains poorly understood. The median time from the first anti-TNF exposure to the need for a DI varied widely among the studies, from 2.7 to 18 months. However, there is increasing evidence showing that such events occur mostly within the first year of anti-TNF therapy [186].
In our study, no differences were found in the rate of DI for the short term, 12 and 36 months of follow-up, supporting the fact that the LOR and consequent DI occur mainly during the first year of treatment.

4.3. Medical Baseline Condition

Another relevant finding in our study was that a DI was required more frequently in UC than in CD patients. Previous data indicated that some patients with active UC have a higher inflammatory burden and accelerated anti-TNF clearance [194,195,196]; therefore, they could require a higher drug exposure to achieve a response to TNF antagonists. This could be the rational explanation UC patients need for an earlier and more frequent DI than CD patients [110,120,167]. However, there is also evidence not supporting these results [174]. Further research should be conducted, as no randomized trials have focused on this subgroup of patients; they seem to have the highest DI rate and could benefit the most from alternative treatment strategies.

4.4. Anti-TNF Agent

The comparison between the IFX and ADA DI rates is also a matter of interest. Immunogenicity is believed to be a common cause of LOR due to the formation of antidrug antibodies. Some authors have argued that the chimeric nature of IFX, as opposed to the fully humanized ADA, could render the former more prone to generate an antibody response. However, in our study, we did not find significant differences in the DI rate between IFX and ADA patients, as in previous comparative reports [115].

4.5. Dose Intensification Efficacy

Several clinical trials and open-label cohorts included in a previous review reported DI to restore the response in 50–70% of patients [186]. Billioud et al. also found that DI restored the response in 71% and remission in 40% of the patients [189].
In our study, the response and remission rates to empirical DI in naïve patients were 63% and 48%, respectively. Although no significant differences were reported between the naïve and non-naïve patients, either in the response or remission rates, a trend towards a reduced DI efficacy in the patients with prior anti-TNF exposure was shown.
Our findings support that using all the available treatment options with the first anti-TNF agent through DI (even if it is not based on therapeutic drug monitoring) should be considered before switching to another anti-TNF agent or to another therapeutic target. Nevertheless, it should be noted that almost all studies do assess the DI efficacy in the short term; additional research regarding the long-term response and remission rates after DI should be performed.

4.6. Limitations

Our study had some limitations. First of all, the DI can result in an equivocal interpretation of the LOR if it is done without accurately confirming the disease activity. In addition, there were also some possible predictors for the LOR or DI that were not evaluated in our study, such as the concomitant use of immunomodulators. However, recent guidelines (three) have suggested monotherapy with anti-TNF in patients with long-term remission rather than the use of a combination therapy. Finally, we excluded studies in which the DI was made based on therapeutic drug monitoring, with the aim to assess the effectiveness of empirical DI. In this respect, the current guidelines (three) do not recommend either proactive or reactive therapeutic drug monitoring as a standard clinical practice due to insufficient evidence. Finally, we did not perform a quality assessment of all the included studies given the high heterogeneity of the observational studies encountered in terms of the design and number. It was decided to perform a risk of bias assessment exclusively in RCTs, which represented no more than 1.5% of the total of patients included in our systematic review but, including 512 patients, was a sufficient sample size to drawn robust conclusions. In terms of quality, most studies showed a low risk of bias for the majority of the items assessed, highlighting both an adequate random sequence generation and allocation concealment, as well as blinding: items that were usually preserved. Additionally, a subgroup analysis was performed to control for heterogeneity in terms of study design, and no significant differences in the DI requirement between the RCTs and observational studies were reported.

5. Conclusions

A LOR to anti-TNF agents―and, consequently, DI―occurs frequently in inflammatory bowel disease, with an overall rate of DI requirement of approximately one-fourth at one year and one-third at three years. DI is required more frequently in patients with prior exposure to anti-TNF agents and in UC patients. Empirical DI is a relatively effective therapeutic option, achieving a response in two-thirds and remission in one-half of those patients naïve to anti-TNF treatment.

Author Contributions

Conceptualization, O.P.N., M.C. and J.P.G.; methodology and software, L.G., O.P.N. and J.P.G.; validation, O.P.N., M.C. and J.P.G.; formal analysis, investigation, resources and data curation, L.G., O.P.N. and J.P.G.; writing—original draft preparation, L.G. and O.P.N.; writing—review and editing, J.P.G. and M.C. and supervision and project administration, J.P.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

Dr. Gisbert served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene, Gilead, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical and Vifor Pharma. Dr. Chaparro served as a speaker or has received research or educational funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma and Tillotts Pharma.

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