Efficacy,Acceptability,and Safety of Intravenous Immunoglobulin Administration for Mild-To-Moderate Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Abstract

A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer’s disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate AD.

Keywords

Efficacy intravenous immunoglobulin meta-analysis mild-to-moderate Alzheimer’s disease safety systematic review

INTRODUCTION

Alzheimer’s disease (AD) pathology includes the accumulation of extracellular senile plaques primarily comprising amyloid-β (Aβ) and intracellular neurofibrillary tangles comprising abnormally hyperphosphorylated tau, a microtubule-associated protein [1]. A considerable number of clinical trials of Aβ-specific antibodies for the treatment of patients with AD have been conducted. A recent meta-analysis [2] demonstrated that one of the Aβ-specific antibodies, bapineuzumab, was not superior to placebo in terms of the improved score of the Alzheimer’s Disease Assessment Scale (ADAS)-Cog11 [3] and Mini-Mental State Examination (MMSE) [4]. Conversely, bapineuzumab administration was associated with a higher incidence of treatment-emergent adverse events and cerebral vasogenic edema than placebo; therefore, the authors recommended that bapineuzumab should not be used to treat patients with AD [2]. Phase III clinical trials of solanezumab also demonstrated that this Aβ-specific antibody was not superior to placebo in terms of improved ADAS-cog11, Neuropsychiatric Inventory (NPI) [5], and the Alzheimer s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) [6] scores in the patients with mild-to-moderate AD [7]. Further, solanezumab administration was not associated with a higher incidence of any adverse events than placebo [7].

Intravenous immunoglobulin (IVIG), containing human immunoglobulin G antibodies, has been used to treat autoimmune and systemic inflammatory diseases as well as in the supportive therapy of immune deficient patients [8]. IVIG contains antibodies of Aβ peptides and oligomers [9, 10]. Human anti-Aβ antibodies block fibril formation or disrupt the formation of fibrillar structures and exhibit neuroprotective properties in vitro [11]. Additionally, IVIG improves cognitive performance and decrease Aβ₄₂/Aβ₄₀ ratios and Aβ oligomers concentrations in brains of mouse models of AD [12]. IVIG may involve unknown antibodies that are effective for the treatment of patients with AD [13]. On the basis of above reports, IVIG can be a potential treatment option for AD.

In fact, six randomized placebo-controlled trials (RCTs) have been conducted to evaluate effects of IVIG in patients with AD (Table 1) [14 –19]. All RCTs have reported that there was no significant difference in the improvement of cognitive function scores in patients with AD between IVIG and placebo treatment groups. However, these results might be a type II error considering that the statistical power of results in the improvement of cognitive function scores in these RCTs ranged 5.7–29.6%, at an alpha error of 0.05. Therefore, the accurate estimation of IVIG efficacy is difficult in an RCT owing to low statistical power. Meta-analysis provides weighted summary results, with more weight given to studies with larger sample sizes. By combining results from multiple RCTs, a meta-analysis can elevate the statistical power of individual RCT [20]. Therefore, we conducted a systematic review and meta-analysis to examine whether IVIG was beneficial for the treatment of patients with AD.

Table 1
Characteristics of included double-blind, randomized controlled trials

Study, country, sponsorship Total n Methods
(1) Study design
(2) Duration
(3) Analyzed population Patients
(1) Diagnosis
(2) Inclusion criteria
(3) Study defined disease severity Age (mean ± SD), y Male (%) Race (%) Baseline cognitive function scales (mean ± SD) Intervention, dose (mg/day), frequency of medication n Efficacy outcomes^a

Arai 2014 [14], Japan, Industry 16 (1) DB-RCT
(2) 26 w (12 w dosing period and 14 w observation period)
(3) ITT (1) AD, NINCDS-ADRDA
(2) age 50–89 y, MMSE 16–26, RMHIS 4≥
(3) mild to moderate 72.6 18.8 Japanese: 100 MMSE: 20.0 IVIG (GAM), 0.4 g/kg, every 2 w 6 IVIG = PLA: MMSE

IVIG (GAM), 0.2 g/kg, every 2 w 6

PLA, every 2 w 4

Dodel 2013 [15], Germany and USA, Industry 58 (1) DB-RCT(2) 24 w(3) ITT (1) AD, NINCDS-ADRDA(2) age 50–85 y, MMSE 16–26, RMHIS 5>(3) mild to moderate 70.1 56.7 Caucasian: 94.5, Others: 5.5 ADAS-cog: 20.8MMSE: 21.5 IVIG (OCT), 0.8 g/kg, every 4 w 7 IVIG > PLA: FDG-PET (changes in CMRglc in right middle temporal gyrus and left parahippocampal gyrusIVIG = PLA: ADAS-cog, ADCS-ADL, MMSE, MRI (total brain and hippocampal volume)IVIG < PLA: CDR-SOB

IVIG (OCT), 0.5 g/kg, every 4 w 8

IVIG (OCT), 0.2 g/kg, every 4 w 7

PLA, every 4 w 7

IVIG (OCT), 0.4 g/kg, every 2 w 7

IVIG (OCT), 0.25 g/kg, every 2 w 7

IVIG (OCT), 0.1 g/kg, every 2 w 7

PLA, every 2 w 8

Kile 2017 [16], USA, Industry 52 (1) DB-RCT(2) 104 w (10 w dosing period and 94 w observation period)(3) OC (1) MCI due to AD, NIA-AA, NINCDS-ADRDA, Petersen criteria(2) age 50–84 y, CDR 0.5≥, MMSE 24–30(3) MCI 72.3 42.9 NR ADAS-cog: 10.5MMSE: 26.6 IVIG (OCT), 0.4 g/kg, every 2 w 26 IVIG = PLA: ADAS-cog, CDR-SOB, MMSE, MRI (annualized per cent change in ventricular volume)

PLA, every 2 w 26

Relkin 2008 [17], USA Industry 24 (1) DB-RCT(2) 26 w(3) NR (1) AD, NINCDS-ADRDA(2) age≥50 y, MMSE 14–26, RMHIS 5≥(3) mild to moderate NR NR NR NR IVIG (GAM) 16 IVIG > PLA: ADCS-CGICIVIG = PLA: ADAS-cog

PLA, every 2 w 8

NCT01524887 [18]^b, USA, Industry 261 (1) DB-RCT(2) 78 w(3) OC (1) AD, NINCDS-ADRDA(2) age 50–89 y, MMSE 16–26, RMHIS 4 ≥(3) mild to moderate 70.8±9.0 47.4 Caucasian: 94.8, AA: 2.0 Asian: 1.6 NH/OPI: 0.8 AI/AN: 0.4 Others: 0.4 NR IVIG (GAM), 0.4 g/kg, every 2 w 85 IVIG = PLA: ADAS-cog, ADCS-ADL (IVIG, 0.2 g/kg), ADCS-CGIC, NPI 12 (IVIG, 0.4 g/kg), MMSE, MRI (rate of whole brain atrophy and ventricular enlargement), QOL-AD, IADCQ IVIG < PLA: ADCS-ADL (IVIG, 0.4 g/kg), NPI 12 (IVIG, 0.2 g/kg)

IVIG (GAM), 0.2 g/kg, every 2 w 90

PLA, every 2 w 86

Relkin 2017 [19], USA and Canada, Industry 390 (1) DB-RCT(2) 78 w(3) ITT (1) AD, NINCDS-ADRDA(2) age 50–89 y, MMSE 16–26,(3) mild to moderate 70.3±9.3 45.4 Caucasian: 97.7, AA: 1.5, Asian: 0.3, Others: 0.5 ADAS-cog: 20.5 MMSE: 21.3±3.2 IVIG (GAM), 0.4 g/kg, every 2 w 129 IVIG = PLA: ADAS-cog, ADCS-ADL, ADCS-CGIC, FDG PET (frontal cortex), MMSE, MRI (whole brain, ventricular, and hippocampal volume), NPI, QOL-AD

IVIG (GAM), 0.2 g/kg, every 2 w 138

PLA, every 2 w 123

^aprimary outcomes in each study are underlined; ^bunpublished study. AA, African-American: AD, Alzheimer disease: ADAS-cog, Alzheimer’s Disease Assessment Scale-cognitive subscale: ADCS-ADL, Alzheimer’s Disease Cooperative Study–Activities of Daily Living: ADCS-CGIC, Alzheimer’s Disease Cooperative Study–Clinical Global Impressions of Change: AI/AN, American Indian or Alaska native: CDR(-SOB), Clinical Dementia Rating scale(–sum of boxes): CMRgl, cerebral metabolic rates for glucose: DB-RCT, double-blind randomized controlled trial: FDG-PET, fluorodeoxy glucose positron emission tomography: GAM, gammagard: IADCQ, Impact of Alzheimer's Disease on Caregiver Questionnaire: ITT, intention to treat: IVIG, intravenous immunoglobulin: MCI, mild cognitive impairment: MMSE, Mini-Mental State Examination: MRI, magnetic resonance imaging: n, number of patients: NH/OPI, native Hawaiian or other pacific islander: NIA-AA, National Institute on Aging-Alzheimer’s Association: NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association: NPI, Neuropsychiatric Inventory: NR, not reported: OC, observed case: OCT, octagam: PLA, placebo: QOL-AD, Quality of Life in Alzheimer's Disease: RMHIS, Rosen modification of Hachinski ischemic score: SD, standard deviation: USA, United States of America: w, weeks; y, years.

METHODS

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Supplementary Table 1) [21]. The review has been registered with PROSPERO (http://www.crd.york.ac.uk/PROSPERO/. CRD42017068709).

Search strategy and inclusion criteria

A systematic literature search was conducted according to the following Patient, Intervention, Comparator, and Outcomes [P: AD or mild cognitive impairment (MCI), I: IVIG, C: placebo, O: efficacy and safety outcomes].

To identify relevant studies, two of the authors (M.O. and S.M.) independently searched MEDLINE, Cochrane library, and Scopus without language restrictions from the date of inception of these databases to October 9, 2018, using the following search strategy: (“Alzheimer Disease”[Mesh] OR “Alzheimer disease” OR “Alzheimer’s disease” OR “Cognitive Dysfunction”[Mesh] OR “Mild Cognitive Impairment”) AND (“Immunoglobulins, Intravenous”[Mesh] OR “immunoglobulins, intravenous” OR “IVIG” OR “gammagard” OR “gamunex” OR “newgam” OR “octagam” OR “flebogamma” OR “privigen”) AND (“randomized” OR “random” OR “randomly”). The authors also searched ClinicalTrials.gov (http://clinicaltrials.gov/), ISRCTN registry (http://clinicaltrials.gov/), and International Clinical Trials Registry Platform (https://www.isrctn.com/) to ensure the comprehensive inclusion of randomized controlled trials and to minimize the possibility of publication bias. Only double-blind RCTs of IVIG treatment in patients with AD or MCI lasting≥2 weeks were included. Studies with an observation period following treatment period were included in this systematic review and meta-analysis. The authors independently assessed the inclusion/exclusion criteria and selected the relevant studies. The references to the included articles and reviews were also searched for citations of additional relevant published and unpublished studies, including conference abstracts.

Data synthesis and outcome measures

Two primary outcomes including an efficacy measure, improvement in ADAS-cog, and a safety measure, all-cause discontinuation, were assessed. Secondary outcomes for efficacy included scores of MMSE; Neuropsychiatric Inventory; ADCS-ADL; and global function-related scales [the Alzheimer’s Disease Cooperative Study-Clinical Global Impressions of Change (ADCS-CGIC) [22], Clinical Dementia Rating scale–Sum of Boxes [23], and the quality of life in Alzheimer’s disease (QOL-AD) [24]]. Secondary outcomes for safety included discontinuation due to adverse events or death and the incidence of individual adverse events. For three-arm (IVIG, 0.4 g/kg/every 2 weeks; IVIG, 0.2 g/kg/every 2 weeks; and placebo/every 2 weeks) studies [18], the data of the IVIG 0.4 g/kg/every 2 weeks arm was combined with that of the IVIG 0.2 g/kg/every 2 weeks arm. For an eight-arm study (IVIG, 0.8 g/kg/every 4 weeks; IVIG, 0.5 g/kg/every 4 weeks; IVIG, 0.2 g/kg/every 4 weeks; placebo/every 4 weeks; IVIG, 0.4 g/kg/every 2 weeks; IVIG, 0.25 g/kg/every 2 weeks; IVIG, 0.1 g/kg/every 2 weeks; and placebo/every 2 weeks) study [15], the data of all IVIG treatment doses (0.8 g/kg/every 4 weeks, 0.5 g/kg/every 4 weeks, 0.2 g/kg/every 4 weeks, 0.4 g/kg/every 2 weeks, 0.25 g/kg/every 2 weeks, and 0.1 g/kg/every 2 weeks) were combined into the IVIG group, whereas the data of all placebo treatments (every 4 weeks and 2 weeks) were combined into the placebo group.

Data extraction

Two authors (M.O. and S.M.) independently extracted data from the included studies. Where possible, an intention-to-treat (ITT) or a full analysis set (FAS) population was used. When such data were unavailable, the results for observed case (OC) analysis were extracted from each study. When the data required for meta-analysis were missing, investigators or the industries of the relevant research were contacted and requested to provide unpublished data.

Meta-analysis methods

The meta-analysis was conducted using the Review Manager software (version 5.3 for Windows; http://tech.cochrane.org/revman). Random effects model was selected for meta-analysis because of the potential heterogeneity across studies. Dichotomous outcomes were presented as risk ratios (RRs) with 95% confidence intervals (CIs). When the random effects model showed significant differences between the groups, the number needed to harm (NNH) was calculated. Then, NNH values were derived from risk difference (RD) using the following formula: NNH = 1/RD. Continuous outcomes were analyzed using mean difference (MD) or standardized mean difference for studies using different scales. Lower MMSE, ADCS-ADL, and QOL-AD scores indicate more impairment or more severe symptoms; thus, the algebraic sign of the numerical scores was reversed for these scales. The methodological quality of the selected trials was assessed according to the risk-of-bias criteria in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0; http://handbook.cochrane.org/front_page.htm). Study heterogeneity was tested using the I² statistic, considering I²≥50% to reflect considerable heterogeneity [25]. Although sensitivity analysis was planned for primary outcomes with considerable heterogeneity, no considerable heterogeneity was noted among the selected trials. However, several subgroup analyses, including tests for subgroup differences, were performed, and the following confounding factors for primary outcomes for efficacy were identified: analyzed population (ITT/FAS population versus OC population), diagnosis (MCI versus AD), intervention and observation period (study with only intervention period versus study with intervention and observation period), and IVIG (gammagard versus octagam). A meta-regression analysis was performed to evaluate the association between the result of meta-analysis on ADAS-cog and certain modulators [mean dose (every two weeks), patient age, sample size, study duration, and proportion of male participants (%)] using the Comprehensive Meta-Analysis software version 2 (Biostat Inc., Englewood, NJ, USA). Funnel plots were visually examined to assess the possibility of publication bias in primary outcomes when >10 studies were included [25].

RESULTS

3.1 Study characteristics

A total of six studies (n = 801) were identified (Fig. 1) [14 –19]. The studies included five cases of IVIG administration for mild-to-moderate AD [14 , 17–19] and one case of IVIG administration for MCI due to AD [16]. For the included studies, mean study duration was 56 weeks, mean patient age was 70.6 years, the mean proportion of male participants (%) was 46.2, and mean IVIG dose was 0.3 g/kg/every 2 weeks. Although two studies used OC populations in their analyses [16, 18]. Two studies included an observation period following the treatment [14, 16]. The Relkin 2008 study did not report any available data for performing our meta-analysis [17].

Fig.1

The Preferred Reporting Items for Systematic reviews and Meta-Analysis Flow Diagram. RCT, randomized controlled trial.

Three studies did not provide detailed information regarding random sequence generation and blinding [14 , 18]. Two studies used OC populations [16, 18]. One study which was published as a conference abstract did not report detailed information of analyzed populations [17]. Two studies did not report results of all outcomes [17, 19]. One study was unpublished [18]. All studies were sponsored by pharmaceutical companies and did not provide detailed information regarding allocation concealment [14 –19].

Results of the meta-analysis regarding efficacy outcomes

There was no significant difference in ADAS-cog scores between the IVIG and placebo treatment groups (Fig. 2-1).

Fig.2-1

Forest plots of Alzheimer’s Disease Assessment Scale-cognitive subscale scores. Fig. 2-2. Forest plots of Neuropsychiatric Inventory scores. Fig. 2-3. Forest plots of all-cause discontinuation rates. Fig. 2-4. Forest plots of risk of rash development. 95% CIs, 95% confidence intervals; V, inverse variance; IVIG, intravenous immunoglobulin; M-H, Mantel-Haenszel; SD, standard deviation.

For subgroup analyses in term of the primary outcome, there were no significant subgroup differences and considerable heterogeneities among all subgroups. Meta-regression analysis of primary outcomes revealed no associations between the effect size for the pooled IVIG treatment in terms of mean dose, patient age, sample size, study duration, or proportion of male participants.

IVIG administration was inferior to placebo administration in terms of NPI scores (MD = 2.19, 95% CI = 0.02, 4.37, p = 0.05, I² = 0%; Fig. 2-2). There were no significant differences between the pooled IVIG and placebo treatment groups in terms of other efficacy outcomes.

Results of the meta-analysis regarding safety outcomes

There was no significant difference in all-cause discontinuation between the IVIG and placebo treatment groups (Fig. 2-3). However, IVIG administration was associated with a higher incidence of rash (RR = 2.91, 95% CI = 1.41–6.00, p = 0.004, I = 0%, NNH = 17; Fig. 2-4) than placebo administration. There were no significant differences in other adverse events between the treatment groups.

DISCUSSION

This is the first comprehensive meta-analysis of RCTs evaluating the efficacy, acceptability, and safety of IVIG administration for treating mild to moderate AD. Although there were no significant differences in the improvement of cognitive function scores between the IVIG and placebo treatment groups, IVIG deteriorated behavioral and psychological symptoms of dementia in mild-to-moderate AD. Moreover, our results do not support the dose-dependent effect of IVIG administration because no association was observed between the effect size of IVIG for ADAS-cog scores and IVIG dose in our meta-regression analysis. It was not known why improvements in the cognitive function scores were similar between the groups. Furthermore, IVIG administration was associated with a risk of rash development. Although the number of studies included in this meta-analysis was small, our results do not favor IVIG administration to treat mild to moderate AD.

In this meta-analysis, IVIG administration was considerably inferior to placebo administration in NPI scores. The pathophysiology of this negative effect may be associated with inflammation in the brain due to IVIG. The exact mechanism underlying worsened behavioral and psychological symptoms of dementia in patients with AD following IVIG administration remains unclear. Reportedly, CSF anti-inflammatory cytokine Interleukin-10 (IL-10) in patients with AD may be negatively associated with total NPI score [26]. In vitro study using activated B cells have reported that IVIG suppressed IL-10 production [27]. Considering this evidence, the inhibition of IL-10 production by IVIG may be associated with the progression of behavioral and psychological symptoms of dementia in patients with AD.

The current study did not include the following subgroup analyses: 1) patients with mild to moderate AD versus patients with severe AD and 2) apolipoprotein E4 carrier or not.

In conclusion, our results suggest that IVIG is not effective for mild to moderate AD and can be harmful. IVIG worsens behavioral and psychological symptoms of dementia in patients with mild to moderate AD. Although a limited number of studies were included in our meta-analysis, the results disfavor IVIG administration for mild to moderate AD treatment.

Footnotes

ACKNOWLEDGMENTS

This study was supported by an unrestricted grant from Daiichi Sankyo.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

References

Ittner

, Gotz

(2011) Amyloid-beta and tau–a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12, 65–72.

Abushouk

, Elmaraezy

, Aglan

, Salama

, Fouda

, AlSafadi

(2017) Bapineuzumab for mild to moderate Alzheimer’s disease: A meta-analysis of randomized controlled trials. BMC Neurol 17, 66.

Rosen

, Mohs

, Davis

(1984) A new rating scale for Alzheimer’s disease. Am J Psychiatry 141, 1356–1364.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.

Cummings

, Mega

, Gray

, Rosenberg-Thompson

, Carusi

, Gornbein

(1994) The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314.

Galasko

, Bennett

, Sano

, Ernesto

, Thomas

, Grundman

, Ferris

(1997) An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 11(Suppl 2), S33–39.

Doody

, Thomas

, Farlow

, Iwatsubo

, Vellas

, Joffe

, Kieburtz

, Raman

, Sun

, Aisen

, Siemers

, Liu-Seifert

, Mohs

Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370, 311–321.

Vani

, Elluru

, Negi

, Lacroix-Desmazes

, Kazatchkine

, Bayry

, Kaveri

(2008) Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev 7, 440–444.

Dodel

, Neff

, Noelker

, Pul

, Du

, Bacher

, Oertel

(2010) Intravenous immunoglobulins as a treatment for Alzheimer’s disease: Rationale and current evidence. Drugs 70, 513–528.

10.

Szabo

, Relkin

, Weksler

(2008) Natural human antibodies to amyloid beta peptide. Autoimmun Rev 7, 415–420.

11.

Dodel

, Hampel

, Depboylu

, Lin

, Gao

, Schock

, Jackel

, Wei

, Buerger

, Hoft

, Hemmer

, Moller

, Farlow

, Oertel

, Sommer

, Du

(2002) Human antibodies against amyloid beta peptide: A potential treatment for Alzheimer’s disease. Ann Neurol 52, 253–256.

12.

St-Amour

, Pare

, Tremblay

, Coulombe

, Bazin

, Calon

(2014) IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Abeta pathology. J Neuroinflammation 11, 54.

13.

Hung

, Fu

(2017) Drug candidates in clinical trials for Alzheimer’s disease. J Biomed Sci 24, 47.

14.

Arai

, Ichimiya

, Shibata

, Nakajima

, Sudoh

, Tokuda

, Sujaku

, Yokokawa

, Hoshii

, Noguchi

, Bille

(2014) Safety and tolerability of immune globulin intravenous (human), 10% solution in Japanese subjects with mild to moderate Alzheimer’s disease. Psychogeriatrics 14, 165–174.

15.

Dodel

, Rominger

, Bartenstein

, Barkhof

, Blennow

, Forster

, Winter

, Bach

, Popp

, Alferink

, Wiltfang

, Buerger

, Otto

, Antuono

, Jacoby

, Richter

, Stevens

, Melamed

, Goldstein

, Haag

, Wietek

, Farlow

, Jessen

(2013) Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: A phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 12, 233–243.

16.

Kile

, Au

, Parise

, Rose

, Donnel

, Hankins

, Chan

, Ghassemi

(2017) IVIG treatment of mild cognitive impairment due to Alzheimer’s disease: A randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. J Neurol Neurosurg Psychiatry 88, 106–112.

17.

Relkin

, Tsakanikas

, Adamiak

, Assuras

, Shenoy

, Flores

, Shah

, Ravdin

, Szabo

, Weksler

(2008) A double blind, placebo-controlled, phase II clinical trial of intravenous immunoglobulin (IVIG) for treatment of Alzheimer’s disease. pp. A. Annual Meeting of the American Academy of Neurology, Chicago, IL, pp. A393.

18.

ClinicalTrials.gov. NCT01524887. Phase 3 IGIV, 10% in Alzheimer’s disease. https://clinicaltrials.gov/ct2/show/NCT01524887.

19.

Relkin

, Thomas

, Rissman

, Brewer

, Rafii

, van Dyck

, Jack

, Sano

, Knopman

, Raman

, Szabo

, Gelmont

, Fritsch

, Aisen

, Alzheimer’s Disease Cooperative Study (2017) A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 88, 1768–1775.

20.

Cohn

, Becker

(2003) How meta-analysis increases statistical power. Psychol Methods 8, 243–253.

21.

Moher

, Liberati

, Tetzlaff

, Altman

, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339, b2535.

22.

Schneider

, Clark

, Doody

, Ferris

, Morris

, Raman

, Reisberg

, Schmitt

(2006) ADCS Prevention Instrument Project: ADCS-clinicians’ global impression of change scales (ADCS-CGIC), self-rated and study partner-rated versions. Alzheimer Dis Assoc Disord 20, S124–138.

23.

Morris

(1993) The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 43, 2412–2414.

24.

Logsdon

, Gibbons

, McCurry

, Teri

(2002) Assessing quality of life in older adults with cognitive impairment. Psychosom Med 64, 510–519.

25.

Higgins

, Thompson

, Deeks

, Altman

(2003) Measuring inconsistency in meta-analyses. BMJ 327, 557–560.

26.

Holmgren

, Hjorth

, Schultzberg

, Larksater

, Frenkel

, Tysen-Backstrom

, Aarsland

, Freund-Levi

(2014) Neuropsychiatric symptoms in dementia-a role for neuroinflammation? Brain Res Bull 108, 88–93.

27.

Tanaka

, Hirano

, Sakamoto

, Sugahara-Tobinai

, Endo

, Ito-Matsuoka

, Nakano

, Inui

, Nitschke

, Takai

(2012) Intravenous immunoglobulin suppresses IL-10 production by activated B cells. Open J Immunol 2, 149–160.

Study, country, sponsorship	Total n	Methods (1) Study design (2) Duration (3) Analyzed population	Patients (1) Diagnosis (2) Inclusion criteria (3) Study defined disease severity	Age (mean ± SD), y	Male (%)	Race (%)	Baseline cognitive function scales (mean ± SD)	Intervention, dose (mg/day), frequency of medication	n	Efficacy outcomes^a
Arai 2014 [14], Japan, Industry	16	(1) DB-RCT (2) 26 w (12 w dosing period and 14 w observation period) (3) ITT	(1) AD, NINCDS-ADRDA (2) age 50–89 y, MMSE 16–26, RMHIS 4≥ (3) mild to moderate	72.6	18.8	Japanese: 100	MMSE: 20.0	IVIG (GAM), 0.4 g/kg, every 2 w	6	IVIG = PLA: MMSE
								IVIG (GAM), 0.2 g/kg, every 2 w	6
								PLA, every 2 w	4
Dodel 2013 [15], Germany and USA, Industry	58	(1) DB-RCT(2) 24 w(3) ITT	(1) AD, NINCDS-ADRDA(2) age 50–85 y, MMSE 16–26, RMHIS 5>(3) mild to moderate	70.1	56.7	Caucasian: 94.5, Others: 5.5	ADAS-cog: 20.8MMSE: 21.5	IVIG (OCT), 0.8 g/kg, every 4 w	7	IVIG > PLA: FDG-PET (changes in CMRglc in right middle temporal gyrus and left parahippocampal gyrusIVIG = PLA: ADAS-cog, ADCS-ADL, MMSE, MRI (total brain and hippocampal volume)IVIG < PLA: CDR-SOB
								IVIG (OCT), 0.5 g/kg, every 4 w	8
								IVIG (OCT), 0.2 g/kg, every 4 w	7
								PLA, every 4 w	7
								IVIG (OCT), 0.4 g/kg, every 2 w	7
								IVIG (OCT), 0.25 g/kg, every 2 w	7
								IVIG (OCT), 0.1 g/kg, every 2 w	7
								PLA, every 2 w	8
Kile 2017 [16], USA, Industry	52	(1) DB-RCT(2) 104 w (10 w dosing period and 94 w observation period)(3) OC	(1) MCI due to AD, NIA-AA, NINCDS-ADRDA, Petersen criteria(2) age 50–84 y, CDR 0.5≥, MMSE 24–30(3) MCI	72.3	42.9	NR	ADAS-cog: 10.5MMSE: 26.6	IVIG (OCT), 0.4 g/kg, every 2 w	26	IVIG = PLA: ADAS-cog, CDR-SOB, MMSE, MRI (annualized per cent change in ventricular volume)
								PLA, every 2 w	26
Relkin 2008 [17], USA Industry	24	(1) DB-RCT(2) 26 w(3) NR	(1) AD, NINCDS-ADRDA(2) age≥50 y, MMSE 14–26, RMHIS 5≥(3) mild to moderate	NR	NR	NR	NR	IVIG (GAM)	16	IVIG > PLA: ADCS-CGICIVIG = PLA: ADAS-cog
								PLA, every 2 w	8
NCT01524887 [18]^b, USA, Industry	261	(1) DB-RCT(2) 78 w(3) OC	(1) AD, NINCDS-ADRDA(2) age 50–89 y, MMSE 16–26, RMHIS 4 ≥(3) mild to moderate	70.8±9.0	47.4	Caucasian: 94.8, AA: 2.0 Asian: 1.6 NH/OPI: 0.8 AI/AN: 0.4 Others: 0.4	NR	IVIG (GAM), 0.4 g/kg, every 2 w	85	IVIG = PLA: ADAS-cog, ADCS-ADL (IVIG, 0.2 g/kg), ADCS-CGIC, NPI 12 (IVIG, 0.4 g/kg), MMSE, MRI (rate of whole brain atrophy and ventricular enlargement), QOL-AD, IADCQ IVIG < PLA: ADCS-ADL (IVIG, 0.4 g/kg), NPI 12 (IVIG, 0.2 g/kg)
								IVIG (GAM), 0.2 g/kg, every 2 w	90
								PLA, every 2 w	86
Relkin 2017 [19], USA and Canada, Industry	390	(1) DB-RCT(2) 78 w(3) ITT	(1) AD, NINCDS-ADRDA(2) age 50–89 y, MMSE 16–26,(3) mild to moderate	70.3±9.3	45.4	Caucasian: 97.7, AA: 1.5, Asian: 0.3, Others: 0.5	ADAS-cog: 20.5 MMSE: 21.3±3.2	IVIG (GAM), 0.4 g/kg, every 2 w	129	IVIG = PLA: ADAS-cog, ADCS-ADL, ADCS-CGIC, FDG PET (frontal cortex), MMSE, MRI (whole brain, ventricular, and hippocampal volume), NPI, QOL-AD
								IVIG (GAM), 0.2 g/kg, every 2 w	138
								PLA, every 2 w	123