Type I interferons for induction of remission in ulcerative colitis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective of this review is to systematically evaluate the efficacy of type I IFN therapy (including IFN‐β‐1a, IFN‐β‐1b, IFN‐α‐2a, IFN‐α‐2b and associated pegylated formulations) in inducing remission in ulcerative colitis. The secondary objectives are to determine improvement in disease activity aside from inducing remission (including quality of life) and to evaluate adverse events associated with IFN therapy for the treatment of UC.
Background
Ulcerative colitis
Ulcerative colitis (UC) is characterized by chronic or recurrent contiguous inflammation of the colonic mucosa resulting in symptoms such as bloody diarrhea, abdominal discomfort, urgency and tenesmus. Inflammation typically arises in the distal colon and extends in a proximal direction. The disease can be subcategorised by anatomic extent. Left sided colitis is defined by inflammation which does not extend beyond the splenic flexure, and pancolitis where there is more proximal involvement. UC varies in severity and patients often experience cycles of relapses and remissions. While the exact cause of the disorder remains to be determined, environmental factors are thought to modify disease presentation in genetically predisposed individuals (Hanauer 2006). From an immunological perspective, the naive T cells (Th0) preferentially differentiate into Th2 (T‐helper) lymphocytes, which express a predominant interleukin‐4 (IL‐4), IL‐5, IL‐13 cytokine profile (Bouma 2003). However, UC represents an 'atypical' Th2 disease as increased circulating levels of interferon‐γ and TNF‐α (tumour necrosis factor‐α) have also been identified (Tsukada 2002). It is hypothesized that this imbalance in circulating pro‐inflammatory and anti‐inflammatory cytokines underlies the chronic disease state (Baumgart 2007).
The mainstay of UC treatment comprises anti‐inflammatory agents in the form of 5‐aminosalicylic acid compounds (Travis 2006), glucocorticoids (Truelove 1955), and immunomodulators (Timmer 2007). These standard medical therapeutic options vary in efficacy, and importantly, toxicity. While surgery may be considered 'curative' by some, this is often not ideal, rendering some patients with permanent ostomies and others with ongoing symptomatology, including that associated with suboptimal ileoanal pouch function. Therefore, alternative treatments are continually being evaluated, including the use of biologic agents targeting specific cytokines (Van Assche 2006).
Interferons
Interferons (IFNs) are cytokines which may be released in response to viruses, bacteria, parasites and tumour cells. Interferons possess immunoregulatory, antiviral and anti‐cancer properties. Interferons have been used to successfully treat a number of chronic inflammatory disorders including multiple sclerosis (Anonymous 1998; Anonymous 2001) and chronic viral hepatitis (Hoofnagle 2006). There are two main classes of IFNs: type I IFNs (which include the α, β, ε, Ω, κ isoforms) and type II IFNs (γ isoform) (Ghosh 2006).
This systematic review will focus on the use of type I IFNs for the induction of remission in UC, specifically IFN‐α and IFN‐β which are marketed in both standard recombinant or pegylated forms. IFN‐α has been shown to enhance human Th1 responses. This helps to re‐establish the Th1/Th2 balance in Th2 predominant diseases by down‐regulating Th2 cytokines such as IL‐4, IL‐5 and IL‐13 (Shibuya 2005; Brassard 2002). IFN‐β increases the expression of anti‐inflammatory IL‐10, inhibits IFN‐γ, TNF‐α, and enhances regulatory T lymphocyte and NK (natural killer) cell activity (Graber 2007). As IFN‐α and IFN‐β share a cellular surface receptor, they both induce IL‐1Ra. The adverse effect profile of IFNs include flu‐like symptoms, skin rashes, psychological disturbances, perturbations in the haematological profile, and, in keeping with their immunomodulatory effects, the IFNs may also induce autoimmune complications including thyroid disorders, diabetes mellitus and alopecia (Borg 2007; Okanoue 1996).
Commercially available type I IFNs have different pharmacokinetic profiles, and consequently there is variation in the frequency and mode of administration. Type I IFNs can be administered on alternate days, thrice weekly, or once a week by subcutaneous or intramuscular injection. Some of the IFNs are available in pegylated forms to reduce clearance. Pegylation is the process by which the biologically inert polyethylene glycol (PEG) chains are cross linked to the active moeity, in this setting, the IFN protein, to optimise overall pharmacokinetics (Foster 2004). Currently available type I IFNs include IFN α‐2a (Roferon A® ‐ Roche), IFN α‐2b (Intron A® ‐ Schering), pegylated IFN α‐2a (Pegasys® ‐ Roche), pegylated IFN α‐2b (Pegatron® ‐ Schering), IFN β‐1a (Rebif® ‐ Pfizer, EMD Serono), IFN β‐1a (Avonex® ‐ Biogen Idec), IFN β‐1a (CinnoVex® ‐ CinnaGen, Fraunhofer Gessellschaff Institute), and IFN β‐1b (Betaseron® ‐ Bayer HealthCare).
Importance of this review
In an effort to improve the management of UC, alternative therapeutic options need to be evaluated. As type I IFNs have been used successfully to treat other TH2 chronic inflammatory disorders, this suggests they may be useful in UC. However, there is limited clinical information on the use of IFN therapy for UC, and there are concerns regarding its adverse effect profile. Furthermore, there is variation in the types of IFN (IFN‐α, IFN‐β), their formulations (standard versus pegylated), the doses and dosing schedules used. Therefore, a systematic review is planned to assess the role of type I IFN therapy in inducing remission in UC.
Objectives
The primary objective of this review is to systematically evaluate the efficacy of type I IFN therapy (including IFN‐β‐1a, IFN‐β‐1b, IFN‐α‐2a, IFN‐α‐2b and associated pegylated formulations) in inducing remission in ulcerative colitis. The secondary objectives are to determine improvement in disease activity aside from inducing remission (including quality of life) and to evaluate adverse events associated with IFN therapy for the treatment of UC.
Methods
Criteria for considering studies for this review
Types of studies
Randomised, double blind trials reporting either the primary or secondary objective and published in any language, with the following study designs: parallel arm placebo‐controlled trials and trials comparing two active agents, will be considered for this review. Studies published in abstract form will only be included if enough data are provided to assess the validity of the study and reported outcomes.
Types of participants
UC is usually diagnosed using a combination of clinical, radiologic, endoscopic and histologic criteria. Patients (both paediatric and adult) with active UC at the time of recruitment will be included. It is anticipated that there will be heterogeneity in defining disease activity, therefore the definitions used by the authors of the primary studies will be accepted. This may include the following published disease activity indices: the Colitis Activity Index (CAI) (Rachmilewitz 1989), the Powell‐Tuck Index (Powell‐Tuck 1978), the Simple Clinical Colitis Activity Index (SCCAI) (Walmsley 1998), Beattie's Colitis Symptom Score (Beattie 1996), Lichtiger Symptom Score for Acute Ulcerative Colitis (Lichtiger 1990), the Mayo Index (Schroeder 1987), the Seo Index (Seo 1992), and the Truelove and Witt's Index (Truelove 1955).
Types of interventions
Trials assessing type I IFNs (IFN‐α or IFN‐β) versus placebo, or different regimens of interferon or an active comparator will be included. Trials comparing type I IFNs (IFN‐α or IFN‐β) with various co‐interventions will be permitted if the co‐interventions are balanced between the study groups. There are no exclusions based on type, dose or duration of IFN treatment.
Types of outcome measures
Primary outcome
The primary outcome will be induction of clinical remission. Clinical remission will be defined by the primary studies (see disease activity indices described under 'Types of participants') and will be expressed as the percentage of patients randomised (intention to treat analysis).
Secondary outcome
The secondary outcomes that will be documented include:
1. Endoscopic remission;
2. Time to remission;
3. The mean change in the disease activity index score;
4. Clinical, histological or endoscopic improvement as defined by the authors;
5. Improvement in quality of life as defined by a validated quality of life tool; and
6. Adverse events associated with IFN therapy for the treatment of UC.
Four different outcome measures will be used to evaluate the safety of type I IFNs:
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The percentage of patients experiencing adverse events (which may include but are not limited to flu‐like symptoms, skin rashes, psychological disturbances, perturbations in the haematological profile, and autoimmune complications such as thyroid disorders, diabetes mellitus and alopecia);
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The percentage of patient withdrawals due to adverse events;
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The percentage of patients undergoing colectomy; and
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The percentage of mortality.
Search methods for identification of studies
See: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group methods used in reviews.
Search sources
A. Electronic searching
1. MEDLINE (1950 ‐ present)
2. EMBASE (1980 ‐ present)
3. Cochrane Central Register of Controlled Trials
4. Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders (IBD/FBD) Group Specialised Trial Register
5. Ongoing trials will be identified from the registry link http://ClinicalTrials.gov
B. Hand searching using reference lists of trials and review articles identified by means of the computer‐assisted search.
C. Proceedings from major gastroenterology meetings
(American Gastroenterology Association, British Society of Gastroenterology, United European Gastroenterology Week) will be manually searched from 2002 onwards.
D. Pharmaceutical and personal contacts
Relevant pharmaceutical companies that have or are involved in the development of the type I IFNs, and leaders in the field of inflammatory bowel disease will be contacted to try and identify further unpublished studies.
Search terms
MEDLINE (from 1950 ‐ present)
1. Colitis, Ulcerative/ or Inflammatory Bowel Diseases/
2. exp Interferons/ or interferons (nm) or interferon:.mp.
3. 1 and 2
4. limit 3 to (controlled clinical trial or randomized controlled trial)
5. (rct or rcts or random: or (control: adj5 trials:)).mp. or controlled clinical trials/ or randomised controlled trials/
6. 3 and 5
7. 4 or 6
EMBASE (from 1980 ‐ present)
1. Ulcerative Colitis/ or (inflammatory adj5 bowel).ti,ab.
2. exp INTERFERON/ or interferon:.mp. or 76543‐88‐9.rn.
3. exp Interferon/ct
4. controlled study/ or randomised controlled trial/ or (random: or rct or rcts or cct or ccts).mp. or (control: adj5 trial:).mp.
5. 1 and 2
6. 4 and 5
7. 1 and 3
8. 6 or 7
Data collection and analysis
Study selection
All the article abstracts identified by the above search strategies will be reviewed for eligibility. The full text articles of potentially relevant studies will be reviewed independently by two authors (CHS and EIB) for inclusion in the review. Review articles will also be retrieved and reference lists will be manually searched. Disagreements will be resolved by consensus with AHS and AMG. Trials published in abstract form only will only be included if full details of the protocol and results can be obtained from the authors.
Data collection
The eligible articles will be independently reviewed by two authors (CHS, EIB) and the results of the trials will be abstracted onto specially designed data extraction forms. The following information will be recorded:
1. General article information: Study title, first author, and year of publication;
2. Study design: Randomisation process, allocation concealment, and blinding;
3. Patient cohort: Countries in which study was performed, years patients were entered into the study, total number of patients screened and randomised, inclusion/exclusion criteria, baseline characteristics (demographics, disease extent, disease severity);
4. Intervention: Type of IFN (α versus β), formulation of IFN (standard versus pegylated), route of administration, dosing schedule;
5. Control: No treatment, placebo, or details of co‐intervention;
6. Primary outcome: Proportion of patients achieving remission in the intervention and control groups;
Where available, the median number of days to remission and the mean change in the disease activity index score will be recorded; and
7. Secondary outcomes: Data on other clinical, histologic, endoscopic measures of disease activity; quality of life information; adverse events; withdrawal of participants from either the intervention or control group, where provided.
Assessment of methodological quality of included studies
The Jadad scale, (Jadad 1996) which assesses randomisation, blinding and withdrawals/dropouts will be used to assess the quality of eligible studies. The five point ordinal scale will be independently completed by CHS and EIB; and any disagreement will be resolved by consensus with AHS and AMG. Articles with a Jadad score of 0‐2 (poor quality) will be considered for subgroup analysis of low‐quality studies. A sensitivity analysis taking into account study quality will also be performed (See 'Sensitivity analysis').
Statistical analysis
Measures of treatment effect
Data will be extracted from the original studies and converted into individual 2 x 2 tables (e.g. remission versus no remission x IFN versus control) for each study. The proportion of patients who enter remission will be calculated and reported as a relative risk (RR) and 95% confidence interval (95% CI). Where appropriate, the number needed to treat (NNT) and risk difference (RD) will also be calculated. This will be based on an intention to treat analysis, based on the total number of patients randomised to each of the two groups, and the number of patients in remission at the end of follow‐up in each group. For continuous variables, the results will be presented as the weighted mean difference (WMD) and 95% CI or the standardised mean difference (SMD) if the outcomes are not comparable. Where available, individual 2 x 2 tables for strata within studies will also be abstracted.
Meta‐analysis
The 2 x 2 tables will be synthesised into a summary test statistic using a random or fixed effects model depending on clinical and statistical heterogeneity. Studies will be weighted using the Mantel‐Haenszel method if a fixed effects model is used, or the DerSimonian & Laird method for a random effects model.
Assessment of heterogeneity
The studies will be independently assessed for clinical or methodological heterogeneity. Then, the I2 measure will be used to quantify inconsistency. This describes the percentage of total variation across studies that is due to heterogeneity rather than chance, and interpreted as follows: 25% ‐ low heterogeneity, 50% ‐ moderate heterogeneity, 75% ‐ high heterogeneity (Higgins 2003). The Cochran chi‐square test (Q test) will also be performed. As this is a relatively insensitive test for the presence of heterogeneity, a p‐value < 0.10 will be considered as statistically significant.
Subgroup analysis
A priori subgroup analyses are planned for the different types of type I IFN (IFN‐a versus IFN‐b), different formulations of IFN (standard versus pegylated), different doses, different durations of treatment, paediatric versus adult, and left‐sided colitis versus pancolitis.
Sensitivity analysis
This will be performed including and excluding poor quality studies, and including or excluding those published only in abstract form. If sufficient eligible trials are identified, a 'funnel plot' will be used to assess publication bias (Egger 1997).
Analyses will be performed using Review Manager software (RevMan 4.2.10, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2006).
