Corticosteroids for the long‐term treatment in multiple sclerosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review was to determine whether long term treatment of MS patients with corticosteroids:
1) prevents or significantly delays disability progression at long term follow‐up;
2) reduces the risk of exacerbations, increasing the proportion of relapse‐free patients during the follow‐up;
3) is well tolerated and safe.
We selected progression of disease rather than the occurrence of exacerbations as primary outcome measure, both because exacerbations do not necessary correlate with clinical evidence of disease progression, a more meaningful parameter than the occurrence of symptoms and signs that can remit, and because we aim to consider also progressive forms of the disease.
We also wish to evaluate the effect of different doses, drugs, routes of administration, regimens (i.e. pulsed or continuous) and length of treatment and whether the effect of treatment is different according to types of disease (relapsing/remitting, relapsing/progressive [RP], secondary progressive or primary progressive [PP]).
Background
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system whose aetiology is still unknown. Treatment is based on the assumption that an autoimmune disorders plays a major role in the pathogenesis of disease (Compston 2002; Rizvi 2004a; Rizvi 2004b; Frohman 2005).
Corticosteroids inhibit lymphocyte proliferation and the synthesis of almost all known proinflammatory cytokines and cell surface molecules required for immune function with a mechanism that involves a specific corticosteroid receptor (Sloka 2005). For their potent anti‐inflammatory effect, corticosteroids are used to treat MS patients since the 1950s and today are considered the standard treatment for acute exacerbations (Compston 2002; Rizvi 2004b; Frohman 2005). However, corticosteroids, being also immunosuppressive drugs, might prevent or delay the occurrence of future episodes of inflammatory demyelination (Gold 2001).
A previous Cochrane review showed that a short term high dose intravenous methylprednisolone (IVMP) course within 8 weeks of acute exacerbation of MS, improve symptoms and short term disability without relevant side effects but data were insufficient to estimate the effect on prevention of new exacerbations and reduction of long term disability (Filippini 2000). In the present review, instead, we would like to consider corticosteroids administered as a long term treatment specifically to prevent and not to treat acute exacerbations.
The idea that corticosteroids might prevent new exacerbations, reduce long term disability, and therefore, change the natural history of MS, comes from several observations:
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the results of the Optic Neuritis Treatment Trial (ONTT) suggested that IVMP delays the development of clinically definite MS following optic neuritis (Beck 1993);
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a phase II randomized controlled trial (RCT) in relapsing‐remitting (RR) MS comparing the efficacy of pulsed IVMP with IVMP at the same dosage regimen but administered only for relapses, showed that pulsed IVMP slowed the development of destructive lesions (T1 black holes), the rate of whole‐brain atrophy progression and the development of sustained physical disability (Zivadinov 2001);
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another phase II RCT of bimonthly IVMP pulses in patients with secondary progressive (SP) MS showed a beneficial effect on time to onset of sustained progression of disability with the high‐dose regimen(Goodkin 1998a);
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one non randomized trial with historical controls suggested that patients with MS treated with high dose IV corticosteroids during the six months of post‐partum period might reduce the childbirth‐associated risk of acute exacerbation (de Seze 2004);
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some studies indicated that pulsed IVMP produces a rapid and dose dependent reduction in gadolinium enhancement at cerebral MRI that lasts for up to 6 months (Barkhof 1994; Smith 1993; Goodkin 1998b).
The effect of corticosteroid in the long term treatment of MS has been already investigated in a systematic review (Brusaferri 2000) that included 4 RCTs, for a total of 637 randomised patients, comparing the effects of ACTH, prednisolone and methylprednisolone, given continuously for 9‐18 months, to placebo. It reported no significant effect on long‐term disability and on relapse prevention. The review also reported the occurrence of both minor and major side effects including severe Cushing's, hypertension, herpes simplex, herpes zoster, severe ankle oedema, femoral fracture and gastrointestinal bleeding (Brusaferri 2000).
Pulsed regimens of administration have renewed the interest for corticosteroids as they are reported to be well‐tolerated and safe, with only minor and dose‐related side effects, such as insomnia, transient mood disorders, acneiform‐rash, heartburn, headache and myalgias (Pozzilli 2004). The rational for pulsed administration is based on the hypothesis that these drugs may have a long‐lasting immunosuppressive effect, as indicated by the above mentioned studies, and that MS may be a restless, progressive disease even when, as in the RR form, the clinical course between two exacerbations is stable (Stone 1995). The subgroup meta‐analysis in the Brusaferri 2000 review is in line with this idea, since it showed that high dose and short term corticosteroids achieved a significant 30‐day improvement in disability and a marginally significant benefit on relapses prevention (p<0.05) but needs to be confirmed by an ad hoc meta‐analysis.
No marketing interest may economically sustain the realization of large RCTs today. Moreover the planning of placebo‐controlled RCTs appear unethical when disease‐modifying drugs as interferon betas, glatiramer acetate and mitoxantrone are available (Rizvi 2004a; Rizvi 2004a). Thus, a systematic review of RCT to gather all data available to date on long term use of corticosteroids appears worthwhile.
Objectives
The objective of this review was to determine whether long term treatment of MS patients with corticosteroids:
1) prevents or significantly delays disability progression at long term follow‐up;
2) reduces the risk of exacerbations, increasing the proportion of relapse‐free patients during the follow‐up;
3) is well tolerated and safe.
We selected progression of disease rather than the occurrence of exacerbations as primary outcome measure, both because exacerbations do not necessary correlate with clinical evidence of disease progression, a more meaningful parameter than the occurrence of symptoms and signs that can remit, and because we aim to consider also progressive forms of the disease.
We also wish to evaluate the effect of different doses, drugs, routes of administration, regimens (i.e. pulsed or continuous) and length of treatment and whether the effect of treatment is different according to types of disease (relapsing/remitting, relapsing/progressive [RP], secondary progressive or primary progressive [PP]).
Methods
Criteria for considering studies for this review
Types of studies
We aim to consider firstly all apparently unconfounded RCTs, with or without blinding, of long term treatment with corticosteroid(s) in MS.
Types of participants
Patients with definite MS according to clinical and paraclinical diagnostic criteria (Poser 1983; McDonald 2001; Polman 2005) irrespective of their disease course (RR, RP, SP or PP). Studies describing only clinical criteria will be accepted as well (McDonald 1977).
Types of interventions
Active treatment: long term courses (i.e. longer than 6 months) of any type of corticosteroid, continuous or intermittent, provided that they were not started for relapses (i.e. started more than 2 months after a relapse), whatever the administration route and dosage.
Control: placebo or no treatment. Short courses (i.e. maximum 21 days of duration) of corticosteroid will be permitted, provided they were administered for relapses.
Types of outcome measures
Efficacy
We shall study the following measures in either treatment group at 1 and 2 years and at the end of the scheduled follow‐up period:
Primary outcome
1. Patients who progressed. Whenever unspecified, progression has been defined as a persistent worsening of at least one point in EDSS (Kurtzke 1983), recorded whilst not in relapse. However, other definitions of progression could be accepted, including a persistent half‐point increase starting from EDSS score 5.5, as it is often reported in the literature.
Secondary outcomes
2. Patients experiencing at least one exacerbation during the scheduled treatment period and the follow‐up period. Exacerbation is defined as the acute or subacute appearance/reappearance of neurological signs and symptoms for at least 24 hours, in the absence of fever or infection.
3. Relapse free survival, if available.
Safety
Safety outcome will be assessed among primary endpoints by unique measures cumulating all events occurring throughout the trial:
1. Number of patients with severe side effects. If not otherwise specified, side effects have been defined as severe when leading to one of the following: death, hospitalisation, treatment discontinuation.
2. We will extract any available information about safety in both the corticosteroid and control groups.
Search methods for identification of studies
We will search the following bibliographic databases: Cochrane MS Group trials register, the Cochrane Central Register of Controlled Trails (CENTRAL), MEDLINE and EMBASE.
We will handsearch recent main neurology journals, the abstracts of neurological and multiple sclerosis congresses and symposia, conference proceedings, dissertations and other forms of reports where trials relevant to the review are likely to have been published.
We will search for unpublished studies by contacting researchers who were known to be involved in this field.
We will contact manufacturers of corticosteroids in order to identify any unpublished trials.
The proposed MEDLINE strategy is given below and will be modified to suit other databases.
Database MEDLINE (Ovid)
1. Multiple Sclerosis [MESH]
2. Myelitis, Transverse [MESH:NOEXP]
3. Demyelinating Diseases [MESH:NOEXP]
4. Encephalomyelitis, Acute Disseminated[MESH]
5. 1 OR 2 OR 3 OR 4
6. (multiple sclerosis).tw
7. (transverse myelitis).tw
8. (optic neuritis).tw
9. devic.tw
10. adem.tw
11. ( neuromyelitis optica).tw
12. 6 OR 7 OR 8 OR 9 OR 10 OR 11
13. 5 OR 12
14 limit13: (Clinical Trial).pt OR (Controlled Clinical Trial).pt OR (Multicenter Study).pt OR (Randomized Controlled Trial).pt
15. Clinical Trials.mh
16. Cross‐Over Studies.mh
17. Single‐Blind Method.mh
18. Double‐Blind Method.mh
19. Random Allocation.mh
20. Research Design.mh noexp
21. Follow‐up Studies.mh
22. Prospective Studies.mh
23. Randomized Controlled Trials.mh
24. Controlled Clinical Trials.mh
25. Placebos.mh
26. placebo.tw
27. (random* OR clinical trial*).tw
28. (singl* OR double* OR trebl* OR tripl*).tw
29. (mask*OR blind* ).tw
30.(cross over OR crossover OR follow up).tw
31. (multicenter OR multicentr*).tw
32. (comparative study).tw
33. 15 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 OR 32
34. 13 AND (14 OR 33)
35. corticosteroids[tw]
36. ADRENAL CORTEX HORMONES explode tree 1 (MeSH)
37. steroids[tw]
38. STEROIDS explode all trees (MeSH)
39. methylprednisolone[tw]
40. METHYLPREDNISOLONE explode all trees (MeSH)
41. MP[tw]
42. prednisone[tw]
43. prednisolone[tw]
44. PREDNISONE explode all trees (MeSH)
45. dexamethasone[tw]
46.DEXAMETHASONE explode all trees (MeSH)
47. acth[tw]
48. (corticotrophic AND hormone) [tw]
49. 35‐48/OR
50. 34 AND 49
Abstracts of references with titles of interest will be examined to determine relevance. Where relevance is unclear from the abstract, or where no abstract is available, a copy of the article will be obtained.
Data collection and analysis
We will select trials for inclusion in the review from all studies found by the method outlined in the previous section. Disagreement will be resolved by discussion. We will extract information, for each included trial, about the method of randomisation, blinding of outcome evaluators, and whether all the randomised patients were accounted for in the analysis. The authors of the trials will be contacted if the above information is not available in the published reports. This information will be used to evaluate quality. Reviewers will assess the quality of the trials independently. Concealment of randomisation (allocation given by telephoning to a central office, by first entering the data into a computer, by the pharmacy, by using identical numbered containers, or by sequential, sealed, opaque envelopes), blinding in outcome evaluation and intention‐to‐treat analysis will be evaluated and graded as present, absent or unclear. The three criteria to assess quality will be used to derive an overall assessment of validity for each study. The approach to doing this will be to use three categories: A (low risk of bias, all of the criteria present), B (moderate risk of bias, one or more criteria unclear), C (high risk of bias, one or more criteria absent). The interobserver agreement in the overall quality score will be summarised using the weighted kappa statistic.
We will independently extract data for outcome and safety assessments, according to measures defined in the 'Type of outcome measures' section. We plan to use intention‐to‐treat analysis, extracting the number of patients originally allocated to each treatment group irrespective of compliance. If numbers extracted by the two authors are different, differences will be resolved by discussion.
Data analysis
The efficacy analyses will be based on the results of the individual trials for disability at one year or longer after treatment initiation, the safety analyses on the results for severe side effects. The analysis on secondary outcomes and on less severe side effects will be used to support the data on primary outcome. A weighted estimate of the treatment effects across trials (odds ratio) will be calculated using a fixed effect model. For interpreting the results, 95% confidence intervals will be used. Inconsistency across studies will be quantified using I2, i.e. by describing the percentage of the variability in the effect estimates that is due to heterogeneity rather than sampling error. A value greater than 50% will be considered substantial heterogeneity.
Sensitivity analyses
If patients are excluded or lost to follow up after randomisation, further information will be sought by correspondence with the trialists. If the data about these patients remain unavailable, a worst‐case scenario analysis for the outcome of "disability progression" will be provided to ensure significance of the results. In this analysis, it will be assumed that those patients who were lost to follow up in the treatment group had the worst outcome while those patients who were lost to follow up in the control group had the best outcome. If the effects of primary and worst‐case meta‐analyses are in the same direction and magnitude, a definite conclusion about the treatment effectiveness will be made; otherwise no definite conclusion will be made.
Subgroup analyses
If substantial heterogeneity is found on efficacy analysis, we will explore heterogeneity with the following subgroup analyses:
(1) comparison of trials with quality A with trials with quality B or C;
(2) comparison of the efficacy of treatment in patients treated within one year versus those treated after one year of MS onset;
(3) comparison of the effect of different doses, drugs, routes of administration, regimens (i.e. intermittent or continuous) and length of treatment;
(4) comparison of the efficacy of treatment in RR, RP, SP or PP patients
The overlap of the confidence intervals of the summary estimates in the groups of comparison will be considered (non‐overlap of the confidence intervals will indicate statistical significance).
