Biological interventions for induction of mucosal healing in Crohn’s disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this systematic review is to determine the efficacy and safety of biologics for inducing mucosal healing in CD.
Background
Description of the condition
Crohn's disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract. Unchecked transmural inflammation often progresses to fibrostenotic and fistulizing complications (Cosnes 2002). As a result, 50% of individuals need a surgical intervention within 10 years of diagnosis (Peyrin‐Biroulet 2010). Treating to the endpoint of alleviating symptoms has not changed the natural history of CD (Cosnes 2005). In addition, clinical symptoms, reflected by clinical activity indices like the Crohn's Disease Activity Index (CDAI), show poor correlation with endoscopic inflammation (De Cruz 2013). On the other hand, there is mounting evidence that mucosal healing (MH) is associated with favourable long‐term outcomes in CD, such as a reduced need for surgery (Shah 2016). MH has therefore gained attention as a potentially superior endpoint in CD. In keeping with this, most recent clinical trials examining therapeutic agents in CD have included endoscopic healing as an outcome. Although there is no validated definition for mucosal healing (Sandborn 2002), MH is generally understood to entail resolution of ulcerations seen on baseline endoscopy. Whether complete MH or just partial improvement in mucosal inflammation is required to observe a clinical benefit is unclear. The Crohn's Disease Endoscopic Index of Severity (CDEIS) (Mary 1989) and the Simple Endoscopic Score for Crohn’s Disease (SES‐CD) (Daperno 2004) are the endoscopic indices most frequently used in CD. The SES‐CD was developed as a simpler alternative to the CDEIS, which is used primarily in research settings. The CDEIS ranges from 0 to 44. Investigators empirically defined complete remission as a score of less than three and endoscopic remission as a score of less than six (Mary 1989). Levels of disease severity have been described as CDEIS scores of less than 5 (mild), 5 to 15 (moderate) and greater than 15 (severe) (Geboes 2005). The SES‐CD ranges from 0 to 60. Investigators empirically created the following categories of disease activity: 0 to 2 (remission), 3 to 6 (mild), 7 to 16 (moderate) and greater than 16 (severe) (Daperno 2004). There is no agreed upon definition for endoscopic response using either of these indices and various definitions have been proposed for both (Khanna 2014; Khanna 2016; Levesque 2015).
Description of the intervention
The advent of biologics roughly 15 years ago radically altered the treatment paradigm for inflammatory bowel disease (IBD). The introduction of these highly effective agents made the target of MH more attainable and played an important role in the movement toward targeting MH above mere symptom control. Despite the recognized relevance of MH, there remains a paucity of data regarding the effectiveness of biologics for achieving MH in CD, compared to clinical outcomes.
How the intervention might work
A dysregulated immune system is thought to cause the chronic inflammation of CD. The biologic agents used to treat CD block pro‐inflammatory cytokines and adhesion molecules that enable this inflammatory response. Infliximab was the first biologic used to treat CD. It is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that targets tumour necrosis factor alpha (TNFα). Several other anti‐TNFα agents were developed after infliximab, including adalimumab, certolizumab and golimumab. All of these agents are humanized monoclonal antibodies. Ustekinumab is a fully humanized IgG1 monoclonal antibody against the common p40 subunit of interleukin‐12 and interleukin‐23 (IL‐12/23p40). Tocilizumab is directed against IL‐6. Natalizumab, vedolizumab and etrolizumab belong to a different class of biologics, called anti‐integrins. These agents work by blocking adhesion between endothelial cells and white blood cells to prevent white blood cell trafficking.
Why it is important to do this review
In light of the rapidly growing number of available biologics, sound evidence is needed to guide treatment choices. Many consider MH to be the most clinically salient endpoint in IBD given its link to meaningful long‐term outcomes. Safety is also of critical importance when considering the use of biologics, particularly because these agents are relatively new and work by modulating the immune system. Concerns around the risk of infection and malignancy have been raised. A systematic review of biologic agents for inducing MH in CD, with a risk of bias assessment, has not yet been undertaken. This review will synthesize the existing evidence from randomized controlled trials (RCTs) pertaining to the efficacy and safety of biologics for inducing MH in CD.
Objectives
The objective of this systematic review is to determine the efficacy and safety of biologics for inducing mucosal healing in CD.
Methods
Criteria for considering studies for this review
Types of studies
RCTs will be considered for inclusion. Abstracts will be eligible for inclusion. Study designs other than RCTs will be excluded. Randomized withdrawal designs will be excluded.
Types of participants
Participants will be required to have luminal Crohn's disease of the distal small bowel, colon or both, as assessed endoscopically, with or without stricturing or penetrating disease. CD will be defined as per standard clinical, radiographic and endoscopic criteria. Isolated upper gastrointestinal CD and isolated perianal CD without luminal involvement will be excluded. Participants will need to demonstrate endoscopic evidence of active CD at the outset of the induction study. Patients who develop an endoscopically proven disease recurrence after surgical resection will be eligible for inclusion. There will be no restrictions based on age, sex, disease duration or previous therapy. The authors acknowledge that endoscopy is best suited for assessing patients with colonic involvement and less ideal for assessing small bowel disease as only the terminal ileum is visualized during ileocolonoscopy.
Types of interventions
RCTs assessing the efficacy of a biologic, alone or combined with another agent, for inducing MH in humans with CD, in comparison to placebo or an active medical treatment, will be included. Biologic therapy in this review will include monoclonal antibodies only. As such, small molecules like tofacitinib will not be included. Only FDA‐approved monoclonal antibodies targeting TNF‐α (infliximab, adalimumab, certolizumab, golimumab), IL12/23p40 (ustekinumab) or integrins (natalizumab, vedolizumab), alone or in combination with another active agent, will be considered for inclusion. The required treatment duration will be 4 to 26 weeks. All doses, frequencies and routes of administration will be considered.
Types of outcome measures
Primary outcomes
The primary outcome will be MH, defined as the absence of ulcers during endoscopy, among patients with endoscopic evidence of active disease at baseline. Only studies with a clear, reproducible definition for MH will be considered. The timing of outcome assessment will be 4 to 26 weeks.
Secondary outcomes
Secondary outcomes will include:
endoscopic response, defined as a relative or absolute decrease in either the CDEIS or SES‐CD compared to baseline, assessed at 4 to 26 weeks;
adverse events;
serious adverse events; and
disease‐specific quality of life (QOL), using the IBD Questionnaire or Short IBD Questionnaire.
Given the lack of an agreed upon definition for endoscopic improvement in CD, the definition of endoscopic response used in this review will not entail a specific magnitude of change in CDEIS or SES‐CD but, rather, the definition used by the authors of the included studies will be used.
Search methods for identification of studies
Electronic searches
We will search the following databases from inception to date:
1. MEDLINE;
2. EMBASE;
3. Cochrane Central Register of Controlled Trials (CENTRAL); and
4. The Cochrane IBD Group Specialized Trials Register.
The search strategies are reported in Appendix 1.
Searching other resources
We will search reference lists of key publications to identify studies potentially missed by the computer‐guided search. We will also search proceedings from major gastroenterology meetings from 2002 to the present. Leaders in the field (B. Feagan and W. Sandborn) and representatives of pharmaceutical companies engaged in drug development for IBD will also be contacted. The trial database clinicaltrials.gov will be searched to identify ongoing studies.
Data collection and analysis
Selection of studies
Two authors (AR and HHS) will screen titles and abstracts. Studies meeting study inclusion criteria will be retained. If any uncertainty exists about the appropriateness of a study for inclusion, the full text will be reviewed. Disagreements will be resolved by discussion and consensus, with third party input (CHS) as needed.
Data extraction and management
Two authors (AR and PC) will independently extract and record pertinent data on standardized data extraction sheets. Disagreements will be resolved by discussion and consensus, with third party input (CHS) as needed. We will contact study authors as necessary for missing information. The authors abstracting data will not be blinded to author, institution or journal. Data will be entered into Review Manager 5.3. The following data will be collected:
General study information ‐ title, first author, year of publication;
Participant population details ‐ number of patients screened, randomized to each arm, who completed each arm and lost to follow‐up, geographic location (country), year of patient enrolment;
Participant characteristics ‐ age, sex, disease location, severity, disease duration, previous therapy, previous resection;
Intervention details ‐ type of biologic, dose, route, frequency, duration;
Control group details ‐ type of placebo or active medical agent, dose, route, frequency, duration;
Details pertaining to concomitant medications received in each study arm;
Outcome details ‐ exact definition used for MH, timing of outcome assessment, number and proportion of patients achieving MH and endoscopic response in each study arm, number and proportion of patients experiencing adverse events and serious adverse events in each study arm, quality of life information for each study arm; and
Study methodology details ‐ randomization, allocation concealment, blinding, inclusion and exclusion criteria.
Assessment of risk of bias in included studies
We will assess the methodological quality of the included studies using the Cochrane risk of bias tool (Higgins 2011a). The following items will be taken into consideration:
Random sequence generation;
Allocation concealment;
Blinding of participants, personnel and outcome assessors;
Incomplete outcome data;
Selectve outcome reporting; and
Other potential sources of bias.
Studies will be assigned a 'low' risk of bias if all six factors are rated as low risk, a 'high' risk of bias if one or more factors are rated as high risk and an 'unclear' risk of bias if one or more factors are rated as unclear risk. Two authors (AR and PC) will independently perform the risk of bias assessment. Disagreements will be resolved by discussion and consensus with third party input (CHS) as needed. Study authors will be contacted as necessary for missing information. The authors performing the risk of bias assessment will not be blinded to study author, institution or journal.
The overall quality of the evidence supporting the primary outcome and selected secondary outcomes will be assessed using the GRADE instrument (Schünemann 2011). As per GRADE, outcomes derived from RCTs start as high quality evidence but can be downgraded due to high risk of bias (methodological quality), indirectness, inconsistency (unexplained heterogeneity), imprecision (sparse data) or reporting (publication) bias. The quality of the evidence will be graded as high (i.e. further research is very unlikely to influence the degree of confidence in the effect estimate), moderate (i.e. further research is likely to have an important influence on the degree of confidence in the effect estimate and may change the estimate), low (i.e. further research is very likely to have an important influence on the degree of confidence in the effect estimate and is likely to change the estimate) or very low (i.e. very uncertain about the estimate).
Measures of treatment effect
Review Manager (RevMan version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) will be used for data analysis. Abstracted data will be converted into 2x2 tables. An estimate of treatment effect will be provided for each separate intervention‐comparator pair. Dichotomous outcomes, including MH and endoscopic response, will be presented as risk ratios (RR) with 95% confidence intervals (CIs). An intention‐to‐treat analysis will be used. Continuous outcomes will be presented as the mean difference (MD) with corresponding 95% CI if the same instrument or scale was used across studies for a given outcome, or as the standardized mean difference (SMD) with corresponding 95% CI if different instruments or scales were used to measure the same underlying construct.
Unit of analysis issues
If cluster randomized trials are encountered, approximate analyses will be performed by calculating effective sample sizes, as described in Section 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). For cross‐over studies, only the first treatment period will be taken into consideration. In the setting of trials with more than two arms, study groups will be combined, as appropriate, to generate single pair‐wise comparisons (Higgins 2011b).
Dealing with missing data
If data are missing despite attempts to contact study authors, a conservative intention‐to‐treat analysis that assumes the worst outcome will be used for dichotomous outcomes. For continuous outcomes, no such assumptions will be made and only patients with available data will be analyzed.
Assessment of heterogeneity
We will investigate clinical and statistical heterogeneity. For statistical heterogeneity, the Chi2 test and I2 statistic will be used. A Chi2 test with a P value of < 0.10 will be considered statistically significant heterogeneity and I2 values will be interpreted as follows: 0% to 40% ‐ might not be important; 30% to 60% ‐ may represent moderate heterogeneity; 50% to 90% ‐ may represent substantial heterogeneity; and 75% to 100% ‐ considerable heterogeneity. If the I2 statistic shows a moderate to high degree of heterogeneity and the Chi2 test is statistically significant, heterogeneity will first be assessed by visually inspecting the forest plots for obvious outliers. If applicable, a sensitivity analysis will then be performed excluding the outlier to see if this explains the heterogeneity. In addition, if possible, subgroup analyses will be performed to explore sources of clinical and methodological heterogeneity.
Assessment of reporting biases
A funnel plot will be used to assess publication bias, as per Egger's method (Egger 1997), where sufficient studies (≥10) exist.
Data synthesis
Data will only be pooled if studies appear to be estimating the same underlying treatment effect. By extension, a decision was made a priori not to pool treatment effect estimates for different types of biologics. Results will be pooled with the Mantel‐Haenszel method and a random‐effects model, with weights assigned as per the DerSimonian and Laird method. We will calculate the pooled RR with corresponding 95% CI for dichotomous outcomes. For continuous outcomes, we will calculate the pooled MD or SMD with corresponding 95% CI as appropriate.
Subgroup analysis and investigation of heterogeneity
If possible, we will perform a subgroup analysis comparing biologic‐naive and biologic‐exposed individuals to examine sources of clinical heterogeneity.
Sensitivity analysis
As mentioned, a sensitivity analysis excluding outliers will be performed if significant heterogeneity is identified. In addition, if the data permit, sensitivity analyses restricted to low risk of bias studies, and to studies assessing endoscopic outcomes with a validated endoscopic scoring tool, will be performed.
