Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review)

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1 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Burton JM, O Connor PW, Hohol M, Beyene J This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 12

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Improvement in EDSS after treatment with oral vs. intravenous steroids, Outcome 1 decrease in EDSS after steroid treatment at week Analysis 1.2. Comparison 1 Improvement in EDSS after treatment with oral vs. intravenous steroids, Outcome 2 decrease in EDSS after steroid treatment at week Analysis 2.1. Comparison 2 Proportion of patients with improvement on EDSS after treatment with oral vs. intravenous steroids, Outcome 1 Proportion of patients with improvement on EDSS after steroid treatment at 4 weeks.. 39 Analysis 3.1. Comparison 3 Change in Ambulation Index after treatment with oral vs. intravenous steroids, Outcome 1 Change in Ambulation Index at week 1 after treatment with oral vs. intravenous steroids Analysis 3.2. Comparison 3 Change in Ambulation Index after treatment with oral vs. intravenous steroids, Outcome 2 Change in Ambulation Index at week 4 after treatment with oral vs. intravenous steroids Analysis 4.1. Comparison 4 Longterm relapse rate after treatment with oral vs. intravenous steroids, Outcome 1 Relapse rate 6 months after treatment with oral vs. intravenous steroids Analysis 4.2. Comparison 4 Longterm relapse rate after treatment with oral vs. intravenous steroids, Outcome 2 Relapse rate at one year after treatment with oral vs. intravenous steroids Analysis 4.3. Comparison 4 Longterm relapse rate after treatment with oral vs. intravenous steroids, Outcome 3 Relapse rate at years 1-2 after treatment with oral vs. intravenous steroids Analysis 4.4. Comparison 4 Longterm relapse rate after treatment with oral vs. intravenous steroids, Outcome 4 Relapse rate at two years after treatment with oral vs. intravenous steroids Analysis 4.5. Comparison 4 Longterm relapse rate after treatment with oral vs. intravenous steroids, Outcome 5 Proportion relapse free at 2 years after treatment with oral vs. intravenous steroids Analysis 5.1. Comparison 5 Days to next relapse after treatment with oral vs. intravenous steroids, Outcome 1 number of days to next relapse after treatment with oral vs. intravenous steroids Analysis 6.1. Comparison 6 EDSS at first relapse after treatment with oral vs. intravenous steroids, Outcome 1 change in EDSS at first relapse within 2 year period after treatment with oral vs. intravenous steroids Analysis 7.1. Comparison 7 Proportion hospitalized for relapse after treatment with oral vs. intravenous steroids, Outcome 1 Proportion hospitalized at week 1 after treatment with oral vs. intravenous steroids Analysis 7.2. Comparison 7 Proportion hospitalized for relapse after treatment with oral vs. intravenous steroids, Outcome 2 Proportino hospitalized at week 4 after treatment with oral vs. intravenous steroids Analysis 8.1. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 1 Area under curve for steroid absorption at 1 hour with oral vs. intravenous steroids Analysis 8.2. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 2 Area under curve for steroid absorption at 2 hours with oral vs. intravenous steroids Analysis 8.3. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 3 Area under curve for steroid absorption at 4 hours with oral vs. intravenous steroids Analysis 8.4. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 4 Area under curve for steroid absorption at 8 hours with oral vs. intravenous steroids i

3 Analysis 8.5. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 5 Area under curve for steroid absorption at 8 hours with oral vs. intravenous steroids (SA, outlier removed) Analysis 8.6. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 6 Area under curve for steroid absorption at 24 hours with oral vs. intravenous steroids Analysis 8.7. Comparison 8 Bioavailability of oral vs. intravenous steroids, Outcome 7 Area under curve for steroid absorption at 48 hours with oral vs. intravenous steroids Analysis Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 1 percentage reduction in gadolinium lesions on MRI weeks Analysis Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 2 percentage reduction in gadolinium positive MRI lesions weeks Analysis Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 3 change in gadolinium enhancing lesions on MRI between weeks 0 and Analysis Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 4 change in gadolinium enhancing lesions on MRI between week 0 and Analysis Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 5 Proportion with gadolinium enhancing lesions on MRI at week Analysis Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 6 Proportion with gadolinium enhancing lesions at week Analysis Comparison 11 Changes in T2 lesion number, Outcome 1 change in T2 lesions at week 1 with respect to baseline in T2 lesion number between oral and iv Analysis Comparison 11 Changes in T2 lesion number, Outcome 2 change in T2 lesions at week 4 with respect to week Analysis Comparison 12 Proportion with HTN, Outcome 1 Proportion with HTN Analysis Comparison 13 Proportion with rash, Outcome 1 Proportion with rash Analysis Comparison 14 Proportion with hypertricosis, Outcome 1 Proportion with hypertricosis Analysis Comparison 15 Proportion with anxiety, Outcome 1 Proportion with anxiety Analysis Comparison 16 Proportion with insomnia, Outcome 1 Proportion with insomnia Analysis Comparison 17 Proportion with dysgeusia, Outcome 1 Proportion with dysgeusia Analysis Comparison 18 Proportion with hiccups, Outcome 1 Proportion with hiccups Analysis Comparison 19 Proportion with hyperglycemia, Outcome 1 Proportion with hyperglycemia Analysis Comparison 20 Proportion with headache, Outcome 1 Proportion with headache Analysis Comparison 21 Proportion with mood disturbance (euphoria, depression), Outcome 1 Proportion with mood disturbance Analysis Comparison 22 Proportion with hot flashes/flushing, Outcome 1 Proportion with hot flashes Analysis Comparison 23 Proportion with swelling, Outcome 1 Proportion with swelling Analysis Comparison 24 Proportion with pirosis, Outcome 1 Proportion with pirosis ADDITIONAL TABLES APPENDICES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS ii

4 [Intervention Review] Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Jodie M Burton 1, Paul W O Connor 2, Marika Hohol 2, Joseph Beyene 3 1 Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. 2 Division of Neurology, St. Michael s Hospital, Toronto, Canada. 3 Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada Contact address: Jodie M Burton, Department of Clinical Neurosciences, University of Calgary, th St NW, Calgary, Alberta, T2N 2T9, Canada. jodie.burton@albertahealthservices.ca. Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, Review content assessed as up-to-date: 13 June Citation: Burton JM, O Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD DOI: / CD pub3. Background A B S T R A C T This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD DOI: / CD pub2). Multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), is characterized by recurrent relapses of CNS inflammation ranging from mild to severely disabling. Relapses have long been treated with steroids to reduce inflammation and hasten recovery. However, the commonly used intravenous methylprednisolone (IVMP) requires repeated infusions with the added costs of homecare or hospitalization, and may interfere with daily responsibilities. Oral steroids have been used in place of intravenous steroids, with lower direct and indirect costs. Objectives The primary objective was to compare efficacy of oral versus intravenous steroids in promoting disability recovery in MS relapses <= six weeks. Secondary objectives included subsequent relapse rate, disability, ambulation, hospitalization, immunological markers, radiological markers, and quality of life. Search methods A literature search was performed using Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group s Trials Register (January 2012), abstracts from meetings of the American Academy of Neurology ( ), the European Federation of Neurological Sciences ( ), the European Committee for Treatment and Research in Multiple Sclerosis and American Committee for Treatment and Research in Multiple Sclerosis ( ) handsearching. No language restrictions were applied. Selection criteria Randomized or quasi-randomized trials comparing oral versus intravenous steroids for acute relapses (<= six weeks) in patients with clinically definite MSover age 16 were eligible. 1

5 Data collection and analysis Three review authors (JB, PO and MH) participated in the independent assessment of all published articles as potentially relevant to the review. Any disagreement was resolved by discussion among review authors. We contacted study authors for additional information. Methodological quality was assessed by the same three review authors. Relevant data were extracted, and effect size was reported as mean difference (MD), mean difference (MD), odds ratio (OR) and absolute risk difference (ARD). Main results With this current update, a total of five eligible studies (215 patients) were identified. Only one outcome, the proportion of patients with Expanded Disability Status Scale (EDSS) improvement at four weeks, was common to three trials, while two trials examined magnetic resonance imaging (MRI) outcomes. The results of this review shows there is no significant difference in relapse recovery at week four (MD -0.22, 95% confidence interval (95% ), 0.71 to 0.26, P = 0.20) nor differences in magnetic resonance imaging (MRI) gadolinium enhancement activity based on oral versus intravenous steroid treatment. However, only two of the five studies employed more current and rigorous methodological techniques, so these results must be taken with some caution. The Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial and the Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses (COPOUSEP) trial, designed to address such limitations, are currently underway. Authors conclusions The analysis of the five included trials comparing intravenous versus oral steroid therapy for MS relapses do not demonstrate any significant differences in clinical (benefits and adverse events), radiological or pharmacological outcomes. Based on the evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy in the treatment of MS relapses. P L A I N L A N G U A G E S U M M A R Y A comparison of the efficacy of oral versus intravenous steroids in relapsing-remitting multiple sclerosis (RRMS) RRMS is characterized by periods of disability (relapse) due to inflammation in the central nervous system. All research has shown that a speeding up of recovery is obtained by use of corticosteroids, given most often in intravenous form. If oral steroids worked as well as intravenous ones for relapse events, they would be easier to take and are more affordable. The objective of this review was to assess if oral and intravenous steroids are equally effective and safe in aiding in the recovery from relapses. Among the pertinent literature, only five studies met the inclusion criteria, comprising a total of 215 participants. Despite some limitations in the methods used to conduct the studies (i.e. incomplete reporting of the participants who dropped out the studies and appropriateness of the sample size) and in the analysis of the data, all five studies found that there were no significant differences in term of benefits and adverse events and in the pharmacological and radiological outcomes in patients taking oral or intravenous steroids. Both treatments appear to be equally effective and safe. Based on this evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy for the treatment of MS relapses. B A C K G R O U N D Description of the condition Multiple sclerosis (MS) is the most common neurodegenerative autoimmune disease in young adults in North America and Eu- 2

6 rope (Noseworthy 2000). In the majority of patients, the hallmark of the disease is the relapse, defined as an episode of neurological dysfunction lasting > 24 hours not in the context of fever and infection (Noseworthy 2000). Clinical relapses are believed to be the result of demyelination, inflammation of the white matter in the central nervous system (CNS), with subsequent recovery and remyelination (Noseworthy 2000). On average, a patient will experience one relapse every two years, and these events can range from extremely mild to significantly disabling, at times requiring hospitalization and supportive care (Confavreux 2006). Steroid preparations have been used to treat MS relapse events for over 50 years, with adrenocorticotrophin (ACTH) and cortisone being the common medications used at that time (Jonsson 1951; Tourtellotte 1965 ). In recent years, methylprednisolone and prednisone have become the mainstay of relapse therapy. Description of the intervention The vast majority of glucocorticoid activity in most mammals is from cortisol. The physiological actions of glucocorticoids occur in many cell types including hepatocytes, epithelial cells, neurons and immune cells. In these cell types, the glucocorticoid receptor regulates numerous genes that encode enzymes of carbohydrate and amino acid metabolism, hormones, hormone receptors, acutephase proteins, antibacterial actions and serum proteins (Necela 2004). Glucocorticoid medications in demyelinating disease have multiple mechanisms of action in this context as well. Most of the cellular and physiological effects of glucocorticoids occur via the glucocorticoid receptor (one of a nuclear receptor superfamily) that impacts gene transcription and signaling (Schweingruber 2011). Glucocorticoids will either interact with the membrane glucocorticoid receptor or cytosolic receptor. Binding in the cytosol allows the receptor to be released from heat shock proteins such that it is able to impact gene transcription. Another method by which glucocorticoids impact on gene transcription is their interaction with other transcription factors such as activating protein-1 (AP-1), nuclear factor kappa B (NfkB) and camp-responsive chemotaxis element binding protein (Andersson 1998). How the intervention might work Multiple sclerosis is a disease most associated with dysfunction in the inflammatory cascade, with a shift towards the pro-inflammatory or Th1 state, and away from the anti-inflammatory of Th2 state. Certain T-cell populations and cytokines highly complicit in disease immunopathology are significantly impacted by exogenous glucorticoid use. Steroids are postulated to positively impact on MS at the molecular level by many mechanisms including the reduction of adhesion molecule production (which is a step in leukocyte diapedesis) and protection of the blood brain barrier, the reduction of pro-inflammatory cytokine levels and circulating CD4 T-lymphocytes and B lymphocytes and apoptosis of certain T-cell subtypes (Andersson 1998; Schweingruber 2011). Specifically, glucorticoids suppress the production of such pro-inflammatory cytokines as interferon gamma, tumor necrosis factor alpha, IL-2 and IL-12 and also suppress nitric oxide synthesis while anti-inflammatory cytokines such as IL-4 and transforming growth factor beta are upregulated (Schweingruber 2011). There is the perception that intravenous steroids work faster compared with oral preparations, although this has not been established (Tremlett 1998). However, the efficacy of steroids versus placebo, specifically ACTH and intravenous methylprednisolone (IVMP), in reducing short-term disability associated with relapse events, has been established in a recent Cochrane review involving 377 participants (Filippini 2000). Steroid therapy also presents the risk of numerous adverse events, ranging from mild to lifethreatening. Such adverse events include weight gain and edema, sleep and mood disturbance including depression and psychosis, myopathy, cataracts, osteoporosis, hypertension, impaired glucose tolerance, gastrointestinal dysfunction, pancreatitis and vascular necrosis, although such outcomes are more typical in long-term steroid therapy (Andersson 1998). Why it is important to do this review While intravenous steroid therapy has been proven to be efficacious in hastening relapse recovery, it can be a cumbersome and costly treatment. A cost analysis in a major Canadian hospital in demonstrated that the cost, on average, for a four-day IVMP treatment regimen was approximately $1,110 Canadian for inpatients and $700 for outpatients (Robson 1998). A more recent review of relapse treatment costs in the United States revealed that the cost of setting up a single dose of IVMP is roughly $99, with homecare visitation for a four-day course of this therapy costing approximately $3,800 per patient (O Brien 2003). Hospitalization for treatment increases the cost several fold (O Brien 2003). Additionally, there are indirect costs associated with intravenous therapy, including lost productivity and work-force related costs, potential discomfort, risk of complications with intravenous placement, and the stigma of appearing ill or disabled. Orally administered steroid use is less expensive, and less demanding on healthcare resources and patients compared with intravenous regimens (O Brien 2003). Evidence from randomized trials of oral corticosteroids versus placebo in MS relapses (Sellebjerg 1998) and clinically isolated optic neuritis (Sellebjerg 1999) have shown that 500 mg of oral methylprednisolone (oral MP) for five days is significantly more effective than placebo in promoting neurological recovery as early as three weeks, with a reduction in pro-inflammatory immunological markers in cerebrospinal fluid (CSF) (Sellebjerg 2000). Troiano 1985 (Troiano 1985) demonstrated that higher doses of prednisone ( mg daily) versus lower doses ( mg alternating days) for a minimum of one week had fewer gadolinium enhancing lesions on magnetic 3

7 resonance imaging (MRI) performed an average of five weeks after relapse onset, although the trial was neither controlled nor blinded. While there are trials that support the superiority of oral steroids over placebo for treating MS relapses, the evidence for their use is limited in comparison to the evidence for intravenous steroids in this context (Filippini 2000), although one meta-analysis of steroids in MS and optic neuritis included four studies of oral steroid therapy out of a total of 12 trials, all placebo-controlled (Brusaferri 2000). In this study, subgroup analysis was not performed on oral steroids as they were taken to be equivalent to other regimens based on pharmacological equivalence calculations. Comparisons were made between low- versus high-dose regimens however, of which only one oral trial was considered highdose, therefore dose, not route, may have been the more important variable (Brusaferri 2000). While there are several publications touting the equivalency of oral and intravenous steroids in MS care, concluding that these therapies are equivalent based on trials that do not compare these agents is methodologically unacceptable If oral steroids prove to be a viable replacement for intravenous steroids in relapse treatment, they could be taken at the patient s convenience with discretion, and could potentially minimize lost productivity and other indirect costs. It is therefore necessary to determine the efficacy and safety of oral steroid preparations compared with their intravenous counterparts in a systematic and methodologically rigorous fashion. This is an update of a Cochrane review first published in 2009 which aims to evaluate the efficacy and safety of this treatment (Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD DOI: / CD pub2). O B J E C T I V E S The objective of this review is to test the hypothesis that intravenous steroid treatment and oral steroid treatment in the context of acute MS relapses are equally efficacious and safe. The main objective is to determine if there is a difference in efficacy with respect to the degree of disability recovery between oral versus intravenous steroid treatment given at the time of relapse in patients with a diagnosis of MS. M E T H O D S Only randomized and quasi-randomized trials were considered for this review. As well, trials had to be designed to directly compare efficacy (e.g. clinical, biochemical, pharmacological, immunological, radiological, cost effectiveness) or safety outcomes between oral versus intravenous steroid treatments given at the time of an acute MS relapse Types of participants Participants in eligible trials must have had a diagnosis of clinically definite relapsing (relapsing-remitting (RR) or relapsing-progressive (RP) MS based on the accepted criteria at the time of the study (Schumacher 1965; Poser 1983; McDonald 2001; Polman 2005) with an acute relapse event. Patients had to be 16 years or older, and have experienced a relapse event felt to merit steroid therapy. Patients must have received treatment within 30 days of the onset of the event. Patients also must have had their first posttreatment reassessment of neurological disability status for the study relapse event within six weeks. Relapse was defined as an episode of neurological dysfunction lasting >24 hours not in the context of fever and infection (Noseworthy 2000). However, other definitions were accepted at the review authors discretion. Types of interventions The two therapies compared in this review were any intravenous form of a steroid compared with any oral form of steroid. As there is no standard form of oral steroid therapy for MS relapse events, there was no restriction on form or dose. Typically, corticosteroids have been used, including oral prednisone, methylprednisolone and prednisolone. Intravenous steroid type and dose was also not restricted, although at the present time, the most common intravenous form of steroid therapy in MS by far is methylprednisolone. Types of outcome measures Trials with at least one of the following outcome comparisons between oral and intravenous steroid groups were evaluated. The following is a list of outcomes (primary and secondary) and the headings under which they fall. Primary outcomes The degree of recovery from relapse at < six weeks as measured by the mean change in Kurtzke s Expanded Disability Status Scale (EDSS) (Kurtzke 1983). Criteria for considering studies for this review Secondary outcomes Types of studies Relapse Recovery 4

8 1. The degree of recovery from relapse at < six weeks as measured by mean change in the Multiple Sclerosis Functional Composite (MSFC), a single composite score computed from scores on tasks for cognition, arm function and ambulation (Fisher 1999). 2. The proportion of patients with improvement from the relapse event < six weeks. 3. The proportion of patients requiring re treatment in the oral versus intravenous group. 4. The mean change in Ambulation Index between groups < six weeks. Subsequent Relapses and Disability Status 1. Relapse rate following treatment, measured as the mean annualized relapse rate. 2. Time to next relapse measured in days. 3. Long-term disability status measured as mean change in EDSS at a minimum of six months (Rio 2006). 4. Proportion relapse-free patients at a minimum of one1 month with no maximum limit. Pharmacological Efficacy 1. Bioavailability measured as mean serum concentration and mean area under the curve. Immunological Markers of Disease Status 1. Immunological markers assessed by measuring the change of mean titers of cytokines and matrix-metalloproteinases (MMPs) in serum and CSF. Radiological Efficacy 1. Magnetic resonance imaging (MRI) response measured by mean change and volume of gadolinium enhancing lesions and T2 lesion count and volume and mean new number of gadolinium and T2 lesions. Adverse Events 1. Proportion with the following non-serious adverse events. Weight gain/edema Insomnia Mood disturbance Nausea/vomiting Dyspepsia Headache Hyperglycemia (transient) Flushing Myopathy 2. Proportion with the following serious adverse events. Pancreatitis Diabetes Cataracts Bone density changes/osteoporosis Avascular necrosis Non-traumatic fractures Adrenal insufficiency Myopathy Infection Direct and Indirect Costs 1. monetary costs associated with medications, homecare services, hospital stay and consultations. 2. monetary costs of lost work productivity. Hospitalization 1. The mean length-of-stay in days for hospital for relapse and/or treatment. 2. The proportion requiring hospitalization for relapse and/or treatment. Quality of Life 1. Quality of life measured as mean change in validated scales that are both specific to MS and disease in general as per the patient and family/proxy. Search methods for identification of studies All publications describing randomized controlled trials of a direct comparison of oral versus intravenous steroid preparations given at the time of an acute MS relapse were sought. Electronic searches Electronic searches were performed by review author JB and the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Working Group on using the Cochrane MS Group Trials Register (2008-January 2012) which among other sources, contains CENTRAL, MEDLINE, EMBASE, NAHL, LILACS, PEDRO. The search terms are listed in Appendix 1 Searching other resources Handsearching was performed using the guidelines of the Cochrane Multiple Sclerosis Working Group (described in the Search Strategies for identification of studies ) section within the editorial information pertaining to the Cochrane Multiple Sclerosis Working Group in The Cochrane Library. We also handsearched 5

9 cited trials in review papers and reference lists, conference proceedings, dissertations and abstracts where appropriate. Specifically, we searched abstracts from the annual meetings of the American Academy of Neurology ( ), the European Federation of Neurological Sciences ( ), the European Committee for Treatment and Research in Multiple Sclerosis ( ) and the American Committee for Treatment and Research in Multiple Sclerosis ( ). Additional data were sought by reviewing trials listed in registries and contacting study authors and investigators as necessary ( There was no restriction on language. Letters, reviews, editorials and commentaries not containing original data were excluded. Data collection and analysis Selection of studies Three review authors (JB, PO and MH) participated in the independent assessment of all published articles as potentially relevant to the review. In order to be eligible for inclusion in the review, a trial must have met the following criteria. The study population was >= 16 years of age. The trial compared outcomes of oral steroid preparations directly to intravenous steroid preparations.; The intervention was in the context of an acute MS relapse. The intervention was offered within 30 days of the onset of the relapse event. The first assessment of response with respect to the relapse event occurred within six weeks of treatment. The trial was randomized or quasi-randomized. The trial used the EDSS or MSFC clinical scales to measure outcomes of disability. Assessment of risk of bias in included studies Methodological quality was assessed by two review authors (JB and PO) following the domain-based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions 5.0 ( Higgins 2011) The following domains were assessed as Yes (i.e. low risk of bias), Unclear (uncertain risk of bias) or No (i.e. high risk of bias): sequence generation; allocation concealment; blinding (of participants, personnel and outcome assessors); incomplete outcome data and use of intention-to-treat analyses; selective outcome reporting. rationale for sample size use of non-inferiority design and methods The review authors reported on each of these assessments in the Risk of bias in included studies table. Disagreements between review authors were resolved with the third author acting as an arbiter. Measures of treatment effect SAS (SAS Institute Inc., Casey, N.C.) was used to generate descriptive statistics for raw data when necessary, and RevMan 5 was used for all statistical analyses. Statistical parameters included odds ratio (OR), absolute risk difference (ARD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH), mean difference (MD) and standardized mean difference (SMD) as appropriate. Ninety-five percent confidence intervals () were reported for parameters of treatment effects. Unit of analysis issues Slight differences in the unit of measurement (e.g. EDSS versus MSFC) were given their own analysis. When possible, units were converted to those specified a priori for this review. Data extraction and management Two review authors (JB, and PO) independently extracted the data using standardized data collection forms. In keeping with an intention-to-treat analysis, whenever possible, the total number of patients assigned to each group was identified and noted, regardless of compliance, whether or not they received treatment, or were otherwise excluded from the originally published trial analysis. For continuous outcomes, mean and standard deviation, and the number in whom the outcome was observed, were extracted. For binary outcomes, the number of patients and the number of events within each group were extracted. When complete patient data were not available, we contacted the primary author or principal investigator of the trial requesting the data. Dealing with missing data Imputation was planned to address missing data, however, two trials with missing data no longer had raw data available to assess, and the third trial had data missing for only two of 80 patients. Assessment of heterogeneity Tests of heterogeneity for between study differences were undertaken including calculating the Q and I 2 values to determine the appropriateness of combining studies. If there was significant heterogeneity, defined by the Cochrane Multiple Sclerosis Working Group as an I 2 > 50% (D Amico 2007), we used a random-effects model. If heterogeneity was not significant, we used a fixed-effect 6

10 model for meta-analyses. If a meta-analysis was not possible, a qualitative review of the trials was undertaken. Assessment of reporting biases A funnel plot to determine if publication biased was present was planned, but there was no evidence that trials eligible for inclusion in this review went unpublished. Sensitivity analysis If the data supported it, sensitivity analyses (e.g. types of relapses, different forms of steroids within the oral or intravenous domains) were to be performed, however, it was determined that there was not a significant degree of variation in trial design or methodology to support such analyses in the eligible and included trials. Data synthesis Outcomes of interest in this review include continuous and dichotomous measures. Continuous outcomes were analyzed by calculating MD between groups, while dichotomous analyses were analyzed by ORs and RD to compare groups. A random-effects model was used for this meta-analysis. In this conservative model, the assumption is that while intervention effects are related between studies, there are still inherent differences in outcomes and studies, and so an adjustment in the weighting of the study contribution is made based on the variation or heterogeneity among intervention effects (Higgins 2011). Subgroup analysis and investigation of heterogeneity Additional pre-specified subgroup analyses for steroid type used, age, baseline EDSS, time to treatment, relapse type (optic neuritis, brainstem event, myelopathy or other ) and prior annualized relapse rate were chosen a priori to explain significant heterogeneity if indicated. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. See Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies. Results of the search The above strategies, including the present update (January 2012), yielded a total of 709 articles, (630 references identified through the previous search and 79 by the new search) four abstracts and seven listings on clinicaltrials.gov (see table Results of Literature Search for Eligible Trials ) (Table 1). See details of the trial detection and process selection in Figure 1. 7

11 Figure 1. Study flow diagram. 8

12 The original and updated search yielded 35 articles, four abstracts and three clinicaltrials.gov listings initially selected for further assessment, based on which a total of five trials (with two additional papers reporting additional outcomes from one of these trials) were eligible for inclusion while the remaining trials were excluded (see Table Characteristics of excluded studies for details). Four of these trials were found in the original review, and one new trial was included based on this update (see Included studies). These five eligible trials included a total of 215 patients including withdrawals and drop-outs. Clinical details regarding the participants, interventions and outcomes are given in the table Characteristics of included studies. Two of the identified trials for assessment are ongoing (OMEGA 2007; COPOUSEP 2009) and when results become available, they will be included in this review s subsequent update. Included studies Treatment Regimens and Settings Alam 1993, Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 used oral methylprednisolone ( oral MP) versus intravenous methylprednisolone (IVMP) for the two patient groups compared. Alam 1993 used equivalent doses of 500 mg per day for a total of three days. The oral MP group received sham IV solution and the IVMP group received sham tablets. Martinelli 2008 also used equivalent dosing, with 1000 mg of oral MP or IVMP for a total of five days while Ramo-Tello 2011 used 1000 mg IVMP versus 1250 mg of oral MP for three days. Barnes 1997 had groups receive significantly non-equivalent dosing. The oral MP group received 48 mg once daily for seven days, then 24 mg once daily for seven days and finally 12 mg once daily for seven days. The IVMP group received 1000 mg of methylprednisolone intravenously once daily for three consecutive days, Sham oral and intravenous interventions were used for blinding as well. Morrow 2004 had groups receive either one dose of 1250 mg of oral prednisone or one gram of IVMP. Oral prednisone was given as mg-tablets and the IVMP was given in 100 ml normal saline infused over one hour. No sham interventions were used. This study was performed at an outpatient MS clinic. All trials appear to have been performed in the outpatient setting of a hospital-based MS care center. Countries in Which the Studies were Conducted Alam 1993 and Barnes 1997 were both performed in the United Kingdom. Martinelli 2008 was performed in Italy, Morrow 2004 was performed in Alberta, Canada and Ramo-Tello 2011 was performed in Spain. Duration of Trials Alam 1993 enrolled patiens who had experienced a relapse within the previous 28 days, treated over three days, and were evaluated at baseline, day five and day 28 following treatment. Patients were scored by a blind assessor using the EDSS score at baseline, and again at five and 28 days following treatment. Martinelli 2008 enrolled patients within 14 days of their relapse event and evaluated MRI and clinical outcomes over a 28-day period as well. Barnes 1997 also enrolled patients who had experienced a relapse within the previous 28 days. Patients in the oral MP group were treated for 21 days while the IVMP group received treatment over five days. Patients were evaluated at enrollment, weeks one, four and 12. Morrow 2004 treated patients with a single dose of medication and evaluated gastric tolerance over the following 48 hours. The duration between relapse and treatment was not published, but additional data provided showed that some patients in fact were treated outside of the six-week window, but given the fact that this would not impact on gastric tolerance measures, the trial was still included. Ramo-Tello 2011 enrolled patients within 15 days of a relapse and monitored their response to treatment (three days) for the following 28 days, evaluating them at baseline, weeks one, four, 12 and 28 (unpublished data provided up to week 12 at the time it was solicited) Participants Alam 1993 enrolled 38 patients (mean age 41.5 years) with clinically definite MS with a mean disease duration of 5.4 years, and a sex ratio of 26 women to nine men. Twenty patients received IVMP and 18 received oral MP. Thirty-five patients completed the trial and three drop-outs were not included in the final analysis. Martinelli 2008 enrolled 40 patients (20 per group with clinically definite MS (mean age 36 years in the oral MP group and 31 years in the IVMP group) with a sex ratio of 14 women to six men in each group. disease duration was 10 years in the oral MP group and seven years in the IVMP group. Barnes 1997 enrolled 80 adults (mean age 37 years in the IVMP group and 38 years in the oral MP group) with clinically definite MS and a sex ratio of 51 women to 49 men. Thirty-eight patients received IVMP and 42 received oral MP. Morrow 2004 enrolled 16 adults with MS with a mean age of 39 years, a mean disease duration of 5.7 years and a mean EDSS of 4.0. Eight patients were randomized to each of the two groups. The sex ratio was 13 women to four men. Ramo-Tello 2011 enrolled 48 adults with MS and a mean age of 38 years and a sex ratio 40 women to eight men. of See Table Characteristics of Included Studies for details. Types of comparisons 9

13 Only the comparison of oral versus intravenous steroids was reviewed. Four of five trials (Alam 1993; Barnes 1997; Martinelli 2008; Ramo-Tello 2011) used methylprednisolone in both groups, while the fifth, Morrow 2004, compared IVMP with prednisone. Excluded studies The most common reasons for exclusion were: absence of an active comparator group, lack of randomization, or one of the two agents being compared not being oral. See Table Characteristics of excluded studies. Risk of bias in included studies The information was extracted from the published papers and from data obtained by contacting the primary authors. See Table 1 Characteristics of included studies and Figure 2 ( Risk of bias summary) for further details. Disagreements between review authors were resolved with the third author acting as an arbiter. 10

14 Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included study. 11

15 Allocation Randomization methods and concealment of allocation All five trials (Alam 1993; Barnes 1997; Morrow 2004; Martinelli 2008; Ramo-Tello 2011) were randomized. Barnes 1997 clearly documented the method of randomization and provided clear evidence of concealment of allocation. Specifically, patients were randomized through the hospital pharmacy according to a list of trial codes and medications provided in sealed envelopes, with randomization codes generated by a random number generator in blocks of four. This trial was given a grade of low risk of bias. As well, Martinelli 2008, and Ramo-Tello 2011used appropriate randomization techniques thus both also received a low risk of bias score. Alam 1993 and Morrow 2004 however did not clearly indicate methods used for randomization, and so they both received a score of unclear risk of bias for randomizaiton. Barnes 1997 and Ramo-Tello 2011 also clearly specified concealment of allocation/masking of intervention (low risk of bias) while such methods were not clear for Alam 1993 or Morrow 2004 (unclear risk of bias). Martinelli 2008 did not appear to utilize concealment of allocation and thus received a grade of high risk of bias Blinding Blinding of participants and assessors and tests of blinding Three of the five trials (Alam 1993; Barnes 1997; Ramo-Tello 2011) were double-blinded and used sham interventions, and were all given a grade of low risk of bias. Barnes 1997 also reported on testing of blinding by having both the physicians and the patients guess their group assignment with results no better than by chance in both groups. Martinelli 2008 employed blinding of the evaluating physicians and radiologists, but not of patients or treating physicians, and was given a grade of unclear bias. Contact with the authors of Morrow 2004 revealed that blinding was used only in those performing laboratory analyses, with no apparent blinding of clinical evaluators or patients, and was given a grade of unclear bias, although the primary pharmacological outcome was presumably not vulnerable to bias. Incomplete outcome data Complete follow-up with documentation of the number of patients lost to follow-up and those who withdrew and ability to perform intention-to-treat (ITT) analysis Alam 1993, Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 all provided clear data about the number and nature of withdrawals. Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 included a clear flow-chart to detail this aspect of the study, and thus these three trials received a grade of low risk of bias and ITT analysis was possible. Alam 1993 was however was graded as unclear risk of bias based on a lack of detail about patient losses. Morrow 2004 did not appear to have any withdrawals or drop-outs based on the published trial, but a review of the data clearly shows an additional patient not mentioned in the publication. It was therefore graded as unclear risk of bias. Selective reporting While there did not appear to be evidence of intentional selective reporting in any of the five trials, there were some instances of missing a priori identified endpoints. Barnes 1997 presented a significant challenge for analysis with published data. In this trial, the primary endpoint was reported to be the proportion of participants who improved by a minimum of one1 EDSS point at 28 days, although this value never appeared in the results or elsewhere in the manuscript. Furthermore, medians and interquartile ranges were presented for four different time periods, but the comparison of groups employed adjusted mean values. As well, in Barnes 1997, while adverse events were reported to be minor, there was no detailed information supplied. Therefore Barnes 1997 received a score of unclear risk for selective reporting. Alam 1993 did not report the results at day five, nor the standard deviations or confidence intervals for post-treatment values at day 28. Alam 1993 also reported that no significant adverse events occurred, but there was no further detail available on this measure in this trial. Therefore, Alam 1993 also received a grade of unclear risk of bias for selective reporting. Martinelli 2008 and Ramo-Tello 2011 included all patients in the final analysis with clear documentation of all planned outcomes, thus they both received a grade of low risk of bias for selective reporting. Morrow 2004 provided bar graphs and P values in the original publication but no data values for outcomes and therefore the published data presented an unclear risk of bias for selective reporting, however, the supervising author forwarded the appropriate data set for analysis. Other potential sources of bias Other statistical and design methodology was assessed for potential bias. 12

16 Rationale for sample size All trials documented the statistical rationale behind the sample size chosen. Barnes 1997, using a previous trial s results and standard deviation, calculated that a sample size of 38 participants per arm, using a two-tailed analysis with alpha of 0.05, would have a power of 90% and thus provides a low risk of bias. Alam 1993 reported that based on previous trials, their sample size calculations had the power to detect a 25% difference in disability grade improvement between groups, however, the actual value of 1-ß is not indicated making risk of bias unclear. In Martinelli 2008, the sample size was estimated to guarantee a power of 80% to demonstrate non-inferiority; with the assumption that IVMP was able to reduce by 90% the number of enhancing lesions detected during a relapse, and with a non-inferiority margin as a percentage reduction of 20%, and so it received a low risk of bias grade. Morrow 2004 has a high risk of bias having reported that the trial did not have a sample size that was appropriate to test bioequivalence between oral and intravenous steroids of 20%, but the data generated would allow for estimating sample sizes, presumably in future trials. Ramo-Tello 2011 calculated that 22 patients per group were required for a power of 0.80 to reject the null hypothesis of the absence of non-inferiority (with a non-inferiority margin of one EDSS scale point and assuming a standard deviation of 1.13 and a significance level of 2.5% ( 97.5%, unilateral) and therefore, has a low risk of bias. Use of non-inferiority design and analysis methods Martinelli 2008 used an equivalence design an their study clearly indicates the range and confidence interval a priori, thus receiving a grade of low risk of bias. Ramo-Tello 2011 also reported using a non-inferiority design indicating a non-inferiority margin of one EDSS point and a significance level of 2.5% ( 97.5%). Despite this, in the data and analyses provided by Ramo-Tello 2011, the reporting of results did not conform to this design (however, these data are not formally published) such that the risk of bias is unclear. None of the remaining three trials employed this methodology although the rationale behind all three trials was clearly to show bioequivalence and/or non-inferiority and therefore have a high risk of bias in this category. This has significant implications for sample size and effect estimates, as well as interpretation of results. However, at the time, the understanding of equivalence trial methodology might not have been common-place. Effects of interventions Primary outcome Comparison 1: Relapse recovery in first six weeks: Outcome 01 - Degree of MS relapse recovery with steroid treatment as change in Expanded Disability Status Scale (EDSS) at one week Alam 1993 measured EDSS at five days following treatment, but the data were not available. Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 reported clinical outcomes in the first week of treatment in a total of 168 patients with a mean difference (MD) for change in EDSS between groups at one week of (95% confidence interval () to 0.28), which is not statistically significant. Outcome 02 - Degree of MS relapse recovery with steroid treatment as change in EDSS at four weeks Alam 1993, Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 all reported the change in EDSS four weeks after treatment with either IVMP or oral steroid therapy. Alam 1993 used equivalent doses of intravenous and oral MP (500 mg once daily for three days) while Barnes 1997 used 500 mg once daily of IVMP for three days versus oral MP at 48 mg once daily for seven days, then 24 mg once daily for seven days and finally 12 mg once daily for seven days. Unfortunately, Alam 1993 could not be included in the pooled analysis secondary to an absence of required data (standard error information), although there was a statistically significant reduction in EDSS from pre-treatment to that time in both groups (4.85 to 3.5 in the IVMP group and 4.80 to 3.67 in the oral MP group) with no statistically significant difference in the magnitude of this improvement between groups. The pooled analysis of Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 (165 patients total) resulted in a MD change in EDSS between groups at four weeks of (95% to 0.26), again, not statistically significant. Comparison 2: Proportion of patients with relapse recovery with steroid treatment at four weeks Alam 1993, Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 all reported the proportion of patients experiencing improvement in EDSS and relapse recovery after steroid treatment in a total of 200 patients. The odds ratio (OR) of improvement with oral MP versus IVMP was 0.60 (95% 0.28 to 1.26) which is not statistically significant. Secondary outcomes Relapse recovery as measured by the Multiple Sclerosis Functional Composite (MSFC) The eligible trials did not include this outcome. Patients requiring additional courses of treatment for original relapse 13

17 The eligible trials did not include this outcome. Comparison 3: Change in Ambulation Index in first six weeks Outcome 01 - change in Ambulation Index at week one Barnes 1997 reported the mean change in Ambulation Index between groups at week one was 0.00 (95% to 0.39). Outcome 02 - change in Ambulation Index at week four Barnes 1997 reported the mean change in Ambulation Index between groups at week four was 0.40 (95% to 0.91), which was not statistically significant. Comparison 4: Long-term relapse rate following treatment Sharrack 2000 (patient group from Barnes 1997) analyzed relapse rate at six months, one year and two years following intervention. Outcome 01 - Relapse rate at six months post-treatment The relapse rate in the oral MP group at six months was 0.55 (0.74) compared with 0.34 (0.48) in the IVMP group for a MD of 0.21 (95% to 0.48) which was not statistically significant. Outcome 05 - Proportion of patients relapse-free at two years post-treatment Ten of 42 patients in the oral MP group compared with 11/38 patients in the IVMP group were relapse-free at two years posttreatment for an OR of 0.77 (95% 0.28 to 2.08) and an absolute risk difference (ARD) (95% to 0.14). These results are not statistically significant. Comparison 5: Days to next relapse after treatment with steroids Sharrack 2000 (based on Barnes 1997) measured the EDSS at the time of first relapse subsequent to the steroid treatment in Barnes 1997, with a MD between oral and IVMP groups of -47 days (95% to 56.53), which is not statistically significant but the trend favors the oral group. Comparison 6: EDSS at first relapse after treatment with oral versus intravenous steroids Barnes 1997 found the mean EDSS at the time of the next relapse following the study relapse was 1.56 in the oral MP group and 1.53 in the IVMP group for a MD of 0.03 (95% to 0.53) which is not statistically significant. Comparison 7: Proportion of patients hospitalized for relapse event Outcome 02 - Relapse rate at year one post-treatment The relapse rate in the oral MP group at one year was 1.26 (1.31) compared with 0.92 (0.78) in the IVMP group for a MD of 0.34 (95% to 0.81) which was not statistically significant. Outcome 01 - Proportion of patients hospitalized for relapse after treatment with oral vs intravenous steroids at week one Barnes 1997 found that 11 of 42 patients on oral MP and 10 of 38 patients on ivmp were hospitalized for their relapse at one week for a OR of 0.99 (95% 0.37 to 2.69) which is not statistically significant. Outcome 03 - Relapse rate at year two post-treatment The relapse rate in the oral MP group in the second year was 0.86 (0.90) compared with 0.65 (0.79) in the IVMP group for a MD of 0.21 (95% to 0.58) which was not statistically significant. Outcome 04 - Overall relapse for two-year period posttreatment The overall annualized relapse rate for the two-year period in the oral MP group was 1.06 (0.98) compared with 0.78 (0.65) in the IVMP group for a MD of 0.28 (95% to 0.64) which was not statistically significant. Outcome 02 - Prorportion of patients hospitalized for relapse after treatment with oral vs intravenous steroids at week four Barnes 1997 found that two of 42 patients on oral MP and one of 38 patients on ivmp were hospitalized for their relapse at week four for a OR of 1.85 (95% 0.16 to 21.26) which is not statistically significant. Outcome 03 - Hospital length of stay The raw data were not available to analyze this as a continuous outcome. 14

18 Comparison 8: Pharmacological bioavailability of steroids Morrow 2004 measured the mean serum concentration and mean area under the curve of serum concentration of steroid measured at hours one, two, four, eight, 24 and 48 hours. Although the area under the curve was significantly greater in the IVMP group than the prednisone group at hours one, two and four hours. However, by eight hours, there was no statistically significant difference between groups. Outcome 03 - change in number of gadolinium enhancing lesions on MRI between weeks zero and one Both Martinelli 2008 and Ramo-Tello 2011 measured the mean change in number of gadolinium enhancing lesions on MRI between weeks zero and one, which when pooled in 85 participants showed a MD of (95% of to 0.84) between oral MP and IVMP groups, which is not statistically significant. Comparison 9: Immunological differences in titers of cytokines Pitzallis 1997 (Barnes 1997) examined the titers of TNF-alpha, LFA-1, LFA-3, ICA1, CD2, CD4, CD8, CD45Ra and CD45Ro at days one, four, 28 and 90 after steroid treatment. The actual data were not available for analysis, although all P values for group comparisons were not statistically significant. Outcome 04 - change in number of gadolinium enhancing lesions on MRI between weeks zero and four Both Martinelli 2008 and Ramo-Tello 2011 measured the mean change in number of gadolinium enhancing lesions on MRI between weeks zero and four, which when pooled in 84 participants showed a MD of (95% of 1.47 to 1.10), which is not statistically significant. Comparison 10: Gadolinium enhancing lesions on magnetic resonance imaging (MRI) Both Martinelli 2008 and Ramo-Tello 2011 had MRI endpoints focused on gadolinium enhancing lesions and while both reported using an equivalence design, this was not apparent in the unpublished data and analyses supplied by Ramo-Tello In Martinelli 2008, an equivalence-designed trial, the mean percentage change in gadolinium enhancing lesion number between groups was considered equivalent if the upper limit of the 95% of the oral group mean percentage lesion change was lower than 20% of the mean percentage lesion change of the IV group. Outcome 05 - Proportion with gadolinium enhancing lesions on MRI at week one In Martinelli 2008 and Ramo-Tello 2011, 19 of 42 patients in the oral MP and 21 of 43 in the IVMP groups had gadolinium enhancing lesions on MRI at week one, for an OR of 0.86 (95% 0.37 to 2.03), which is not statistically significant. Outcome 06 - Proportion with gadolinium enhancing lesions on MRI at week four In Martinelli 2008 and Ramo-Tello 2011, 12 of 42 patients in the oral MP group and 11 of 42 patients in the IVMP group had gadolinium enhancing lesions on MRI at week four, for an OR of 1.13 (95% 0.43 to 2.99), which is not statistically significant. Outcome 01 - percentage reduction in gadolinium enhancing lesions on MRI between weeks zero and one The MD between IVMP and oral MP in Martinelli 2008 was (95% of to 0.09) while in Ramo-Tello 2011 it was 0.14 (95% of to 0.38) for a pooled MD of (95% of to 0.29), which is not statistically significant (and thus equivalent by Martinelli 2008 s requirements). Comparison 11: T2 Lesions on MRI Outcome 01 - change in T2 lesion number at week one versus baseline In Ramo-Tello 2011, the MD between oral MP and iv MP groups is (-0.33 to 0.15) - not statistically significant. Outcome 02 - percentage reduction in gadolinium enhancing lesions on MRI between weeks zero and four The MD between IVMP and oral MP in Martinelli 2008 was (95% of to 0.33) while in Ramo-Tello 2011 it was (95% of to 0.28) for a pooled MD of (95% of to 0.21), which is not statistically significant (and thus equivalent by Martinelli 2008 s requirements). Outcome 02 - change in T2 lesion number at weeks four versus week one In Ramo-Tello 2011, the MD between oral MP and ivmp groups is 0.14 (-0.24 to 0.52) - not statistically significant. Comparisons 12-24: Adverse events See Table 2 Adverse Event Outcomes for detailed results. 15

19 Cost (direct medical service cost and indirect costs of lost productivity) The eligible trials did not include this outcome. groups. There was a trend towards more cases of dysgeusia (impaired sense of taste) and mood disturbance with oral steroid treatment. Quality of life The eligible trials did not include this outcome. Subgroup Analysis Planned subgroup analyses according to age, baseline EDSS status, time to treatment and steroid type were not performed due to the paucity of available data. Assessment of publication bias by funnel plot analysis was not possible due to the absence of evidence of unpublished eligible trials. One observational trial comparing tolerability of oral versus IVMP was found (Le Page 2007), but was not eligible for inclusion in this review. Overall completeness and applicability of evidence Overall, all five trials had very thorough data reporting with virtually all patients accounted for. The results presented in these trials are the common outcomes of interest in the clinical care of patients with MS, and so these results would be quite generalizable and applicable with one caveat - not all patients have access to medical care or can be assessed within the first week of relapse. Furthermore, given that steroids hasten, but do not necessarily increase the degree of recovery from a relapse, those care providers and centers under resource constraints may elect not to see patients urgently with episodes considered mild in the early days of a relapse. D I S C U S S I O N Summary of main results Despite good evidence of the effectiveness of high-dose oral steroid therapy for relapse events (Beck 1992; Alejandro 1994; Sellebjerg 1998), only five randomized trials with a total of 215 patients have directly compared the efficacy and safety of these therapies. Four of five trials used bioequivalent dosing, while one (Barnes 1997) used a low, but lengthy dosing regimen (three weeks) of oral MP versus the conventional 1000 mg of IVMP. With respect to the primary outcome of EDSS status at four weeks post steroid treatment, there was no statistically significant difference between the two routes of steroid administration. In addition, both based on the patient groups in Barnes 1997, Sharrack 2000 (Barnes 1997) provided evidence that relapse rates and disability status up to two years after treatment did not differ significantly between groups. Martinelli 2008 and Ramo-Tello 2011 demonstrated that the degree of improvement in gadolinium enhancing lesion burden at four weeks was equivalent between oral MP and IVMP. While gadolinium enhancement within one week of treatment may be a very brief period of time over which to measure, the fourweek assessment correlates better with both gadolinium persistence and clinical length of relapse (Swanton 2007). Ramo-Tello 2011 also showed that T2 lesion number does not differ in the month following relapse between treatment groups. A small pilot trial (Morrow 2004) suggested steroid absorption does not differ significantly between bioequivalent doses of oral prednisone and IVMP in patients with relapsing MS. Only two trials (Martinelli 2008; Ramo-Tello 2011) clearly reported adverse event rates, most of which were evenly distributed between oral and intravenous Quality of the evidence While all trials demonstrated an absence of significant efficacy or safety differences between steroid regimens, there were methodological limitations which make inferences about the equivalence of oral and intravenous steroid therapy challenging at this stage. Ramo-Tello 2011 and Martinelli 2008 both reported using a noninferiority/equivalence methodology, but only Martinelli 2008 clearly used this design to estimate a target range of outcomes, sample size calculations, and analysis. However, such designs are more recent additions to clinical trial methodology. While Martinelli 2008 employed proper equivalence design techniques, the absence of blinding in patients or clinical evaluators for such outcomes as EDSS and adverse events could be a significant source of bias and error. Additionally, the largest trial (Barnes 1997), used an oral steroid dosing regimen that was not bioequivalent to the intravenous arm. Had bioequivalent dosing been used, the oral treatment arm could have potentially outperformed the intravenous arm, or conversely, been beset by a greater rate of adverse events. Furthermore, only Barnes 1997 and Ramo-Tello 2011 used reliable concealment of allocation, the absence of which can be as detrimental to the accuracy of trial results as the failure to randomize participants (Kunz 1998). Finally, all trials, save Martinelli 2008 allowed participants to enroll up to one month following a relapse, a time at which most patients with MS are entering the resolution phase of relapse activity. Enrolling participants within days and not weeks of a relapse event, could provide a more favorable window of opportunity to determine if the route of administration is a significant factor in the degree and timing of relapse recovery. Many of the limitations of these trials are being addressed by the ongoing randomized double-blinded phase III Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Scle- 16

20 rosis (OMEGA, OMEGA 2007) based out of the Mount Sinai School of Medicine and the Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses trial (COPOUSEP 2009). The OMEGA 2007 trial addresses the particular limitations of the delay to treatment seen in several existing trials (which may miss an hypothetical window in which oral and intravenous steroid therapy differ in efficacy), as well as the limited number of trials using bioequivalent dosing of oral and intravenous steroids when addressing clinical outcomes. Patients aged with clinically definite relapsing forms of MS presenting with an objective relapse significant enough to merit steroid therapy will be considered for this trial. Patients will be randomly assigned to receive five consecutive days of either 1000 mg of IVMP (total 5000 mg) or 1400 mg of oral MP (bioequivalent to 1000 mg IVMP) within seven days of the onset of a relapse. A total of 120 participants will be recruited, although the statistical basis for this calculation was not available. The primary hypothesis is that oral and intravenous therapy will be equivalent with respect to EDSS status measured between days zero and 28 following treatment. Improvement in EDSS in this setting is defined as any magnitude of reduction in EDSS that meets statistical significance. Secondary endpoints of change in the MSFC, improvement in the subscale of the EDSS in which the relapse occurred, and the relapse rate up to one year following treatment with either steroid regimen. Enrolment for the OMEGA trial began in 2003 and recruitment is currently ongoing. The COPOUSEP 2009 trial will enroll patients ages after a clinical relapse (timing after onset not specified). Patients will be randomly assigned to receive consecutive three days of either 1000 mg of IVMP or 1000 mg or oral MP with the primary outcome of a minimum of a one-point reduction on the Kurtzke functional scale 28 days after treatment. While there have not been other meta-analyses of oral versus intravenous steroids in MS relapses published at this time, trials of oral steroids versus placebo have suggested the results are similar to trials of intravenous steroids. Additionally, trials looking at certain demyelinating events not formally diagnosed as MS (Beck 1992) suggest symptom resolution is similar between oral and intravenous steroids preparations. A U T H O R S C O N C L U S I O N S Implications for practice Despite some limitations in trial number and number of patients, design heterogeneity and methodology, the analysis of the five eligible trials comparing intravenous and oral steroid therapy for MS relapses fails to demonstrate any significant differences in clinical (benefits and adverse events), radiological or pharmacological outcomes. Therefore, it would appear that based on the evidence, oral steroids for MS relapse events are a reasonable treatment alternative to intravenous steroids. Implications for research Larger scale trials such as OMEGA 2007 and COPOUSEP 2009, should provide further data and sufficient power with which to make judgements about comparisons of the two regimens. Any future trials comparing oral and intravenous steroid treatment for relapses should employ a non-inferiority or equivalency design and the sample size determination that follows, as well as concealment of allocation, definitive methods of randomization, double blinding, masking of intervention and clear and meaningful endpoints. Potential biases in the review process While efforts were made to seek out unpublished reports of oral versus intravenous steroid use in MS relapses (e.g. conference abstracts), some unpublished material may have been missed. Agreements and disagreements with other studies or reviews A C K N O W L E D G E M E N T S The authors would like to thank Dr. Luanne Metz, Dr. Richard Hughes, Dr. Vittorio Martinelli, Dr. Cristina Ramos and Dr. Ferran Torres or providing unpublished data for statistical analyses. The authors also thank Dr. Fred Lublin for providing additional information on the ongoing OMEGA trial and Dr. Armando Lorenzo for his assistance in translating. Finally, the authors express their gratitude for the assistance and guidance of Dr. Prakeshkumar Shah in the preparation of this review. 17