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Review

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

by
Laura Guberna
1,2,
Olga P. Nyssen
1,2,
María Chaparro
1,2 and
Javier P. Gisbert
1,2,*
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
Submission received: 31 March 2021 / Revised: 7 May 2021 / Accepted: 7 May 2021 / Published: 14 May 2021
(This article belongs to the Special Issue Novel Insight into the Diagnosis and Management of Crohn’s Disease)
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Review Reports Versions Notes

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).
The description of each included study is summarized in Table 1.
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).

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).

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).

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).
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).

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).
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.

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.

Informed Consent 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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Jcm 10 02132 g001 550
Figure 1. PRISMA flowchart of the screening and selection.
Figure 1. PRISMA flowchart of the screening and selection.
Jcm 10 02132 g001
Jcm 10 02132 g002a 550Jcm 10 02132 g002b 550
Figure 2. Dose intensification requirements after the 12-month follow-up in anti-TNF naïve and non-naïve patients.
Figure 2. Dose intensification requirements after the 12-month follow-up in anti-TNF naïve and non-naïve patients.
Jcm 10 02132 g002aJcm 10 02132 g002b
Jcm 10 02132 g003 550
Figure 3. Dose intensification requirements after the 36-month follow-up in anti-TNF naïve patients.
Figure 3. Dose intensification requirements after the 36-month follow-up in anti-TNF naïve patients.
Jcm 10 02132 g003
Jcm 10 02132 g004 550
Figure 4. Response rate after the empirical dose intensification in anti-TNF naïve vs. non-naïve patients.
Figure 4. Response rate after the empirical dose intensification in anti-TNF naïve vs. non-naïve patients.
Jcm 10 02132 g004
Jcm 10 02132 g005 550
Figure 5. Remission rates after the empirical dose intensification in anti-TNF naïve vs. non-naïve patients.
Figure 5. Remission rates after the empirical dose intensification in anti-TNF naïve vs. non-naïve patients.
Jcm 10 02132 g005
Table
Table 1. Studies included in the meta-analysis.
Table 1. Studies included in the meta-analysis.
Author and YearStudy DesignPopulationMedical ConditionAnti-TNFPrior Anti-TNFFOLLOW up (Months)nNDI Rate (%)Intensification RegimenResponse/Remissionn’N’DI Efficacy (%)
1Afif 2009 [25]PAUCADANaïve and non-naïve672035
2Albisi 2019 [26]RCCDADANon-naïve123447IDResponse2367
3Armuzzi 2013 [27]RAUCADANaïve and non-naïve12318835
4Assa 2013 [28]RCUC+CDIFX+ADA-201010210
5Baert 2014 [29]RAUCADANon-naïve12227330
6Baert 2013 [30]RACDADANaïve and non-naïve1420860534RIResponse13920867
CDADANaïve144020819
CDADANon-naïve1416436545
7Baki 2015 [31]RAUCIFXNaïve and non-naïve5265448
UCADANaïve and non-naïve4173746
8Balint 2018 [32]PAUCIFXNaïve12206133
9Balint 2016 [33]PA+CUCADANaïve and non-naïve12137318
10Bhalme 2013 [34]RACDIFXNaïve134765
ADANaïve1121513
ADANon-naïve1193923
ADANaïve and non-naïve11115420
11Black 2016 [35]RAUCADANaïve126615543
ADANon-naïve12173647
12Bor 2017 [36]RACDIFXNaïve and non-naïve-144829IDRemission31421
13Bortlik 2013 [37]RACDIFXNaïve and non-naïve246847
14Bossuyt 2019 [38]PAUCGOLNaïve and non-naïve68919
15Bouguen 2015 [39]PACDADANaïve and non-naïve -Response234255
Remission144233
16Bramuzzo 2019 [40]RCUC+CDIFXNaïve124417226
17Brandes 2019 [41]RAUC+CDADANaïve and non-naïve127650215
18Bultman 2012 [42]PACDADANaïve12234947-Response204643
CDADANon-naïve12237331.5
19Cameron 2015 [43]RCUC+CDIFXNaïve23237232
UC+CDADANaïve and non-naïve14192966
20Casanova 2019 [21]RAUC+CDIFX+ADA+CZPNon-naïve18230112220.5RI or IDRemission16123042
21Casellas 2015 [44]PACDADANaïve and non-naïve3632811
22Castaño 2015 [45]RACDADANaïve1294620RIRemission3933
23Caviglia 2007 [46]RAUCIFX-240100
CDIFX-243407.5
24Cesarini 2014 [47]RAUCIFXNaïve24 RI or IDResponse374190
Remission194146
RIResponse242692
Remission92635
IDResponse131587
Remission101567
25Chaparro 2011 [48]RACDIFXNaïve41127309 RI + IDResponse12212796
Remission7112756
26Chaparro 2012 [49]RACDIFXNaïve223319717-Response263379
Remission113333
27Cheng, 2017 [50]RCUCIFXNaïve246011353RI or IDResponse366060
CDIFXNaïve24193554RI or IDResponse123534
28Choi 2014 [51]RACDADANaïve1853614
IFXNaïve180360
29Choi 2017 [52]RCCDIFXNaïve16142948RI or IDResponse172180
UCIFXNaïve1671070
30Church 2014 [53]RCCDIFXNaïve217915750
31Clark 2019 [54]RACDIFXNon-naïve24101759
32Cohen 2012 [55]RACDADANaïve and non-naïve55317541
33Cordero 2011 [56]PACDADANon-naïve12182572
34DeRidder 2008 [57]RCCDIFXNaïve41406661
35DeBruyn 2017 [58]RCCDIFXNaïve1910217857
36D’Haens 2018 [10]PACDIFXNaïve12164040
37Dignass 2019 [17]RAUCIFXNaïve247511466
UCADANaïve244912539
UCGOLNaïve24274757
38Dreesen 2018 [59]RACDIFXNaïve RI, ID, RI+IDResponse6510363
IDResponse244553
RIResponse334573
RI + IDResponse81361
39Dubinsky 2016 [60]PCCDADANaïve and non-naïve12359338RIResponse203557
RIRemission113531
Naïve12185135RIResponse131872
RIRemission51828
Non-naïve12174240RIResponse71741
RIRemission31718
40Dumitrescu 2015 [61]RAUCIFXNaïve RI or IDResponse8715755
Remission2815718
41Dupont 2016 [62]RCCDIFXNaïve-6518735
42Duveau 2016 [63]RACDADANaïve and non-naïve-12443029RI or IDResponse9912480
43Echarri 2015 [64]PACDADANaïve24126818RIRemission91275
44Falaiye 2014 [65]RAUC+CDIFXNaïve12182962RI or IDResponse71839
45Fernandes 2019 [66]RAUC+CDIFXNaïve and non-naïve122514917
UC+CDIFXNaïve and non-naïve243814925.5
46Fernández-Salazar 2015 [67]RAUCIFXNaïve385314437
47Fiorino 2017 [68]PA+CUC+CDIFXNaïve and non-naïve37439916
48Fortea-Ormaechea 2011 [69]RACDADANaïve and non-naïve95717433
49Frederiksen 2014 [70]RAUC+CDADANo naïve9215737
50García bosch 2013 [71]RAUCADANaïve and non-naïve12184837.5-Response151883
-Remission81844
51Ghaly 2015 [72]RACDIFX+ADANaïve and non-naïve 4073 -Response407355
52Gofin 2019 [73]RCCDIFX+ADANaïve19189818
53Gonczi 2017 [74]PAUC+CDADANaïve and non-naïve122211220
243311229
54Gonzaga 2009 [75]RACDIFXNaïve495611150
55González Lama 2008 [76]RACDIFXNaïve281511413RI or IDResponse101567
56Grover 2014 [77]RCCDIFXNaïve12134728-Response71354
57Guerbau 2017 [78]PACDIFXNaïve and non-naïve124314030
58Guidi 2018 [79]PAUC+CDIFXNaïve3375271
59Ho 2008 [80]RACDADANon-naïve12132259
60Ho 2009 [81]RA+CCDADANaïve and non-naïve6249824
CDADANaïve1221020
CDADANon-naïve12288832
CDADANaïve and non-naïve24549855
61Hussey 2016 [82]RAUCADANaïve and non-naïve19135524
62Hyams 2010 [83]PCUCIFXNaïve30113433
63Hyams 2007 [11]PCCDIFXNaïve1295217IDResponse5956
64Iborra 2017 [84]RAUCADANaïve and non-naïve129326335
ADANaïve12218724
ADANon-naïve127217641
65Inokuchi 2019 [85]RACDIFXNaïve835418329.5
CDADANaïve436807.5
66Juillerat 2015 [86]RACDIFXNaïve and non-naïve-7725031
67Juliao 2013 [87]RAUCIFXNaïve2742814RIResponse44100
68Kang 2016 [88]PCCDIFXNaïve1277210
69Karmiris 2009 [89]PACDADANon-naïve2010215665RIResponse7310272
70Katz 2012 [90]RACDIFXNaïve- RI or IDResponse12316873
RIResponse375666
IDResponse8611277
71Kelly 2017 [91]RAUC+CDIFXNaïve RI or IDResponse8214357
Remission6914348
72Kierkus 2015 [12]PCCDIFXNaïve12168419
73Kiss 2011 [92]RACDADANaïve and non-naïve123320116
74Knyazev 2018 [22]PACDCRPNaïve and non-naïve243398
75Knyazev 2016 [93]RAUCIFXNaïve-54511-Remission4580
76Knyazev 2017 [94]PACDADANaïve and non-naïve286709
77Kopylov 2011 [95]RACDIFXNaïve RIResponse385570
CDIFXNaïve IDResponse263967
78Kunovski 2020 [96]RAUCIFXNaïve124339611
ADANaïve123417220
79Lam 2014 [97]RACDIFXNaïve12346850
80Lees 2009 [98]RA+CUC+CDADANon-naïve12163053
81Lin 2012 [99]RACDIFXNaïve60349436RI or IDResponse243080
82Lindsay 2013 [100]RA+CCDIFXNaïve1293802
IFXNaïve24193805
83Lindsay 2017 [101]RAUCIFX+ADA 2413953826
CDIFX+ADANaïve2412665719
84Ling 2018 [102]RCCDIFXNaïve24264360RI or IDResponse142654
85Llaó 2016 [103]PAUCIFX-1881553
86Lofberg 2012 [104]PACDADANaïve and non-naïve513194514RIRemission4613135
87Lopez Palacios 2008 [105]RACDADANon-naïve2462227RIResponse4666
88Ma 2015 [106]RAUCIFXNaïve158366654
UCADANaïve139183650
89Ma 2014 [107]RACDIFXNaïve406011751
CDADANaïve28233861
CDADANon-naïve28416365
90Ma 2016 [108]RACDIFX+ADANaïve3811619061
91Ma 2014 (bis) [109]RACDADANaïve and non-naïve- -Response749280
92Magro 2014 [110]RACDIFXNaïve845516334
UCIFXNaïve84195237
93Martineau 2017 [19]RACDGOLNon-naïve185111544-Response275153
94Merras 2016 [20]PCCDGOLNon-naïve*1617
95Molnar 2012 [111]RACDIFXNaïve123359
CDADANaïve1231030
CDADANon-naïve12131681
96Moon 2015 [23]RACDCZPNaïve and non-naïve264335812
97Motoya 2018 [112]PA+CCDADANaïve and non-naïve RIResponse162857
CDADANaïve and non-naïve RIRemission102835
ADANaïve RIResponse6967
ADANaïve RIRemission5956
ADANon-naïve RIResponse101953
ADANon-naïve RIRemission51926
98Moroi 2019 [113]RACDIFXNaïve36176227
ADANaïve36070
99Murthy 2015 [114]RAUCIFXNaïve125911651
100Narula 2016 [115]PACDIFXNaïve243525114
CDADANaïve2491118
101Nedelkopoulou 2018 [116]RCUCIFXNaïve2021020
102Ng 2009 [117]PACDADANon-naïve122729RIResponse22100
103Nichita 2010 [118]RACDADANaïve and non-naïve12135524RI or IDResponse81362
Remission61346
104Nuti 2014 [119]RCCDIFX+ADANaïve and non-naïve36277835
105O’Donnell 2015 [120]RA+CCDIFXNaïve3613328746
UCIFXNaïve368412567
106Olivares 2019 [121]PAUC+CDADANaïve18.153345
UC+CDADANon-naïve18.375370
UCADANaïve and non-naïve6.74316
CDADANaïve and non-naïve6.214349
UCADANaïve and non-naïve18.244356
CDADANaïve and non-naïve20.284365
107Orlando 2012 [122]PACDADANaïve and non-naïve14.1511014
108Osterman 2017 [123]RACDIFXNaïve124238111
ADANaive12161968
109Oussalah 2009 [124]RACDADANon-naïve3675313RIRemission6786
110Oussalah 2010 [125]RAUCIFXNaïve18368045
111Panaccione 2010 [126]PACDADANaïve127126027
2410526040
112Paredes 2020 [127]PAUC+CDIFXNaïve122316
UC+CDIFXNaïve24123139-Response61250
UCIFXNaïve2433110
CDIFXNaïve2493129
113Pariente 2012 [128]RAUC+CDIFXNaïve RI or IDResponse273969
114Park 2016 [129]RACDIFXNaïve368658215
115Patel 2017 [130]RACDIFX+ADA+
CZP+GOL		Naïve6640456914
Naïve121097456924
Naïve241553456934
Naïve361782456939
UCIFX+ADA+
CZP+GOL		Naïve6272169916
Naïve12475169928
Naïve24680169940
Naïve36748169944
116Paul 2013 [131]PAUC+CDIFXNaïve and non-naïve IDRemission305258
117Peters 2014 [132]RACDADANaïve244516727
CDADANon-naïve2413527150
118Peyrin 2007 [133]PACDADANon-naïve1262425
119Pollinger 2019 [134]RAUCADANaïve124815431
120Preda 2016 [135]RACDIFXNaïve362612920-Remission112642
CDADANaïve201913614-Remission161984
121Qazi 2016 [136]PAUC+CDIFXNaïve24107513
122Regueiro 2007 [137]RACDIFXNaïve and non-naïve305410850RI or IDResponse415476
123Reinisch 2013 [138]PAUCADANaïve1211044525
124Renna 2016 [139]PAUCADANon-naïve< 61166
125Renna 2018 [140]RAUCADANaïve and non-naïve105011842RIResponse235046
126Riis 2012 [141]RACDIFXNaïve59105817
CDADANaïve361195
127Roblin 2014 [142]PAUC+CDADANaïve RIRemission308236
128Roblin, 2016 [143]PACDIFXNaïve and non-naïve203011925
129Roblin 2015 [144]PAUC+CDIFXNaïve20109311
130Rostholder 2012 [145]RAUCIFXNaïve12275054RI or IDRemission52719
131Rubin 2012 [146]RACDANTI TNF-24531139838
132Russo 2009 [147]RAUCIFXNaïve152385RI or IDResponse020
133Rutka 2016 [148] UCADANaïve and non-naïve12137318
134Sandborn 2007 [13]PACDADANaïve128920444-Remission378942
135Sandborn 2016 [149]RAUCIFXNaïve1116642439
UCADANaïve1113838036
136Sands 2004 [14]PACDIFXNaïve12289629RIResponse122157
137Sartini 2018 [150]RAUCADANaïve and non-naïve24173253
CDADANaïve and non-naïve245814939
138Sazuka 2012 [151]RACDIFXNaïve21307440
139Schnitzler 2009 [152]PACDIFXNaïve5521854740
140Seo 2017 [153]RACDADANaïve and non-naïve174525418
141Seow 2010 [154]PAUCIFXNaïve147411564RI or IDRemission297439
142Shapiro 2015 [155]RCUC+CDIFXNaïve12358740RI or IDResponse303586
143Sierra 2016 [156]RACUADANaïve and non-naïve12163743
144Sprakes 2012 [157]PACDIFXNaïve241817310
145Srinivasan 2018 [158]RACDIFX+ADANaïve and non-naïve125542313
146Stein 2014 [24]RACDCZPNaïve and non-naïve124108711
147Steendholt 2015 [15]PACDIFXNaïve RIResponse193653
148Sutharsan 2013 [159]PACDADANaïve RIResponse91464
CDADANaïve Remission81457
159Suzuki 2015 [160]P CDIFXNaïve IDResponse233959
CDIFXNaïve Remission133936
150Suzuki 2019 [161]RACDADANaïve and non-naïve12149515IDRemission81267
CDADANaïve1297812 Remission5862.5
CDADANon-naïve1251729 Remission2450
151Suzuki 2017 [162]PAUCADANaïve363619019
152Swoger 2010 [163]RACDADANaïve125911850
153Tajiri 2018 [164]PCCDIFXNaïve1251436IDRemission3560
154Takeuchi 2019 [165]RCUC+CDIFXNaïve12111765
UCIFXNaïve124580
CDIFXNaïve1271258
155Taxonera 2015 [166]RAUCIFXNaïve -Response547968
RAUCIFXNaïve -Remission417952
156Taxonera 2014 [167]RACDIFXNaïve13165927
RAUCIFXNaïve9163842
157Taxonera 2017 (bis) [168]RAUCADANaïve24126818RI or IDResponse71258
RI or IDRemission21217
ADANon-naïve246411655RI or IDResponse266441
RI or IDRemission136420
158Taxonera 2017 [169]RAUCGOLNaïve and non-naïve123111427RI or IDResponse223171
159Taxonera 2011 [170]RAUCADANon-naïve12113037RIResponse81173
160Tigue 2017 [171]RAUCIFX + ADA-123388
CDIFX + ADA 122248
161Tkacz 2014 [172]RACDIFXNaïve91810617
162Tursi 2018 [173]RAUCADANaïve and non-naïve1895616
163Vahabnezhad 2014 [174]RA+CCDIFXNaïve30658973RI or IDResponse406562
UCIFXNaïve2571354RI or IDResponse4757
164Vanassche 2012 [175]PACDIFXNaïve1263716
165Vandevondel 2018 [176]RAUCADANaïve and non-naïve612923156RIResponse7712960
166Vatansever 2014 [177]PACDIFX+ADA-123359
167Verstock 2018 [178]RACDADANaïve122711623-Response192770
CDADANaïve184311637
168Viazis 2015 [179]PACDIFX+ADANaïve283113223RI or IDRemission253181
169Watanabe 2014. [180]PACDADANaïve and non-naïve34407951DIResponse88100
Remission6875
170West 2008 [181]RACDADANo naïve1283027RIResponse6875
171Wolf 2014 [182]PAUCADANaïve and non-naïve32012316RIResponse92045
Remission42020
172Yamada 2014 [183]RAUCIFXNaïve36172471RI or IDRemission161794
173Yokoyama 2016 [184]RACDIFX+ADANaïve and non-naïve1881077
DI: Dose intensification. R: Retrospective. P: Prospective. UC: Ulcerative colitis. CD: Crohn’s disease. IFX: Infliximab. ADA: Adalimumab. CZP: Certolizumab pegol. GOL: Golimumab. n: number of patients undergoing dose intensification. N: total number of patients included. ID: Increase of dose. RI: Reduction of the interval of administration. n’: number of patients with a clinical response or remission after dose intensification. N’: total number of patients undergoing dose intensification.
Table
Table 2. Dose intensification rate after the 12-month follow-up by the anti-TNF agent and medical condition.
Table 2. Dose intensification rate after the 12-month follow-up by the anti-TNF agent and medical condition.
Anti-TNFUC/CDDI Requirement
(%, 95% CI)		I2 (%)Number of
Included Studies
IFXUC+CD29 (22–36)9626
IFXUC40 (24–56)978
IFXCD21 (15–28)9215
ADAUC+CD28 (22–34)9316
ADAUC29 (23–35)866
ADACD28 (17–38)9410
Anti-TNF: anti-tumor necrosis factor. UC: ulcerative colitis. CD: Crohn’s disease. DI: dose intensification. IFX: Infliximab. ADA: Adalimumab.
Table
Table 3. The DI rate after 36-month follow-up by the anti-TNF agent and medical condition.
Table 3. The DI rate after 36-month follow-up by the anti-TNF agent and medical condition.
Anti-TNFUC/CDDI Requirement
(%, 95% CI)		I2 (%)Number of
Included Studies
IFXUC+CD38 (30–46)9615
IFXUC48 (34–62)824
IFXCD35 (26–43)9612
ADAUC+CD24 (7–40)924
ADAUC34 (3–64)922
ADACD3 (−4–11)802
Anti-TNF: anti-tumor necrosis factor. UC: ulcerative colitis. CD: Crohn’s disease. DI: dose intensification. IFX: Infliximab. ADA: Adalimumab.
Table
Table 4. Response rate by the anti-TNF agent and medical condition.
Table 4. Response rate by the anti-TNF agent and medical condition.
Anti-TNFUC/CDResponse Rate
(%, 95% CI)		I2 (%)Number of
Included Studies
IFXUC+CD65 (49–80)9926
IFXUC62 (29–95)998
IFXCD67 (59–75)9116
ADAUC+CD63 (55–70)05
ADAUC58 (48–68)NA1
ADACD69 (58–80)04
Anti-TNF: anti-tumor necrosis factor. UC: ulcerative colitis. CD: Crohn’s disease. IFX: Infliximab. ADA: Adalimumab.
Table
Table 5. Remission rate by the anti-TNF agent and medical condition in naïve patients.
Table 5. Remission rate by the anti-TNF agent and medical condition in naïve patients.
Anti-TNFUC/CDRemission Rate
(%, 95% CI)		I2 (%)Number of
Included Studies
IFXUC+CD46 (34–59)9314
IFXUC50 (25–74)967
IFXCD43 (33–53)606
ADAUC+CD44 (31–58)8610
ADAUC17 (07–27)NA1
ADACD50 (36–64)798
Anti-TNF: anti-tumor necrosis factor. UC: ulcerative colitis. CD: Crohn’s disease. IFX: Infliximab. ADA: Adalimumab.
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Guberna, L.; Nyssen, O.P.; Chaparro, M.; Gisbert, J.P. Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis. J. Clin. Med. 2021, 10, 2132. https://doi.org/10.3390/jcm10102132

AMA Style

Guberna L, Nyssen OP, Chaparro M, Gisbert JP. Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis. Journal of Clinical Medicine. 2021; 10(10):2132. https://doi.org/10.3390/jcm10102132

Chicago/Turabian Style

Guberna, Laura, Olga P. Nyssen, María Chaparro, and Javier P. Gisbert. 2021. "Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis" Journal of Clinical Medicine 10, no. 10: 2132. https://doi.org/10.3390/jcm10102132

APA Style

Guberna, L., Nyssen, O. P., Chaparro, M., & Gisbert, J. P. (2021). Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis. Journal of Clinical Medicine, 10(10), 2132. https://doi.org/10.3390/jcm10102132

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