Methotrexate for multiple sclerosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review will assess the benefits and risks of oral methotrexate for the secondary prevention of relapses and delay of progression of multiple sclerosis.
Background
Multiple sclerosis is an inflammatory disease of the brain and spinal cord. The initial disease course can be characterised by a series of relapses and remissions (relapsing remitting MS), but given time, multiple sclerosis will become a disabling disorder (Hawkins 1999). In some patients the disease is progressive from its onset (primary progressive MS) and in others a period of progression follows a period of relapses and remissions (secondary progressive MS). Treatments which reduce relapse rates or delay disease progression are a priority. The most promising avenues for treatment are immunomodulatory therapies (Hunter 1997). Methotrexate is a potent immunosuppressant, whose mode of action is predominantly through its inhibition of dihydrofolate reductase (Calabresi 1990), although there are other anti‐inflammatory effects which do not rely upon this specific mechanism (Cronstein 1993). However, long term methotrexate administration is associated with serious side‐effects including hepatic fibrosis (Colsky 1955). It is important to establish the efficacy of methotrexate, to ensure that people with MS are not subject to long term exposure with a potentially toxic drug without good evidence of efficacy.
Objectives
This review will assess the benefits and risks of oral methotrexate for the secondary prevention of relapses and delay of progression of multiple sclerosis.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials of at least 3 months duration which assess the efficacy and tolerability of oral methotrexate for multiple sclerosis will be analysed. Non‐randomised or quasi‐randomised trials will be excluded.
Types of participants
Patients will have a diagnosis of definite multiple sclerosis according to the criteria of Poser et al (Poser 1983), irrespective of disease course. Trials which did not use the criteria of Poser will be included if they specified a recognisable diagnostic criteria, but will be excluded if diagnostic criteria were unclear. Sub‐group analyses will be performed for (a) relapsing remitting MS, (b) secondary progressive MS and (c) primary progressive MS if sufficient data are available. Definitions of disease course are those described by Lublin (Lublin 1996).
Types of interventions
This review is restricted to controlled trials of oral methotrexate at a dose of at least 7.5 mg per week. The minimum treatment period should be 3 months, although it is accepted that this time may be insufficient to detect differences in EDSS score between treatment groups. Oral and intravenous corticosteroids are permitted for relapse treatment, but such treatment must have been allowed in both treated and control groups.
Types of outcome measures
Each outcome measure will be assessed at the end of the treatment period. The primary outcomes for this review are:
1. Progression of disease assessed by the Expanded Disability Status Scale (EDSS)(Kurtzke 1983), where disease progression is defined by sustained worsening (for at least one 3 month period within the duration of a trial) of the EDSS entry score by greater than or equal to 1.0 points for those with an entry score of less than 5.5, or by greater than or equal to 0.5 for those with an entry score of greater than or equal to 5.5.
2. Relapse rate, expressed as the number of relapses per annum in each treatment arm. Relapses should fulfil the criteria of Poser (Poser 1983) ‐ the appearance of a new or recurrence of an old symptom for at least 24 hours in the absence of fever, which is preceded by a period of disease stability or improvement for at least 30 days.
3. The proportion of patients remaining relapse free at the end of the treatment period.
The following are considered secondary outcomes:
1. Time to sustained disease progression (as defined above in 1).
2. Time to first relapse (as defined above in 2).
3. Number of new or enlarging lesions on brain T2 weighted Magnetic Resonance Imaging (MRI).
4. Number of gadolinium enhancing lesions on T1 weighted MRI scans
5. Total MRI lesion burden on T2 weighted scans expressed as a volume in cubic millimetres
6. Number or rate of treated relapses (defined as a relapse needing corticosteroid treatment or admission to hospital)
7. Side‐effect reports, including reports of significant immunosuppression, opportunistic infection or hepatic fibrosis.
A single of trial, which is eligible for this review used a composite outcome measure (Goodkin 1995). As this measure is not widely accepted in MS trials, we will not accept this as an outcome measure for the purposes of this review, although it influences the conclusions of the review it will be discussed once the review is complete.
Search methods for identification of studies
See MS Review Group Search Strategy for randomised controlled trials.
Relevant articles will be identified using the following mechanisms:
1. MEDLINE search using the search strategy for randomised controlled trials suggested by the multiple sclerosis review group, specifying the search for 'multiple sclerosis' and "methotrexate"
2. EMBASE search as above for MEDLINE
3. Reference lists from identified trials, and reviews of multiple sclerosis treatment, including recent textbooks with chapters on multiple sclerosis treatments.
4. Personal communication with first authors of identified clinical trials or reviews
5. Science Citation Index (SCISEARCH) on identified RCTs
6. Manufacturers of methotrexate (Pharmacia Upjohn, Lederle, Faulding DBL)
7. Multiple sclerosis Review Group Specialised Trial Registry
8. CENTRAL database of the Cochrane Collaboration
9. Handsearch of the following journals for abstracts of meetings at which papers are likely to have been presented; (1) Neurology ‐ American Academy of Neurology, (2) Annals of Neurology ‐ American Association of Neurology, (3) Journal of Neurology, Neurosurgery and Psychiatry ‐Association of British Neurologists, (4) Journal of Neurology ‐ European Neurological Society, excluding those journals already searched by other Cochrane Groups. The New England Cochrane Centre will be consulted to ensure that no hand‐search is duplicated.
10. The secretariat of ECTRIMS and ACTRIMS (European and American Committee on Treatment and Research in Multiple Sclerosis) will be contacted to obtain books of abstracts of their annual meetings
11. British Medical Journal Register of unpublished clinical trials
Unpublished trials will be detected from mechanisms 4, 6, 9, 10, 11.
Data collection and analysis
Titles and abstracts of papers identified from the above strategy will be screened independently by two reviewers (OG and GM) to identify studies of possible relevance. Agreement will be reached by consensus, including review of full text if necessary. The full text of all studies remaining after screening will be scrutinised independently by two reviewers (OG and GM) to determine whether the pre‐specified selection criteria are met. Two reviewers (OG and RF) will then independently abstract patient and study characteristics (including diagnostic criteria, disease type, drug dosage, follow‐up period, outcome measures). Consensus will be used to resolve disagreement. Authors of trials will be contacted to obtain missing data or to clarify disputed methodological points.
Methodological quality
The Cochrane Reviewer's Handbook discusses methodological quality under the following headings: (1) Selection bias, (2) Performance bias, (3) Attrition bias and (4) Detection bias.
(1) Selection bias will be determined by assessing allocation concealment and matching of groups. Allocation concealment will be classified as (A) adequate, (B) unclear, (C) inadequate and (D) not used. It will be noted whether groups of treated and control patients had comparable baseline demographic and clinical characteristics. If groups were comparable at baseline there were no differences in the reported sociodemographic (age, sex) and clinical characteristics (pre‐treatment relapse rate, EDSS score, non‐drug treatments, disease duration) of each group at conventional levels of significance.
(2) If performance bias was absent then each group and the treating physician will have been blinded to treatment allocation during the trial.
(3) It will be assumed that attrition bias is unlikely to have occurred if analysis of a trial was by intention to treat.
(4) If a separate evaluating physician and treating physician were employed, detection bias will be acceptably low.
A trial will be of best (class 'A') methodological quality if (1) allocation concealment was adequate (Unclear allocation concealment will be accepted if every other methodological factor was of the best possible standard), (2) Treated and non‐treated groups had adequate baseline comparability, (3) patients and treating physician were blind to treatment allocation, (4) analysis was intention to treat, (5) a separate evaluating and treating physician were employed. Moderate (class 'B') methodological quality will be indicated if the criteria for class A quality are met, but the standard could be relaxed to include trials which were not intention to treat, or which did not have a separate evaluating and treating physician. A methodologically poor trial (class 'C') will be indicated if allocation concealment was inadequate or not used, there was no blinding, analysis was not intention to treat and a separate evaluating physician was not used.
Class 'C' trials will be excluded as unsuitable for analysis. A sensitivity analysis will explore the effect of including class 'B' trials. The primary analysis will be restricted to class 'A' trials, and will specify disease course.
Analysis of outcomes
For outcomes with continuous data, weighted mean differences will be calculated (differences in relapse rate, or treated relapses). For dichotomous outcome measure odds ratios will be used to estimate the effect of treatment. If trials have used different doses of methotrexate or differ in duration of follow‐up, heterogeneity analyses will explore the effect of dose or duration of treatment upon the outcomes stated above (if sufficient data is available). Sensitivity and subgroup analyses are planned as stated above. Each analysis will be separated for disease course (relapsing remitting, secondary progressive, primary progressive), and a secondary analysis will consider all people with multiple sclerosis ‐ irrespective of disease course. For secondary outcomes (1‐ EDSS progression) and (2 ‐ relapse rate), an approximation of a survival analysis will be made by estimating the proportion with disease progression or at least one relapse at 6, 12, 18 and 24 months. To undertake a formal survival analysis, individual patient data would be required, but this is not planned at present.
