Thalidomide for induction of remission in Crohn's disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1. To evaluate the efficacy of oral thalidomide for induction of remission in Crohn's disease.
2. To evaluate the adverse events associated with use of thalidomide in Crohn's disease.
Background
Crohn's disease is a chronic relapsing inflammatory disorder of the gastrointestinal tract. Despite a number of management options such as corticosteroids, enteral nutrition, immunosuppressive and biologic agents, many patients with Crohn's disease remain refractory to treatment. Several of these patients also become steroid‐dependent (i.e. disease flares upon withdrawal of steroids) while others become steroid‐resistant (i.e. inadequate or no response to steroid treatment) leading to increased risk of developing steroid‐related adverse effects (Creed 2007).
Tumor necrosis factor‐alpha (TNF‐α), a proinflammatory cytokine plays a fundamental role in the pathogenesis of Crohn's disease. Infliximab, a monoclonal antibody to TNF‐α has been shown to be effective for induction (Targan 1997; Akobeng 2003) and maintenance of remission (Hanauer 2002) in Crohn's disease. Thalidomide, best known as a major teratogen that caused birth defects in up to 12,000 children in the 1960's (McBride 1961) has been found to be effective for several inflammatory and autoimmune disorders including erythema nodosum leprosum, graft versus host disease, Bechet's syndrome, discoid lupus erythematosus, rheumatoid arthritis, cancers like multiple myeloma and Crohn's disease where conventional therapies have been unsuccessful (Sands 1999).
Thalidomide is believed to exert its manifold anti‐inflammatory effects by promoting degradation of TNF‐α mRNA (Moreira 1993), inhibition of TNF‐alpha production by monocytes (Sampaio 1991), inducing monocyte apoptosis (Gockel 2004) and inhibiting monocyte IL‐12 production (Moller 1997). Other postulated mechanisms of action include reduced expression of intracellular adhesion molecule ‐1, vascular cell adhesion molecule ‐ 1 and vascular endothelial derived growth factor, the latter responsible for its angiogenic effects (Gordon 2003) and antigen presentation by langerhans cells (Deng 2003).
Thalidomide has been shown to reduce inflammation in experimental colitis (Kenet 2001). In clinical studies, it has been found to induce clinical response and disease remission in patients with refractory Crohn's disease (Ehrenpreis 1999; Vasiliauskas 1999; Facchini 2001; Bariol 2002; Plamondon 2007; Lazzerini 2007). Thalidomide has been used to maintain infliximab induced remission in chronically active and fistulizing refractory Crohn's disease (Sabate 2002) and as salvage therapy for patients with hypersensitivity to infliximab (Kane 2002).
Thalidomide is associated with a number of potential adverse events including teratogenicity, peripheral neuropathy, drowsiness, deep vein thrombosis, mood disturbances, leucopenia, skin rashes, abdominal pain, constipation, xerostomia and sebhorrheic dermatitis. The aim of this systematic review is to summarise the current evidence on the use of thalidomide for the induction of remission in Crohn's disease.
Objectives
1. To evaluate the efficacy of oral thalidomide for induction of remission in Crohn's disease.
2. To evaluate the adverse events associated with use of thalidomide in Crohn's disease.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials
Types of participants
Patients of any age with active Crohn's disease. Crohn's disease should have been diagnosed by conventional clinical, radiographic, endoscopic and histologic criteria. Active disease should have been defined using a recognised Crohn's disease activity index.
Types of interventions
Studies comparing thalidomide to placebo or active comparator will be considered for inclusion.
Types of outcome measures
1. Primary outcome: Clinical remission as defined by the primary studies and expressed as a percentage of the number of patients randomised (intention to treat analysis).
2. Secondary outcomes: Clinical response as defined by the primary studies, quality of life, growth in children, and adverse events.
Search methods for identification of studies
See: Inflammatory Bowel Disease Group search strategy.
A. Electronic search
The following electronic databases will be searched for relevant studies:
1. MEDLINE (1966‐to date);
2. EMBASE (1984‐to date);
3. Cochrane Central Register of Controlled Trials; and
4. Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialised Trial Register.
The search strategy will not be limited by language.
B. Reference searching
The references of all identified studies will be inspected for more trials.
C. Personal contacts
Leaders in the field will be contacted to identify other studies.
D. Drug companies
Manufacturers of thalidomide will be contacted for additional information.
MEDLINE on PUBMED will be searched using the following search strategy:
1. Crohn* disease
2. crohn disease (MeSH)
3. Crohn disease OR Crohn's disease
4. regional enteritis
5. ileitis
6. ileitis (MeSH)
7. inflammatory bowel disease
8. inflammatory bowel diseases (MeSH)
9. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8
10. Thalidomide OR Thalidomid
11. Thalidomide (MeSH)
12. Lenalidomide
13. Lenalidomide (MeSH)
14. 10 OR 11 OR 12 OR 13
15. remission OR relapse
16. disease‐free survival (MeSH)
17. 15 OR 16
18. 9 AND 14 AND 17
The above search strategy will be adapted and used to search the other databases
Data collection and analysis
Step 1. Using the above search strategy, papers that appear to be potentially relevant will be identified by two authors.
Step 2. The authors, after reading the full texts, will independently assess the eligibility of all trials identified using an ad hoc eligibility based on the inclusion criteria above. Disagreement among authors will be discussed and agreement reached by consensus.
Step 3. The methodological quality of selected trials will be assessed independently by two authors using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005) and the Jadad scale (Jadad 1996). The former is based on the evidence of a strong relationship between allocation concealment and direction of effect. The categories are defined below:
A. adequate allocation concealment;
B. allocation concealment unclear; and
C. inadequate allocation concealment.
The Jadad scale is a validated five point scale which measures some important factors that impact on the quality of a trial. This is summarised below:
a. was the study described as randomised?
b. was the method of randomisation well described and appropriate?
c. was the study described as double blind?
d. was the double blinding well described and appropriate?
e. were withdrawals and dropouts described?
Each item will be given a score of 1 if the answer is 'yes' and 0 if the answer is 'no'. One point will be deducted if the described method of randomisation or blinding is inappropriate.
DATA COLLECTION
A data extraction form will be developed and used to extract information on relevant features and results of included studies. Two authors will independently extract and record data on the predefined checklist. Extracted data will include the following items:
a. characteristics of patients: age, sex, disease distribution, disease duration, disease activity index;
b. total number of patients originally assigned to each intervention group;
c. intervention: thalidomide
e. control: no intervention, placebo or other interventions;
f. concurrent medications; and
g. outcomes: time of assessment, type of Crohn's disease activity index used, remission rates, quality of life, adverse events.
STATISTICAL ANALYSIS
The Cochrane Collaboration review manager (RevMan) software (version 5.0.9) will be used for data analysis. Data will be analysed according to the intention to treat principle. Patients with final missing outcomes will be assumed to be treatment failures.
Dichotomous variables
Odds ratios (OR) and their 95% confidence interval (CI) will be calculated based on a fixed effects model.
Continuous variables
Weighted mean difference (WMD) when outcomes are measured in the same units, or the standardised mean difference (SMD) where different scales are used to evaluate the same outcome will be calculated as appropriate. Similar studies will be pooled using fixed effects WMD or SMD and 95% CI.
Heterogeneity
Heterogeneity among trial results will be assessed by inspection of graphical presentations and by calculating the chi square test of heterogeneity (a P value of 0.10 will be regarded as statistically significant). The I2 value will be calculated to quantify the effect of heterogeneity (Higgins 2003). A random effects model will be used in situations of unexplained heterogeneity. When there is significant heterogeneity, we will further examine the included studies for sources of clinical and methodological heterogeneity.
Publication Bias
The possibility of a publication bias will be investigated through the construction of funnel plots (trial effects versus trial size).
Subgroup analysis
Subgroup analysis will be performed based on:
a. duration of treatment;
b. duration of disease; and
c. disease location (pure colonic disease versus small bowel involvement).
Sensitivity analyses
Sensitivity analyses will be conducted based on the following:
a. only including patients whose outcome is known (i.e. number of patients who completed the study used as denominator);
b. random effects versus fixed effects models; and
c. study quality.
