safety and effectiveness assessment of intravenous...

Original Articlehttp://mjiri.iums.ac.ir Medical Journal of the Islamic Republic of Iran (MJIRI)

Iran University of Medical Sciences

____________________________________________________________________________________________________________________1. Assistant Professor, National Institute for Health Research, Tehran University of Medical Sciences, Tehran, Iran. [email protected]. (Corresponding author) MSc Student in Health Technology Assessment at Health School Department of Yazd University of Medical Sci-ences, Iran. [email protected]. Assistant Professor, PhD in Health Economics, Kerman University of Medical Sciences, Kerman, Iran. [email protected]. MD, Assistant Professor of Neurology, Shahid Sadooghi Hospital, Yazd University of Medical Science, Yazd, [email protected]

Safety and effectiveness assessment of intravenousimmunoglobulin in the treatment of relapsing-remitting multiple

sclerosis: A meta-analysis

Alireza Olyaeemanesh1, Mahbobeh Rahmani*2, Reza Goudarzi3Abulghasem Rahimdel4

Received: 14 September 2015 Accepted: 14 November 2015 Published: 23 February 2016

AbstractBackground: Intravenous immunoglobulin (IVIG) is an established treatment of immune mediated

demyelinating neuropathy including Guillain-Barré syndrome and chronic inflammatory demyelinat-ing polyneuropathy. Recent trials suggest its efficacy in treating relapsing- remitting multiple sclero-sis. IVIG exerts a number of effects, which may be beneficial in treating multiple sclerosis (MS):Reduction of inflammation, inhibition of macrophages, and promotion of remyelination. The aim ofthis study was to provide an overall assessment of the existing trials of safety and effectiveness ofIVIG in relapsing- remitting MS compared to other drugs currently available for the treatment ofdisease activity in MS.

Methods: A systematic search strategy was applied to MEDLINE (PubMed and Ovid Medline(1990- Nov 2014)), Cochrane Library 2014, and Trip Database 2014, CRD. The reference lists fromthe identified trials, MS clinical handbooks and guidelines for the use of IVIG were studied. Thisarticle was conducted without language restrictions. Randomized controlled trials of IVIG in MSwere selected. Sixteen double-blinded trails were randomly selected. Ten trials were excluded andwe performed a meta-analysis on the six trials (537 participants) of IVIG in comparison to placebo.The methodological quality of the trials was assessed using Jadad checklist.

Results: The meta-analysis showed a significant beneficial effect on proportion of relapse-free pa-tients (OR: 1.693; 95% CI-1.205-2.380), on the proportion of patients who improved (OR:2.977;95% CI 1.769-5.010; p=0.0001) and deteriorated (OR:0.522; 95% CI0.330-0.827; p=0.006) betweenplacebo and IVIG-treated patients. In addition, there was a reduction in the annual relapse rate in theIVIG group compared to placebo, which was statistically significant (SMD=-0.218; 95% CI-0.412 to-0.024; p=0.028). The results of the meta-analysis did not show significant differences between Ex-panded Disability Status Scale (EDSS) changes from baseline (SMD,-0.025; 95% CI,-0.211 to 0.161;p=0.860).

Conclusion: IVIG can be considered as an alternative therapeutic option, second-line therapy oradjuvant therapy, considering its beneficial effects (high tolerance, need to be injected with longerintervals, etc.) for treating relapsing–remitting MS patients.

Keywords: Multiple sclerosis, Relapsing–remitting Multiple Sclerosis, Intravenous Immunoglobu-lin, Meta-analysis.

Cite this article as: Olyaeemanesh A, Rahmani M, Goudarzi R, Rahimdel A. Safety and effectiveness assessment of intravenous immu-noglobulin in the treatment of relapsing-remitting multiple sclerosis: A meta-analysis. Med J Islam Repub Iran 2016 (23 February). Vol.30:336.

IntroductionMultiple sclerosis (MS) is a chronic and

debilitating, progressive inflammatory anddegenerative disease of the central nervous

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20

http://mjiri.iums.ac.ir/article-1-3577-en.html

Meta-analysis of IVIg

2 Med J Islam Repub Iran 2016 (23 February). Vol. 30:336.http://mjiri.iums.ac.ir

system (CNS) which affects the brain andspinal cord, in which infiltrating lympho-cytes, predominantly T-cells and macro-phages lead to damage of the myelin sheath(1-5).

The cause and pathogenesis of MS re-main to be unknown (6,7), although it isthought to be autoimmune in nature. A va-riety of genetic, immunological, and envi-ronmental factors have been implicated intriggering the onset and progression of thedisease, which is characterized by im-mune- mediated tissue injury directedagainst CNS myelin antigens(8).

MS is one of the most common contribu-tors to neurological disability among youngand middle-aged adults. The peak age ofthe onset is approximately 30 years, and thedisease occurs in twice as many women asmen (2,8).

The estimated number of people with MShas increased from 2.1 million in 2008 to2.3 million in 2013. The MS prevalencerate in Tehran, capital city of Iran, is esti-mated to be 51.9 per 100,000 population in2010; and in Isfahan, one of the large citiesof Iran, is estimated to be 43.8 per 100,000population in 2007 (10).

Intravenous immunoglobulin (IVIG) is ablood product, which is prepared frompools of plasma of at least three thousandand up to a hundred thousand healthy blooddonors. Initially used at a ‘‘replacementdose’’ for patients who have antibodydeficiencies, IVIG is now increasingly be-ing used for the treatment of autoimmuneand systemic inflammatory diseases as animmunomodulatory agent (11).

IVIG exerts may have a number of posi-tive effects on multiple sclerosis (MS): Re-duction of inflammation, inhibition of mac-rophages and promotion of remyelination,and increased number of activated pro-inflammatory T-cells (Th1); a reducednumber of regulatory T-cells (Th2), and anincreased number of B-cells produce IVIGantibodies against myelin proteins (12,13).

A number of trails have indicated effectson MS (Sorensen et al., 1998; Lewanska etal., 2002,….). It is, therefore, important to

establish the efficacy of intravenous immu-noglobulin treatment to ensure that peoplewith MS are not exposed to a potentiallyharmful drug without good evidence of ef-ficacy, and that resources are not unneces-sarily devoted to an unproven therapy.

ObjectiveWe conducted a meta-analysis of the tri-

als in order to provide an overall evaluationof the safety and effectiveness of IVIG inrelapsing–remitting MS compared to otherdrugs currently available for the treatmentof disease activity in MS.

MethodsCriteria for Considering the Studies for

Meta-analysisTypes of Studies: We searched random-

ized controlled trials, which assessed thesafety, efficacy and effectiveness of intra-venous immunoglobulins for MS.

Types of Participants: Trial participantswere diagnosed with definite MS(accordingto the McDonald diagnostic criteria)(4).Participants may have had relapsing- remit-ting MS.

Types of Interventions: We limited thismeta-analysis to trials of intravenous im-munoglobulins for relapsing- remitting MS.

Types of Outcome Measures:Progression of the disease was evaluated

using the Expanded Disability Status Scale(EDSS).

1) The proportion of patients remainingrelapse- free at the end of the treatmentperiod

2) Annualized relapse rate, relapse rate,expressed as the number of relapses perannum in each treatment arm

3) The proportion of patients improvedin EDSS

4) The proportion of patients deteriorat-ed in EDSS.

Search Methods to Identify the StudiesElectronic Searches: A systematic search

was conducted (From 1990 to2014, whichwas updatedin2015/6) to identify all rele-vant published and unpublished random-

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20


A. Olyaeemanesh, et al.

3Med J Islam Repub Iran 2016 (23 February). Vol. 30:336. http://mjiri.iums.ac.ir

ized controlled trials (Fig. 5).For this review, the following databases

were searched: MEDLINE (PubMed andOvid Medline), Cochrane library, CRD,Trip Database, FDA, Google scholar, andNAHTA (Table 7).

Searching other Resources: To find moreresources and studies that may have notbeen found in the electronic search, wesearched the reference lists of the identifiedtrials. Moreover, the clinical handbooks ofMultiple sclerosis and guidelines for theuse of intravenous immunoglobulin weresearched.

Data Collection and AnalysisFrom 748 sources of the initial search, we

identified 16 trials. To be included in thereview, a trial had to meet the followingcriteria: (1) Allocation concealment had tobe adequate (Unclear allocation conceal-ment was accepted if every other methodo-logical factor was of the best possiblestandard); (2) Treated and non-treatedgroups had adequate baseline comparabil-ity; (3) Patients and the treating physicianswere blind to the treatment allocation; (4)All analyses had to be intended- to- treatanalyses.

We excluded 10 trials: Five trials differedin the type of drug used in the controlgroup, and three trials did not measure thedesired outcomes, one trial was conductedonly on pregnant women, and one trial didnot clearly specify the target group. Weperformed a quality evaluation of evidencefor trails in this review by Cochrane Re-viewer’s Handbook, which discusses themethodological quality under the followingheadings: (1) Selection bias; (2) Perfor-mance bias; (3) Attrition bias; and (4) De-tection bias. In addition, we performed aquality evaluation of evidence for trials in-cluded in this review by Jadad checklist.

For the quantitative outcomes of EDSSscore and annual relapse rate, the combina-tion of results was based on the use of theeffect size (SMD), Δ/σ, where Δ is the dif-ference in the mean results for IVIG andplacebo and σ is the common (population)

standard deviation (SD). These quantitiesare estimated for each study by the differ-ence in the mean scores and the pooled es-timated SD, σ. Note that the ratio of theseestimates is biased and a bias adjustment asdescribed by Begg's test was considered inthe analysis. These results were pooled to-gether using weights based on the samplesize for each trial and study preparation,using basic techniques described by Begg'stest. However, before pooling all of the re-sults, a chi-square test for homogeneity wasconducted. If this test was significant, anattempt was made to eliminate the result(s)that may have caused the heterogeneity,and the remaining findings were then com-bined.

For the qualitative outcomes of relapse-free, improved and deterioration rates, ef-fect size is simply the difference in the pro-portions between the active and placebogroups. These values are weighted based onthe difference in proportions. A test of ho-mogeneity of results was also used follow-ing a simple modification of the chi-squareprocedure mentioned above. In addition,odds ratios were computed for each studyand overall, 95% confidence interval wasassumed. These calculations were imple-mented using Stata / SE 11.

ResultsPatients and Study DesignWe identified six published studies,

which met our inclusion criteria (Fazekas etal., 1997; Achiron et al., 1998; Strasser etal., 2000; Lewanska et al., 2002; Kocer etal., 2004; Fazekas et al., 2008). Also, weconsidered a meta-analysis by Sorensen etal., (2002) which included four trials, and ameta-analysis by Gray et al., (2009) whichincluded 10 randomized trials of intrave-nous immunoglobulins for the treatment ofMS (4,14). Thus, we performed a morecomprehensive meta-analysis.

In the six included trials, 537 patientswere enrolled. Patient characteristics, IVIGdosage, and trial duration, etc. are present-ed in Table 1. The dosage of IVIG variedconsiderably from 0.15 to 0.2g/kg body-

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




weight monthly in the study by Fazekas etal. (1997) to 0.4 g/kg bodyweight monthlyin the study by Fazekas et al. (2008) andLewanska et al. (2002). All the six trialshad used a parallel-group design.

Description of StudiesIn the study by Fazekas et al. (1997), the

primary outcome measures were the changein EDSS and the proportion of patients whoimproved, remained stable or worsened indisability, defined as an increase or de-crease of at least 1.0 point in the EDSSscore by the end of the study. Secondaryoutcome measures included the annual re-lapse rate and the proportion of relapse-freepatients (15).

In the Achiron et al. (1998) study, theyused the annual relapse rate, proportion ofrelapse-free patients and median time tofirst relapse as the primary study endpoints.The changes in neurological disabilitymeasured on the EDSS scale, mean annualseverity of exacerbations and mean MRIlesion score were used as the secondaryoutcome endpoint. Alloutcomes weremeasured at baseline and after 1 and 2years (16).

In the study of Strasser et al. (2000), thechange in EDSS and the proportion of pa-tients who improved, remained stable orworsened in disability were the primary

outcomes measured. The secondary end-points were the number of confirmed re-lapses, the annual relapse rate, time to firstrelapse during the study period and pro-portion of relapse-free patients (17).

In the study of Lewanska et al. (2002),two groups were treated with two doses ofIVIG 0.4 g/kg and 0.2 g/kg, and one groupwith placebo. The annual relapse rate and acomparison between pre-study relapse rateand relapse rate during the study periodwere considered as primary outcomes. Thesecondary clinical outcomes included theproportion of relapse-free patients, meanchanges in the EDSS, and the proportion ofpatients with worsening, mean changes inthe NRSS (Neurological Rating ScaleScore), change of mean lesion volume onT2-weighted, the mean number of new le-sions on T2-weighted and the mean numberof gadolinium-enhancing lesions on T1–weighted scans every 3 months (18).

In the study of Kocer et al. (2004), end-points measured included the proportion ofpatients who improved, remained stable ordeteriorated of clinical disability, changesin the EDSS, the number and volume oflesions on MRI in all sites (19).

In the Fazekaset al. (2008) study, theyused the proportion of relapse-free patientsand annualized relapse rate as the primaryefficacy endpoint. Secondary outcome

Table 1. Design, Patient Characteristics, IVIG Doses and Trial DurationDose

(months)Trial

durationEDSSMean age

(years)MS

duration(years)

NDesignRCT Study

0.15–0.2g/kg24IVIG:3.3Placebo:3.3

IVIG:36.7±2.4Placebo:37.2±2.3

IVIG:6.8Placebo:7.3

IVIG:75Placebo:73

PGFazekaset al. (1997)

0.4g/kg24IVIG:2.9 Place-bo:2.82

IVIG:35.4±2.1Placebo:33.8±2.4

IVIG:4.1Placebo:3.95

IVIG:20Placebo:20

PGAchironet al. (1998)

0.2g/kg24IVIG:3.33±1.39Place-

bo:3.37±1.67

IVIG:36.7±10.4Placebo:37.3±9.8

IVIG:6.8±4.6Placebo:7.3±5.7

IVIG:75Placebo:75

PGStrasseret al. (2000)

0.2g/kg0.4g/kg

12IVIG:3.0±1.35IVIG:3.0±2.08

Place-bo:2.97±1.58

IVIG:38±6.96IVIG:31.1±6.08

Place-bo:41.8±6.98

IVIG:10.7±7.57IVIG:7.2±5.48

Placebo:7.5±4.7

IVIG:17IVIG:15

Placebo:17

PGLewanskaet al. (2002)

0.4g/kg9IVIG:2.46±1.82Place-

bo:1.96±1.60

IVIG:22-56 Pla-cebo:22-39

IVIG:2-14 Pla-cebo:2-14

IVIG:12Placebo:12

PGKoceret al. (2004)

0.2g/kg0.4g/kg

12IVIG:1.8±0.9IVIG:2.1±1.1

Placebo:2.1±1.2

IVIG:31.9±7.5IVIG:34.4±7.9

Placebo:33.0±8.7

IVIG:2.8±1.9IVIG:2.7±2.1

Placebo:2.3±1.5

IVIG:44IVIG:42

Placebo:41

PGFazekaset al. (2008)

PG= parallel groups; IVIG= intravenous immunoglobulin; EDSS= Expanded Disability Status Scale; MS= multiple sclerosis

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




measures included change in burden of dis-ease volume, change in brain parenchymalfraction, ratio and cumulative number ofunique newly active lesions (20).

Progression of Disease (Disability)The five trials enrolling patients had not

showed significant differences betweenEDSS from baseline (SMD,-0.025; 95% CI,-0.211 to 0.161; p= 0.860; Table 2, Fig. 1),Thus, the trials were comparable in this re-spect. There were no evidence of heteroge-neity among the studies (p= 0.860, χ2=2.57, I2=0.0%).

Four trials showed a trend towards a re-duction in EDSS score during the IVIGtreatment when compared to the baseline.

The decrease in EDSS score was defined asan effect size (SMD) -0.052 with a 95%confidence interval from -0.288 to 0.183(p= 0.663), and the difference was not sta-tistically significant (Table 3, Fig. 2). Therewas evidence of heterogeneity among thestudies although it was not statistically sig-nificant.

Four studies reported the proportion ofpatients who improved, and five studiesprovided an analysis of the proportion ofpatients who deteriorated. Fazekas et al.(1997)and Achiron et al. (1998) definedimprovement and deterioration by a changeof one point or more in the EDSS at the endof the study; Strasser et al. (2000) changedat least 1.0 EDSS grade during the trailand Kocer et al. (2004) did not determinethe definition improvement. The meta-analysis revealed a significant difference inthe proportion of patients who improved onIVIG compared to placebo treatment. A testfor heterogeneity across the studies wassignificant for this variable (p= 0.0001).Also, the meta-analysis revealed a strongtrend in the proportion that deteriorated be-tween placebo and IVIG-treated patients(Table 4). However, there was a large de-gree of heterogeneity in these results(p=0.009).

Proportion of Relapse-free Patients: Fourtrails reported the proportion of relapse-freepatients (Fazekas et al. 1997; Achiron et al.

Table 2. EDSS in Baseline (Mean ± SD)% Weight[95% Conf. Interval]SMDStudy

8.95-0.422 0.8210.199Achiron (1998)33.30-0.348 0.296-0.026Strasser (2000)7.17-0.678 0.7110.016Lewanska (2002) 0.4g/kg7.65-0.632 0.7130.041Lewanska (2002) 0.2g/kg5.34-0.513 1.0970.292Koçer (2004)

18.68-0.430 0.4300.000Fazekas (2008) 0.4g/kg18.91-0.712 0.143-0.284Fazekas (2008) 0.2g/kg

p=0.860-0.211 0.161-0.025I-V pooled SMDSMD= Standardized mean difference; IVIG=Intravenous immunoglobulin; EDSS= Expanded Disability Status Scale

Table 3. Change in EDSS (Mean ± SD)% Weight[95% Conf. Interval]SMDStudy

53.37-0.250 0.3950.073Fazekas (1997)14.35-0.831 0.412-0.209Achiron (1998)12.22-0.842 0.505-0.168Lewanska (2002) 0.4g/kg11.46-0.868 0.523-0.172Lewanska (2002) 0.2g/kg8.59-1.044 0.563-0.240Koçer (2004)

P=0.633-0.288 0.183-0.052I-V pooled SMDSMD= Standardized mean difference; IVIG=Intravenous immunoglobulin; EDSS= Expanded Disability Status Scale

Fig. 1. EDSS in Baseline (Mean ± SD)

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




1998; Lewanska et al. 2000; Fazekas et al.2008). This proportion was statisticallyhigher for those treated with IVIg with apooled odds Ratio (OR) of 1.693 with a95% confidence interval of 1.205- 2.380.The difference was statistically significantwith a p-value of 0.002. In addition, no ev-idence of heterogeneity was found amongthe studies (p= 0.007), indicating that theresults were consistent over the trials. Theodds-ratios for being relapse-free with 95%confidence intervals for each study and the

overview results are given in Table 5, Fig.3.

Relapse Rate: Four studies reported theannual relapse rate in patients at baseline,which the meta-analysis did not show anysignificant difference between IVIG andplacebo groups (SMD= 0.136; 95%CI, -0.090 to 0.361; p= 0.238) (Fig. 4).

Table 6 demonstrates the changes in theannual relapse rate in four trails (Fazekas etal. 1997; Achiron et al. 1998; Lewanska etal. 2000; Fazekas et al. 2008) after treat-

Fig. 2. Change in EDSS (Mean ± SD)

Table 4. Proportion of Patients with Improvement or Deterioration in EDSS% WeightOR (95%CI)PlaceboIVIGStudy

Improved42.202.787 (1.217-6.379)0.140.31Fazekas (1997)9.433.000 (0.507-17.740)0.110.24Achiron (1998)

46.653.343 (1.473-5.585)0.140.34Strasser (2000)4.723.667 (0.323-41.590)0.0830.25Koçer (2004)

3.080 (1.769-5.282)M-H pooled ORDeteriorated

30.310.627 (0.276-1.427)0.230.16Fazekas et al. (1997)7.120.706 (0.136-3.658)0.170.14Achiron et al. (1998)

29.350.756 (0.333-0.857)0.230.18Strasser et al.(2000)12.810.346 (0.080-1.507)0.470.24Lewanska et al. (2002) 0.2g/kg14.660.080 (0.009-0.756)0.470.07Lewanska et al. (2002) 0.4g/kg5.760.273 (0.024-3.093)0.250.08Kocer (2004)

0.534 (0.333-0.857)M-H pooledORIVIG= Intravenous immunoglobulin; EDSS=Expanded Disability Status Scale; OR= odds ratio

Table 5. Proportion of Relapse-free Patients% WeightOR (95%CI)PlaceboIVIGStudy

NonEventsEventsNonEventsEvents24.012.066 (1.068-3.996)47263540Fazekas (1997)1.378.143 (0.878-75.479)191146Achiron (1998)

24.012.066 (1.068-3.996)49263540Strasser (2000)2.076.667 (1.151-38.598)15298Lewanska (2002) 0.2g/kg1.718.571 (1.430-51.362)15278Lewanska (2002) 0.4g/kg

24.440.611 (0.251-1.485)31281925Fazekas (2008) 0.2g/kg22.400.611 (0.251-1.485)31282525Fazekas (2008) 0.4g/kg

1.690 (1.202-2.375)207113136152D+L pooled OR

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




ment with IVIG, or placebo. The pooled re-sults revealed significant differences in thenumber of relapses experienced on an annualbasis in favor of IVIG (SMD= -0.218; 95%CI -0.412 to -0.024; p=0.028) (Fig. 5).

DiscussionThe present research confirms that intra-

venous immunoglobulin has a beneficialeffect on the annual relapse rate, proportionof relapse-free patients, on the proportionof patients deteriorated and improved, andon clinical disability in patients with relaps-ing–remitting MS. Despite the differencebetween the included trials (design, dura-tion, dose and endpoint), the results seemed

Fig. 3. Proportion of Relapse-Free Patients

Fig. 4. Annual Relapse Rate at Baseline

Table 6. Annual Relapse Rate% Weight[95% Conf. Interval]SMDStudy

35.23-0.809 -0.155-0.482Fazekas (1997)8.21-1.892 -0.538-1.215Achiron (1998)8.20-1.025 0.330-0.347Lewanska (2002) 0.2g/kg7.63-1.128 0.277-0.425Lewanska (2002) 0.4g

20.54-0.113 0.7440.315Fazekas (2008) 0.2g20.19-0.197 0.6670.235Fazekas (2008) 0.4g

p=0.001-0.412 -0.024-0.218I-V pooled SMDSMD=Standardized mean difference; IVIG=Intravenous immunoglobulin

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




remarkably consistent in the meta-analysis.The results of the present overview re-

vealed that IVIg does not have an effect onthe EDSS scores compared to placebo; andalthough it was decreased, it was not statis-tically significant. The difference in the an-nual relapse rate between IVIG and place-bo-treated patients was a result of a strong

reduction in the annual relapse rate on ther-apy compared to baseline in the IVIGgroup. The proportion of relapse-free pa-tients increased in the IVIg compared toplacebo treatment. The increase in the pro-portion of the patients improved clinicallyindicated a positive association with receiv-ing IVIg treatment compared to placebo in

Fig. 5. The Process of Identifying Related Articles

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




patients.The results of similar studies that have

been done in this field in other countries(Sorensen 2002 (14), Fergusson 2004 (21)

and Gary 2009 (4)) are largely similar tothe results obtained in this study.

The studies that were entered into themeta- analysis used different doses of IVIG

Table 7. Ovid MEDLINE(R) 1946 to June Week 2 20141837 or 3839127 and 12 and 3238186 and 11 and 3137

106limit 35 to humans3610834 or 3335897 and 12 and 2034

1086 and 11 and 1933117585or/23-3032131483or/21-293149981(Meta Analysis or Systematic Review or Biomedical Technology Assessment or Eco-

nomic Evaluation).sh. [Embaseterms]30

2431(meta regression$ or metaregression$ or mega regression$).ti,ab.2961061(meta analy$ or metaanaly$ or met analy$ or metanaly$ or health technology assess-

ment$ or HTA or HTAs or biomedical technology assessment$ or bio-medical tech-nology assessment$).ti,ab.

28

5121(handsearch$ or hand search$).ti,ab.2712169(data synthes$ or data extraction$ or data abstraction$).ti,ab.265368((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or over-

view$)) or pool$ analy$).ti,ab.25

936((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ oroverview$))).ti,ab.

24

49971((systematic$ adj (literature review$ or review$ or overview$)) or (methodologic$ adj(literature review$ or review$ or overview$))).ti,ab.

23

23081Meta-Analysis as Topic.sh. or exp Technology Assessment, Biomedical/ [Med-lineterms]

22

49981Meta-Analysis.pt. [Medlineterm]21950487or/15-1820

1220916or/13-171988875*Major Clinical Study/ or *Multicenter Study/) or exp Controlled Clinical Trial/ [Em-

baseterms](18

263773(control$ adj2 (study or studies or trial$)).ti,ab.17339((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or

mask$))).ti,ab.16

786960(random$ or rct$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or(doubl$ adj (blind$ or dumm$ or mask$))).ti,ab.

15

577370(Multicenter Study or Randomized Controlled Trial or Controlled Clinical Trial).pt.[Medlineterms]

14

313388exp Controlled Clinical Trials as Topic/ or Double-Blind Method.sh. or Random Allo-cation.sh. or Single-Blind Method.sh. or Multicenter Studies as Topic.sh. [Med-

lineterms]

13

218492or/9-1012218492or/8-91139830multiple sclerosis".sh. [Embaseterm]"10212879(sclerosis Multiple $ or multiple sclerosis$ or MS).ti,ab.939830multiple sclerosis".sh. [Medlineterm]"813515or/2-5716941or/1-46

0Immunoglobulin".sh. [Embaseterm]52936(alphaglobin$ or baygam$ or endobulin$ or gamagard$ or gamimmune$ or gam-

imune$ or gamunex$ or gammimune$ or gammimmune$ or gam?agard$ orgam?aguard$ or gammaglobulin$ or gammonativ$ or (globulin adj n) or igivnex$ orintraglobin$ or intraglobulin$ or iveegam$ or octagam$ or polygam$ or sandoglobu-

lin$ or venimmune$ or venoglobulin$).ti,ab.

4

5208(ivig or igiv or igv or ivigg or ivgg).ti,ab.39879((intravenous$ adj (antibod$ or gammaglobulin$ or gamma globulin$ or immuno-

globulin? or immune globulin?)) or iv immunoglobulin? or intravenous ig or modifiedimmune globulin?).ti,ab.

2

9826Immunoglobulins Intravenous".sh. [Medlineterm]"1

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




and only two trails compared two differentdoses of IVIG with placebo (Lewanska etal. 2000; Fazekas et al. 2008), and thesetwo trails can help select the optimal doseof IVIG. However, the decisions made con-sidering the use of each of the doses areassociated with the frequent and severe sideeffects. Unfortunately, the two mentionedstudies did not show any difference be-tween the two doses.

Several studies have shown that immuno-globulin was well tolerated, and did not re-port any severe related side effects; themost common mild side effects includedheadache, nausea, fever, dizziness, chills,rash and fatigue.

Most of the studies compared the effec-tiveness of this drug with placebo. Howev-er, to determine the effectiveness of thisdrug, it needs to be compared with otherMS drugs. However, unfortunately, fewstudies (3 trials and one intervention study)have done this comparison. The study con-ducted by Kalanie et al. 2004 (22) com-pared the efficacy of this drug with inter-feron beta-1a (Avonex) in RRMS patients.Thisstudy showed a reduction of relapserates by using IVIG compared to interferonbeta-1a better safety profile for IVIG in thestudiedIranian population. In the two otherstudies (Visser et al. 2004 and Sorensen etal. 2004), IVIG was used as add-on tomethylprednisolone and was compared toIV methylprednisolone only in the treat-ment of relapses in MS, and in both studiesthere was no significant difference betweenthe groups in terms of relapse and meas-ured outcomes (23,24).

Although studies have shown beneficialeffects of immunoglobulin in measuringvariable diseases activities, the evidence,with regards to the short duration and thenumber of participants in the trials, was notsufficient, and more accurate assessment ofthe patients is needed. Thus, based on theresults of this meta-analysis, immunoglobu-lin can be considered as an alternative op-tion, second-line therapy, or adjuvant ther-apy considering its beneficial effect (hightolerance, need to be injected with longer

intervals, etc.) for treating relapsing–remitting MS patients.

AcknowledgmentsWe thank the National Institute of Health

Research and Yazd University of MedicalSciences for providing facilities for this re-view. It should also be noted that this arti-cle has been adapted from a Master's thesis.

References1. Achiron A, Kishner I, Sarova-Pinhas I, Raz H,

Faibel M, Stern Y, et al. Intravenousimmunoglobulin treatment following the firstdemyelinating event suggestive of multiplesclerosis: a randomized, double-blind, placebo-controlled trial. Archives of Neurology 2004;61(10):1515-20.

2. Yamamoto D, Campbell JD. Cost-effectivenessof multiple sclerosis disease-modifying therapies: asystematic review of the literature. Autoimmunediseases 2012;2012.

3. Tsang BK, Macdonell R. Multiple sclerosis-diagnosis, management and prognosis. Aust FamPhysician 2011 Dec;40(12):948-55.

4. Gray O MG, Forbes RB. Intravenousimmunoglobulins for multiple sclerosis. CochraneDatabase of Systematic Reviews 2010.

5. Sorensen PS. The role of intravenousimmunoglobulin in the treatment of multiplesclerosis. J Neurol Sci 2003 Feb 15;206(2):123-30.

6. Lewanska M, Selmaj K. [Immunotherapy ofintravenous immunoglobulin preparations inneurologic diseases]. Postepy Hig Med Dosw2002;56 Suppl:69-83.

7. Clegg A, Bryant J, Milne R. Disease-modifyingdrugs for multiple sclerosis: a rapid and systematicreview. Health Technology Assessment(Winchester, England) 2000;4(9):i-iv, 1-101.

8. Achiron A, Miron S. Intravenousimmunoglobulin and multiple sclerosis. Clin RevAllergy Immunol 2005 Dec;29(3):247-54.

9. Organization WH. Multiple scherosis resourcesin the world 2013. 2013.

10. Ebrahimi HA, Sedighi B. Prevalence ofmultiple sclerosis and environmental factors inKerman province, Iran. Neurology Asia 2013;18(4).

11. Sibéril S, Elluru S, Negi V-S, Ephrem A,Misra N, Delignat S, et al. Intravenousimmunoglobulin in autoimmune and inflammatorydiseases: more than mere transfer of antibodies.Transfusion and Apheresis Science 2007;37(1):103-7.

12. Sorensen PS. Treatment of multiple sclerosiswith intravenous immunoglobulin: review of clinicaltrials. Neurol Sci 2003 Oct;24 Suppl 4:S227-30.

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20




13. Fernández Liguori N, Rojas JI, Klajn DS,Ciapponi A. Intravenous immunoglobulin to preventrelapses during pregnancy and postpartum inmultiple sclerosis. The Cochrane Library. 2013.

14. Sorensen PS, Fazekas F, Lee M. Intravenousimmunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur JNeurol 2002 Nov;9(6):557-63.

15. Fazekas F, Deisenhammer F, Strasser-Fuchs S,Nahler G, Mamoli B. Randomised placebo-controlled trial of monthly intravenousimmunoglobulin therapy in relapsing-remittingmultiple sclerosis. Austrian Immunoglobulin inMultiple Sclerosis Study Group. Lancet 1997 Mar1;349(9052):589-93.

16. Achiron A, Gabbay U, Gilad R, Hassin-BaerS, Barak Y, Gornish M, et al. Intravenousimmunoglobulin treatment in multiple sclerosisEffect on relapses. Neurology 1998;50(2):398-402.

17. Strasser-Fuchs S, Fazekas F, Deisenhammer F,Nahler G, Mamoli B. The Austrian Immunoglobulinin MS (AIMS) study: final analysis. Mult Scler 2000Oct;6 Suppl 2:S9-13.

18. Lewańska M, Siger‐Zajdel M, Selmaj K. Nodifference in efficacy of two different doses ofintravenous immunoglobulins in MS: clinical andMRI assessment. European Journal of Neurology2002;9(6):565-72.

19. Kocer B, Yildirim-Gurel S, Tali ET, Irkec C,

Isik S. The role of qualitative and quantitative MRIassessment of multiple sclerosis lesions according totheir in evaluating the efficacy of intravenousimmunoglobulin G. Neuroradiology 2004 Apr;46(4):287-90.

20. Fazekas F, Lublin FD, Li D, Freedman MS,Hartung HP, Rieckmann P, et al. Intravenousimmunoglobulin in relapsing-remitting multiplesclerosis: a dose-finding trial. Neurology 2008 Jul22;71(4):265-71.

21. Fergusson D, Hutton B, Sharma M, TinmouthA, Wilson K, Cameron DW, et al. Use ofintravenous immunoglobulin for treatment ofneurologic conditions: a systematic review.Transfusion 2005 Oct;45(10):1640-57.

22. Kalanie H, Gharagozli K, Hemmatie A,Ghorbanie M, Kalanie AR. Interferon Beta-1a andintravenous immunoglobulin treatment for multiplesclerosis in Iran. Eur Neurol 2004;52(4):202-6.

23. Visser LH, Beekman R, Tijssen CC, UitdehaagBM, Lee ML, Movig KL, et al. A randomized,double-blind, placebo-controlled pilot study of i.v.immune globulins in combination with i.v.methylprednisolone in the treatment of relapses inpatients with MS. Mult Scler 2004 Feb;10(1):89-91.

24. Sorensen PS, Haas J, Sellebjerg F, Olsson T,Ravnborg M. IV immunoglobulins as add-ontreatment to methylprednisolone for acute relapsesin MS. Neurology 2004;63(11):2028-33.

Dow

nloa

ded

from

mjir

i.ium

s.ac

.ir a

t 9:5

6 IR

DT

on

Wed

nesd

ay A

ugus

t 12t

h 20

20


safety and effectiveness assessment of intravenous...

Documents