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

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

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 http://www.thecochranelibrary.com Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S 1 HEADER . 1 ABSTRACT . 2 PLAIN LANGUAGE SUMMARY .

2 BACKGROUND . 4 OBJECTIVES . 4 METHODS . 7 RESULTS . Figure 1 . 8 Figure 2 . 11 16 DISCUSSION . 17 AUTHORS’ CONCLUSIONS . 17 ACKNOWLEDGEMENTS . 18 REFERENCES . 20 CHARACTERISTICS OF STUDIES . 31 DATA AND ANALYSES . Analysis 1.1. Comparison 1 Improvement in EDSS after treatment with oral vs. intravenous steroids, Outcome 1 Mean decrease in EDSS after steroid treatment at week 1 . 37 Analysis 1.2. Comparison 1 Improvement in EDSS after treatment with oral vs. intravenous steroids, Outcome 2 Mean decrease in EDSS after steroid treatment at week 4 . 38 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 . 40 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 . 40 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 . 41 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 . 41 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 . 42 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 . 42 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 . 43 Analysis 5.1. Comparison 5 Days to next relapse after treatment with oral vs. intravenous steroids, Outcome 1 Mean number of days to next relapse after treatment with oral vs. intravenous steroids . 43 Analysis 6.1. Comparison 6 EDSS at first relapse after treatment with oral vs. intravenous steroids, Outcome 1 Mean change in EDSS at first relapse within 2 year period after treatment with oral vs.

intravenous steroids . 44 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 . 44 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 . 45 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 . 45 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 . 46 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 . 46 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 . 47 i Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

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 . 47 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 . 48 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 . 48 Analysis 10.1. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 1 Mean percentage reduction in gadolinium lesions on MRI weeks 0-1 .

49 Analysis 10.2. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 2 Mean percentage reduction in gadolinium positive MRI lesions weeks 0-4 . 49 Analysis 10.3. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 3 Mean change in gadolinium enhancing lesions on MRI between weeks 0 and 1 . 50 Analysis 10.4. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 4 Mean change in gadolinium enhancing lesions on MRI between week 0 and 4 . 51 Analysis 10.5. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 5 Proportion with gadolinium enhancing lesions on MRI at week 1 .

51 Analysis 10.6. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 6 Proportion with gadolinium enhancing lesions at week 4 . 52 Analysis 11.1. Comparison 11 Changes in T2 lesion number, Outcome 1 Mean change in T2 lesions at week 1 with respect to baseline in T2 lesion number between oral and iv . 53 Analysis 11.2. Comparison 11 Changes in T2 lesion number, Outcome 2 Mean change in T2 lesions at week 4 with respect to week 1 . 53 Analysis 12.1. Comparison 12 Proportion with HTN, Outcome 1 Proportion with HTN . 54 Analysis 13.1. Comparison 13 Proportion with rash, Outcome 1 Proportion with rash .

54 Analysis 14.1. Comparison 14 Proportion with hypertricosis, Outcome 1 Proportion with hypertricosis . 55 Analysis 15.1. Comparison 15 Proportion with anxiety, Outcome 1 Proportion with anxiety . 55 Analysis 16.1. Comparison 16 Proportion with insomnia, Outcome 1 Proportion with insomnia . 56 Analysis 17.1. Comparison 17 Proportion with dysgeusia, Outcome 1 Proportion with dysgeusia . 56 Analysis 18.1. Comparison 18 Proportion with hiccups, Outcome 1 Proportion with hiccups . 57 Analysis 19.1. Comparison 19 Proportion with hyperglycemia, Outcome 1 Proportion with hyperglycemia . 58 Analysis 20.1.

Comparison 20 Proportion with headache, Outcome 1 Proportion with headache . 58 Analysis 21.1. Comparison 21 Proportion with mood disturbance (euphoria, depression), Outcome 1 Proportion with mood disturbance . 59 Analysis 22.1. Comparison 22 Proportion with hot flashes/flushing, Outcome 1 Proportion with hot flashes . 59 Analysis 23.1. Comparison 23 Proportion with swelling, Outcome 1 Proportion with swelling . 60 Analysis 24.1. Comparison 24 Proportion with pirosis, Outcome 1 Proportion with pirosis . 60 61 ADDITIONAL TABLES . 61 APPENDICES . 62 WHAT’S NEW . 62 HISTORY . 62 CONTRIBUTIONS OF AUTHORS .

62 DECLARATIONS OF INTEREST . 62 SOURCES OF SUPPORT . 63 INDEX TERMS . ii Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review] Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Jodie M Burton1, Paul W O’Connor2, Marika Hohol2, Joseph Beyene3 1Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. 2Division of Neurology, St. Michael’s Hospital, Toronto, Canada. 3Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada Contact address: Jodie M Burton, Department of Clinical Neurosciences, University of Calgary, 1403 29th 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, 2012. Review content assessed as up-to-date: 13 June 2012. 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.: CD006921. DOI: 10.1002/14651858.CD006921.pub3. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. A B S T R A C T Background This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2009, Issue 3.

Art. No.: CD006921. DOI: 10.1002/14651858.CD006921.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

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% CI), 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 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 ex- perience 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 be- ing the common medications used at that time (Jonsson 1951; Tourtellotte 1965 ).

In recent years, methylprednisolone and pred- nisone 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, acute- phase 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 superfam- ily) that impacts gene transcription and signaling (Schweingruber 2011). Glucocorticoids will either interact with the membrane glucocorticoid receptor or cytosolic receptor. Binding in the cy- tosol 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 in- teraction with other transcription factors such as activating pro- tein-1 (AP-1), nuclear factor kappa B (NfkB) and cAMP-respon- sive 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-inflam- matory or “Th1” state, and away from the anti-inflammatory of “Th2” state. Certain T-cell populations and cytokines highly com- plicit 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 in- cluding 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 cir- culating 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-in- flammatory cytokines as interferon gamma, tumor necrosis fac- tor 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” com- pared with oral preparations, although this has not been estab- lished (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 life- threatening. 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 effica- cious in hastening relapse recovery, it can be a cumbersome and costly treatment. A cost analysis in a major Canadian hospital in 1994-1995 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 re- vealed 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).

Hos- pitalization for treatment increases the cost several fold (O’Brien 2003). Additionally, there are indirect costs associated with intra- venous 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 demand- ing on healthcare resources and patients compared with intra- venous regimens (O’Brien 2003). Evidence from randomized tri- als 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) demon- strated that higher doses of prednisone (60-120 mg daily) ver- sus lower doses (50-100 mg alternating days) for a minimum of one week had fewer gadolinium enhancing lesions on magnetic 3 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

resonance imaging (MRI) performed an average of five weeks af- ter 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-anal- ysis of steroids in MS and optic neuritis included four studies of oral steroid therapy out of a total of 12 trials, all placebo-con- trolled (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 calcula- tions.

Comparisons were made between low- versus high-dose reg- imens however, of which only one oral trial was considered high- dose, therefore dose, not route, may have been the more impor- tant variable (Brusaferri 2000). While there are several publica- tions 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 unac- ceptable 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 com- pared 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.: CD006921. DOI: 10.1002/14651858.CD006921.pub2). O B J E C T I V E S The objective of this review is to test the hypothesis that intra- venous 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 in- travenous steroid treatment given at the time of relapse in patients with a diagnosis of MS.

M E T H O D S Criteria for considering studies for this review Types of studies 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, immunolog- ical, 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-progres- sive (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 “post- treatment” 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 feverand 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 intra- venousformof steroidtherapyinMS byfarismethylprednisolone. 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). Secondary outcomes Relapse Recovery 4 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. Mean monetary costs associated with medications, homecare services, hospital stay and consultations. 2. Mean 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, CINAHL, 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 Sclero- sis Working Group in The Cochrane Library. We also handsearched 5 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

cited trials in review papers and reference lists, conference proceed- ings, dissertations and abstracts where appropriate.

Specifically, we searched abstracts from the annual meetings of the American Academy of Neurology (2008-2012), the European Federation of Neurological Sciences (2008-2012), the European Committee for Treatment and Research in Multiple Sclerosis (2008-2012) and the American Committee for Treatment and Research in Multiple Sclerosis (2008-2012). Additional data were sought by reviewing trials listed in registries and contacting study authors and investi- gators as necessary (www.clinicaltrials.gov).

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 inde- pendent 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. 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, re- gardless of compliance, whether or not they received treatment, or were otherwise excluded from the originally published trial analy- sis.

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 prin- cipal investigator of the trial requesting the data. 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 9.3.1 (SAS Institute Inc., Casey, N.C.) was used to gener- ate descriptive statistics for raw data when necessary, and RevMan 5 was used for all statistical analyses. Statistical parameters in- cluded 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 (CI) 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. 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 under- taken including calculating the Q and I2 values to determine the appropriateness of combining studies. If there was significant het- erogeneity, defined by the Cochrane Multiple Sclerosis Working Group as an I2 > 50% (D’Amico 2007), we used a random-effects model.

If heterogeneity was not significant, we used a fixed-effect 6 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. Data synthesis Outcomes of interest in this review include continuous and di- chotomous measures. Continuous outcomes were analyzed by cal- culating 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 be- tween studies, there are still inherent differences in outcomes and studies, and so an adjustment in the weighting of the study con- tribution 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 re- lapse rate were chosen a priori to explain significant heterogeneity if indicated. 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.

R E S U L T S Description of studies See: Characteristicsof includedstudies; Characteristicsof 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 detec- tion and process selection in Figure 1.

7 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Figure 1. Study flow diagram. 8 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

The original and updated search yielded 35 articles, four abstracts and three clinicaltrials.gov listings initially selected for further as- sessment, 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 with- drawals 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)forthe twopatientgroupscompared. 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 interven- tions 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 25- 50 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 per- formed 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 clin- ically 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. Mean 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 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Only the comparison of oral versus intravenous steroids was re- viewed. Four of five trials (Alam 1993; Barnes 1997; Martinelli 2008; Ramo-Tello2011)usedmethylprednisolone inboth groups, while the fifth, Morrow 2004, compared IVMP with prednisone. Excluded studies The most common reasons for exclusion were: absence of an ac- tive 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 au- thors were resolved with the third author acting as an arbiter. 10 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study. 11 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 evi- dence of concealment of allocation.

Specifically, patients were ran- domized through the hospital pharmacy according to a list of trial codes and medications provided in sealed envelopes, with random- ization 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 random- ization 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 conceal- ment of allocation/masking of intervention (low risk of bias) while such methods were not clear for Alam 1993 or Morrow 2004 (un- clear risk of bias). Martinelli 2008 did not appear to utilize con- cealment 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 evalu- ating 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 presum- ably 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 with- drawals. Barnes 1997, Martinelli 2008 and Ramo-Tello 2011 in- cluded 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 anal- ysis 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 there- fore 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, me- dians 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 val- ues 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 re- ceived 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 anal- ysis.

Other potential sources of bias Otherstatistical anddesignmethodologywasassessedforpotential bias. 12 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Rationale for sample size All trials documented the statistical rationale behind the sample size chosen. Barnes 1997, using a previous trial’s results and stan- dard 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 calcula- tions 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 demon- strate 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 reduc- tion 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 be- tween oral and intravenous steroids of 20%, but the data gener- ated 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% (CI 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% (CI 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 un- clear. None of the remaining three trials employed this method- ology 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 -0.05 (95% confidence interval (CI) -0.38 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 sig- nificant 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 -0.22 (95% CI -0.71 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% CI 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 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

The eligible trials did not include this outcome. Comparison 3: Change in Ambulation Index in first six weeks Outcome 01 - Mean change in Ambulation Index at week one Barnes 1997 reported the mean change in Ambulation Index be- tween groups at week one was 0.00 (95% CI -0.39 to 0.39). Outcome 02 - Mean change in Ambulation Index at week four Barnes 1997 reported the mean change in Ambulation Index be- tween groups at week four was 0.40 (95% CI -0.11 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% CI -0.06 to 0.48) which was not statistically significant. 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% CI -0.13 to 0.81) which was 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% CI -0.16 to 0.58) which was not statistically significant.

Outcome 04 - Overall relapse for two-year period post- treatment 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% CI -0.08 to 0.64) 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 post- treatmentforanORof 0.77(95%CI0.28to2.08)andanabsolute risk difference (ARD) -0.05 (95% CI -0.24 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% CI -150.53 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% CI -0.47 to 0.53) which is not statistically significant. Comparison 7: Proportion of patients hospitalized for relapse event 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% CI 0.37 to 2.69) which is 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% CI 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 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. How- ever, by eight hours, there was no statistically significant difference between groups. Comparison 9: Immunological differences in titers of cytokines Pitzallis 1997 (Barnes 1997) examined the titers of TNF-al- pha, LFA-1, LFA-3, ICAM-1, 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. 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 un- published data and analyses supplied by Ramo-Tello 2011. In Martinelli 2008, an equivalence-designed trial, the mean per- centage change in gadolinium enhancing lesion number between groups was considered equivalent if the upper limit of the 95% CI of the oral group mean percentage lesion change was lower than 20% of the mean percentage lesion change of the IV group.

Outcome 01 - Mean percentage reduction in gadolinium enhancing lesions on MRI between weeks zero and one The MD between IVMP and oral MP in Martinelli 2008 was - 0.16 (95% CI of -0.41 to 0.09) while in Ramo-Tello 2011 it was 0.14 (95% CI of -0.10 to 0.38) for a pooled MD of -0.01 (95% CI of -0.30 to 0.29), which is not statistically significant (and thus equivalent by Martinelli 2008’s requirements). Outcome 02 - Mean percentage reduction in gadolinium enhancing lesions on MRI between weeks zero and four The MD between IVMP and oral MP in Martinelli 2008 was - 0.01 (95% CI of -0.35 to 0.33) while in Ramo-Tello 2011 it was -0.02 (95% CI of -0.32 to 0.28) for a pooled MD of -0.02 (95% CI of -0.24 to 0.21), which is not statistically significant (and thus equivalent by Martinelli 2008’s requirements).

Outcome 03 - Mean 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 be- tween weeks zero and one, which when pooled in 85 participants showed a MD of -0.14 (95% CI of -1.11 to 0.84) between oral MP and IVMP groups, which is not statistically significant. Outcome 04 - Mean 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 be- tween weeks zero and four, which when pooled in 84 participants showed a MD of -0.18 (95% CI of 1.47 to 1.10), which is not statistically significant.

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% CI 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% CI 0.43 to 2.99), which is not statistically significant.

Comparison 11: T2 Lesions on MRI Outcome 01 - Mean change in T2 lesion number at week one versus baseline In Ramo-Tello 2011, the MD between oral MP and iv MP groups is -0.09 (-0.33 to 0.15) - not statistically significant. Outcome 02 - Mean 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 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Comparison: Cost (direct medical service cost and indirect costs of lost productivity) The eligible trials did not include this outcome. Comparison: 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.

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 bur- den 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 four- week assessment correlates better with both gadolinium persis- tence 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 groups. There was a trend towards more cases of dysgeusia (im- paired sense of taste) and mood disturbance with oral steroid treat- ment.

Overall completeness and applicability of evidence Overall, all five trials had very thorough data reporting with virtu- ally 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. Further- more, 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.

Quality of the evidence While all trials demonstrated an absence of significant efficacy or safety differences between steroid regimens, there were method- ological 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 non- inferiority/equivalence methodology, but only Martinelli 2008 clearly used this design to estimate a target range of outcomes, sam- ple 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 accu- racy 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 activ- ity.

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 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

rosis (OMEGA, OMEGA 2007) based out of the Mount Sinai School of Medicine and the Efficacy and Safety of Methylpred- nisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS)Relapsestrial (COPOUSEP2009).

The OMEGA2007 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 18-50 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 ran- domly 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 hypoth- esis is that oral and intravenous therapy will be equivalent with respect to EDSS status measured between days zero and 28 fol- lowing treatment. Improvement in EDSS in this setting is defined as any magnitude of reduction in EDSS that meets statistical sig- nificance. Secondary endpoints of change in the MSFC, improve- ment 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 andrecruitmentiscurrentlyongoing. The COPOUSEP 2009 trial will enroll patients ages 18-55 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. 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 ab- stracts), some unpublished material may have been missed.

Agreements and disagreements with other studies or reviews While there have not been other meta-analyses of oral versus in- travenous steroids in MS relapses published at this time, trials of oral steroids versus placebo have suggested the results are simi- lar 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 in- travenous 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 eli- gible trials comparing intravenous and oral steroid therapy for MS relapses fails to demonstrate any significant differences in clini- cal (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 al- ternative 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 blind- ing, masking of intervention and clear and meaningful endpoints. 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. Fer- ran 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 Lorenzoforhisassistance intranslating. Finally, the authorsexpress their gratitude for the assistance and guidance of Dr. Prakeshku- mar Shah in the preparation of this review.

17 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

R E F E R E N C E S References to studies included in this review Alam 1993 {published data only} ∗ Alam SM, Kyriskides T, Lowden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. Journal of Neurology, Neurosurgery and Psychiatry 1993;56: 1219–20. Barnes 1997 {published and unpublished data} ∗ Barnes D, Hughes RAC, Morris RW, Wade-Jones O, Brown P, Britton T, et al.Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis.

Lancet 1997;349:902–6. Pitzalis C, Sharrack B, Gray IA, Lee A, Hughes RAC. Comparison of the effects of oral versus intravenous methylprednisolone regimens on peripheral blood T lymphocyte adhesion molecule expression, T cell subsets distribution and TNF alpha concentrations in multiple sclerosis. Journal of Neuroimmunology 1997;74(1-2):62–8. Sharrack B, Hughes RAC, Morris RW, Soudain S, Wade- Jones O, Barnes D, et al.The effect of oral and intravenous methylprednisolone treatment of subsequent relapse rate in multiple sclerosis. Journal of the Neurological Sciences 2000; 173:73–7.

Martinelli 2008 {published and unpublished data} ∗ Martinelli V, Pulizzi A, Annovazzi P, Rocca MA, Bucello S, Esposito F, et al.A single blind, randomised MRI study comparing high-dose oral and intravenous methylprednisolone in treating MS relapses A single blind, randomised MRI study comparing high-dose oral and intravenous methylprednisolone in treating MS relapses. Neurology 2009;73(22):1842–1848. Morrow 2004 {published and unpublished data} ∗ Morrow SA, Stoian CA, Dmitrovic J, Chan SC, Metz LM. The bioavailability of iv methylprednisolone and oral prednisone in multiple sclerosis. Neurology 2004;63: 1079–80.

Ramo-Tello 2011 {unpublished data only} ∗ Ramo-Tello C, Grau-Lopez L, Giner P, Ramio-Torrenta L, Brieva L, Saiz A, et al.A multicentre, randomized clinical and MRI study of highdose oral versus intravenous methylprednisolone in MS. Multiple Sclerosis 2011;17(10): Suppl 1 (S91-S92). References to studies excluded from this review Alejandro 1994 {published data only} ∗ Alejandro PM, Castanon Gonzalez JA, Miranda Ruiz R, Edgar Echeverria R, Adriana Montano M. Comparative treatment of acute optic neuritis with “boluses” of intravenous methylprednisolone or oral prednisone. Gaceta Medica de Mexico 1994;130(4):227–30.

Beck 1992 {published data only} ∗ Beck RW, Cleary PA, Anderson MM Jr, Keltner JL, Shults WT, Kaufman DI, et al.A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. New England Journal of Medicine 1992;326(9):581–8.

De Keyser 1999 {published data only} ∗ De Keyser J, Zwanikken CM, Zorgdrager A, Oenema D, Boon M. Treatment of acute relapses in multiple sclerosis at home with oral dexamethasone: a pilot study. Journal of Clinical Neuroscience 1999;6(5):382–4. Demirkiran 1995 {published data only} ∗ Demirkiran M, Sarica Y, Karatas M, Bozdemir H. Efficacy of intravenous methylprednisolone and oral prednisone in multiple sclerosis. Annals of Medical Science 1995;4:91–5. Huen 1989 {published data only} ∗ Huen R, Emser W, Schimrigk S. Evoked potentials with intrathecal and systemic corticosteroid therapy in multiple sclerosis Evoked potentials with intrathecal and systemic corticosteroid therapy in multiple sclerosis.

EEG-EMG Zeitschrift für Elektroenzephalographie, Elektromyographie und verwandte Gebiete 1989;20(2):88–91. La Mantia 1994 {published data only} ∗ La Mantia L, Eoli M, Milanese C, Salmaggi A, Dufour A, Torri V. Double-blind trial of dexamethasone versus methylprednisolone in multiple sclerosis acute relapses. European Neurology 1994;34(4):199–203. Le Page 2007 {published data only} ∗ Le Page E, Veillard D, Lavat C, Edan G. Intravenous versus oral tolerance of methylprednisolone high doses in multiple sclerosis: an observational study of 97 patients. Multiple Sclerosis. 2007; Vol. 13:S176.

Metz 1999 {published data only} ∗ Metz LM, Sabuda D, Hilsden R, Enns R, Meddings JB. Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis. Neurology 1999;53:2093. Milanese 1989 {published data only} ∗ Milanese C, La Mantia L, Salmaggi A, Campi A, Eoli M, Scaioli V, et al.Double-blind randomized trial of ACTH versus dexamethasone versus methylprednisolone in multiple sclerosis bouts. Clinical, cerebrospinal fluid and neurophysiological results. European Neurology 1989;29(1): 10–14.

Murray 1999 {published data only} ∗ Murray J. Oral methylprednisolone improved symptoms and disability resulting from multiple sclerosis attacks.

Evidence-Based Medicine 1999;4(3):73. Rohrbach 1988 {published data only} ∗ Rohrbach E, Kappos L, Stadt D, Hennes A. Effects, side- effects and pharmacokinetics of intrathecal versus oral corticosteroids in spinal symptoms of multiple sclerosis: results of a double-blind controlled trial. Journal of Neurology. 1988; Vol. 235:S40–1. [: CN–00225511] Sellebjerg 1998 {published data only} ∗ Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. Double blind, randomized, placebo-controlled study of oral, high- 18 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

dose methylprednisolone in attacks of MS. Neurology 1998; 51(2):529–34. Sellebjerg 1999 {published data only} ∗ Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen J. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999; 52(7):1479–84. Tankisi 1997 {published data only} ∗ Tankisi H, Oztekin N, Oztekin MF, Ozbakir S, Guven H, Guven B. Relative efficacy of intravenous methylprednisolone and oral prednisolone in the treatment of acute relapse in multiple sclerosis. Multiple Sclerosis. 1997; Vol. Suppl 3:352. [: CN–00625757 (EMBASE)] Thompson 1989 {published data only} ∗ Thompson AJ, Kennard C, Swash M, Summers B, Yuill GM, Shepherd DI, et al.Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS.

Neurology 1989;39(7):969–71. Toczolowski 1995 {published data only} ∗ Toczolowski J, Lewandowska-Furmanik M, Stelmasiak Z, Wozniak D, Chmiel M. Treatment of acute optic neuritis with large doses of corticosteroids. Klinika Oczna 1995;97: 122–5.

Tourtellotte 1965 {published data only} ∗ Tourtellotte WW, Haerer AF. Use of an oral corticosteroid in the treatment of multiple sclerosis. A double -blind study. Archives of Neurology 1965;12:536–45. References to ongoing studies COPOUSEP 2009 {unpublished data only} Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses (COPOUSEP). Ongoing study March 2008. OMEGA 2007 {unpublished data only} ∗ Lublin F. Oral megadose corticosteroid therapy of acute exacerbations of multiple sclerosis (OMEGA) NCT00418145. www.clinicaltrials.gov 2007.

Additional references Andersson 1998 Andersson P-B, Goodkin DE. Glucocorticosteroid therapy for multiple sclerosis: a critical review. Journal of the Neurological Sciences 1998;160:16–25. Brusaferri 2000 Brusaferri F, Candelise L. Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials. Journal of Neurology 2000;247:435–42. Confavreux 2006 Confavreux C, Vukusic S. The natural history of multiple sclerosis. Revue du Practicien 2006;56(12):1313–20. D’Amico 2007 D’Amico R, Ebers G, Filippini G, Fredrikson S, Rice GPA, Simi S, et al.Cochrane Multiple Sclerosis Group.

About The Cochrane Collaboration (Cochrane Review Groups (CRGs)) 2007, issue 2:Art.No.:MS.

Filippini 2000 Filippini G, Brusaferri F, Sibley WA, Citterio A, Ciucci G, Midgard R, et al.Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database of Systematic Reviews 2000, Issue 4. [DOI: 10.1002/ 14651858.CD001331] Fisher 1999 Fisher JS, Rudick RA, Cutter GR, Reingold SC for the National MS Society Clinical Outcomes Assessment Task Force. The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment. Multiple Sclerosis 1999;5(4):244–50. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions.

Chichester: John Wiley & Sons, 2011.

Jonsson 1951 Jonsson B, Von Reis G, Sahlgren E. Experience of ACTH and cortisone treatment in some organic neurological cases. Acta Psychiatrica et Neurologica Scandinavica Supplementum 1951;74:60–5. Kunz 1998 Kunz R, Oxman AD. The unpredictability paradox: review of empirical comparisons of randomised and non- randomised clinical trials. BMJ (Clinical research ed.) 1998; 317(7167):1185–90. [PUBMED: 9794851] Kurtzke 1983 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444–52.

McDonald 2001 McDonald IW, Compston A, Edan G, Goodkin D, Hartung H-P, Lublin FD, et al.Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.

Annals of Neurology 2001;50(1):121–7. Necela 2004 Necela BM, Cidlowski JA. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proceedings of the American Thoracis Society 2004;1(3): 239–46. Noseworthy 2000 Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. New England Journal of Medicine 2000;343(13):938–52.

O’Brien 2003 O’Brien JA, Ward AJ, Patrick AR, Cairo J. Cost of managing an episode of relapse in multiple sclerosis in the United States. BMC Health Services Research 2003;3:17. Polman 2005 Polman CH, Reingold SC, Edan G, Filippi M, Hartung H- P, Kappos L, et al.Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Annals of Neurology 2005;58(6):840–6. 19 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Poser 1983 Poser CM, Paty DW, Scheinberg L, McDonald I, Davis SA, Ebers GC, et al.New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

Annals of Neurology 1983;13(3):227–31. Rio 2006 Río J, Nos C, Tintoré M, Téllez N, Galán I, Pelayo R, et al.Defining the response to interferon-beta in relapsing- remitting multiple sclerosis patients. Annals of Neurology 2006;59(2):344–52. Robson 1998 Robson LS, Bain C, Beck S, Guthrie S, Coyte PC, O’Connor P. Cost analysis of methylprednisolone treatment of multiple sclerosis patients. Canadian Journal of Neurological Sciences 1998;25(3):222–9. Schumacher 1965 Schumacker GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, et al.Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis.

Annals of the New York Academy of Science 1965; 122:552-68.

Schweingruber 2011 Schweingruber A, Reichardt SD, Reichardt HM. Mechanisms of glucocorticoids in control of neuroinflammation. Journal of Neuroendocrinology 2011;24: 174–82. Sellebjerg 2000 Sellebjerg F, Christiansen M, Jensen J, Frederiksen JL. Immunological effects of oral high-dose methylprednisolone in acute optic neuritis and multiple sclerosis. European Journal of Neurology : the official journal of the European Federation of Neurological Societies 2000;7(3):281–9. [PUBMED: 10886311] Swanton 2007 Swanton JK, Rovira A, Tintore M, Altmann DR, Barkhof F, Filippi M, et al.MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study.

Lancet Neurology 2007;6(8):677–86. Tremlett 1998 Tremlett HL, Luscombe DK, Wiles CM. Use of corticosteroids in multiple sclerosis by consultant neurologists in the United Kingdom. Journal of Neurology, Neurosurgery and Psychiatry 1998;65(3):362–5. Troiano 1985 Troiano RA, Hafstein MP, Zito G, Ruderman MI, Dowling PC, Cook SD. The effect of oral corticosteroid dosage on CT enhancing multiple sclerosis plaques. Journal of the Neurological Sciences 1985;70:67–72. References to other published versions of this review Burton 2009 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 2009, Issue 3. [DOI: 10.1002/14651858.CD006921.pub2] ∗ Indicates the major publication for the study 20 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Alam 1993 Methods 1.Concealment of allocation and randomization methods - can not tell 2.Blindingof assessorsandparticipantsandtestsof blinding -yesblinding of participants, but can not tell if tests of blinding done 3.Masking of intervention - yes 4.Rationale for sample size - yes 5.Use of non-inferiority design and analysis methods - no 6Use of ITT analysis possible with published data - yes 7. Complete follow-up with documentation of the number of patients lost to follow-up and those who withdrew Participants 38 adults with clinically definite MS presenting with a relapse

Alam 1993 (Continued) Incomplete outcome data (attrition bias) All outcomes Unclear risk Patients lost to follow-up/withdrawals doc- umented although exact reasons not clear, use of ITT with published data possible Selective reporting (reporting bias) Unclear risk No clear evidence that data intentionally left undocumented although some enpoint data not reported Rationale for sample size Unclear risk A sample size calculation was provided but a power value was not Use of non-inferiority design and methods High risk This design was not employed Barnes 1997 Methods 1.Concealment of allocation and randomization methods - yes 2.Blinding of assessors and participants and tests of blinding - yes to both 3.Masking of intervention - yes 4.Rationale for sample size - yes 5.Use of non-inferiority design and analysis methods - no 6.Use of ITT analysis possible with published data - yes 7.

Complete follow-up with documentation of the number of patients lost to follow-up and those who withdrew - yes Participants 80 adults with clinically definite MS presenting with relapses = 1 point at four weeks, but result not reported; 2.Median EDSS at 0-1 weeks, 0-4 weeks, 0-12 weeks, 0-24 weeks and overall area under the curve; 3.Median ambulation index at 0-1 weeks, 0-4 weeks, 0-12 weeks, 0-24 weeks and overall area under the curve; 4.Median arm index at 0-1 weeks, 0-4 weeks, 0-12 weeks, 0-24 weeks and overall area under the curve; 5.Proportion discharged from hospital at week 1 and week 4; 6.Mean hospital length of stay; 7.Proportion with improvement in pyramidal FSS subscale; 8.Adverse event rates 22 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Barnes 1997 (Continued) Outcomes from Pitzallis 1997: 1.TNF alpha at day 1, 4, 28 and 90; 2.LFA-1 at day 1, 4, 28 and 90; 3.LFA-3 at day 1, 4, 28 and 90; 4.ICAM-1 at day 1, 4, 28 and 90; 5.CD2 at day 1, 4, 28 and 90; 6.CD4 at day 1, 4, 28 and 90; 7.CD8 at day 1, 4, 28 and 90; 8.CD45Ra at day 1, 4, 28 and 90; 9.CD45Ro at day 1, 4, 28 and 90 Outcomes from Sharrack 2000, based on participants from Barnes 1997: 1.Proportion of patients with relapses over 2 years following treatment; 2.Number of relapses over 2 years; 3.Mean relapse rate in first 6 months after therapy; 3.Mean relapse rate in first year following therapy; 4.Mean relapse rate in second year following therapy; 5.Annualized relapse rate over 2 years following therapy; 6.

Number of verified relapses; 7.Number of treated relapses; 8.Mean days until first relapse after treatment; 9.Mean EDSS of first relapse after treatment Notes Articles Pitzallis 1997 and Sharrack 2000 are based on the patients from Barnes 1997. Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Randomization methods adequate Allocation concealment (selection bias) Low risk Proper use and documentation of conceal- ment of allocation Blinding of participants and personnel (performance bias) All outcomes Low risk Blinding methods sufficient Blinding of outcome assessment (detection bias) All outcomes Low risk Tests of blinding performed Incomplete outcome data (attrition bias) All outcomes Low risk Patients lost to follow-up/withdrawals doc- umented, use of ITT with published data possible Selective reporting (reporting bias) Unclear risk No clear evidence that data intentionally left undocumented although some end- points not clearly reported 23 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Barnes 1997 (Continued) Rationale for sample size Low risk Sample size calculations were provided Use of non-inferiority design and methods High risk This design was not employed Martinelli 2008 Methods 1.Concealment of allocation and randomization methods - randomization methods - yes, concealment of allocation - no 2.Blinding of assessors and participants and tests of blinding - no (only radiologists blinded) 3.Masking of intervention - no 4.Rationale for sample size - yes 5.Use of non-inferiority design and analysis methods - yes 6.Use of ITT analysis possible with published data - yes 7.

Complete follow-up with documentation of the number of patients lost to follow-up and those who withdrew - yes Participants 40 adults (< age 55 years) with clinically definite MS presenting with relapses 1gadolinium enhancing lesion on MRI done at time of relapse were randomized to oral MP group (20 patients) or IVMP group (20 patients). Mean age in oral MP group 36.0 years (8 SD) and in IVMP group 31.0 years (7 SD). The mean EDSS is the oral MP group was 2.3 (1.3 SD) and in the IVMP group it was 1.8 (1.1). Mean disease duration in the oral MP group was 10 years (6 SD) while in the IVMP group it was 7 years (6 SD).

The sex ratio was 14 women to 6 men in each group Interventions IVMP group: 1gram/d of intravenous MP given for 5 consecutive days Oral MP group: 500 mg of oral MP given BID for 5 consecutive days. Both groups received sucralfate 2 g for 3 days for gastrointestinal protection Outcomes 1.The range over which reduction the number of gadolinium enhancing lesions on MRI after 1 week from the beginning steroid treatment falls (Oral MP equivalent to IVMP group if the upper limit of the 95% CI of the oral MP group mean percentage lesion change was lower than 20% of the average percentage lesion change of the IVMP group 2.Number of gadolinium enhancing lesions on MRI 4 weeks after steroid treatment 3.

Change in EDSS score 1 week after steroid treatment 4.Change in EDSS score 4 weeks after steroid treatment 5.Safety profile Notes Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Randomization methods adequate 24 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Martinelli 2008 (Continued) Allocation concealment (selection bias) High risk Concealment of allocation not used Blinding of participants and personnel (performance bias) All outcomes Unclear risk Only radiologists blinded, not clear clinical evaluators or patients blinded Blinding of outcome assessment (detection bias) All outcomes Unclear risk Unclear if tests of blinding performed Incomplete outcome data (attrition bias) All outcomes Low risk Patients lost to follow-up/withdrawals doc- umented, use of ITT with published data possible Selective reporting (reporting bias) Low risk No evidence endpoint data undocumented Rationale for sample size Low risk Sample size calculations were provided Use of non-inferiority design and methods Low risk A non-inferiority design was employed Morrow 2004 Methods 1.Concealment of allocation and randomization methods - can not tell 2.Blinding of assessors and participants and tests of blinding - no 3.Masking of intervention - no 4.Rationale for sample size - can not tell 5.Use of non-inferiority design and analysis methods - no 6.Use of ITT analysis possible with published data - no 7.

Complete follow-up with documentation of the number of patients lost to follow-up and those who withdrew - no Participants 16 adults (>18 years of age) with multiple sclerosis presenting with relapse events severe enough to merit steroid therapy were randomized in equal numbers to one of two groups Mean age 39 (24-61) Mean EDSS 4.0 (2-6.5) Mean disease duration 5.7 years (0.6-38 years) Women: Men 13:4 Interventions 16 adults with MS presenting with relapses severe enough to merit steroid treatment were randomized in equal number to oral MP or IVMP. The mean age was 39 years (24- 61), mean EDSS was 4.0 (2-6.5) and mean disease duration was 5.7 years (0.6-38).

The sex ratio was 13 women to 4 men Outcomes 1.Mean absorption of steroid absorption by liquid chromatography/mass spectrometry at 1, 2, 4, 8, 24 and 48 hours following treatment; 2.Meanareaunderthe curve forabsorptionbyliquidchromatography/massspectrometry at 1, 2, 4, 8, 24 and 48 hours following treatment 25 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Morrow 2004 (Continued) Notes Raw data made available reported 17, not 16 patients. Unclear which patient deleted (hence 17 patients when Female: Male numbers reported). As well, only 15 patients used in this review as 2 patients were treated > 30 days after relapse event Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Unclear risk Cannot determine what randomization techniques used Allocation concealment (selection bias) Unclear risk Unclear if concealment of allocation used Blinding of participants and personnel (performance bias) All outcomes Unclear risk Performed only in laboratory evaluators (but outcomes pharmacological) Blinding of outcome assessment (detection bias) All outcomes Unclear risk Not performed (but outcomes pharmaco- logical) Incomplete outcome data (attrition bias) All outcomes Unclear risk Patients lost to follow-up/withdrawals not clearly documented, additional data sup- plied by author Selective reporting (reporting bias) Low risk Some patient data missing in final report but author supplied additional raw data upon request Rationale for sample size High risk The authors report that their sample size does not provide adequate power Use of non-inferiority design and methods High risk This design was not employed Ramo-Tello 2011 Methods 1.Concealment of allocation and randomization methods - yes 2.Blinding of assessors and participants and tests of blinding - yes 3.Masking of intervention - yes 4.Rationale for sample size - yes 5.Use of non-inferiority design and analysis methods - unclear 6.Use of ITT analysis possible with published data - N/A (unpublished data) 7.

Complete follow-up with documentation of the number of patients lost to follow-up and those who withdrew - yes Participants Forty-eight adults with MS and a mean age of 38 years and a sex ratio of 40 women to 8 men presenting with an MS relapse deemed to require steroid therapy 26 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Ramo-Tello 2011 (Continued) Interventions 1.IV Group: 1000 mg IVMP with sham oral agent for 3 consecutive days 2.Oral Group: 250 mg of oral MP for with sham iv agent for 3 consecutive days Outcomes 1.Mean EDSS in oral MP vs IVMP groups at day 7, 28 and month 3 2.Number and volume of new and persistent gadolinium enhancing lesions on MRI brain at day 7, 28 and month 3 3.Number and volume of new and persistent T2 lesions on MRI brain at day 7, 28 and month 3 4.Adverse event rates 5.MFIS 6.MUSIQoL Notes Unpublished data, raw data supplied for all outcomes but unclear if all will be reported Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Randomization methods adequate Allocation concealment (selection bias) Low risk Allocation concealment methods adequate Blinding of participants and personnel (performance bias) All outcomes Low risk Blinding sufficient Blinding of outcome assessment (detection bias) All outcomes Low risk Tests of blinding performed Incomplete outcome data (attrition bias) All outcomes Low risk Unpublished data only, all data available was supplied Selective reporting (reporting bias) Low risk Unpublished data at present, but all re- quested data supplied Rationale for sample size Low risk Sample size calculations were provided and adequate Use of non-inferiority design and methods Unclear risk The authors state a non-inferiority design was employed, but the results are not pre- sented as such (i.e.

they are presented as a comparison of mean values) BID: twice daily d: day(s) 27 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

EDSS: Expanded Disability Status Scale FSS: Fatigue Severity Scale ITT: intention-to-treat IVMP: intravenous methylprednisolone MFIS: Modified Fatigue Impact Scale MP: methylprednisolone MRI: magnetic resonance imaging MS: multiple sclerosis MUSIQoL: Multiple Sclerosis International Quality of Life oral MP: oral methylprednisolone SD: standard deviation vs: versus Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Alejandro 1994 This randomized controlled trial of oral versus intravenous methylprednisolone was performed in patients with optic neuritis, and the majority of patients did not have MS.

Too few participants with MS made analyzing this subgroup of little value Beck 1992 This randomized blinded and controlled trial was performed in patients with optic neuritis only, not those with MS De Keyser 1999 This was a non-randomized trial of MS relapse treatment with oral dexamethasone only Demirkiran 1995 This trial was not a comparison of intravenous versus oral steroids, but rather a study of intravenous + oral steroids versus oral steroids alone. Additionally, not all patients had definite MS, and no breakdown of results based on this parameter Huen 1989 This trial compared intravenous to intrathecal steroid administration in patients with MS La Mantia 1994 This double-blind trial compared intravenous dexamethasone to intravenous methylprednisolone in MS relapses Le Page 2007 This trial was an observational, non-randomized study of consecutive patients with MS treated with either high- dose oral or intravenous MP.

Consecutive patients received either 3-5 days of IVMP or 3-5 days starting on day 1 with IVMP, followed by 2 days with oral MP. Roughly 80% of patients were treated for relapses, the remainder for a test of steroid responsiveness Metz 1999 This trial compared gastric and small bowel permeability between participants on oral prednisone at 1250mg versus 1000 mg of IVMP. Patients chose their treatment, so this was not a randomized trial Milanese 1989 This trial compared methylprednisolone to dexamethasone to ACTH in acute MS relapses. No drug was administered orally Murray 1999 This trial did not have an active comparator for oral methylprednisolone 28 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

(Continued) Rohrbach 1988 This double-blinded randomized controlled trial compared oral and intrathecal corticosteroids to treat myelo- pathic symptoms of MS, not overt relapses Sellebjerg 1998 This randomized controlled trial of treatment for MS relapses used oral methylprednisolone against placebo, not an intravenous steroid preparation Sellebjerg 1999 This randomized controlled trial compared oral methylprednisolone against placebo in patients with optic neuritis, not necessarily MS Tankisi 1997 Patients encountering “acute” relapses were treated with either 1g daily of IVMP followed by oral prednisolone taper or prednisolone taper alone.

The trial was only published in abstract form, is not clearly an RCT, and does not compare intravenous to oral steroids, but intravenous plus oral steroids versus oral steroids alone Thompson 1989 This double-blind randomized trial compared intravenous methylprednisolone to intramuscular ACTH Toczolowski 1995 Upon translation from Polish to English, it was evident that this was not a randomized controlled trial Tourtellotte 1965 This double-blind randomized trial compared oral methylprednisolone to oral cyanocobalamin ACTH: adrenocorticotropic hormone IVMP: intravenous methylprednisolone MP: methylprednisolone MS: multiple sclerosis RCT: randomized controlled trial Characteristics of ongoing studies [ordered by study ID] COPOUSEP 2009 Trial name or title Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses (COPOUSEP) Methods Double-blinded randomized trial of oral versus iv methylprednisolone Participants Patients with clinically definite MS ages 18-55 and EDSS 0-5.0.

All must present with an acute symptomatic exacerbation of MS present for great than 24 hours within 15 days of the event Interventions 1000 mg oral methylprednisolone versus 1000 mg of iv methylprednisolone for three days for relapses within 15 days Outcomes A minimum of a one point reduction in EDSS at day 28 Starting date March 2008 Contact information Emmanuelle LE PAGE, MD, 33-2-9928-5296, emmanuelle.lepage@chu-rennes.fr 29 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

COPOUSEP 2009 (Continued) Notes Principal investigator contacted, no data available to report as of January 2012 OMEGA 2007 Trial name or title Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) Methods Bioequivalent oral dosing methylprednisolone plus intravenous placebo versus IVMP plus oral placebo for objective acute relapses seen within seven days of event. Patients followed for one year Participants Patients with clinically definite MS (by Poser or McDonald criteria) between the ages of 18 and 50 years with an EDSS of 2-6.5 at entry. All must present with an acute symptomatic exacerbation of MS present for great than 24 hours and less than or equal to 7 days at entry with new or worsening symptoms (excluding purely sensory deficits if not optic neuritis).

Signs must be referable to the symptoms and not in the context of fever or active infection.

Participants may continue on their current immunomodulating therapy (such as interferons or glatiramer acetate) throughout the course of the study. Women who become pregnant after the 5-day treatment of steroids will have their immunomodulatory treatment discontinued Interventions Equivalent oral methylprednisolone (1400 mg/day x 5 days plus intravenous placebo) versus IVMP (1000mg/ d x 5 days plus oral placebo) in patients seen within seven days of an acute exacerbation of MS Outcomes The primary outcome measures include EDSS and mean recovery from day 0 to day 28 (time frame: Day 28 and Day 90, Designated as safety issue: Yes) Secondary outcome measures: clinical parameters of the MSFC between oral and IV steroid therapy in participants with relapsing forms of MS (time frame: Day 28 and day 90).

frequency of relapse over time (up to one year)whenparticipantswith relapsingformsof MS are administeredone course of oral methylprednisolone compared with IV administration (time frame: Day 28 and day 90 and day 365),improvement using Targeted Neurological Deficits (TND, time frame: Day 28 and day 90) Starting date September 2003 Contact information Michele Weber (212)-241-4264, Principle Investigator is Dr. Fred Lublin. Notes Principal investigator contacted, no data available to report as of January 2012 Study is currently enrolling final data collection by December 2009. EDSS: Expanded Disability Status Scale IVMP: intravenous methylprednisolone MS: multiple sclerosis MSFC: Multiple Sclerosis Functional Composite 30 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

D A T A A N D A N A L Y S E S Comparison 1. Improvement in EDSS after treatment with oral vs. intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Mean decrease in EDSS after steroid treatment at week 1 3 168 Mean Difference (IV, Random, 95% CI) -0.05 [-0.38, 0.28] 2 Mean decrease in EDSS after steroid treatment at week 4 3 165 Mean Difference (IV, Random, 95% CI) -0.22 [-0.71, 0.26] Comparison 2. Proportion of patients with improvement on EDSS after treatment with oral vs. intravenous steroids Outcome or subgroup title No. of studies No.

of participants Statistical method Effect size 1 Proportion of patients with improvement on EDSS after steroid treatment at 4 weeks 4 200 Odds Ratio (M-H, Random, 95% CI) 0.60 [0.28, 1.26] Comparison 3. Change in Ambulation Index after treatment with oral vs. intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Change in Ambulation Index at week 1 after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.0 [-0.39, 0.39] 2 Change in Ambulation Index at week 4 after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.4 [-0.11, 0.91] 31 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Comparison 4. Longterm relapse rate after treatment with oral vs. intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Relapse rate 6 months after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.21 [-0.06, 0.48] 2 Relapse rate at one year after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.34 [-0.13, 0.81] 3 Relapse rate at years 1-2 after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.21 [-0.16, 0.58] 4 Relapse rate at two years after treatment with oral vs.

intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.28 [-0.08, 0.64] 5 Proportion relapse free at 2 years after treatment with oral vs. intravenous steroids 1 80 Odds Ratio (M-H, Random, 95% CI) 0.77 [0.28, 2.08] Comparison 5. Days to next relapse after treatment with oral vs. intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Mean number of days to next relapse after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) -47.00 [-150.53, 56. 53] Comparison 6. EDSS at first relapse after treatment with oral vs.

intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Mean change in EDSS at first relapse within 2 year period after treatment with oral vs. intravenous steroids 1 80 Mean Difference (IV, Random, 95% CI) 0.03 [-0.47, 0.53] 32 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Comparison 7. Proportion hospitalized for relapse after treatment with oral vs. intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion hospitalized at week 1 after treatment with oral vs. intravenous steroids 1 80 Odds Ratio (M-H, Random, 95% CI) 0.99 [0.37, 2.69] 2 Proportino hospitalized at week 4 after treatment with oral vs. intravenous steroids 1 80 Odds Ratio (M-H, Random, 95% CI) 1.85 [0.16, 21.26] Comparison 8. Bioavailability of oral vs. intravenous steroids Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Area under curve for steroid absorption at 1 hour with oral vs.

intravenous steroids 1 15 Mean Difference (IV, Random, 95% CI) -4952.20 [-6614.77, -3289.63] 2 Area under curve for steroid absorption at 2 hours with oral vs. intravenous steroids 1 15 Mean Difference (IV, Random, 95% CI) -11686.14 [-15975. 95, -7396.33] 3 Area under curve for steroid absorption at 4 hours with oral vs. intravenous steroids 1 15 Mean Difference (IV, Random, 95% CI) -257758.03 [- 731488.63, 215972.

57] 4 Area under curve for steroid absorption at 8 hours with oral vs. intravenous steroids 1 15 Mean Difference (IV, Random, 95% CI) -12587.31 [-26739. 27, 1564.65] 5 Area under curve for steroid absorption at 8 hours with oral vs. intravenous steroids (SA, outlier removed) 1 14 Mean Difference (IV, Random, 95% CI) -14286.81 [-25124. 20, -3449.42] 6 Area under curve for steroid absorption at 24 hours with oral vs. intravenous steroids 1 15 Mean Difference (IV, Random, 95% CI) -2853.38 [-17964. 42, 12257.66] 7 Area under curve for steroid absorption at 48 hours with oral vs. intravenous steroids 1 15 Mean Difference (IV, Random, 95% CI) -845.48 [-16182.93, 14491.97] 33 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Comparison 10. Changes in gadolinium enhancing lesions on MRI Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Mean percentage reduction in gadolinium lesions on MRI weeks 0-1 2 85 Mean Difference (IV, Random, 95% CI) -0.01 [-0.30, 0.29] 2 Mean percentage reduction in gadolinium positive MRI lesions weeks 0-4 2 84 Mean Difference (IV, Random, 95% CI) -0.02 [-0.24, 0.21] 3 Mean change in gadolinium enhancing lesions on MRI between weeks 0 and 1 2 85 Mean Difference (IV, Random, 95% CI) -0.14 [-1.11, 0.84] 4 Mean change in gadolinium enhancing lesions on MRI between week 0 and 4 2 84 Mean Difference (IV, Random, 95% CI) -0.18 [-1.47, 1.10] 5 Proportion with gadolinium enhancing lesions on MRI at week 1 2 85 Odds Ratio (M-H, Random, 95% CI) 0.86 [0.37, 2.03] 6 Proportion with gadolinium enhancing lesions at week 4 2 84 Odds Ratio (M-H, Random, 95% CI) 1.13 [0.43, 2.99] Comparison 11.

Changes in T2 lesion number Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Mean change in T2 lesions at week 1 with respect to baseline in T2 lesion number between oral and iv 1 44 Mean Difference (IV, Random, 95% CI) -0.09 [-0.33, 0.15] 2 Mean change in T2 lesions at week 4 with respect to week 1 1 45 Mean Difference (IV, Random, 95% CI) 0.14 [-0.24, 0.52] Comparison 12. Proportion with HTN Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with HTN 1 40 Odds Ratio (M-H, Random, 95% CI) 2.11 [0.18, 25.35] 34 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Comparison 13. Proportion with rash Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with rash 2 89 Odds Ratio (M-H, Random, 95% CI) 0.72 [0.23, 2.26] Comparison 14. Proportion with hypertricosis Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with hypertricosis 1 40 Odds Ratio (M-H, Random, 95% CI) 0.47 [0.04, 5.69] Comparison 15. Proportion with anxiety Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with anxiety 2 89 Odds Ratio (M-H, Random, 95% CI) 0.95 [0.37, 2.44] Comparison 16.

Proportion with insomnia Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with insomnia 2 89 Odds Ratio (M-H, Random, 95% CI) 2.63 [0.63, 11.01] Comparison 17. Proportion with dysgeusia Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with dysgeusia 2 89 Odds Ratio (M-H, Random, 95% CI) 4.30 [1.36, 13.63] 35 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Comparison 18. Proportion with hiccups Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with hiccups 1 40 Odds Ratio (M-H, Random, 95% CI) 3.15 [0.12, 82.16] Comparison 19. Proportion with hyperglycemia Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with hyperglycemia 1 40 Odds Ratio (M-H, Random, 95% CI) 0.32 [0.01, 8.26] Comparison 20. Proportion with headache Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with headache 1 48 Odds Ratio (M-H, Random, 95% CI) 2.54 [0.75, 8.63] Comparison 21.

Proportion with mood disturbance (euphoria, depression) Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with mood disturbance 1 48 Odds Ratio (M-H, Random, 95% CI) 2.87 [0.87, 9.45] Comparison 22. Proportion with hot flashes/flushing Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with hot flashes 1 48 Odds Ratio (M-H, Random, 95% CI) 1.65 [0.53, 5.18] 36 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Comparison 23. Proportion with swelling Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with swelling 1 48 Odds Ratio (M-H, Random, 95% CI) 0.44 [0.12, 1.59] Comparison 24. Proportion with pirosis Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Proportion with pirosis 2 89 Odds Ratio (M-H, Random, 95% CI) 0.98 [0.36, 2.67] Analysis 1.1. Comparison 1 Improvement in EDSS after treatment with oral vs. intravenous steroids, Outcome 1 Mean decrease in EDSS after steroid treatment at week 1.

Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 1 Improvement in EDSS after treatment with oral vs.

intravenous steroids Outcome: 1 Mean decrease in EDSS after steroid treatment at week 1 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 0.5 (0.8) 38 0.4 (0.7) 34.0 % 0.10 [ -0.23, 0.43 ] Martinelli 2008 20 0.6 (0.53) 20 0.98 (0.52) 34.2 % -0.38 [ -0.71, -0.05 ] Ramo-Tello 2011 24 0.64 (0.7) 24 0.5 (0.57) 31.8 % 0.14 [ -0.22, 0.50 ] Total (95% CI) 86 82 100.0 % -0.05 [ -0.38, 0.28 ] Heterogeneity: Tau2 = 0.06; Chi2 = 5.80, df = 2 (P = 0.05); I2 =66% Test for overall effect: Z = 0.30 (P = 0.76) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours intravenous Favours oral 37 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 1.2. Comparison 1 Improvement in EDSS after treatment with oral vs. intravenous steroids, Outcome 2 Mean decrease in EDSS after steroid treatment at week 4. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 1 Improvement in EDSS after treatment with oral vs. intravenous steroids Outcome: 2 Mean decrease in EDSS after steroid treatment at week 4 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 0.9 (1.2) 38 0.8 (1.1) 45.9 % 0.10 [ -0.40, 0.60 ] Martinelli 2008 20 0.95 (0.63) 20 1.45 (0.72) 54.1 % -0.50 [ -0.92, -0.08 ] Ramo-Tello 2011 22 1.09 (0.98) 23 1.19 (93) 0.0 % -0.10 [ -38.11, 37.91 ] Total (95% CI) 84 81 100.0 % -0.22 [ -0.71, 0.26 ] Heterogeneity: Tau2 = 0.07; Chi2 = 3.22, df = 2 (P = 0.20); I2 =38% Test for overall effect: Z = 0.91 (P = 0.37) Test for subgroup differences: Not applicable -2 -1 0 1 2 Favours intravenous Favours oral 38 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Alam 1993 10/15 16/20 24.0 % 0.50 [ 0.11, 2.32 ] Barnes 1997 8/42 10/38 50.7 % 0.66 [ 0.23, 1.89 ] Martinelli 2008 17/20 20/20 6.2 % 0.12 [ 0.01, 2.53 ] Ramo-Tello 2011 19/22 20/23 19.1 % 0.95 [ 0.17, 5.30 ] Total (95% CI) 99 101 100.0 % 0.60 [ 0.28, 1.26 ] Total events: 54 (Oral), 66 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 1.44, df = 3 (P = 0.70); I2 =0.0% Test for overall effect: Z = 1.35 (P = 0.18) Test for subgroup differences: Not applicable 0.1 0.2 0.5 1 2 5 10 Favours intravenous Favours oral 39 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 0.4 (0.9) 38 0.4 (0.9) 100.0 % 0.0 [ -0.39, 0.39 ] Total (95% CI) 42 38 100.0 % 0.0 [ -0.39, 0.39 ] Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours intravenous Favours oral 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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 0.8 (1.3) 38 0.4 (1) 100.0 % 0.40 [ -0.11, 0.91 ] Total (95% CI) 42 38 100.0 % 0.40 [ -0.11, 0.91 ] Heterogeneity: not applicable Test for overall effect: Z = 1.55 (P = 0.12) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours intravenous Favours oral 40 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 0.55 (0.74) 38 0.34 (0.48) 100.0 % 0.21 [ -0.06, 0.48 ] Total (95% CI) 42 38 100.0 % 0.21 [ -0.06, 0.48 ] Heterogeneity: not applicable Test for overall effect: Z = 1.52 (P = 0.13) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours oral Favours intravenous 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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 1.26 (1.31) 38 0.92 (0.78) 100.0 % 0.34 [ -0.13, 0.81 ] Total (95% CI) 42 38 100.0 % 0.34 [ -0.13, 0.81 ] Heterogeneity: not applicable Test for overall effect: Z = 1.43 (P = 0.15) Test for subgroup differences: Not applicable -2 -1 0 1 2 Favours oral Favours intravenous 41 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 0.86 (0.9) 38 0.65 (0.79) 100.0 % 0.21 [ -0.16, 0.58 ] Total (95% CI) 42 38 100.0 % 0.21 [ -0.16, 0.58 ] Heterogeneity: not applicable Test for overall effect: Z = 1.11 (P = 0.27) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours oral Favours intravenous 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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 1.06 (0.98) 38 0.78 (0.65) 100.0 % 0.28 [ -0.08, 0.64 ] Total (95% CI) 42 38 100.0 % 0.28 [ -0.08, 0.64 ] Heterogeneity: not applicable Test for overall effect: Z = 1.52 (P = 0.13) Test for subgroup differences: Not applicable -2 -1 0 1 2 Favours oral Favours intravenous 42 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Barnes 1997 10/42 11/38 100.0 % 0.77 [ 0.28, 2.08 ] Total (95% CI) 42 38 100.0 % 0.77 [ 0.28, 2.08 ] Total events: 10 (Oral), 11 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.52 (P = 0.60) Test for subgroup differences: Not applicable 0.1 0.2 0.5 1 2 5 10 Favours intravenous Favours oral Analysis 5.1.

Comparison 5 Days to next relapse after treatment with oral vs. intravenous steroids, Outcome 1 Mean number of days to next relapse after treatment with oral vs. intravenous steroids. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 5 Days to next relapse after treatment with oral vs. intravenous steroids Outcome: 1 Mean number of days to next relapse after treatment with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 236 (288) 38 283 (176) 100.0 % -47.00 [ -150.53, 56.53 ] Total (95% CI) 42 38 100.0 % -47.00 [ -150.53, 56.53 ] Heterogeneity: not applicable Test for overall effect: Z = 0.89 (P = 0.37) Test for subgroup differences: Not applicable -500 -250 0 250 500 Favours oral Favours intravenous 43 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

Analysis 6.1. Comparison 6 EDSS at first relapse after treatment with oral vs. intravenous steroids, Outcome 1 Mean change in EDSS at first relapse within 2 year period after treatment with oral vs. intravenous steroids. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 6 EDSS at first relapse after treatment with oral vs. intravenous steroids Outcome: 1 Mean change in EDSS at first relapse within 2 year period after treatment with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Barnes 1997 42 1.56 (1.11) 38 1.53 (1.16) 100.0 % 0.03 [ -0.47, 0.53 ] Total (95% CI) 42 38 100.0 % 0.03 [ -0.47, 0.53 ] Heterogeneity: not applicable Test for overall effect: Z = 0.12 (P = 0.91) Test for subgroup differences: Not applicable -2 -1 0 1 2 Favours oral Favours intravenous 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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Barnes 1997 11/42 10/38 100.0 % 0.99 [ 0.37, 2.69 ] Total (95% CI) 42 38 100.0 % 0.99 [ 0.37, 2.69 ] Total events: 11 (Oral), 10 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.01 (P = 0.99) Test for subgroup differences: Not applicable 0.1 0.2 0.5 1 2 5 10 Favours oral Favours intravenous 44 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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 Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Barnes 1997 2/42 1/38 100.0 % 1.85 [ 0.16, 21.26 ] Total (95% CI) 42 38 100.0 % 1.85 [ 0.16, 21.26 ] Total events: 2 (Oral), 1 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.49 (P = 0.62) Test for subgroup differences: Not applicable 0.1 0.2 0.5 1 2 5 10 Favours oral Favours intravenous 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.

Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 8 Bioavailability of oral vs. intravenous steroids Outcome: 1 Area under curve for steroid absorption at 1 hour with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Morrow 2004 8 899.36 (422.91) 7 5851.56 (2209.16) 100.0 % -4952.20 [ -6614.77, -3289.63 ] Total (95% CI) 8 7 100.0 % -4952.20 [ -6614.77, -3289.63 ] Heterogeneity: not applicable Test for overall effect: Z = 5.84 (P < 0.00001) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours intravenous Favours oral 45 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 8 Bioavailability of oral vs. intravenous steroids Outcome: 2 Area under curve for steroid absorption at 2 hours with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Morrow 2004 3288.71 (1103.93) 8 14974.85 (5697.99) 7 100.0 % -11686.14 [ -15975.95, -7396.33 ] Total (95% CI) 8 7 100.0 % -11686.14 [ -15975.95, -7396.33 ] Heterogeneity: not applicable Test for overall effect: Z = 5.34 (P < 0.00001) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours intravenous Favours oral 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.

Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 8 Bioavailability of oral vs. intravenous steroids Outcome: 3 Area under curve for steroid absorption at 4 hours with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Ran Morrow 2004 9392.19 (1972.26) 8 267150.22 (639485.29) 7 -257758.03 [ -731488.63, 215972.57 ] Total (95% CI) 8 7 -257758.03 [ -731488.63, 215972.57 ] Heterogeneity: not applicable Test for overall effect: Z = 1.07 (P = 0.29) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours intravenous Favours oral 46 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 8 Bioavailability of oral vs. intravenous steroids Outcome: 4 Area under curve for steroid absorption at 8 hours with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Morrow 2004 18870.17 (15527.19) 8 31457.48 (12409.46) 7 100.0 % -12587.31 [ -26739.27, 1564.65 ] Total (95% CI) 8 7 100.0 % -12587.31 [ -26739.27, 1564.65 ] Heterogeneity: not applicable Test for overall effect: Z = 1.74 (P = 0.081) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours intravenous Favours oral 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). Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis 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) Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Morrow 2004 18870.17 (5527.19) 8 33156.98 (12670.12) 6 100.0 % -14286.81 [ -25124.20, -3449.42 ] Total (95% CI) 8 6 100.0 % -14286.81 [ -25124.20, -3449.42 ] Heterogeneity: not applicable Test for overall effect: Z = 2.58 (P = 0.0098) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours treatment Favours control 47 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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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. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 8 Bioavailability of oral vs. intravenous steroids Outcome: 6 Area under curve for steroid absorption at 24 hours with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Morrow 2004 33472.67 (12080.76) 8 36326.05 (16982.1) 7 100.0 % -2853.38 [ -17964.42, 12257.66 ] Total (95% CI) 8 7 100.0 % -2853.38 [ -17964.42, 12257.66 ] Heterogeneity: not applicable Test for overall effect: Z = 0.37 (P = 0.71) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours intravenous Favours oral 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.

Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 8 Bioavailability of oral vs. intravenous steroids Outcome: 7 Area under curve for steroid absorption at 48 hours with oral vs. intravenous steroids Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Morrow 2004 35480.57 (12661.02) 8 36326.05 (16982.1) 7 100.0 % -845.48 [ -16182.93, 14491.97 ] Total (95% CI) 8 7 100.0 % -845.48 [ -16182.93, 14491.97 ] Heterogeneity: not applicable Test for overall effect: Z = 0.11 (P = 0.91) Test for subgroup differences: Not applicable -1000 -500 0 500 1000 Favours intravenous Favours oral 48 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 10.1. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 1 Mean percentage reduction in gadolinium lesions on MRI weeks 0-1. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 10 Changes in gadolinium enhancing lesions on MRI Outcome: 1 Mean percentage reduction in gadolinium lesions on MRI weeks 0-1 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Martinelli 2008 20 -0.74 (0.38) 20 -0.58 (0.44) 48.9 % -0.16 [ -0.41, 0.09 ] Ramo-Tello 2011 22 -0.29 (0.4) 23 -0.43 (0.42) 51.1 % 0.14 [ -0.10, 0.38 ] Total (95% CI) 42 43 100.0 % -0.01 [ -0.30, 0.29 ] Heterogeneity: Tau2 = 0.03; Chi2 = 2.83, df = 1 (P = 0.09); I2 =65% Test for overall effect: Z = 0.04 (P = 0.96) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours oral‘ Favours iv Analysis 10.2.

Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 2 Mean percentage reduction in gadolinium positive MRI lesions weeks 0-4. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 10 Changes in gadolinium enhancing lesions on MRI Outcome: 2 Mean percentage reduction in gadolinium positive MRI lesions weeks 0-4 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Martinelli 2008 20 -0.59 (0.62) 20 -0.58 (0.46) 44.0 % -0.01 [ -0.35, 0.33 ] Ramo-Tello 2011 22 -0.44 (0.46) 22 -0.42 (0.55) 56.0 % -0.02 [ -0.32, 0.28 ] Total (95% CI) 42 42 100.0 % -0.02 [ -0.24, 0.21 ] Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 0.97); I2 =0.0% Test for overall effect: Z = 0.14 (P = 0.89) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours oral Favours iv 49 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 10.3. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 3 Mean change in gadolinium enhancing lesions on MRI between weeks 0 and 1. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 10 Changes in gadolinium enhancing lesions on MRI Outcome: 3 Mean change in gadolinium enhancing lesions on MRI between weeks 0 and 1 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Martinelli 2008 20 3.15 (4.78) 20 2.05 (4.44) 11.7 % 1.10 [ -1.76, 3.96 ] Ramo-Tello 2011 22 1.05 (1.63) 23 1.35 (1.92) 88.3 % -0.30 [ -1.34, 0.74 ] Total (95% CI) 42 43 100.0 % -0.14 [ -1.11, 0.84 ] Heterogeneity: Tau2 = 0.0; Chi2 = 0.81, df = 1 (P = 0.37); I2 =0.0% Test for overall effect: Z = 0.27 (P = 0.78) Test for subgroup differences: Not applicable -4 -2 0 2 4 Favours oral Favours iv 50 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 10.4. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 4 Mean change in gadolinium enhancing lesions on MRI between week 0 and 4. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 10 Changes in gadolinium enhancing lesions on MRI Outcome: 4 Mean change in gadolinium enhancing lesions on MRI between week 0 and 4 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Martinelli 2008 20 2.45 (3.87) 20 2.15 (4.5) 24.3 % 0.30 [ -2.30, 2.90 ] Ramo-Tello 2011 22 1.57 (1.99) 22 1.91 (2.91) 75.7 % -0.34 [ -1.81, 1.13 ] Total (95% CI) 42 42 100.0 % -0.18 [ -1.47, 1.10 ] Heterogeneity: Tau2 = 0.0; Chi2 = 0.18, df = 1 (P = 0.67); I2 =0.0% Test for overall effect: Z = 0.28 (P = 0.78) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours oral Favours iv Analysis 10.5.

Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 5 Proportion with gadolinium enhancing lesions on MRI at week 1.

Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 10 Changes in gadolinium enhancing lesions on MRI Outcome: 5 Proportion with gadolinium enhancing lesions on MRI at week 1 Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 9/20 11/20 47.1 % 0.67 [ 0.19, 2.33 ] Ramo-Tello 2011 10/22 10/23 52.9 % 1.08 [ 0.33, 3.51 ] Total (95% CI) 42 43 100.0 % 0.86 [ 0.37, 2.03 ] Total events: 19 (Oral), 21 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 0.30, df = 1 (P = 0.58); I2 =0.0% Test for overall effect: Z = 0.34 (P = 0.74) Test for subgroup differences: Not applicable 0.1 0.2 0.5 1 2 5 10 Favours oral Favours iv 51 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 10.6. Comparison 10 Changes in gadolinium enhancing lesions on MRI, Outcome 6 Proportion with gadolinium enhancing lesions at week 4. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 10 Changes in gadolinium enhancing lesions on MRI Outcome: 6 Proportion with gadolinium enhancing lesions at week 4 Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 4/20 4/20 39.4 % 1.00 [ 0.21, 4.71 ] Ramo-Tello 2011 8/22 7/22 60.6 % 1.22 [ 0.35, 4.27 ] Total (95% CI) 42 42 100.0 % 1.13 [ 0.43, 2.99 ] Total events: 12 (Oral), 11 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0% Test for overall effect: Z = 0.25 (P = 0.80) Test for subgroup differences: Not applicable 0.1 0.2 0.5 1 2 5 10 Favours oral Favours iv 52 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 11.1. Comparison 11 Changes in T2 lesion number, Outcome 1 Mean change in T2 lesions at week 1 with respect to baseline in T2 lesion number between oral and iv. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 11 Changes in T2 lesion number Outcome: 1 Mean change in T2 lesions at week 1 with respect to baseline in T2 lesion number between oral and iv Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Ramo-Tello 2011 22 0.09 (0.43) 22 0.18 (0.39) 100.0 % -0.09 [ -0.33, 0.15 ] Total (95% CI) 22 22 100.0 % -0.09 [ -0.33, 0.15 ] Heterogeneity: not applicable Test for overall effect: Z = 0.73 (P = 0.47) Test for subgroup differences: Not applicable -100 -50 0 50 100 Favours oral Favours iv Analysis 11.2.

Comparison 11 Changes in T2 lesion number, Outcome 2 Mean change in T2 lesions at week 4 with respect to week 1.

Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 11 Changes in T2 lesion number Outcome: 2 Mean change in T2 lesions at week 4 with respect to week 1 Study or subgroup Oral Intravenous Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Ramo-Tello 2011 22 0.36 (0.7) 23 0.22 (0.6) 100.0 % 0.14 [ -0.24, 0.52 ] Total (95% CI) 22 23 100.0 % 0.14 [ -0.24, 0.52 ] Heterogeneity: not applicable Test for overall effect: Z = 0.72 (P = 0.47) Test for subgroup differences: Not applicable -100 -50 0 50 100 Favours oral Favours iv 53 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 12.1. Comparison 12 Proportion with HTN, Outcome 1 Proportion with HTN. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 12 Proportion with HTN Outcome: 1 Proportion with HTN Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 2/20 1/20 100.0 % 2.11 [ 0.18, 25.35 ] Total (95% CI) 20 20 100.0 % 2.11 [ 0.18, 25.35 ] Total events: 2 (Oral), 1 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.59 (P = 0.56) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv Analysis 13.1.

Comparison 13 Proportion with rash, Outcome 1 Proportion with rash. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 13 Proportion with rash Outcome: 1 Proportion with rash Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 1/20 3/20 23.4 % 0.30 [ 0.03, 3.15 ] Ramo-Tello 2011 6/25 6/24 76.6 % 0.95 [ 0.26, 3.48 ] Total (95% CI) 45 44 100.0 % 0.72 [ 0.23, 2.26 ] Total events: 7 (Oral), 9 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 0.71, df = 1 (P = 0.40); I2 =0.0% Test for overall effect: Z = 0.56 (P = 0.58) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv 54 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 14.1. Comparison 14 Proportion with hypertricosis, Outcome 1 Proportion with hypertricosis. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 14 Proportion with hypertricosis Outcome: 1 Proportion with hypertricosis Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 1/20 2/20 100.0 % 0.47 [ 0.04, 5.69 ] Total (95% CI) 20 20 100.0 % 0.47 [ 0.04, 5.69 ] Total events: 1 (Oral), 2 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.59 (P = 0.56) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv Analysis 15.1.

Comparison 15 Proportion with anxiety, Outcome 1 Proportion with anxiety. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 15 Proportion with anxiety Outcome: 1 Proportion with anxiety Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 3/20 3/20 29.6 % 1.00 [ 0.18, 5.67 ] Ramo-Tello 2011 11/25 11/24 70.4 % 0.93 [ 0.30, 2.86 ] Total (95% CI) 45 44 100.0 % 0.95 [ 0.37, 2.44 ] Total events: 14 (Oral), 14 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 0.94); I2 =0.0% Test for overall effect: Z = 0.11 (P = 0.91) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv 55 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 16.1. Comparison 16 Proportion with insomnia, Outcome 1 Proportion with insomnia. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 16 Proportion with insomnia Outcome: 1 Proportion with insomnia Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 5/20 4/20 53.5 % 1.33 [ 0.30, 5.93 ] Ramo-Tello 2011 23/25 16/24 46.5 % 5.75 [ 1.08, 30.72 ] Total (95% CI) 45 44 100.0 % 2.63 [ 0.63, 11.01 ] Total events: 28 (Oral), 20 (Intravenous) Heterogeneity: Tau2 = 0.42; Chi2 = 1.64, df = 1 (P = 0.20); I2 =39% Test for overall effect: Z = 1.32 (P = 0.19) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv Analysis 17.1.

Comparison 17 Proportion with dysgeusia, Outcome 1 Proportion with dysgeusia. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 17 Proportion with dysgeusia Outcome: 1 Proportion with dysgeusia Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 5/20 1/20 26.2 % 6.33 [ 0.67, 60.16 ] Ramo-Tello 2011 21/25 14/24 73.8 % 3.75 [ 0.98, 14.35 ] Total (95% CI) 45 44 100.0 % 4.30 [ 1.36, 13.63 ] Total events: 26 (Oral), 15 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 0.15, df = 1 (P = 0.69); I2 =0.0% Test for overall effect: Z = 2.48 (P = 0.013) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours intravenous 56 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 18.1. Comparison 18 Proportion with hiccups, Outcome 1 Proportion with hiccups. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 18 Proportion with hiccups Outcome: 1 Proportion with hiccups Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 1/20 0/20 100.0 % 3.15 [ 0.12, 82.16 ] Total (95% CI) 20 20 100.0 % 3.15 [ 0.12, 82.16 ] Total events: 1 (Oral), 0 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.69 (P = 0.49) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv 57 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 19.1. Comparison 19 Proportion with hyperglycemia, Outcome 1 Proportion with hyperglycemia. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 19 Proportion with hyperglycemia Outcome: 1 Proportion with hyperglycemia Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 0/20 1/20 100.0 % 0.32 [ 0.01, 8.26 ] Total (95% CI) 20 20 100.0 % 0.32 [ 0.01, 8.26 ] Total events: 0 (Oral), 1 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.69 (P = 0.49) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv Analysis 20.1.

Comparison 20 Proportion with headache, Outcome 1 Proportion with headache. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 20 Proportion with headache Outcome: 1 Proportion with headache Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Ramo-Tello 2011 18/24 13/24 100.0 % 2.54 [ 0.75, 8.63 ] Total (95% CI) 24 24 100.0 % 2.54 [ 0.75, 8.63 ] Total events: 18 (Oral), 13 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 1.49 (P = 0.14) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours intravenous 58 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 21.1. Comparison 21 Proportion with mood disturbance (euphoria, depression), Outcome 1 Proportion with mood disturbance. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 21 Proportion with mood disturbance (euphoria, depression) Outcome: 1 Proportion with mood disturbance Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Ramo-Tello 2011 13/24 7/24 100.0 % 2.87 [ 0.87, 9.45 ] Total (95% CI) 24 24 100.0 % 2.87 [ 0.87, 9.45 ] Total events: 13 (Oral), 7 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 1.73 (P = 0.083) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours intravenous Analysis 22.1.

Comparison 22 Proportion with hot flashes/flushing, Outcome 1 Proportion with hot flashes. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 22 Proportion with hot flashes/flushing Outcome: 1 Proportion with hot flashes Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Ramo-Tello 2011 14/24 11/24 100.0 % 1.65 [ 0.53, 5.18 ] Total (95% CI) 24 24 100.0 % 1.65 [ 0.53, 5.18 ] Total events: 14 (Oral), 11 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 0.86 (P = 0.39) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours intravenous 59 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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Analysis 23.1. Comparison 23 Proportion with swelling, Outcome 1 Proportion with swelling. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 23 Proportion with swelling Outcome: 1 Proportion with swelling Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Ramo-Tello 2011 5/24 9/24 100.0 % 0.44 [ 0.12, 1.59 ] Total (95% CI) 24 24 100.0 % 0.44 [ 0.12, 1.59 ] Total events: 5 (Oral), 9 (Intravenous) Heterogeneity: not applicable Test for overall effect: Z = 1.26 (P = 0.21) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours intravenous Analysis 24.1.

Comparison 24 Proportion with pirosis, Outcome 1 Proportion with pirosis. Review: Oral versus intravenous steroids for treatment of relapses in multiple sclerosis Comparison: 24 Proportion with pirosis Outcome: 1 Proportion with pirosis Study or subgroup Oral Intravenous Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Martinelli 2008 6/20 5/20 52.2 % 1.29 [ 0.32, 5.17 ] Ramo-Tello 2011 4/25 5/24 47.8 % 0.72 [ 0.17, 3.10 ] Total (95% CI) 45 44 100.0 % 0.98 [ 0.36, 2.67 ] Total events: 10 (Oral), 10 (Intravenous) Heterogeneity: Tau2 = 0.0; Chi2 = 0.31, df = 1 (P = 0.58); I2 =0.0% Test for overall effect: Z = 0.05 (P = 0.96) Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours oral Favours iv 60 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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A D D I T I O N A L T A B L E S Table 1. Results of Search Strategies for Eligible Trials Publication MEDLINE (1950-Jul 08) EMBASE (1980-Jul 08) CENTRAL (Jul 08) Abstracts Citations Found 243 305 82 6 Abstracts Considered for Eligibility 12 10 16 4 Included Studies 2 2 3 1 Table 2. Adverse Event Outcomes Outcome Patients with Outcome Oral Group Patietns with Outcome IV Group Odds Ratio in Favour of Outcome in Oral Group (95% CI) Statistically Significant? (Y/N) hypertension 2/20 1/20 2.11 (0.18, 25.35) N rash 7/45 9/44 0.72 (0.23, 26) N hypertrichosis 1/20 2/20 0.47 (0.04, 5.69) N anxiety 14/45 14/44 0.95 (0.37, 2.44) N insomnia 28/45 20/44 2.63 (0.63, 11.01) N dysgeusia 26/45 15/44 4.30 (1.36, 13.63) Y hiccups 1/20 0/20 3.15 (0.12, 82.16) N hyperglycemia 0/20 1/20 0.32 (0.01, 8.26) N headache 18/24 13/24 2.54 (0.75, 8.63) N mood disturbance 13/24 7/24 2.87 (0.87, 9.45) N hot flashes 14/24 11/24 1.65 (0.53, 5.18) N edema 5/24 9/24 0.44 (0.12, 1.59) N pirosis 10/24 10/24 0.98 90.36, 2.67) N 61 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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A P P E N D I C E S Appendix 1. Keywords {acth} OR {adrenal cortex hormone\*} OR {corticosteroids} OR {glucocorticoids} OR {methylprednisolone} OR {prednisolone} OR {prednisone} OR {steroid\*} AND {oral} OR {peroral} OR {oral administration} OR {intravenous} W H A T ’ S N E W Last assessed as up-to-date: 13 June 2012. Date Event Description 13 June 2012 New citation required but conclusions have not changed One additional trial added in keeping with conclusions from original review 3 January 2012 New search has been performed New search run: one trial added. H I S T O R Y Protocol first published: Issue 1, 2008 Review first published: Issue 3, 2009 C O N T R I B U T I O N S O F A U T H O R S Dr.

Burton selected trials, assessed trial quality, determined inclusion and exclusion criteria, extracted and analyzed data and was the primary author of the review.

Dr. O’Connor independently reviewed abstracts for trial selection and quality, participated in data extraction and analysis and helped edit the review. Dr. Hohol independently reviewed abstracts for trial selection and quality and will helped edit the review. Dr. Beyene provided assistance and guidance in the statistical analysis of the data. D E C L A R A T I O N S O F I N T E R E S T The authors have no conflict of interest to disclose. 62 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

S O U R C E S O F S U P P O R T Internal sources • Department of Health Policy, Management and Evaluation, Canada. • Division of Neurology, St. Michael’s Hospital, Canada. External sources • No sources of support supplied I N D E X T E R M S Medical Subject Headings (MeSH) Administration, Oral; Anti-Inflammatory Agents [administration & dosage]; Glucocorticoids [∗administration & dosage]; Injections, Intravenous; Methylprednisolone [administration & dosage]; Multiple Sclerosis, Relapsing-Remitting [∗drug therapy]; Prednisone [administration & dosage]; Randomized Controlled Trials as Topic; Recurrence MeSH check words Humans 63 Oral versus intravenous steroids for treatment of relapses in multiple sclerosis (Review) Copyright © 2012 The Cochrane Collaboration.

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