Corticosteroids for the long-term treatment in multiple sclerosis

Corticosteroids for the long-term treatment in multiple

sclerosis (Review)

Ciccone A, Beretta S, Brusaferri F, Galea I, Protti A, Spreaﬁco C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2008, Issue 1

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Corticosteroids for the long-term treatment in multiple sclerosis (Review)

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Corticosteroids versus placebo or open control, Outcome 1 Disability progression at end of

follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Analysis 1.2. Comparison 1 Corticosteroids versus placebo or open control, Outcome 2 Disability progression at end of

follow-up: sensitivity analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Analysis 1.3. Comparison 1 Corticosteroids versus placebo or open control, Outcome 3 Disability progression at year 1. 18

Analysis 1.4. Comparison 1 Corticosteroids versus placebo or open control, Outcome 4 Disability progression at year 1:

sensitivity analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Analysis 1.5. Comparison 1 Corticosteroids versus placebo or open control, Outcome 5 Disability progression at year 2. 19

Analysis 1.6. Comparison 1 Corticosteroids versus placebo or open control, Outcome 6 Disability progression at year 2:

sensitivity analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Analysis 1.7. Comparison 1 Corticosteroids versus placebo or open control, Outcome 7 New exacerbations at end of

follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Analysis 1.8. Comparison 1 Corticosteroids versus placebo or open control, Outcome 8 New exacerbations at year 1. 20

Analysis 1.9. Comparison 1 Corticosteroids versus placebo or open control, Outcome 9 New exacerbations at year 2. 21

21ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23WHAT’S N EW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iCorticosteroids for the long-term treatment in multiple sclerosis (Review)

[Intervention Review]

Corticosteroids for the long-term treatment in multiple

sclerosis

Alfonso Ciccone

, Sandro Beretta

, Fabio Brusaferri

, Ian Galea

, Alessandra Protti

, Chiara Spreaﬁco

Department of Neurology, Azienda Ospe dale Niguarda Ca’ Granda, Milano, Italy.

Neurology, A.O. Ospedale Civile di Vimercate

e Desio, Vimercate, Italy.

U.O. Neurology, Ospedale Maggiore di Crema, Crema, Italy.

Department of Neurology, Wessex Neuro-

sciences Centre, Southampton, UK

Contact address: Alfonso Ciccone, Department of Neurology, Azienda Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3,

Milano, 20162, Italy.

alfonso.ciccone@ospedaleniguarda.it.

Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.

Review content assessed as up -to-date: 2 August 2007.

Citation: Ciccone A, Beretta S, Brusaferri F, Galea I, Protti A, Spreaﬁco C. Corticosteroids for the long-term treatment in multiple

sclerosis. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006264. DOI: 10.1002/14651858.CD006264.pub2.

A B S T R A C T

Background

Short term high dose corticosteroid treatment improves symptoms and short term disability after an acute exacerbation of multiple

sclerosis (MS) but it is unknown whether its long-term use can reduce the accumulation of disability.

Objectives

To determine the efﬁcacy and safety of long-term corticosteroid use in MS.

Search methods

We searched The Cochrane MS Group Trials Register (February 2007),the Cochrane Central Register of Controlled Trials (The

Cochrane Library 2007, Issue 1), MEDLINE (1966 to February 2007) and EMBASE (1980 to February 2007). In an effort to identify

further published, unpublished and ongoing trials we searched reference lists and contacted trial authors and one pharmaceutical

company.

Selection criteria

We considered controlled, randomised trials (RCTs), with or without blinding, of long term treatment (i.e. longer than 6 months) of

any type of corticosteroid in MS, irrespective of disease course.

Data coll ection and analysis

Reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information.

Main results

Three trials, all classiﬁed at high risk of bias, contributed to this review (Miller 1961; BPSM 1995; Zivadinov 2001) resulting in a

total of 183 participants (91 treated). Corticosteroid therapy did not reduce the risk of being worse at the end of follow-up (odds ratio

[OR] 0.51, 95% conﬁdence interval [CI] 0.26 to 1.02) but there was a substantial heterogeneity between studies (I

: 78.4%). I. v.

periodic high dose methylprednisolone (MP) was associated with a signiﬁcant reduction in the risk of disability progression at 5 years

in relapsing-remitting (RR) MS (OR 0.26, 95% CI 0.10 to 0.66), while oral continuous low dose prednisolone was not associated

1Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

with any risk reduction in disability progression at 18 months (OR 1.23, 95% CI 0.43 to 3.56). Risk of experiencing at least one

exacerbation at end of follow-up was not signiﬁcantly reduced with corticosteroid treatment (OR 0.36; 95% CI 0.10 to 1.25).

Only one study recorded adverse events: in one patient i. v. MP was discontinued after the fourth pulse when he developed acute

glomerulonephritis; a second patient was removed from the study after the ﬁf th i. v. MP pulse because of severe osteoporosis.

Authors’ conclusions

There is no enough evidence that long-term corticosteroid treatment delays progression of long term disability in patients with MS.

Since one study at high risk of bias showed that the administration of pulsed high dose i. v. MP is associated with a signiﬁcant reduction

in the risk of long term disability progression in patients with RR MS, an adequately powered, high quality RCT is needed to investigate

this ﬁnding.

P L A I N L A N G U A G E S U M M A R Y

The l ong-term use of anti-inﬂammatory corticosteroids for treating multiple sclerosis

Multiple sclerosis is an inﬂammatory disease affecting the brain and spinal cord. It results in episodes of neu rological deﬁcit which recover

(relapses) as well as accumulation of sustained disability with the passage of time. Corticosteroids are potent anti-inﬂammatory drugs.

It is postulated that long-term use of steroids may reduce the accumulation of disability. The reviewers found three studies addressing

this issue. A meta-analysis showed a trend towards a beneﬁcial effect of long-term corticosteroids on accumulation of disability; however

only two small studies contributed to this result. It was not possible to reliably comment on the effect of long-term corticosteroids on

the frequency of relapses. Side effects were poorly documented. Therefore rigorous randomised controlled trials of this treatment are

warranted.

B A C K G R O U N D

Multiple sclerosis (MS) is a chronic inﬂammatory demyelinating

disease of the central nervous system whose aetiology is still un-

known. Treatment is based on th e assumption that autoimmunity

plays a major r ole in the pathogenesis of disease (

Compston 2002;

Rizvi 2004a; Rizvi 2004b; Frohman 2005).

Corticosteroids inhibit lymphocyte proliferation and the synthe-

sis of most known proinﬂammatory cytokines and cell surface

molecules required for immune function with a mechanism that

involves a speciﬁc corticosteroid receptor (

Sloka 2005). Because of

their potent anti-inﬂammatory effects, corticosteroids have been

used to treat MS patients since the 1950s and today are considered

the standard treatment for acute exacerbations (

Compston 2002;

Rizvi 2004b; Frohman 2005). However, corticosteroids, being im-

munosuppressive drugs, might prevent or delay the occurrence of

future episodes of inﬂammatory demyelination (

Gold 2001).

A previous Cochrane review showed that a short term high dose

intravenous methylprednisolone (i. v. MP) course within 8 weeks

of acute exacerbation of MS, improved symptoms and short term

disability without signiﬁcant side effects but data were insufﬁcient

to estimate the effect on prevention of new exacerbations and

reduction of long term disability (

Filippini 2000). In the present

review we wanted to consider long term cor ticosteroid treatment

to speciﬁcall y prevent disease progression rather than to treat acute

exacerbations.

The idea that corticosteroids might prevent new exacerbations, re-

duce long term disability, and therefore modify the natural history

of MS, comes from several observations:

• the initial results of the Optic Neuritis Treatment Tr ial

suggested that treatment of a ﬁrst episode of optic neuritis with a

single course of i. v. MP followed by a tapering course of oral

prednisone, reduced the 2 year rate of development of clinically

deﬁnite MS (Beck 1993), although this e ffect was lost on further

follow-up extending to 4 years (Beck 1995);

• a phase II randomised controlled trial (RCT) in relapsing-

remitting (RR) MS comparing th e efﬁcacy of repeated pulsed i.

v. MP with i. v. MP at the same dosage regimen but administered

only for relapses, showed that pulse d i. v. MP slowed the

development of destructive lesions (T1 black holes), the rate of

whole-brain atrophy progression and the development of

sustained physical disability (

Zivadinov 2001);

2Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

• another phase II RCT of bimonthly i. v. MP pulses in

patients with secondary progressive (SP) MS showed a beneﬁcial

effect on time to onset of sustained progression of disability with

the high-dose regimen (

Goodkin 1998a);

• one non randomised trial with historical controls suggested

that patients with MS treated with high dose i. v. corticosteroids

during six months post-partum might reduce the childbirth-

associated risk of acute exacerbation (de Seze 2004);

• some studies indicated that pulsed i. v. MP produced a

rapid and dose dependent reduction in gadolinium e nhancement

on cerebral MRI that lasted for up to 6 months ( Gasperini

1997; Goodkin 1998b; Smith 1993; Barkhof 1994).

In a systematic review (

Brusaferri 2000) that included around

500 randomised patients comparing the effects of adrenocorti-

cotrophic hormone (ACTH), prednisolone or MP (with or with-

out azathioprine) versus placebo, no signiﬁcant effect on long-

term disability and relapse prevention was noted. However this

meta-analysis included studies in which these agents were given

for as little as 5-30 days. The review also reported the occurrence

of both minor and major side effects, the latter including severe

Cushing’s syndrome, hypertension, herpes simplex, herpes zoster,

severe ankle oedema, femoral fracture and gastrointestinal bleed-

ing, but these occurred with ACTH or an azathioprine/methyl-

prednisolone combination (

Brusaferri 2000).

Pulsed regimens of administration have renewed interest in corti-

costeroids as they are reported to be well-tolerated and safe, with

only minor and dose-related side effects, such as insomnia, tran-

sient mood disorders, acneiform-rash, heartburn, headache and

myalgias (

Pozzilli 2004). The rationale for repeated pulsed admin-

istration is based on the hypothesis that these drugs may have a

long-lasting immunosuppressive eff ect, as indicated by the above

mentioned studies, and that MS may be a restless, progressive dis-

ease even when, as in the RR form, the clinical course between

two exacerbations is stable (

Stone 1995).

Thus, a systematic review of RCT to gather all data available to

date on long term use of corticosteroids appeared worthwhile.

O B J E C T I V E S

The objective of this review was to determine whether long term

treatment of MS patients with corticosteroids:

1) prevents or signiﬁcantly delays disability progression at long

term follow-up;

2) reduces the risk of exacerbations, increasing the proportion of

relapse-free patients during follow-up;

3) is well tolerated and safe.

We selected progression of disease rather than the occurrence of

exacerbations as the primary outcome measure, both because the

frequency of exacerbations does not necessarily correlate with clin-

ical evidence of disease progression (

Confavreux 2000), a more

meaningful parameter than the occurrence of symptoms and signs

that can remit, and because we also wanted to consider progressive

forms of the disease.

We also wanted to evaluate the effect of different doses, drugs,

routes of administration, regimens (i.e. pulsed or continuous),

length of treatment and whether the effect of treatment was dif-

ferent according to types of disease (relapsing/remitting, relaps-

ing/progressive [RP], secondary progressive or primary progressive

[PP]).

M E T H O D S

Criteria for considering studies for this review

Types of studies

We planned to consider all apparently unconfounded RCTs, with

or without blinding, of l ong ter m treatment with corticosteroids

in MS.

Types of participants

Patients with deﬁnite MS according to clinical and paraclinical

diagnostic criteria (

Poser 1983; McDonald 2001; Polman 2005)

irrespective of their disease course (RR, RP, SP or PP). Studies

describing only clinical criteria were accepted as well (

McDonald

1977

Types of interventions

Active treatment: long term courses (i.e. longer than 6 months) of

any type of corticosteroid, continuous or intermittent, provided

that they were not started for relapses (i.e. started more than 2

months after a relapse), whatever the administration route and

dosage.

Control: placebo or no treatment. Short courses (i.e. maximum

21 days of duration) of corticosteroids were permitted, provided

they were administered for relapses.

Types of outcome measures

Primary outcomes

Efﬁcacy

3Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

We studied the following outcome measures in either treatment

group at 1 and 2 y ears and at the end of the schedule d follow-up

period:

Primary outcome

1. Patients who progressed. Whenever unspeciﬁed, progression

was deﬁned as a persistent worsening of at least one point in EDSS

(

Kurtzke 1983), recorded whilst not in relapse. However, other

deﬁnitions of progression were accepted, including a persistent

half-point increase starting from EDSS score 5.5, as is often re-

ported in the literature.

Safety

Safety outcome was assessed among primary endpoints by unique

measures incorporating all events occurring throughout the trials:

1. Number of patients with severe side effects. If not other wise

speciﬁed, side effects were deﬁned as severe when leading to one of

the following: death, hospitalisation, treatment discontinuation.

2. Extraction of any available information about safety in both

corticosteroid and control groups.

Secondary outcomes

2. Patients experiencing at least one exacerbation, which was de-

ﬁned as the acute or subacute appearance/reappearance of neuro-

logical signs and symptoms for at least 24 hours, in the absence of

fever or infection.

3. Relapse free survival, if available.

Search methods for identiﬁcation of studies

One reviewer (FB) provided references pertinent to this review

already retrieved in the course of two previous systematic reviews

on corticosteroids for multiple sclerosis which he had co-authored

(

Brusaferri 2000; Filippini 2000). The same search strategy was

used in this review to update searches.

Electronic searches

The search strategy we used was drawn from the one developed

by the Multiple Sclerosis Group.

Relevant trials were identiﬁed searching the following sources:

1. The Cochrane MS Group Trials Register (February 2007)

2. The Cochrane Central Register of Controlled Trials (The

Cochrane Library 2007, Issue 1)(

Appendix 1)

3. MEDLINE (January 1998 - February 2007)(

Appendix 2)

4. EMBASE (1998 - February 2007)(

Appendix 3)

Papers inany language were accepted providedthey met the criteria

speciﬁed above.

Searching other resources

4. Reference lists of studies on corticosteroid treatment for MS

5. Abstracts of neurological and multiple sclerosis congresses and

symposia, conference proceedings, dissertations and other forms

of reports where trials relevant to the review are likely to have been

published

6. We searched for unpublished studies by contacting researchers

who were known to be involved in this ﬁeld

7. We contacted Pﬁzer Inc, who had acquired Upjohn, a company

which was known to have an interest in the use of steroids in MS,

in order to identify any unpublished data.

Data c ollection and analysis

Selection of studies

The contact reviewer (AC) divided the search results between co-

reviewers (SB, FB, IG, CS and AP) who decided se parately which

articles to retrieve. Abstracts of references with titles of interest

were examined to determine relevance. When the abstract sug-

gested relevance, or relevance was unclear from the abstract, or

where no abstract was available, a copy of the article was obtained.

Copies of articles identiﬁed in reference lists of papers related to the

use of corticosteroid treatment in MS were also obtained. Trained

reviewers (AC and FB) veriﬁed that the papers thus selected ad-

hered to the inclusion criteria. AC and FB were not blinded to the

names of the authors, their institutions, the journal, or the journal

publisher. Disagreements were resolved by discussion between the

two reviewers.

All studies meeting the inclusion criteria were summarized in the

table Characteristics of Included Studies.

Assessment of methodological quality

Each reviewer (AC, SB, FB, IG, AP and CS) separately extracted

information, for each included trial, regarding the method of ran-

domisation, blinding of outcome evaluators, and whether all the

randomised patients were accounted for in the analysis. One re-

viewer (AC) contacted the authors of the trials if the above infor-

mation was not available in the published reports. In the case of an

unpublished study (

BPSM 1995) this information was extracted

from the protocol approved by local Ethics Committee in 1995.

Since two reviewers (AC and SB) had a leading role in such study,

they did not participate to the assessment of methodological qual-

ity. Reviewers assessed the quality of the trials independently and

were asked to ﬁll in a form shown in Table 1 that was then sent to

the contact reviewer (AC). Concealment of allocation (telephon-

ing to a central ofﬁce, ﬁrst entering the data into a computer,

the pharmacy, using identical numbered containers, or sequential,

sealed, opaque envelopes), blinding in outcome evaluation and

intention-to-treat analysis were evaluated and graded as present,

absent or unclear. The included studies were categorised into one

of three quality categories (protection against bias), based on those

described in the Cochrane Handbook for Systematic Reviews of

Interventions 4.2.6 (section 6.7.1): A (low risk of bias, all of the

criteria present), B (moderate risk of bias, one or more criteria un-

clear), C (high risk of bias, one or more criteria absent) (

Higgins

4Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

2005). We planned to summarise the interobserver agreement in

the overall quality score using the weighted kappa statistic.

Data extraction

All the reviewers (AC, SB, FB, IG, AP and CS) independently

extracted data for outcome and safety assessments according to

measures deﬁned in the ’Types of outcome measures’ section, ﬁll-

ing a form shown in

Table 2. Forms were then sent to the contact

reviewer (AC) who summarized the data. The same forms were

used to ask original authors for unpublished data.

We planned to use intention-to-treat analysis, extracting the num-

ber of patients originally allocated to each treatment group irre-

spective of compliance. When numbers extracted by two or more

reviewers varied, differences were resolved by discussion.

Data analysis

The efﬁcacy analyses were based on th e results of the individual tri-

als for disability at one year or more after treatment initiation and

the safety analyses on the results for severe side effects. The anal-

yses on secondary outcomes and on minor side effects were used

to support the data on primary outcomes. A weighted estimate of

the treatment effects across trials (odds ratio) was calculated using

a ﬁxed effect model. For interpreting the results, 95% conﬁdence

intervals were used. Heterogeneity across studies was quantiﬁed

using I

, i.e. by describing the percentage of the variability in the

effect estimates that is due to heterogeneity rather than sampling

error. A value greater than 50% was considered substantial he tero-

geneity. (Higgins 2002)

Sensitivity analyses

If patients were excluded or lost to follow up after randomisation,

further information was sought by correspondence with the tr ial-

ists. If the data about these patients remained unavailable, a worst-

case scenario analysis for the outcome of “disability progression”

was undertaken to ensure signiﬁcance of the results. In this anal-

ysis, it was assumed that those patients who were lost to follow

up in the treatment group had th e worst outcome while those

patients who were lost to follow up in the control group had the

best outcome. We planned to make a deﬁnite conclusion about

the treatment e ffectiveness if the effects of primary and worst-case

meta-analyses were in the same direction and magnitude.

Subgroup analyses

If substantial heterogeneity was found on efﬁcacy analysis, we

planned to explore this heterogeneity using the followingsubgroup

analyses:

(1) comparison of trials with quality A with trials with quality B

or C;

(2) comparison of the efﬁcacy of treatment in patients treated

within one year versus those treated after one year of MS onset;

(3) comparison of the effect of different doses, drugs, routes of ad-

ministration, regimens(i.e. intermittent or continuous) and length

of treatment;

(4) comparison of the efﬁcacy of treatment in RR, RP, SP or PP

patients

We planned to use the overlap of the conﬁdence intervals of the

summary estimates in the groups of comparison (lack of overlap

between conﬁdence intervals indicating statistical signiﬁcance).

R E S U L T S

Description of studies

We identiﬁed 2270 articles (previous systematic reviews 111;

CENTRAL 170; MEDLINE 1741; EMBASE 242 ; hand search-

ing 4; unpublished 2; drug manufacturers zero).

Ten possible RCTs involving long-term administration of steroids

in MS were selected by reviewers on the basis of inclusion criteria

after reading the abstracts. We excluded seven studies after reading

the full published papers: one study was a dose-comparison trial

of i. v. MP without a control group (

Goodkin 1998a), two studies

used MRI parameters as outcome measures (

Pato-Pato 2003; Then

Bergh 2006), one study was a case series with a historical control

group (

de Seze 2004), two studies were uncontrolled case series

(

Beretta 1997; Pirko 2004); one study was a comparison with

vitamin B12 (

Tourtellotte 1965). (See table of excluded studies).

In total three trials contributed to this review:

Miller 1961, BPSM

1995

and Zivadinov 2001.

Data availability

One study was unpublished (

BPSM 1995) because it was prema-

turely interrupted for organisational problems and lack of fund-

ing. This study’s data were made available by one of the reviewers

(SB) and checked by a second reviewer (CS). The other two RCTs

were published as full papers. However, since the exact number of

patients with disability worsening and experiencing exacerbations

during follow-up could not be extracted from the

Zivadinov 2001

paper, this information was obtained by contacting the authors.

Type of interventions and patients

Both the

BPSM 1995 and Zivadinov 2001 studies used pulsed

high dose i. v. MP in RR MS whilst the study by

Miller 1961 used

continuous oral prednisolone in patients w ith “slowly progressive”,

“ﬂuctuant” and “rapidly progressive” MS (diagnostic criteria were

not given). Patients in the control group were all owed to be treated

with corticosteroids in case of exacerbation in two studies (

BPSM

1995

; Zivadinov 2001) but in one of them (BPSM) the occurrence

of a relapse automatically ended the study for individual patients

(see “Outcomes deﬁnition” in this paragraph for further details).

Treatment duration was 18 months in the

Miller 1961 study, 5

years in the

Zivadinov 2001 study and two years or until the ﬁrst

relapse in the

BPSM 1995 (see table of included studies).

Baseline characteristics

Equivalence between the treatment and control group in the base-

line participants’ characteristics was present in the three selected

RCTs.

5Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

Outcomes deﬁnition

- The

Miller 1961study used different clinical outcome measures

(see table of characteristics of included studies). To extract data

on progression of disability we used the reported number of pa-

tients who “deteriorated” at the “patients’ own assessment” at 18

month (that outcome was divided in “improved”, “deteriorated”

and “remained unchanged” in the paper), making due allowance

for the potential biases involved in such deﬁnition. “Acute exac-

erbation” was not deﬁned and data was reported for individual

relapses rathe r than for the number of patients experiencing at

least one exacerbation. Since we could not get further clariﬁcation

about acute relapses in the Miller study we could not consider

such study for analysis on prevention of new exacerbations.

- Inthe

BPSM 1995 study, progression of disability was deﬁned but

patients were not followed-up after the ﬁrst exacerbation, contrary

to what was pl anned. Since patients not experiencing a relapse in

the two years of the study were just 2, we did not have any data on

long-term disability progre ssion for the majority of the patients.

- The Zivadinov 2001 study deﬁned progression of disability as

at least a 1.0-point worsening from baseline for patients who en-

tered at or below an EDSS score of 5.0 or a 0.5-point worsening

from baseline for patients who entered at an EDSS score of 5.5.

Worsening was required to persist for at least two consecutive 4-

month visits during the ﬁrst 3 years of the study or at le ast two

consecutive 6-month visits during the fourth and ﬁfth years of the

study. Relapses were deﬁned as the appearance or reappearance

of one or more symptoms, attributable to MS, accompanied by

objective deter ioration on neurologic examination, lasting at least

24 hours, in the absence of fever, preceded by neurologic stability

for at least 30 days and in the absence of steroid withdrawal within

60 days of the new event.

Risk of bias in included studies

Randomisation and concealment allocation

The method of randomisation was centralised, providing adequate

concealment of allocation in two trials (

BPSM 1995; Zivadinov

2001

): in the BPSM 1995 study randomisation and allocation

were generated by computer by personnel not involved in patients

management and in the

Zivadinov 2001 study this was done by

a statistician “who had no contact with the study subjects”. In

the

Miller 1961 the method of randomisation was classiﬁed as

“unclear” by al l the reviewers independently, since the method of

randomisation was not described.

Blinding

The

BPSM 1995 and Miller 1961studies were double blinded.

During the

Zivadinov 2001 study blindness to treatment of pa-

tients and clinical examiners was not warranted (although partici-

pants did not know the allocation group into which th ey will have

been allocated at the randomisation step); radiologists conducting

image analysis were blinded.

Intention-to-treat analysis, excluded and losses to follow-up

An intention-to-treat analysis was impossible for all the three tri-

als. In the

BPSM 1995 study th e intention to treat analysis was

planned but not performed and th ere were 10 patients (7 treated)

lost to follow-up (28% overall). Moreover, patients experiencing

an exacerbation were not followed up although a two year follow-

up was planned. In the Zivadinov 2001 and Miller 1961 tr ials a

total of 11 participants (7% overall) were excluded afte r randomi-

sation or lost to follow-up (see details in table of included studies).

No information was available on the outcome me asures in these

participants.

Overall assessment of validity

The three included RCTs were classiﬁed at high risk of bias (see

table of included studies).

The inter-observer agreement in the overall quality score was not

summarised with the kappa statistic since there was a 100% agree-

ment among the reviewers.

Effects of interventions

A total of 183 (91 treatment, 92 control) out of 210 randomised

participants were considered (27 patients assigned to calcium as-

pirin in the

Miller 1961study were excluded from the analysis).

PREVENTION OF DISABILITY WORSENING (PRIMARY

OUTCOME)

(1) at the end of follow up

Data from 2 trials (Miller 1961; Zivadinov 2001) with 136 par-

ticipants, 74% of participants included in the review) were avail-

able on this outcome. Corticosteroid therapy was associated with

a non signiﬁcant reduction in the risk of being worse at the end

of follow-up (odds ratio [OR] 0.51, 95% conﬁdence interval [CI]

0.26 to 1.02). There was substantial heterogeneity between the

two trials (I

: 78.4%).

(2) at the end of follow up: se nsitivity analysis

Since information on patients excluded and lost to follow-up was

unavailable, a worst case scenario was carried out as pre-speciﬁed.

Such analysis, performed by considering patients who were ran-

domised to treatment and then excluded as worst outcome events,

did not signiﬁcantly change the result (number of events in treated

= 30/72; number of events in controls = 37/75; OR 0.74, 95%

CI 0.39 to 1.41) and conﬁrmed the inconsistency across the two

studies (I

: 73.7%).

(3) at one year

Only data from the

Zivadinov 2001 study was available, on 81

patients. Corticosteroid therapy was associated with a non signif-

icant reduction in the risk of being worse at 1 year of follow-up

(OR 0.16, 95% CI 0.02 to 1.38).

(4) at one year: sensitivity analysis

Sensitivity analysis of the 88 patients originally randomised did

not change the result (OR 0.86, 95% CI 0.24 to 3.04).

(5) at two years

Only data from the

Zivadinov 2001 study was available, on 81

patients. Corticosteroid therapy was associated with a signiﬁcant

6Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

reduction in the risk of being worse at 2 years of follow-up (OR

0.09, 95% CI 0.02 to 0.42). In absolute terms this means that

330 patients for every 1000 treated (95% CI 170 to 490) avoided

disability progression after two years of treatment.

(6) at two year: sensitivity analysis

Treatment was still associated with a favourable outcome in the

worst case scenario (OR 0.29, 95% CI 0.10 to 0.85).

(7) subgroup analysis

Subgroup analysis was performed since there was substantial het-

erogeneity after efﬁcacy analysis on disability progression at the

end of follow-up. Such analysis should be regarded as a qualitative

rather than quantitative description, since the RCTs considered

were just two (

Miller 1961; Zivadinov 2001). Taking into account

the pre-speciﬁed issues for subgroup analyses, the two trials did not

differ for quality but the y did for type of drug (MP versus pred-

nisolone respectively), route of administration (i. v. versus oral),

regimen (intermittent versus continuous), length of treatment (5

years versus 1 year and a hal f ), disease course (RR versus variable

course), disability progression de ﬁnition (objective versus patients’

own assessment in the

Miller 1961study) and mean disease dura-

tion before entry into the study (6 years versus 12 years).

I. v. periodic h igh dose MP was associated with a signiﬁcant re-

duction in the risk of disability progression at 5 years in RR MS

(OR 0.26, 95% CI 0.10 to 0.66) (

Zivadinov 2001), while oral

continuous low dose prednisolone was not associated with any risk

reduction in disability progression at 18 months (OR 1.23, 95%

CI 0.43 to 3.56) (

Miller 1961).

In absolute terms, 320 patients for every 1000 treated with pul se d

high dose i. v. MP (95% CI 110 to 520) avoided long term dis-

ability progression according to the Zivadinov study.

PREVENTION OF NEW EXACERBATION (SECONDARY

OUTCOME)

(1) At the end of follow-up

Data from two trials (

BPSM 1995; Zivadinov 2001) with 107 par-

ticipants (59% of participants included in the review) was available

on this outcome. Risk of experiencing at least one exacerbation

was not signiﬁcantly reduced with corticosteroid treatment (OR

0.36; 95% CI 0.10 to 1.25). No substantial heterogeneity across

studies was observed (I

: 0%).

(2) At one year

Data was available from two trials (

BPSM 1995; Zivadinov 2001)

with 115 patients. Corticosteroid therapy did non change the risk

of new exacerbations (OR 1.17, 95% CI 0.57 to 2.43).

(3) At two years

Data was available from two trials (

BPSM 1995; Zivadinov 2001)

with 107 patients. Corticosteroid therapy did non change the risk

of new exacerbations (OR 1.48, 95% CI 0.61 to 3.59).

(4) Exacerbation-free time

No data was available from the 3 trials included in the review on

this outcome.

ADVERSE EVENTS

(1) Severe adverse events

In the

Miller 1961, study adverse e vents were poorly de scribed

and two patients allocated corticosteroids were withdrawn because

of hypertension. No other severe adverse effects were reported in

either treatment group.

In the Zivadinov 2001, study 2 patients dropped out in th e pulse d

i. v. MP arm: in one, i. v. MP was discontinued after the fourth

pulse when the patient developed acute glomerulonephritis; the

second patient was removed from the study after the ﬁfth i. v. MP

pulse because of severe osteoporosis. Twenty-ﬁve patients in the i.

v. MP arm and 18 patients in the control arm were followed up 21

months afte r the study with bone mineral densitometry: a further

patient in the pulsed i. v. MP arm and one in the control arm

developed osteoporosis (

Zorzon 2005). There were no fractures

throughout the study.

In the

BPSM 1995 study no severe adverse effects were reported

but 7 out of 19 patients (37%) in the pulsed i. v. MP arm versus

3 out of 17 in the control arm (18%) dropped out for unspeciﬁed

reasons.

(2) Minor adverse events

Almost al l patients treated with i. v. MP in the

Zivadinov 2001

study experienced “metallic taste” after the bolus. Insomnia, py-

rosis, anxiety, constipation, acneiform rash, and polyphagia were

frequently reported in both treated and control groups and did

not require treatment.

In the

Zivadinov 2001 study the following long te r m events that

did not require discontinuation of th e planned therapy were re-

ported without specifying the treatment group: osteoporosis (2

patients), arterial hypertension (1 patient), and recurrent herpetic

infections (1 patient).

In the BPSM 1995 study careful monitoring of minor adverse

events was also planned but not performed.

In the

Miller 1961 study minor adverse events were not reported.

D I S C U S S I O N

Progression of disability

A meta-analysis was not possible for this outcome at one or two

years since data was unavailable. Meta-analysis of two studies for

this outcome at the end of follow up showed a trend towards a

signiﬁcant effect in favour of steroids, but it is possible that the

substantial hete rogeneity between studies diluted the effect of one

of them. Indeed, on the basis of the

Zivadinov 2001 study, periodic

high dose i. v. MP signiﬁcantly prevents progression of long term

disability in patients with RRMS . To quantify the result in terms

of number needed to treat, 3 patients (95% CI 2 to 9) need to

be treated to avoid disability progression in one. This result seems

quite robust as the effects of primary and worst-case meta-analyses

are in the same direction and magnitude. The effect of i. v. MP

7Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

is evident from the second year of treatment and is maintained at

least until the ﬁfth year of treatment.

As opposed to pulse d high dose i. v. MP, continuous low dose

treatment with oral prednisolone did not show any effect neither

on disability progression nor on prevention of new exacerbations.

Different hypotheses could be formulated to explain the difference

in results between the Miller 1961 and Zivadinov 2001 studies:

(a) different drug type (i. v. methylprednisolone in the

Zivadinov

2001 study and oral prednisolone in the Miller 1961 study), (b)

the different length of treatment (5 years in the

Zivadinov 2001

study and 18 months in the Miller 1961 study), (c) different cu-

mulative dose of steroid (23.04g of i. v. methylprednisolone in the

Zivadinov 2001 study and oral prednisolone equivalent to 5.28g

oral methylprednisolone in the

Miller 1961 study, over the ﬁrst

18 months of both studies), (d) different regimens (pulsed in the

Zivadinov 2001 study and continuous in the Miller 1961 study,

(e) the different type of disease (RR course in the

Zivadinov 2001

study and various courses in the Miller 1961 study), (f) difference

in mean disease duration before entry into the study (6 y ears in

the

Zivadinov 2001 study and 12 years in the Miller 1961 study),

(g) different ethnic background (Italian in the Zivadinov 2001

study and English in the Miller 1961 study), (h) a β type error

(i.e. incapability of identifying a difference that exists) due to l ow

sample size in the

Miller 1961 study, (i) lack of blinding in the

Zivadinov 2001 study, (j) different deﬁnition of disability pro-

gression (objective assessment in the

Zivadinov 2001 study and

patients’ own assessment in Miller study), (k) a combination of a,

b, c, d, e, f, g, h, i and/or j. A dose-dependent effect might well be

operative since in a trial comparing 2 doses of i. v. MP pulses in

patients with secondary progressive MS, a relative beneﬁcial effect

on time to onset of sustained progression of disability was observed

with the high-dose regimen compared with the low dose (

Goodkin

1998a). Although in our analysis the beneﬁcial effect of i. v. MP

was ﬁrst detected after two years of treatment, in the

Zivadinov

2001

study the beneﬁcial effect of pulsed i. v. MP became evident

after 8 months of treatment, as shown by the time survival cur ve to

onset of sustained EDSS score worsening; th erefore an effect after

8 months of therapy should have also been visible in the

Miller

1961 study, if everything else was equal.

The use of corticosteroid therapy in the control group in the

Zivadinov 2001study could be another cause of heter ogeneity.

However, this should have hampered rather than favoured the ef-

fect of corticosteroid in the active treatment group in the

Zivadinov

2001

study.

Prevention of acute exacerbation

The secondary objective of this review was to evaluate the effect

of treatment on prevention of acute exacerbations. Although one

more RCT could be included (

BPSM 1995) for this analysis, many

patients were lost to follow up in this study. I. v. MP did not protect

against the occurrence of relapses during the period studied.

[the available evidence was extremely weak since many patients

were lost to follow up in this study. Data was not sufﬁcient to

determine the effect of cor ticosteroid treatment on prevention of

exacerbations; alternatively it could well be that long-term corti-

costeroids do not prevent e xacerbations.]

Adverse events

Only one study (

Zivadinov 2001) included in this review formally

recorded adverse events following corticosteroid treatment but the

list may be incomplete; consequently the lack of evidence cannot

be construed as paucity of adverse events.

Oral corticosteroids cannot be administered continuously at cu-

mulative doses equivalent to pulsed regimens because of side ef-

fects mostly osteoporosis (

Zorzon 2005). This, together with the

negative results from the

Miller 1961 study, shift the risk-to-bene-

ﬁt ratio against continuous oral corticosteroid therapy. Compared

to pulsed i. v. MP, there is therefore less evidence favouring further

study in RCTs. As regards periodic high dose i. v. MP, although it

emerged as effective f r om the present review, routine use in clinical

practice is not yet indicated because the evidence comes from a

single small study that was classiﬁed at high risk of bias and was not

open to intention-to-treat analysis. Therefore the evidence cannot

be considered conclusive but rather suggestive of possible efﬁcacy.

Larger RCTs of pulsed i. v. MP are warranted. Due to the reported

lack of difference between oral and i. v. routes of equivalent high

doses of methylprednisolone (

Alam 1993), RCTs of pulsed oral

high dose MP are also warranted.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There is no enough evidence to justify the routine use of long

term corticosteroids treatment for MS patients. This is because

only three trials, all classiﬁed at high risk of bias, contributed to

this review.

Implications for research

This review is suggestive of a favourable effect of long term use

of pulsed high dose i. v. MP that could modify the disease course

in RR MS patients. Since it is possible that such an effect is sta-

tistically and clinically signiﬁcant without severe adverse effects

as compared to other treatments like interferon beta (

Rice 2001)

or mitoxantrone (

Martinelli 2005), a large and high quality ran-

domised controlled trial is urgently needed to test the efﬁcacy of

pulsed high dose i. v. MP.

No marketing interest may economically sustain the execution of

RCTs on corticosteroids today. Moreover the planning of placebo-

controlled RCTs may be considered unethical when drugs for the

treatment of MS are available. Therefore, the comparison of pulsed

8Corticosteroids for t he long-term treatment in multiple sclerosis (Review)

high dose i. v. MP plus a disease modifying drug versus a disease

modifying dr ug alone could be an option.

A C K N O W L E D G E M E N T S

The authors wish to thank Mrs Vanna Pistotti (Italian Cochrane

Centre) and Mrs Liliana Coco (Cochrane Mul tiple Sclerosis

Group) for assistance in developing and running the search strat-

egy.

R E F E R E N C E S

References t o studies included in th is review

BPSM 1995 {published data only}

∗

Ciccone A, Beretta S, Pellegrini G, and the BPSM Group.

Periodic intravenous methylprednisolone megadoses

to prevent relapses in multiple sclerosis [Boli steroidei

Preventivi per la Sclerosi Multipla (BPSM)]. Protocol

approved by local Ethics Committee (Ospedale “Valduce”,

Como, Italy) 1995.

Miller 1961 {published data only}

∗

Miller H, Newell DJ, Ridley A. Multiple sclerosis. Trials

of maintenance treatment with prednisolone and soluble

aspirin. Lancet 1961;1:127–9.

Zivadinov 2001 {published data only}

Zivadinov R. Steroids and brain atrophy in multiple

sclerosis. Journal of Neurological Sciences 2005;233: 73–81.

∗

Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar

M, et al. Effects of IV methylprednisolone on brain atrophy

in relapsing-remitting MS. Neurology 2001;57(7):1239–47.

Zorzon M, Zivadinov R, Locatelli L, Giuntini D, Toncic

M, Bosco A, et al. Long-term effects of intravenous high

dose methylprednisolone pulses on bone mineral density

in patients with multiple sclerosis. European Journal of

Neurology 2005;12:550–6.

References t o studies excluded from this review

Beretta 1997 {published data only}

Beretta S, Battistel A, Checcarelli N, Garavaglia P,

Guidotti M, Manfredi L, et al. Efﬁcacy of repeated

methylprednisolone megadoses in modifying the prognosis

of relapsing remitting multiple sclerosis. Journal of

Neurology. 1997; Vol. 244:S64.

Beretta S , Checcarelli N, Manfredi L, Adobbati L, Garavaglia

P, Guidotti M, et al. [Efﬁcacia del trattamento con

ripetute megadosi di metilprednisolone nella proﬁlassi delle

ricadute nella sclerosi multipla tipo relapsing–remitting].

XXXVII Congresso Nazionale della Società dei Neurologi

Neurochirurghi e Neuroradiologi Ospedalieri (S.N.O.).

Como, 1997:37–8.

Beretta S, Ciccone A, Manfredi L, Garavaglia P, Adobbati

L, Checcarelli N, et al. Prophylaxis of multiple sclerosis

recurrences using repeated high dose pulses of i.v. steroids.

Journal of Neurology. 1996; Vol. 243 Suppl 2:81.

∗

Beretta S, Ciccone A, Pellegrini G. Efﬁcacy of

methylprednisolone megadoses in preventing exacerbations

of relapsing remitting multiple sclerosis. Rivista di

Neurobiologia 1997;43:389–94.

de Seze 2004 {published data only}

de Seze J, Chapelotte M, Delalande S , Ferriby D,

Stojkovic T, Vermersch P. Intravenous corticosteroids in the

postpartum period for reduction of acute exacerbations in

multiple sclerosis. Multiple Sclerosis 2004;10(5):596–7.

Goodkin 1998a {published data only}

Goodkin DE, Kinkel RP, Weinstock-Guttman B,

VanderBrug-Medendorp S, Secic M, Gogol D, et al. A

phase II study of i.v. methylprednisolone in secondary-

progressive multiple sclerosis. Neurology 1998;51(1):

239–45.

Pato-Pato 2003 {published data only}

Pa to-Pato A, Prieto JM, Lema M, Da pena-Bolaño D,

Abella-Corral J, Pumar JM. Cerebral atrophy in multiple

sclerosis patients treated periodically with boluses of

methylprednisolone. Revista de Neurologia 2003;37(6):

501–6.

Piazza 2000 {unpublished data only}

∗

Piazza G. Italian multicentre randomised controlled

prospective study with parallel groups to compare the

efﬁcacy of the treatment with Interferon beta 1b to

interferon beta 1b plus methylprednisolone in patients with

secondary progressive multiple sclerosis. [Studio prospettico

controllato, randomizzato, multicentrico italiano a gruppi

paralleli per c omparare l’efﬁcacia del trattamento di

Interferon beta 1b rispetto all’associazione tra interferon

beta 1b+metilprednisolone in pazienti con sclerosi multipla

secondariamente progressiva]. Protocol approved by Local

Ethics Committees 04/04/2000.

Pirko 2004 {published data only}

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methylprednisolone therapy in progressive multiple

sclerosis: need for a controlled trial. Archives of Neurology

2004;61(7):1148–9.

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Then Bergh 2006 {published data only}

Then Bergh F, Kümpfel T, Schumann E, Held U,

Schwan M, Blazevic M, et al. Monthly intravenous

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Tour tellotte 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.

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∗

Indicates the major publication for the study

11Corticosteroids for the long-term treatment in multiple sclerosis (Review)

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]

BPSM 1995

Methods C = randomisation by computer.

Double-blind.

Losses to follow-up: 10 (7 assigned MP).

Participants Single centre in Italy;

36 patients with RR clinically deﬁnite MS (Poser 1983 criteria); no relapse in the previous 45 days; EDSS

< 5.5.

21 (58%) female

Mean age 35yr.

Interventions Rx: i.v. MP 2 g in saline solution for 12 hours, every 45-60 days, for two years or until relapse

Control: i.v. saline solution at the same schedule

Outcomes Probability of remaining relapse free (primary end point)

Disability reduction after two years

Safety

Notes Prematurely interrupted at 36 out of 72 planned patients for organisational reasons and lack of funding.

Quality C: high risk of bias (concealment of randomisation: present, blinding in outcome evaluation:

present; intention-to-treat analysis: absent [pl anned but not performed])

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment? Low risk A - Adequate

Miller 1961

Methods C = not described.

Double-blind.

Losses to follow-up: 7 (3 assigned Prednisolone, 1 on “dummy” tablets and 3 on calcium aspirin)

Participants Single center in UK;

86 patients with “slowly progressive”, “ﬂuctuant” and “rapidly progressive” MS (diagnostic criteria not

described).

47 (55%) female

Mean age 33yr.

Interventions Rx: 29 patients on oral prednisolone tablets 15 mg/day for 8 months then 10 mg/day for 10 months

Rx: 27 patients on 9 calcium aspirin tablets (54 g)/day

Control: 30 patients on a correspondent number of “dummy” tablets

12Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Miller 1961 (Continued)

Outcomes Average change in Alexander score

Functional grades at 6 and 18 months

Acute exacerbations

Patients’ own assessment at 18 months

Notes Quality C: high risk of bias (concealment of randomisation: unclear, blinding in outcome evaluation:

present; intention-to-treat analysis: absent)

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment? Unclear risk B - Unclear

Zivadinov 2001

Methods C = treatment assignment generated by statistician who had no contact with study subjects.

Single-blind.

Losses to follow up: 7 (4 assigned MP).

No intention-to-treat analysis.

Participants Single center in Italy;

88 patients with RR clinically deﬁnite MS (Poser 1983 criteria); without exacerbation or progression and

steroid treatment in the previous 3 months; EDSS < or = 5.5.

60 (68%) female

Mean age 32yr.

Interventions Rx: i.v. MP 1 g/day for 5 days with an oral prednisone taper (day 6 and 7 50 mg, day 8 and 9 25 mg),

every 4 months for 3 years, and every 6 months for the subse quent 2 years

Control: i.v. MP, same dose schedule, only for relapses

Outcomes Primary outcome measure: MRI paremeters (T2 and T1 lesion volume and brain parenchymal volume

changes); secondary outcomes: disability progression and relapses

Notes Quality C: high risk of bias (concealment of randomisation: present, blinding in outcome evaluation:

absent (radiologists blinded but clinical examiners unblinded); intention-to-treat analysis: absent)

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment? Low risk A - Adequate

C: concealment of allocation

RR: relapsing remitting

MS: multiple sclerosis

13Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Rx: Treatment

i.v.: intravenous

MP: meth ylprednisolone

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Beretta 1997 Retrospective study on a series of cases

de Seze 2004 Not randomised (se r ies of patients in post-partum period; historical control group)

Goodkin 1998a No control group with placebo or no treatment (randomised controlled trial of two different dose of bimonthly

i. v. MP pulses)

Pato-Pato 2003 No control group (series of cases). No outcome measures useful for this meta-analysis

Piazza 2000 Uncompleted, confounding randomised trial comparing interferon beta 1b to interferon beta 1b plus MP

Pirko 2004 No control group (series of cases).

Then Bergh 2006 Not randomised single-cross-over study with no outcome measures useful for this meta-analysis

Tourtellotte 1965 Confounding randomised trial comparing oral MP with cyanocobalamin: 30 patients in cyanocobalamin group

had been treated with ACTH during the trial

i.v.: intravenous

MP: meth ylprednisolone

14Corticosteroids for the long-term treatment in multiple sclerosis (Review)

D A T A A N D A N A L Y S E S

Comparison 1. Cort icosteroids versus placebo or open control

Outcome or subgrou p title

No. of

studies

No. of

participants

Statistical method Effect size

1 Disability progression at end of

follow-up

2 136 Odds Ratio (M-H, Fixed, 95% CI) 0.51 [0.26, 1.02]

1.1 Intermittent corticosteroid

treatment

1 81 Odds Ratio (M-H, Fixed, 95% CI) 0.26 [0.10, 0.66]

1.2 Continuous corticosteroid

treatment

1 55 Odds Ratio (M-H, Fixed, 95% CI) 1.23 [0.43, 3.56]

2 Disability progression at end of

follow-up: sensitivity analysis

2 147 Odds Ratio (M-H, Fixed, 95% CI) 0.74 [0.39, 1.41]

2.1 Intermittent corticosteroid

treatment

1 88 Odds Ratio (M-H, Fixed, 95% CI) 0.42 [0.18, 1.00]

2.2 Continuous corticosteroid

treatment

1 59 Odds Ratio (M-H, Fixed, 95% CI) 1.61 [0.58, 4.50]

3 Disability progression at year 1 1 81 Odds Ratio (M-H, Fixed, 95% CI) 0.16 [0.02, 1.38]

4 Disability progression at year 1:

sensitivity analysis

1 88 Odds Ratio (M-H, Fixed, 95% CI) 0.86 [0.24, 3.04]

5 Disability progression at year 2 1 81 Odds Ratio (M-H, Fixed, 95% CI) 0.09 [0.02, 0.42]

6 Disability progression at year 2:

sensitivity analysis

1 88 Odds Ratio (M-H, Fixed, 95% CI) 0.29 [0.10, 0.85]

7 New exacerbations at end of

follow-up

2 107 Odds Ratio (M-H, Fixed, 95% CI) 0.36 [0.10, 1.25]

8 New exacerbations at year 1 2 115 Odds Ratio (M-H, Fixed, 95% CI) 1.17 [0.57, 2.43]

9 New exacerbations at year 2 2 107 Odds Ratio (M-H, Fixed, 95% CI) 1.48 [0.61, 3.59]

15Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Analysis 1.1. Comparison 1 C orticosteroids versus placebo or open control, Outcome 1 Disability

progression at end of follow-up.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 1 Disability progression at end of follow-up

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intermittent corticosteroid treatment

Zivadinov 2001 10/39 24/42

73.7 % 0.26 [ 0.10, 0.66 ]

Subtotal (95% CI) 39 42

73.7 % 0.26 [ 0.10, 0.66 ]

Total events: 10 (Treated), 24 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 2.81 (P = 0.0050)

2 Continuous corticosteroid treatment

Miller 1961 13/26 13/29

26.3 % 1.23 [ 0.43, 3.56 ]

Subtotal (95% CI) 26 29

26.3 % 1.23 [ 0.43, 3.56 ]

Total events: 13 (Treated), 13 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.38 (P = 0.70)

Total (95% CI) 65 71

100.0 % 0.51 [ 0.26, 1.02 ]

Total events: 23 (Treated), 37 (Control)

Heterogeneity: Chi

= 4.64, df = 1 (P = 0.03); I

=78%

Test for overall effect: Z = 1.92 (P = 0.055)

0.01 0.1 1 10 100

Favours treatment Favours control

16Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Analysis 1.2. Comparison 1 C orticosteroids versus placebo or open control, Outcome 2 Disability

progression at end of follow-up: sensitivity analysis.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 2 Disability progression at end of follow-up: sensitivity analysis

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Intermittent corticosteroid treatment

Zivadinov 2001 14/43 24/45

73.4 % 0.42 [ 0.18, 1.00 ]

Subtotal (95% CI) 43 45

73.4 % 0.42 [ 0.18, 1.00 ]

Total events: 14 (Treated), 24 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.95 (P = 0.051)

2 Continuous corticosteroid treatment

Miller 1961 16/29 13/30

26.6 % 1.61 [ 0.58, 4.50 ]

Subtotal (95% CI) 29 30

26.6 % 1.61 [ 0.58, 4.50 ]

Total events: 16 (Treated), 13 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.91 (P = 0.36)

Total (95% CI) 72 75

100.0 % 0.74 [ 0.39, 1.41 ]

Total events: 30 (Treated), 37 (Control)

Heterogeneity: Chi

= 3.80, df = 1 (P = 0.05); I

=74%

Test for overall effect: Z = 0.92 (P = 0.36)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

17Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Analysis 1.3. Comparison 1 C orticosteroids versus placebo or open control, Outcome 3 Disability

progression at year 1.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 3 Disability progression at year 1

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Zivadinov 2001 1/39 6/42 100.0 % 0.16 [ 0.02, 1.38 ]

Total (95% CI) 39 42

100.0 % 0.16 [ 0.02, 1.38 ]

Total events: 1 (Treated), 6 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.67 (P = 0.095)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

Analysis 1.4. Comparison 1 C orticosteroids versus placebo or open control, Outcome 4 Disability

progression at year 1: sensitivity analysis.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 4 Disability progression at year 1: sensitivity analysis

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Zivadinov 2001 5/43 6/45 100.0 % 0.86 [ 0.24, 3.04 ]

Total (95% CI) 43 45

100.0 % 0.86 [ 0.24, 3.04 ]

Total events: 5 (Treated), 6 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.24 (P = 0.81)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

18Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Analysis 1.5. Comparison 1 C orticosteroids versus placebo or open control, Outcome 5 Disability

progression at year 2.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 5 Disability progression at year 2

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Zivadinov 2001 2/39 16/42 100.0 % 0.09 [ 0.02, 0.42 ]

Total (95% CI) 39 42

100.0 % 0.09 [ 0.02, 0.42 ]

Total events: 2 (Treated), 16 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 3.07 (P = 0.0021)

0.01 0.1 1 10 100

Favours treatment Favours control

Analysis 1.6. Comparison 1 C orticosteroids versus placebo or open control, Outcome 6 Disability

progression at year 2: sensitivity analysis.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 6 Disability progression at year 2: sensitivity analysis

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Zivadinov 2001 6/43 16/45 100.0 % 0.29 [ 0.10, 0.85 ]

Total (95% CI) 43 45

100.0 % 0.29 [ 0.10, 0.85 ]

Total events: 6 (Treated), 16 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 2.27 (P = 0.023)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

19Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Analysis 1.7. Comparison 1 Corticostero ids versus placebo or op en control, Outcome 7 New exacerbations

at end of follow-up.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 7 New exacerbations at end of follow-up

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

BPSM 1995 11/12 13/14 11.5 % 0.85 [ 0.05, 15.16 ]

Zivadinov 2001 31/39 39/42

88.5 % 0.30 [ 0.07, 1.22 ]

Total (95% CI) 51 56

100.0 % 0.36 [ 0.10, 1.25 ]

Total events: 42 (Treated), 52 (Control)

Heterogeneity: Chi

= 0.41, df = 1 (P = 0.52); I

=0.0%

Test for overall effect: Z = 1.60 (P = 0.11)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

Analysis 1.8. Comparison 1 Corticostero ids versus placebo or op en control, Outcome 8 New exacerbations

at year 1.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 8 New exacerbations at year 1

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

BPSM 1995 9/18 11/16 43.5 % 0.45 [ 0.11, 1.85 ]

Zivadinov 2001 22/39 18/42

56.5 % 1.73 [ 0.72, 4.16 ]

Total (95% CI) 57 58

100.0 % 1.17 [ 0.57, 2.43 ]

Total events: 31 (Treated), 29 (Control)

Heterogeneity: Chi

= 2.49, df = 1 (P = 0.11); I

=60%

Test for overall effect: Z = 0.43 (P = 0.67)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

20Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Analysis 1.9. Comparison 1 Corticostero ids versus placebo or op en control, Outcome 9 New exacerbations

at year 2.

Review: Corticosteroids for the long-term treatment in multiple sclerosis

Comparison: 1 Corticosteroids versus placebo or open control

Outcome: 9 New exacerbations at year 2

Study or subgroup Treated Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

BPSM 1995 11/12 13/14 12.4 % 0.85 [ 0.05, 15.16 ]

Zivadinov 2001 28/39 26/42

87.6 % 1.57 [ 0.61, 3.99 ]

Total (95% CI) 51 56

100.0 % 1.48 [ 0.61, 3.59 ]

Total events: 39 (Treated), 39 (Control)

Heterogeneity: Chi

= 0.16, df = 1 (P = 0.69); I

=0.0%

Test for overall effect: Z = 0.86 (P = 0.39)

0.1 0.2 0.5 1 2 5 10

More in controls More in cases

A D D I T I O N A L T A B L E S

Table 1. Form for quality assessment

Study: Co ncealment Blinding Int-to-treat

Concealment of randomisation Blinding in outcome evaluation Intention-to-treat analysis

present YES/NO YES/NO YES/NO

absent YES/NO YES/NO YES/NO

unclear YES/NO YES/NO YES/NO

Table 2. Data Collection Form

Study Treated N=? Control N=?

Dropped out/excluded after randomisation n=? n=?

Pts who progressed* at 1 yr n=? n=?

Pts who progressed* at 2 yrs n=? n=?

21Corticosteroids for the long-term treatment in multiple sclerosis (Review)

Table 2. Data Collection Form (Continued)

Pts who progressed* at end of follow-up n=? n=?

Pts experiencing at least one exacerbation

at 1 yr

n=? n=?

Pts experiencing at least one exacerbation

at 2 yrs

n=? n=?

Pts experiencing at least one exacerbation

at end of follow-up

n=? n=?

Pts with severe side effects (please specify) n=? n=?

Other side effects (please specify) n=? n=?

* Progression is deﬁned as a persistent

worsening of at least one point in EDSS,

recorded whilst not in relapse. Other def-

initions of progression could be accepted,

including a persistent half-point increase

starting from EDSS score 5.5

A P P E N D I C E S

Appendix 1. CENTRAL search strategy

#1MeSH descriptor Multiple Sclerosis explode all trees

#2MeSH descriptor Demyelinating Diseases, this term only

#3MeSH descriptor Myelitis, Transverse, this term only

#4MeSH descriptor Optic Neuritis explode all trees

#5MeSH descriptor Encephalomyelitis, Acute Disseminated, this term only

#6(multiple sclerosis)

#7(demyelinating disease*)

#8(transverse myelitis)

#9(neuromyelitis optica)

#10(optic neuritis)

#11(encephalomyelitis acute disseminated)

#12(devic)

#13(#1 OR #1 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 O R #12)

#14MeSH descriptor Adrenal Cortex Hormones e xpl ode all trees

#15MeSH descriptor Steroids explode all trees

#16MeSH descriptor Methylprednisolone explode all trees

#17MeSH descriptor Prednisolone, this term only

#18MeSH descriptor Dexamethasone explode all trees

22Corticosteroids for the long-term treatment in multiple sclerosis (Review)

#19(corticosteroids)

#20(steroids)

#21(methylprednisolone)

#22(prednisone)

#23(prednisolone)

#24(dexamethasone)

#25(acth)

#26MP

#27corticotrophic AND hormone

#28(#14 OR 16 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27)

#29(#28 AND #13)

Appendix 2. MEDLINE (PubMed) search strategy

((((“Multiple Sclerosis”[mh]) OR (“Myelitis, Transverse”[mh:noexp]) OR (“Demyelinating Diseases”[mh:noexp]) OR (“En-

cephalomyelitis, Acute Disseminated”[mh:noexp]) OR (“Optic Neuritis”[mh])) OR (((“multiple sclerosis”) OR (“neuromyelitis op-

tica”) OR (“transverse myelitis”) OR (encephalomyelitis) OR (devic) OR (“optic neuritis”)) OR (“demyelinating disease*”) OR

(“acute disseminated encephalomyelitis”))) AND (((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (random-

ized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT ((animals[mh])

NOT ((animals[mh]) AND (human[mh]))))) AN D (((corticosteroids) OR (steroids) OR (methylprednisolone) OR (MP) OR (pred-

nisone) OR (prednisolone) OR (dexamethasone) OR (ACTH) OR (corticotrophic AND hormone)) OR ((“Adrenal Cortex Hor-

mones”[mh]) OR (“Steroids”[mh]) OR (“Methylprednisolone”[mh]) O R (“Prednisone”[mh: noexp]) OR (“Dexamethasone”[mh]) OR

(“prednisolone”[mh:noexp])))

Appendix 3. EMBASE (EMBASE.com) search strategy

(((’encephalomyelitis’/exp) OR (’demyelinating disease’/exp) OR (’multipl e sclerosis’/exp) OR (’myelooptic neuropathy’/exp) OR (’mul-

tiple sclerosis’:ti,ab) OR (’neuromyelitis optica’:ab,ti) OR (encephalomyelitis:ab,ti) OR (devic:ti,ab)) AND ((’crossover pr ocedure’/exp)

OR (’double blind procedure’/exp) OR (’single blind procedure’/exp) OR (’randomized controlled trial’/exp) OR (random*:ab,ti) OR

(factorial*:ab,ti) OR (crossover:ab, ti) OR (cross:ab,ti AND over:ab,ti) OR (placebo:ab,ti) OR (’double blind’:ab,ti) OR (’single blind’:

ab,ti) OR (assign*:ab,ti) OR (allocat*:ab,ti) OR (volunteer*:ab,ti))) AND ((’corticosteroid’/exp) OR (’steroid’/exp AND [embase]/lim)

OR (’methylprednisolone’/exp) OR (’dexamethasone’/exp) OR (’corticotropin’/exp) OR (corticosteroid*:ab,ti OR steroid*:ab,ti OR

methylprednisolone:ab,ti OR prednisolone:ab,ti OR dexamethasone:ab,ti OR corticotropin:ab,ti)) AND [humans]/lim AND [em-

base]/lim

W H A T ’ S N E W

Last assessed as up-to-date: 2 August 2007.

Date Event Description

22 August 2008 Amended Converted to new review format.

23Corticosteroids for the long-term treatment in multiple sclerosis (Review)

C O N T R I B U T I O N S O F A U T H O R S

Dr Alfonso Ciccone conceived and wrote most part of this review that was checked and discussed with the othe r authors who approved

the ﬁnal version. Dr Sandro Beretta, Dr. Fabio Brusaferri, Dr. Ian Gal ea, Dr. Alessandra Protti and Dr. Chiara Spreaﬁco selected the

trials, extracted the data and assessed the quality of the trials. Dr. Fabio Brusaferri checked all references pertinent to this review al ready

used in two systematic reviews on corticosteroids for multiple sclerosis whose he was one of the authors. Dr. Ian Galea contacted one

manufacturer of corticosteroids and active researchers known to have an interest in the use of steroids in MS in order to identify any

unpublished data and wrote the “Synopsis”. Dr. Sandro Beretta shared data of an unpublished trial that was checked with Dr. Chiara

Spreaﬁco. Dr Alfonso Ciccone performed the analyses and Dr. Sandro Beretta assisted in statistical analysis. Dr. Chiara Spreaﬁco and

Dr. Alessandra Protti prepared the abstract.

D E C L A R A T I O N S O F I N T E R E S T

Two reviewers (Alfonso Ciccone and Sandro Beretta) had a l eading role in a randomised controlled trial on pulsed high dose intravenous

methylprednisolone for relapsing remitting multiple sclerosis, included in the review and quoted as

BPSM 1995 (Boli Steroidei Preventivi

nella Sclerosi Multipla).

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗

Long-Term Care; Adrenal Cortex Hormones [adverse effects;

∗

therapeutic use]; Disease Progression; Methylprednisolone [adverse

effects; therapeutic use]; Multiple Sclerosis [

∗

drug therapy]; Prednisolone [adverse effects; therapeutic use]; Randomized Controlled

Trials as Topic

MeSH check words

Humans

24Corticosteroids for the long-term treatment in multiple sclerosis (Review)