Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive or relapsing weakness and numbness of the limbs, developing over at least two months. Uncontrolled studies suggest that intravenous immunoglobulin (IVIg) helps. This review was first published in 2002 and has since been updated, most recently in 2013.

Objectives

To review systematically the evidence from randomised controlled trials (RCTs) concerning the efficacy and safety of IVIg in CIDP.

Search methods

On 4 December 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, issue 11 in the Cochrane Library), MEDLINE and EMBASE to December 2012 and ISI from January 1985 to May 2008. We searched for ongoing trials through two metaRegistries (World Health Organization International Clinical Trials Registry Platform Search Portal and Current Controlled Trials).

Selection criteria

We selected RCTs testing any dose of IVIg versus placebo, plasma exchange or corticosteroids in definite or probable CIDP.

Data collection and analysis

Two authors reviewed literature searches to identify potentially relevant RCTs, scored their quality and extracted data independently. We contacted authors for additional information.

Main results

We considered eight RCTs, including 332 participants, to be eligible for inclusion in the review. These trials were homogeneous and the overall risk of bias low. Five studies, in a total of 235 participants compared IVIg against placebo. One trial with 20 participants compared IVIg with plasma exchange, one trial compared IVIg with prednisolone in 32 participants, and one trial, newly included at this update, compared IVIg with intravenous methylprednisolone in 46 participants.

A significantly higher proportion of participants improved in disability within one month after IVIg treatment as compared with placebo (risk ratio (RR) 2.40, 95% confidence interval (CI) 1.72 to 3.36; number needed to treat for an additional beneficial outcome 3.03 (95% CI 2.33 to 4.55), high quality evidence). Whether all these improvements are equally clinically relevant cannot be deduced from this analysis because each trial used different disability scales and definitions of significant improvement. In three trials, including 84 participants, the disability score could be transformed to the modified Rankin score, on which improvement of one point after IVIg treatment compared to placebo was barely significant (RR 2.40, 95% CI 0.98 to 5.83) (moderate quality evidence). Only one placebo-controlled study included in this review had a long-term follow-up. The results of this study suggest that IVIg improves disability more than placebo over 24 and 48 weeks.

The mean disability score revealed no significant difference between IVIg and plasma exchange at six weeks (moderate quality evidence). There was no significant difference in improvement in disability on prednisolone compared with IVIg after two or six weeks, or on methylprednisolone compared to IVIg after two weeks or six months (moderate quality evidence).

There were no statistically significant differences in frequencies of side effects between the three types of treatment for which data were available (IVg versus placebo or steroids). (moderate or high quality evidence) Mild and transient adverse events were found in 49% of participants treated with IVIg, while serious adverse events were found in six per cent.

Authors' conclusions

The evidence from RCTs shows that IVIg improves disability for at least two to six weeks compared with placebo, with an NNTB of three. During this period it has similar efficacy to plasma exchange, oral prednisolone and intravenous methylprednisolone. In one large trial, the benefit of IVIg persisted for 24 and possibly 48 weeks. Further research is needed to compare the long-term benefits as well as side effects of IVIg with other treatments.

Résumé scientifique

Immunoglobuline intraveineuse pour le traitement de la polyradiculoneuropathie démyélinisante inflammatoire chronique

Contexte

La polyradiculoneuropathie démyélinisante inflammatoire chronique (PDIC) entraîne une faiblesse progressive ou récurrente et un engourdissement des membres, se développant sur une période d'au moins deux mois. Des études non contrôlées suggèrent que l'immunoglobuline intraveineuse (IgIV) est utile. Cette revue a été publiée pour la première fois en 2002 et a depuis lors été mise à jour, le plus récemment en 2013.

Objectifs

Réaliser une revue systématique des preuves issues d'essais contrôlés randomisés (ECR) concernant l'efficacité et l'innocuité de l'IgIV dans la PDIC.

Stratégie de recherche documentaire

Le 4 décembre 2012, nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur les affections neuromusculaires, CENTRAL (2012, numéro 11 dans la Bibliothèque Cochrane), MEDLINE et EMBASE jusqu'à décembre 2012 et ISI de janvier 1985 à mai 2008. Nous avons recherché des essais en cours dans deux méta-registres (World Health Organization International Clinical Trials Registry Platform Search Portal et Current Controlled Trials).

Critères de sélection

Nous avons sélectionné les ECR évaluant n'importe quelle dose d'IgIV par rapport à un placebo, une plasmaphérèse ou des corticostéroïdes dans la PDIC avérée ou probable.

Recueil et analyse des données

Deux auteurs ont examiné les recherches de littérature afin d'identifier des ECR potentiellement pertinents, ils ont évalué leur qualité et extrait les données de manière indépendante. Nous avons contacté les auteurs pour obtenir des informations supplémentaires.

Résultats principaux

Nous avons pris en compte huit ECR, portant sur 332 participants, pour être éligibles pour l'inclusion dans la revue. Ces essais étaient homogènes et le risque de biais global faible. Cinq études, pour un total de 235 participants comparaient l'IgIV à un placebo. Un essai avec 20 participants comparait l'IgIV à la plasmaphérèse, un essai comparait l'IgIV à la prednisolone chez 32 participants, et un essai, récemment intégré à cette mise à jour, comparait l'IgIV à la méthylprednisolone intraveineuse chez 46 participants.

Une proportion significativement supérieure de participants présentaient une amélioration de l'incapacité au cours du mois suivant l'administration d'IgIV par rapport à un placebo (risque relatif (RR) 2,40, intervalle de confiance à 95 % (IC) de 1,72 à 3,36 ; nombre de sujets à traiter pour obtenir un résultat bénéfique supplémentaire de 3,03 (IC à 95 % 2,33 à 4,55), preuves de qualité élevée). On ne peut pas déduire de cette analyse si toutes ces améliorations sont pareillement cliniquement pertinentes car chaque essai utilisait différentes échelles d'incapacité et différentes définitions de l'amélioration significative. Dans trois essais, comprenant 84 participants, le score de l'incapacité pouvait être converti en score de Rankin modifié, pour lequel une amélioration d'un point après l'administration d'IgIV par rapport à un placebo était à peine significative (RR 2,40, IC à 95 % 0,98 à 5,83) (preuves de qualité modérée). Une seule étude contrôlée par placebo inclue dans cette revue effectuait un suivi à long terme. Les résultats de cette étude suggèrent que l'IgIV, plus que le placebo, améliore l'incapacité sur 24 et 48 semaines.

Le score moyen d'incapacité ne révélait aucune différence significative entre l'IgIV et la plasmaphérèse à six semaines (preuves de qualité modérée). Il n'y avait aucune différence significative dans l'amélioration de l'incapacité pour la prednisolone par rapport à l'IgIV après deux ou six semaines, ou pour la méthylprednisolone par rapport à l'IgIV après deux semaines ou six mois (preuves de qualité modérée).

Il n'y avait aucune différence statistiquement significative en termes de fréquence des effets secondaires entre les trois types de traitement pour lesquels les données étaient disponibles (IgIV versus placebo ou stéroïdes) (preuves de qualité modérée ou élevée). Des événements indésirables légers et transitoires étaient observés chez 49 % des participants traités avec l'IgIV, tandis que des événements indésirables graves ont été observés dans six pour-cent des cas.

Conclusions des auteurs

Les preuves issues d'ECR montrent que l'IgIV améliore l'incapacité sur une durée d'au moins deux à six semaines par rapport à un placebo, avec un NST de trois. Pendant cette période, son efficacité est similaire à celle de la plasmaphérèse, de la prednisolone orale et de la méthylprednisolone intraveineuse. Dans un essai à grande échelle, le bénéfice de l'IgIV persistait pendant 24 et peut-être 48 semaines. D'autres recherches sont nécessaires afin de comparer les bénéfices à long terme ainsi que les effets secondaires de l'IgIV avec d'autres traitements.

Plain language summary

Intravenous immunoglobulin for people with chronic inflammatory demyelinating polyradiculoneuropathy

Review question

We performed this review to assess the evidence from randomised trials on how effective and safe intravenous immunoglobulin (IVIg) is for people with CIDP.

Background

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an illness in which nerves become inflamed and this leads to paralysis. The likely cause is that the body attacks its own nerves. CIDP usually requires long-term treatment to prevent further disability. There is much debate about the first choice of treatment. One choice is a medicine called immunoglobulin, which is a product made from purified antibodies from human donor blood and which is given via injection into a vein. Steroid drugs and plasma exchange (a treatment in which the plasma element of a person's blood is replaced), are known to be effective.

Study characteristics

Eight randomised controlled trials including 332 participants with CIDP were eligible for this review. These compared IVIg with placebo (dummy treatment), plasma exchange, or steroid drugs.

Key results and quality of the evidence

We found five randomised trials which together prove that IVIg improves disability more than placebo (dummy treatment). The results showed that three people would need to be treated for one person to improve. In the three trials that compared IVIg with other treatments, results with IVIg were similar to plasma exchange, oral prednisolone or intravenous methylprednisolone. The evidence was of moderate or high quality. In this review, there were mild and short-term side effects in around half of those who received IVIg. Six per cent of those treated with IVIg had serious side effects, which is a similar rate as with plasma exchange or corticosteroids.

Each trial defined improvement in its own way and the trials used different measurement scales, so it is difficult to relate them to changes in the clinical condition of people with CIDP. Only one of the studies that compared IVIg with placebo had a long-term follow-up. It suggested that IVIg improves disability more than placebo over 24 weeks and possibly 48 weeks. Further research is needed to compare the long-term benefits as well as side effects of IVIg with other treatments.

The most recent search for studies was in December 2012 and we updated the review with the results of one additional trial.

Résumé simplifié

Immunoglobuline intraveineuse chez les patients atteints de polyradiculoneuropathie démyélinisante inflammatoire chronique

Question de la revue

Nous avons effectué cette revue afin d'évaluer les preuves issues d'essais randomisés sur l'efficacité et la sécurité de l'immunoglobuline intraveineuse (IgIV) pour les personnes atteintes de PDIC.

Contexte

La polyradiculoneuropathie démyélinisante inflammatoire chronique (PDIC) est une maladie caractérisée par une inflammation des nerfs conduisant à des paralysies. La cause probable est l'attaque par l'organisme de ses propres nerfs. La PDIC nécessite généralement un traitement de long terme pour prévenir une aggravation de l'incapacité. Il existe de nombreux débats sur le traitement à choisir en premier. Un des choix est un médicament appelé immunoglobuline, qui est un produit fabriqué à partir des anticorps purifiés de sang de donneurs humains, administrée par injection dans une veine. Les stéroïdes et l'échange de plasma(plasmaphérèse, un traitement dans lequel on remplace le plasma du sang d'une personne) sont connus pour être efficaces.

Les caractéristiques de l'étude

Huit essais contrôlés randomisés totalisant 332 participants atteints de PDIC étaient éligibles pour cette revue. Ils comparaient l'IgIV à un placebo (médicament factice), à l'échange de plasma ou aux stéroïdes.

Résultats principaux et qualité des preuves

Nous avons identifié cinq essais randomisés démontrant globalement que l'IgIV améliore l'incapacité plus que le placebo (médicament factice). Les résultats ont montré que trois personnes devraient être traitées pour qu'une personne soit améliorée. Dans les trois essais qui comparaient l'IgIV avec d'autres traitements, les résultats avec l'IgIV étaient similaires à la plasmaphérèse, à la prednisolone orale ou à la méthylprednisolone intraveineuse. Les preuves étaient de qualité modérée ou élevée. Dans cette revue, il y avait des effets secondaires légers et de court terme chez environ la moitié de ceux ayant reçu de l'IgIV. Six pour-cent de ceux traités par l'IgIV avaient des effets secondaires graves, la plasmaphérèse ou les corticostéroïdes ont des taux similaires.

Chaque essai avait défini l'amélioration à sa propre façon et les essais utilisaient différentes échelles de mesure, de sorte qu'il est difficile de faire le lien avec les modifications de l'état clinique des personnes atteintes de PDIC. Une seule des études qui comparaient l'IgIV avec un placebo avait un suivi à long terme. Elle suggérait que l'IgIV améliorait plus que le placebo l'incapacité sur 24 semaines et possiblement sur 48 semaines. D'autres recherches sont nécessaires afin de comparer les bénéfices à long terme et les effets secondaires de l'IgIV à d'autres traitements.

La plus récente recherche d'études a été réalisée en décembre 2012 et nous avons mis à jour la revue avec les résultats d'un essai supplémentaire.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. IVIg compared to placebo for chronic inflammatory demyelinating polyradiculoneuropathy
  1. 1 Two studies had a cross-over design (in total 269 treatments in 235 participants).
    2 One study had a cross-over design (in total 90 treatments in 84 participants).
    3 Two studies had a cross-over design (in total 247 treatments in 215 participants).
    4 One study had a cross-over design (in total 90 treatments in 84 participants).
    5 One study had a cross-over design (in total 315 treatments in 288 participants).

IVIg compared to placebo for chronic inflammatory demyelinating polyradiculoneuropathy
Patient or population: people with chronic inflammatory demyelinating polyradiculoneuropathy
Settings: tertiary care centre
Intervention: IVIg
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo IVIg
Significant improvement in disability scale used in original study
Follow-up: 2 to 6 weeks
18 per 100 44 per 100
(32 to 62)
RR 2.4
(1.72 to 3.36)
2691
(5 studies)
⊕⊕⊕⊕
high
The RR corresponds with a number need to treat of 3.03 (95% CI 2.33 to 4.55) for improvement on the originally used disability scale. The use of different scales renders it difficult to assess the clinical significance of this change.
Improvement of 1 point or more on Rankin scale
Better indicated by lower values
Follow-up: 2 to 6 weeks
12 per 100 30 per 100
(12 to 73)
RR 2.4
(0.98 to 5.83)
902
(3 studies)
⊕⊕⊕⊝
moderate
The RR corresponds with a number needed to treat of 5.26 (95% CI 2.78 to 50.00) for 1 point or more improvement on Rankin scale.
Change in mean disability score on scale used in original study
Better indicated by lower values
Follow-up: 2 to 6 weeks
-The mean change in mean disability score on scale used in original study in the intervention groups was
1.37 standard deviations higher
(0.22 to 2.53 lower)
-2473
(5 studies)
⊕⊕⊕⊕
high
Different disability scales were used, making translation to clinical practice difficult. Four of the 5 studies (197 treatments) used disability scales with maximum scores ranging between 5 and 14 points. The difference in change in mean disability between treatments in these studies ranged from 0.17 to 1.15 points in favour of IVIg when compared to placebo. The fifth study (Hahn 1996) used a different disability scale in which the difference of mean change in disability between treatments was 29.4 in favour of IVIg with a mean baseline score of 78.4 in the IVIg group.
Change in mean disability score on Rankin scale
Scale from: 0 to 6. Better indicated by lower values.
Follow-up: 2 to 6 weeks
-The mean change in mean disability score on Rankin scale in the intervention groups was
0.26 higher
(0.05 to 0.48 lower)
--904
(3 studies)
⊕⊕⊕⊕
high
 
Serious side effects
questionnaires
Follow-up: 4 to 24 weeks
8 per 100 7 per 100
(3 to 16)
RR 0.82
(0.36 to 1.87)
3155
(3 studies)
⊕⊕⊕⊕
high
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: risk ratio; IVIg: intravenous immunoglobulin; SMD: standardised mean difference
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 IVIg compared to plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy

Summary of findings 2. IVIg compared to plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy
  1. 1Cross-over study (20 participants, 32 treatments).
    2The authors of this systematic review believe that quality of evidence is not optimal when based on the results of a single trial with a relatively small number of participants, even in case of a high quality trial.

IVIg compared to plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy
Patient or population: patients with chronic inflammatory demyelinating polyradiculoneuropathy
Settings: tertiary care centre
Intervention: IVIg
Comparison: plasma exchange
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Plasma exchange IVIg
Significant improvement in disability scale used in original studySee commentSee commentNot estimable-See commentNot reported
Improvement of 1 point or more on Rankin scaleSee commentSee commentNot estimable-See commentNot reported
Change in mean disability score on scale used in original study
The modified Neuropathy Disability Score (NDS). Better indicated by lower values
Follow-up: 6 weeks
-The mean change in mean disability score on scale used in original study in the intervention groups was
0.06 standard deviations lower
(0.76 lower to 0.63 higher)
-32
(1 study1)
⊕⊕⊕⊝
moderate 2
SMD -0.06 (-0.76 to 0.63).
Change in mean disability score on Rankin scale -See commentSee commentNot estimable-See commentNot reported
Serious side effectsSee commentSee commentNot estimable-See commentNo serious adverse events in the IVIg group.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; SMD: standardised mean difference
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 IVIg compared to prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy

Summary of findings 3. IVIg compared to prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy
  1. 1The authors believe that quality of evidence is not optimal when based on the results of a single trial, even in the case of a high quality trial.

    2Cross-over study (32 participants, 57 treatments).

IVIg compared to prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy
Patient or population: patients with chronic inflammatory demyelinating polyradiculoneuropathy
Settings: tertiary care centre
Intervention: IVIg
Comparison: prednisolone
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
prednisolone IVIg
Significant improvement in disability scale used in original study
INCAT disability scale. Better indicated by lower values
Follow-up: 4 weeks
62 per 100 56 per 100
(31 to 100)
RR 0.91
(0.5 to 1.68)
29
(1 study)
⊕⊕⊕⊝
moderate 1
 
Improvement of 1 point or more on Rankin scaleSee commentSee commentNot estimable-See commentNot reported
Change in mean disability score on scale used in original studySee commentSee commentNot estimable-See commentNot reported
Change in mean disability score on Rankin scaleSee commentSee commentNot estimable-See commentNot reported
Serious side effects
questionnaires
Follow-up: 4 weeks
7 per 100 3 per 100
(0 to 35)
RR 0.45
(0.04 to 4.69)
57
(1 study1)
⊕⊕⊕⊝
moderate 2
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; INCAT: Inflammatory Neuropathy Cause and Treatment; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 IVIg compared to intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy

Summary of findings 4. IVIg compared to intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy
  1. 1The authors believe that quality of evidence is not optimal when based on the results of a single small trial, even in case of a high quality trial.

    2No serious adverse events were observed in participants treated with intravenous methylprednisolone (IVMP). However, this is probably the result of small numbers of treated patients. Observational studies with IVMP in CIDP are lacking. In one large retrospective study including people with multiple sclerosis, serious adverse events were reported in three of 187 (2%) participants (Mult Scler 2009;15(9):1085-91) Based on these data and clinical practice we estimate the risk of serious adverse events due to IVMP at 2 to 5 per 100.

IVIg compared to intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy
Patient or population: chronic inflammatory demyelinating polyradiculoneuropathy
Settings: tertiary care centre
Intervention: IVIg
Comparison: intravenous methylprednisolone
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Intravenous methylprednisolone IVIg
Significant improvement in disability scale used in original study
ONLS disability score, Better indicated by a lower score
Follow-up: 2 weeks
14 per 100 21 per 100
(6 to 77)
RR 1.46
(0.4 to 5.38)
45
(1 study)
⊕⊕⊕⊝
moderate 1
 
Improvement of 1 point or more on Rankin scale
Rankin scale; Better indicated by lower values
Follow-up: 2 weeks
24 per 100 17 per 100
(5 to 54)
RR 0.7
(0.22 to 2.27)
45
(1 study)
⊕⊕⊕⊝
moderate 1
 
Change in mean disability score on scale used in original study
Disability scale used in original study
Follow-up: 2 weeks
 The mean change in mean disability score on scale used in original study in the intervention groups was
0.04 lower
(0.76 lower to 0.68 higher)
 43
(1 study)
⊕⊕⊕⊝
moderate 1
 
Change in mean disability score on Rankin scale
Follow-up: 2 weeks
 The mean change in mean disability score on Rankin scale in the intervention groups was
0.24 lower
(0.63 lower to 0.15 higher)
 43
(1 study)
⊕⊕⊕⊝
moderate 1
 
Serious side effects
questionnaires
Follow-up: 24 weeks
Low RR 4.4
(0.22 to 86.78)
45
(1 study)
⊕⊕⊕⊝
moderate 1
 
2 per 100 9 per 100
(0 to 100)2
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ONLS: Overall Neuropathy Limitation Scale; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterised by progressive or relapsing motor and/or sensory symptoms and signs in more than one limb, developing over at least two months (Barohn 1989; Ad hoc subcom 1991; Feasby 1992; Dyck 1993). Sensory disturbances are usually slight, but are found in approximately 80% of participants. Proximal and distal parts of the limbs are usually affected symmetrically. Atrophy is less marked than weakness. Loss of reflexes is found in almost all participants, but may be confined to the ankles. Cranial nerve involvement, sometimes preceding the neuropathy, has been reported infrequently (Donaghy 1985; Barohn 1989).

The overall crude prevalence of definite and probable CIDP is 1 to 9 per 100,000 adults (Lunn 1999; McLeod 1999; Laughlin 2009) and 0.5 per 100,000 children (McLeod 1999). The estimated crude annual incidence is 0.15 to 1.6 per 100,000 adults. CIDP can cause prolonged periods of disability with 54% of people with CIDP becoming severely disabled (modified Rankin score of four or five) at some time during the illness (Lunn 1999). More than 10% of people remain severely disabled despite treatment (Lunn 1999; Chiò 2007). CIDP can occur at any age, with a peak prevalence in the sixth and seventh decade (McLeod 1999).

The diagnosis of CIDP is based on the clinical, electrophysiological, cerebrospinal fluid features and, to a limited degree, on histopathology. Cerebrospinal fluid protein levels are generally elevated without cellular reaction (Dyck 1993). Electrophysiologically, the disease is characterised by reduced nerve conduction velocities, abnormal temporal dispersion and conduction block (Barohn 1989; van der Meché 1989; van Doorn 1991). The pathological findings include multifocal demyelination, mononuclear cells in close approximation to demyelinated axons, remyelination, fibre loss and 'onion bulbs' (Barohn 1989; Dyck 1993). Lymphocytic infiltration can be found in sural nerve biopsies, but, as may be expected from a predominantly motor neuropathy with multifocal involvement, biopsies are frequently normal (Matsumuro 1994; Molenaar 1998).

CIDP has to be distinguished from Guillain-Barré syndrome (GBS), the inherited demyelinating polyneuropathies, metabolic neuropathies (associated with diabetes, uraemia, acromegaly, hepatitis, amyloidosis, and hypothyroidism), paraneoplastic neuropathies, neuropathies associated with monoclonal gammopathies, neuropathies associated with human immunodeficiency virus or Lyme disease, and multifocal motor neuropathy. CIDP is often considered to be a chronic variant of GBS. Differentiation of the two disorders relies on arbitrary clinical criteria of the time necessary to reach maximum deficit. In GBS this is less than four weeks and in CIDP more than eight weeks (Ad hoc subcom 1991; Feasby 1992). Apart from the time course, the prognosis of CIDP is worse than GBS. More than 80% of participants fail to make a spontaneous recovery. The distinction between CIDP and GBS is important because the course, treatment and outcome are different (Pollard 1987; Simmons 1993).

CIDP is an immune mediated disorder. A beneficial effect of immunosuppressive therapy (e.g. corticosteroids) and plasma exchange has been demonstrated in randomised clinical trials (RCTs) (Server 1979; Gross 1981; Dyck 1982; Dyck 1986; van der Meché 1997; Briellmann 1998; Hahn 1998). Several uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin (IVIg) administration (Vermeulen 1985; van der Meché 1989; Faed 1989; van Doorn 1990b; van Doorn 1991; Cornblath 1991). The mode or modes by which IVIg exerts this beneficial effect in CIDP are not clear, but various mechanisms of improvement after IVIg treatment have been suggested (van Schaik 1994; Yu 1999). Studies in other diseases treated with IVIg have demonstrated that IVIg may inhibit autoantibody production, neutralise pathogenic antibodies, and decrease antibody-dependent cellular cytotoxicity by blocking Fc-receptors on macrophages (Kazatchkine 2001). Furthermore, peripheral blood from patients treated with IVIg shows increased CD8-positive suppressor T-cell function.

No systematic review had been published before the first version of this Cochrane review appeared in 2002. We here provide the most recent update of this systematic review of randomised trials of IVIg for the treatment of CIDP.

Objectives

To review systematically the evidence from RCTs concerning the efficacy and safety of IVIg in CIDP.

Methods

Criteria for considering studies for this review

Types of studies

We searched for all RCTs or quasi-RCTs (alternate or other systematic allocation) examining the effects of IVIg treatment in participants with CIDP.

Types of participants

Eligible studies had to include participants with definite or probable CIDP. This was defined as an illness with symptoms and signs of polyneuropathy in the absence of systemic disease, electrophysiological diagnosis of a demyelinating polyneuropathy (based on reduced nerve conduction velocities and or conduction blocks consistent with demyelination) and progression of weakness exceeding eight weeks. Increased cerebrospinal fluid protein (more than 0.5 g/L) without a pleocytosis was considered supportive, but not essential for the diagnosis. It was necessary for participants to have a normal erythrocyte sedimentation rate, haematocrit, white cell and platelet counts, serum creatinine, serum glucose, and liver and thyroid function tests, absent antinuclear antibodies, cryoglobulins, and monoclonal proteins, and a normal chest radiograph. Participants were excluded if they had mutilation of hands or feet, retinitis pigmentosa, ichthyosis, drug or toxic exposure known to cause a peripheral neuropathy, a family history of demyelinating polyneuropathy, clinical suspicion of a vasculitic disorder, sensory level at examination, or unequivocal sphincter disturbances. A nerve biopsy was not mandatory.

We set no restriction on appropriate settings for trials in this review. However, considering the challenge of diagnosing and treating people with CIDP, hospitals and neuromuscular centres are likely to be the usual settings.

Types of interventions

We considered any dose of immunoglobulin administered intravenously and compared with placebo, plasma exchange or corticosteroids eligible for inclusion. The source of IVIg was not considered to be important as long as the preparation was produced according to the guidelines of the World Health Organization (WHO) (WHO 1982).

Types of outcome measures

Since different studies used different disability scales, we defined the primary outcome measure as the proportion of participants with a significant improvement in disability within six weeks after the onset of treatment as determined and defined by the original authors. In each study the strictest available criteria to define 'significant' improvement were used. Where possible, we transformed disability data to the modified six-point Rankin disability scale (de Haan 1993; Table 1). We asked all authors of included trials for original data to enable this transformation. We defined a significant improvement as at least one point improvement on this scale. No change or worsening on the Rankin scale was rated as no improvement.

Table 1. Transformation of Functional disability scale to Rankin disability scale
  1. FDS: functional disability scale.

FDSRankinFDS descriptionRankin description
00normalasymptomatic
11minor symptoms capable of runningnon-disabling symptoms which do not interfere with lifestyle
22able to walk 30 feet without assistance but unable to runminor disability symptoms which lead to some restriction of lifestyle but do not interfere with the patients' capacity to look after him/herself
33able to walk 30 feet with the assistance of one person, a walker or a canemoderate disability symptoms which significantly interfere with lifestyle or prevent totally independent existence
44unable to walkmoderate severe disability symptoms which clearly prevent independent existence, but do not require constant attention day and night
55requires assisted ventilationseverely disabled, totally dependent, requiring constant attention day and night
6-death-

Secondary outcome measures were:
(i) the change in mean disability score assessed within six weeks after the onset of treatment and compared to baseline;
(ii) the change in mean Medical Research Council (MRC) sum score assessed within six weeks after the onset of treatment and compared to baseline;
(iii) the change in mean disability score at 24 weeks or more;
(iv) the frequency of serious side effects;
(v) the frequency of any side effects.

In these analyses, for clarity of interpretation, we considered the Rankin disability scale and MRC sum score to be quasi-linear scales.

Search methods for identification of studies

Electronic searches

On 4 December 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012 Issue 11 in the Cochrane Library), MEDLINE (January 1985 to December 2012), EMBASE (January 1985 to December 2012), and ISI (1985 to May 2008). We restricted the search to articles published from 1985 onwards because, to our knowledge, IVIg was first used in CIDP in that year. For the detailed search strategies, see the appendices: Appendix 1 (MEDLINE), Appendix 2 (EMBASE), Appendix 3 (ISI) and Appendix 4 (CENTRAL).

Searching other resources

We performed a search of the references listed in the published studies, reviews, textbooks, and relevant conference proceedings. We searched for ongoing trials through two metaRegistries, the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal, and Current Controlled Trials. We contacted investigators identified as active in the field to identify unpublished or overlooked studies. Readers are invited to suggest studies, particularly in other languages, which should be considered for inclusion when the review is next updated.

Data collection and analysis

Selection of studies

Two review authors (IvS and JW in original review, FE and JW in the latest update) independently reviewed titles and abstracts obtained from literature searches to identify potentially relevant trials. We conducted searches of bibliographies and texts to identify additional studies. Using the full text publications, we selected trials which met the selection criteria for inclusion and graded their methodological quality. Review authors were not blinded to author and source institution. We resolved disagreement by consensus.

Data extraction and management

Two review authors extracted data independently using a data extraction tool. Review authors were not blinded to author and source institution. We resolved disagreement by consensus.

Assessment of risk of bias in included studies

In the original protocol and earlier versions of the review we assessed methodological quality using a method as proposed by Mulrow and Gillespie (Mulrow 1997; Gillespie 1998). Following the updated guidance in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 (Higgins 2008, updated Higgins 2011), we completed a 'Risk of bias' table, addressing the following domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other issues. We made a judgement about the risk of bias for each entry, such that a judgement of 'Low' indicated a low risk of bias, 'High' indicated a high risk of bias, and 'Unclear' indicated unclear or unknown risk of bias.

Measures of treatment effect

For dichotomous data, such as the proportion of participants with a significant improvement in disability, we calculated the risk ratio (RR) for each study with 95% confidence intervals (CIs). To assess overall efficacy from all the studies, we calculated pooled RR estimates with 95% CIs. For the primary outcome we also calculated numbers needed to treat for an additional beneficial effect (NNTB) with inversed CIs of the risk differences.

For continuous data we used mean difference (MD) and 95% CI when outcomes were measured on the same scale. We anticipated that different trials would use different scales to measure the same secondary outcomes. In this case we calculated a standardised mean difference (SMD) and 95% CI. SMD is a dimensionless measure of effect for continuous data which is useful in combining results of individual studies in which the same outcome is measured with different instruments or scales. The SMD was defined as the mean change in score of the placebo group minus mean change in score of the treatment group, divided by the pooled standard deviation of the change in scores of the two groups.

Means and standards deviations have been derived by calculation or extraction from the available published or received unpublished data. To assess overall efficacy, we calculated pooled MD or SMD estimates using a random-effects or fixed-effect model depending on heterogeneity of study results.

Unit of analysis issues

We analysed the results from cross-over trials in two ways: (1) we considered cross-over trials as two consecutive parallel design trials assuming that no carryover effect had occurred; this is considered to be a conservative analysis method (Higgins 2008). We included data from participants who did not cross over to the second treatment because of improvement during the first treatment period in analyses for the first treatment only; (2) we analysed cross-over trials making use of the generic inverse variance (GIV) approach, using the natural logarithms of the RR and standard error (SE) which avoids the error of falsely wide CIs of cross-over studies leading to less weight and therefore possibly disguising clinically important heterogeneity (Elbourne 2002; Higgins 2008). In the text pooled RR estimates are given separately for all studies and for the parallel design trials only.

For cross-over studies, we calculated correlation coefficients for all outcomes, when possible. If paired results were not reported in a study, paired analyses were approximated by assuming the correlation between treatment and placebo found in the other studies. We subsequently undertook a sensitivity analysis using different values of correlation to assess the impact of the assumed correlation. We used the GIV method to pool both the SMD and MD of individual cross-over studies.

Dealing with missing data

We contacted authors of all the included trials and asked them to provide original data from their studies. We used intention-to-treat analysis for the primary outcome. Based on published and unpublished data we performed an available case analysis for all other outcomes. We did not therefore include missing data in the analysis. We used a last-observation-carried-forward approach in study participants reaching a premature endpoint, to calculate differences from baseline measurements.

Assessment of heterogeneity

We used the Chi2 statistic to measure heterogeneity among the trials in each analysis. Where there was heterogeneity we looked for an explanation in the characteristics of the trials. If we had identified substantial unexplained heterogeneity we would have reported it and explored possible causes by prespecified subgroup analysis.

Assessment of reporting biases

We did not explore small study biases using a funnel plot as there were too few included studies.

Data synthesis

When the Chi2 statistic showed our data to be heterogeneous, we used the random-effects model of DerSimonian and Laird (Ioannidis 1995). If no heterogeneity could be demonstrated, we used a fixed-effect model (Mantel-Haenszel RR method) (Rothman 1986).

Subgroup analysis and investigation of heterogeneity

We planned to analyse subgroups of interest because of their prognostic importance in previous prospective studies and trials (van Doorn 1991). However, none of the studies provided enough data on subgroups to allow for such analyses.

Sensitivity analysis

We also planned to undertake a sensitivity analysis on the basis of the risk of bias of the studies. As all eligible studies were at unclear or high risk of bias, this was not done.

'Summary of findings' table

In this update we added 'Summary of findings' tables with the following five outcomes: significant improvement in disability scale used in original study, improvement of one point or more on Rankin scale, change in mean disability score on scale used in original study, change in mean disability score on Rankin scale, and serious adverse events. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes) (Schünemann 2011).

Results

Description of studies

Results of the search

The numbers of papers found by the new current searches were as follows: MEDLINE, 220 (of which 46 were new references for this update); EMBASE 140 (36 new references); Cochrane Neuromuscular Disease Group Specialized Register, 56 papers (11 new); CENTRAL, 30 references (30 new). The search strategy turned out to be rather sensitive and not very specific. After removal of duplicates, the search strategy for this update retrieved 90 new papers of which we selected one for full-text review (Nobile-Orazio 2012). Thus, we considered a total of 15 studies to be potentially relevant for this review (see Figure 1). We excluded seven studies and included eight.

Figure 1.

A flow diagram illustrating the study selection process.

Included studies

The eight included RCTs involved a total of 332 participants with CIDP (Vermeulen 1993; Dyck 1994; Hahn 1996; Thompson 1996; Mendell 2001; Hughes 2001; Hughes 2008; Nobile-Orazio 2012). Five RCTs compared intravenous immunoglobulin (IVIg) treatment with placebo, one compared IVIg with plasma exchange (Dyck 1994), one compared IVIg with prednisolone (Hughes 2001) and one compared IVIg with intravenous methylprednisolone (IVMP) (Nobile-Orazio 2012). Four RCTs had a parallel-group design (Vermeulen 1993; Mendell 2001; Hughes 2008; Nobile-Orazio 2012) and four had a cross-over design. A total of 2 g/kg bodyweight of IVIg was administered in each trial over two (Hughes 2001; Mendell 2001), two to four (Hughes 2008; Nobile-Orazio 2012), or five days (Vermeulen 1993; Hahn 1996; Thompson 1996). In one trial the baseline loading dose was followed by a maintenance dose of 1 g/kg every three weeks (Hughes 2008), while in one trial the loading dose of 2 g/kg was equivalent to the maintenance dose, which was administered every four weeks (Nobile-Orazio 2012). In the latter trial, participants treated with IVMP received a total of 2 g of IVMP over four consecutive days every four weeks (Nobile-Orazio 2012). In the trial comparing IVIg with prednisolone, a six-week course of oral prednisolone tapering from 60 mg to 10 mg daily was given (Hughes 2001). One study administered a total of 1.8 g/kg bodyweight of IVIg in a course of six weeks and compared this treatment with plasma exchange twice weekly for three weeks, then once weekly for another three weeks (Dyck 1994). Each study used different outcome measures. More details of these studies are in Characteristics of included studies.

The largest study was a randomised response-conditional cross-over design study (Hughes 2008). Participants who did not achieve improvement upon appointed treatment received the alternate treatment during the first study period. After 24 weeks only those participants who improved during the first study period were re-randomised for an extension phase of another 24 weeks. In both periods, participants switched to the alternate treatment in the event of deterioration on an adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. Primary outcome was defined as the percentage of participants who improved and maintained improvement from baseline at the adjusted INCAT disability score. For the purpose of this review, we analysed only the first treatment period because the sample entering the extension phase was largely biased. The first period can be considered to be a parallel group trial since the cross-over only took place in participants who did not improve. The trial authors provided original data at six weeks from the first study period. We used the number of participants who achieved sufficient improvement by six weeks (and thus were not crossed over by six weeks) in the meta-analysis for the primary outcome of this review.

We obtained Individual patient data from five studies (Vermeulen 1993; Thompson 1996; Hughes 2001; Hughes 2008; Nobile-Orazio 2012). We sent a request for individual patient data to the principal investigators of the other trials. Two investigators have promised to supply us with the necessary information in due course (Hahn 1996; Mendell 2001). One refused because of three reasons: (1) "privacy of patients cannot be protected", (2) "primary investigators no longer have a meaningful input into the handling of their data or its interpretation" and (3) "good data may be lumped with poor data" (Dyck 1994).

Excluded studies

We excluded seven studies (Curro 1987; van Doorn 1990a; Hankey 1994; Baba 1996; Dalakas 1996; Kubori 1999; Zinman 2005). For reasons, see Characteristics of included studies.

Risk of bias in included studies

Figure 2 gives the review authors' judgements for each 'Risk of bias' domain for each trial. One of the five RCTs comparing IVIg with placebo did not contain adequate information to judge allocation sequence generation and concealment (Thompson 1996). In one study the blinding of outcome assessors was not described in detail (Mendell 2001), although risk of bias due to lack of blinding of assessors was considered to be low. In all five studies, all outcomes stated in the methods section were also reported in the results section. In one study, additional treatment was stated but trivial confounding could be expected (Hahn 1996), while in another study additional treatment was not mentioned (Thompson 1996). One study assessed the primary outcome between days 16 and 21, which was just below the cut-off level of three weeks which we took as the lower limit of a clinically appropriate study duration (Vermeulen 1993), while another study assessed outcomes at two weeks, which we considered not to be a clinically appropriate study duration (Thompson 1996). Intention-to-treat analysis was not possible in one study as the outcome data of three participants who dropped out could not be collected (Mendell 2001). One study used a response-conditional cross-over design, which means that not all participants received both treatments (Hahn 1996). Imbalance in recruitment and a prestudy design for block randomisation by participating centres accounted for a discrepancy in the number of participants in the groups (Mendell 2001). One study did not provide electrophysiological criteria for the definition of a demyelinating polyneuropathy (Vermeulen 1993), although it is not likely that this has led to selection bias. The largest study was in essence a parallel design study with a conditional cross-over 'escape' for those participants who did not improve sufficiently (Hughes 2008). The study was of a high quality and provided the longest follow-up.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study. Green = low risk of bias; yellow = unclear risk of bias; red (not shown) = high risk of bias.

The RCT comparing IVIg with plasma exchange did not contain adequate information to judge allocation sequence generation and concealment and did not perform an intention-to-treat analysis (Dyck 1994). Also, participants and treatment providers were not blinded in this study, although we considered that the risk of this introducing bias was low.

In the RCT comparing IVIg with prednisolone, some unblinding of treatment providers was expected to have taken place (Hughes 2001). Not all participants entered the cross-over phase owing to the use of a response-conditional cross-over design. Primary analysis was performed only for participants completing both treatments.

The study comparing IVIg with IVMP was of high quality with an adequate follow-up period of six months during treatment, followed by six months off treatment (Nobile-Orazio 2012). Original data on disability, Rankin score and MRC sum score were provided at 15 days, two months and six months. We used disability and Rankin scores at 15 days for the primary outcome, as the two-month and six-month follow-up were longer than the upper limit of six weeks chosen as an appropriate treatment duration for assessment of short-term efficacy. Except for some nonsignificant imbalances in baseline characteristics between both treatment groups (younger age, less disability, more frequent IVIg treatment prior to study and less comorbidity in the IVIg treatment group), we did not identify other risks of bias.

Effects of interventions

See: Summary of findings for the main comparison IVIg compared to placebo for chronic inflammatory demyelinating polyradiculoneuropathy; Summary of findings 2 IVIg compared to plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy; Summary of findings 3 IVIg compared to prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy; Summary of findings 4 IVIg compared to intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy

IVIg versus placebo

Five trials studied this comparison (Vermeulen 1993; Hahn 1996; Thompson 1996; Mendell 2001; Hughes 2008).

Primary outcomes
Significant improvement in disability within six weeks of onset of treatment as determined and defined by the original authors (Analysis 1.1 and Analysis 1.2).

For this analysis, five RCTs summarising the results of 235 participants were suitable (Vermeulen 1993; Hahn 1996; Thompson 1996; Mendell 2001; Hughes 2008). Outcomes were assessed at 14 days (Thompson 1996), at 16 to 21 days (Vermeulen 1993), at 28 days (Hahn 1996), and at 42 days (Mendell 2001; Hughes 2008). Intravenous immunoglobulin was given 141 times and placebo 128 times. These 269 treatments were given in 198 participants included in three parallel design trials (104 participants assigned to IVIg, 94 to placebo) and 37 participants included in two cross-over trials. Of the 37 participants in the cross-over trials, three participants did not cross over to the second treatment because of improvement during the first treatment period (Hahn 1996). All these participants were subsequently found to be on the active treatment, meaning that 37 IVIg and 34 placebo treatments were administered. These three participants were included in the analysis of the IVIg arm. A significant improvement was reported in 78 out of 141 IVIg treatments and spontaneous improvements in 30 out of 128 placebo treatments. A significantly higher proportion of participants improved after IVIg therapy as compared with placebo, with a pooled RR of 2.40 (95% CI 1.72 to 3.36). The NNTB was 3.03 (95% CI 2.33 to 4.55). The study results were homogeneous (Chi2 statistic 3.34 df = 4, P = 0.50). In analysis of the results of the parallel design trials alone (Vermeulen 1993; Mendell 2001; Hughes 2008), significant improvement was reported in 57 out of 104 IVIg treatments and spontaneous improvements in 25 out of 94 placebo treatments, RR of 2.14 (95% CI 1.48 to 3.09; test for overall effect Z = 4.05 P < 0.0001). NNTB was 3.33 (95% CI 2.38 to 5.88). The study results were homogeneous (Chi2 statistic 1.79, df = 2, P = 0.41).

We used a GIV method to analyse the primary outcome for the cross-over trials separately to account for paired observations in the two cross-over studies (Analysis 1.2). This analysis resulted in almost identical pooled RR estimates for the cross-over trials: 3.52 (95% CI 1.58 to 7.87).

Improvement of one or more points on Rankin scale (Analysis 1.3)

One trial used the Rankin scale to assess disability (Vermeulen 1993). In two trials it was possible to transform the disability scale to a six-point Rankin score. One trial used a functional disability score designed by Hughes (Mendell 2001), which was transformed according to Table 1 for the available cases only. The authors of another trial provided us with individual patient data and scored their participants on the Rankin disability scale (Thompson 1996). In two trials, disability outcome could not be transformed to the Rankin scale with the data available from the papers (Hahn 1996; Hughes 2008). Therefore we analysed three RCTs including 84 participants for this comparison. Six of those 84 participants were included in a cross-over trial, resulting in 90 treatments. An improvement of one or more points on the Rankin scale occurred in 16 out of 50 participants treated with IVIg and in five out of 40 participants treated with placebo.

The proportion of participants with improvement (at least one point decrease on this scale) was higher in the IVIg group compared to the placebo group (RR 2.40 (95% CI 0.98 to 5.83)). This just reached significance. The NNTB was 5.26 (95% CI 2.78 to 50.00). The study results were also homogeneous (Chi2 statistic 1.74, df = 2, P = 0.42). Leaving out the cross-over trial (Thompson 1996), significant improvement was reported in 15 out of 44 IVIg treatments and 5 out of 34 placebo treatments, with an RR of 2.34 (95% CI 0.92 to 5.94), NNTB 5.26 (95% CI 2.7 to 100.00). The study results were homogeneous (Chi2 statistic 1.69, df = 1, P value = 0.19). We did not perform a GIV analysis for this outcome as only one cross-over study including six participants was available for analysis.

Secondary outcomes

All secondary outcomes except for absence of serious or any side effects were assessed at the following times: 14 days (Thompson 1996), 16 to 21 days (Vermeulen 1993), 28 days (Hahn 1996) and 42 days (Mendell 2001; Hughes 2008).

Change in mean disability score on scale used in original study (Analysis 1.4 and Analysis 1.5)

We analysed the disability scores from five trials, including 215 participants. In Hahn 1996, SDs of the MD of the sham group were estimated using the correlation coefficient of 0.5 calculated from the MD and its SD from the IVIg group. A sensitivity analysis showed this to be a somewhat conservative but robust estimate. The results of the five RCTs were highly heterogeneous for this analysis (Chi2 statistic = 54.95, df = 4, P < 0.00001). This is not unexpected since various scales with different numeric intervals and maximal and minimal scores had been used to assess disability. The pooled SMD for all studies was 1.37 (95% CI 0.22 to 2.53). This indicates that the mean of the treated group was approximately one standard deviation higher than the mean of the untreated group.

We used the GIV method to analyse this outcome for the cross-over trials separately, to account for paired observations (Analysis 1.5). The pooled estimate of the SMD was almost the same as in the previous analysis (2.84, 95% CI -1.46 to 7.13).

Change in mean disability score on Rankin scale (Analysis 1.6)

In the three trials in which a Rankin score was used or could be deduced, the mean improvement in disability was between 0.17 and 0.40 points on the Rankin scale in the IVIg-treated groups and between 0.00 and 0.23 points in the placebo groups. This resulted in a MD that was significant, 0.26 (95% CI 0.05 to 0.48). Studies were homogeneous (Chi2 statistic = 2.30, df = 2, P = 0.32). We did not perform GIV analysis as only one cross-over study including six participants with this outcome was available for analysis.

Change in mean MRC sum score (Analysis 1.7)

Two trials (35 participants) reported MRC sum scores (Vermeulen 1993; Thompson 1996). Seven participants received placebo and IVIg in a cross-over trial; 28 participants received either IVIg (n = 15) or placebo (n = 13) in a parallel study design. Mean MRC sum scores were available for a total of 42 treatments. Thompson 1996 used an expanded version of the MRC sum score, with the addition of the first dorsal interosseus muscle so that the maximum score was 70. Vermeulen 1993 used the standard MRC sum score with a total score ranging from 0 to 60. Despite the slight difference in outcome assessment the results between the two studies were homogeneous (Chi2 statistic = 0.37, df = 1, P = 0.54) and we calculated a pooled MD. The MD was 0.78 (95% CI -1.04 to 2.60), which is not statistically significant. GIV approach analysis has not been performed as only one study including seven participants with this outcome was available for analysis.

Change in the mean disability score at 24 weeks or more (Analysis 1.8)

There was only one trial with a longer follow-up in which disability was assessed at 24 weeks on a adjusted INCAT disability score (Hughes 2008). During this first period, 23 of 59 participants that were assigned to IVIg treatment did not respond and were switched to the placebo treatment. In contrast, 45 of the 58 participants that started with placebo treatment did not respond and were switched to IVIg treatment. Mean change from baseline disability was 1.1 (SD 1.8) in the IVIg treatment group and 0.3 (SD 1.3) in the placebo treatment group. The MD was 0.8 (95% CI 0.23 to 1.37) which was a significant improvement (test for overall effect Z = 2.76, P = 0.006).

Serious side effects (Analysis 01.09) and any side effect (Analysis 1.10)

In two trials, side effects were not mentioned (Vermeulen 1993; Thompson 1996). In the largest trial, side effects were reported in 62 of 113 participants treated with IVIg and in 16 of 95 participants treated with placebo during two periods of in total 48 weeks (Hughes 2008). Serious side effects were reported in six of 113 participants (5%) treated with IVIg (9/1096 infusions, 0.8%) and 8 of 95 participants (8%) treated with placebo (11/595 infusions, 1.9%). The most common adverse events in the IVIg group were headache (4% of infusions) and pyrexia (2.4%). In the cross-over trial including 30 participants, one participant on IVIg developed side effects resembling aseptic meningitis and no other side effects were noted (Hahn 1996). In the parallel-group trial including 50 participants (IVIg n = 29; placebo n = 21) headache, nausea, chills, fever and transient hypertension were reported to occur in both treatment groups, although more often in the IVIg group compared to those participants receiving placebo (Mendell 2001).

The RR for the development of serious side effects was not significantly different between IVIg and placebo treatment (RR 0.82, 95% CI 0.36 to 1.87). Considering any side effects, there was a significantly increased risk with IVIg treatment (RR 2.61, 95% CI 1.80 to 3.78). The number needed to treat for an additional harmful outcome, that is, to experience any side effect with IVIg treatment, was 3.3 (95% CI 2.56 to 4.76).

IVIg versus plasma exchange

Primary outcomes

Only one trial compared IVIg with plasma exchange in a cross-over design (Dyck 1994). Seventeen participants completed the trial, receiving IVIg 15 times and plasma exchange 17 times. The primary outcomes of this systematic review could not be assessed, as the proportion of treatment responders was not extractable from the paper (Analysis 2.1).

Secondary outcomes
Change in mean disability score on scale used in original study (Analysis 2.1)

The mean improvement at six weeks on the Neurological Disability Scale (NDS) after IVIg treatment was 36.1 ± 32.0 and after plasma exchange 38.3 ± 34.6. During the wash-out period participants worsened on average by 37.8 ± 44.8 points. The SMD for treatment with IVIg compared to assessment at the end of the wash-out period was 1.92 (95% CI 1.03 to 2.82) and for treatment with plasma exchange versus wash-out period it was 1.92 (95% CI 1.02 to 2.82). Comparing IVIg with plasma exchange revealed no difference. The SMD was -0.06 (95% CI -0.76 to 0.63).

The Neuropathy Disability Score (NDS) could not be transformed to the Rankin score with the data available from the paper. Apart from adverse events, the other secondary outcome measures used in this systematic review were not retrievable from the data available in the published report.
In the plasma exchange group, two problems were reported with catheters, and various minor side effects such as light headedness, nausea and rash were reported to be common without more precise details being mentioned. No serious complications were recorded in the IVIg treatment group. Minor complications were not mentioned.

One other outcome measure was used in this study: the weakness subset of the NDS. Although not a planned analysis, we calculated the MD and CIs for this outcome. The mean improvement on the weakness subset of the NDS was 31.4 ± 31.5 after IVIg treatment and 33.4 ± 29.5 after plasma exchange. During the wash-out period participants worsened by on average 33.4 ± 37.9 points. The MD for treatment with IVIg compared to the wash-out period was 1.81 (95% CI 0.94 to 2.68) and for treatment with plasma exchange versus wash-out period, 1.92 (95% CI 1.09 to 2.75). Comparing IVIg with plasma exchange revealed no difference. The MD was 0.06 (95% CI -0.76 to 0.63).

IVIg versus corticosteroids

Primary outcomes

One trial, including 32 participants, compared IVIg treatment with prednisolone (Hughes 2001). Using a cross-over design, 29 out of 30 IVIg courses and 24 out of 27 prednisolone courses were completed according to the trial protocol. Fifteen participants received prednisolone and 17 participants received IVIg in the first treatment arm. Twenty-four participants completed both treatment arms. Outcomes were assessed at four weeks. The proportion of participants with significant improvement (Analysis 3.1 and Analysis 3.2) could not be extracted from the published paper, but these results were provided by the investigators for the first observation period of the cross-over trial.

Significant improvement in disability within one month of onset of treatment as determined and defined by the original authors (Analysis 3.1)

An improvement of one grade or more on the INCAT disability scale was reported in 9 out of 16 IVIg treatments and in 8 out of 13 prednisolone treatments. The proportion of participants with a significant improvement did not differ significantly between the two treatment arms (RR of 0.91, 95% CI 0.50 to 1.68).

Improvement of one or more points on Rankin scale (Analysis 3.2)

An improvement of one point or more on the Rankin scale was reported in 7 out of 17 IVIg treatments and in 6 out of 14 prednisolone treatments. The proportion of participants with improvement was not higher in the IVIg group compared to the prednisolone group (RR 0.96, 95% CI 0.42 to 2.20).

Secondary outcomes
Change in mean disability score on scale used in original study (Analysis 3.3)

Considering the 24 participants who completed the whole trial and were used for the primary analysis in the original paper, the mean improvement at two weeks on the disability scale used in this study was 0.71 ± 1.27 grades after IVIg treatment and 0.58 ± 0.93 grades after prednisolone treatment, resulting in a MD of 0.13 (95% CI -0.50 to 0.76) in favour of IVIg. This outcome was also assessed in these participants at six weeks, when there was an improvement of 0.71 ± 1.19 grades after IVIg and 0.62 ± 1.53 grades after prednisolone.The MD was 0.09 (95% CI -0.69 to 0.87), favouring IVIg.

In an analysis of the first treatment arm only (IVIg n = 15, prednisolone n = 17), the mean improvement on the disability scale was 1.24 ± 1.75 grades after IVIg treatment and 0.53 ± 0.74 grades after prednisolone treatment, resulting in a MD of 0.71 (95% CI -0.05 to 1.47).

Change in mean disability score on Rankin scale (Analysis 3.4)

The mean Rankin score worsened by 0.38 ± 0.65 after IVIg treatment and 0.17 ± 0.76 after prednisolone treatment. The MD was -0.21 (95% CI -0.61 to 0.19).

Change in mean MRC sum score (Analysis 3.5)

Mean MRC sum scores were available for a total of 46 treatments (IVIg n = 23, prednisolone n = 23). After IVIg the MRC sum score improved on average by 2.3 ± 3.2 and after prednisolone by 1.8 ± 3.2. The MD for change in mean MRC sum score was 0.50 (95% CI -1.35 to 2.35).

Serious side effects (Analysis 3.6) and any side effect (Analysis 3.7)

A total of 30 IVIg treatments and 27 prednisolone courses were given. Serious side effects were reported in three participants: one receiving IVIg and two receiving prednisolone. The RR for developing a serious adverse event was 0.45 (95% CI 0.04 to 4.69). Side effects recorded were headache, indigestion, fever, rash, hypotension, urticaria and psychosis, occurring in 18 out of 30 IVIg courses and in 11 out of 27 prednisolone courses. This resulted in an RR of 1.47 (95% CI 0.86 to 2.53), which was not significant.

Summary of analyses

The figures and graphs display the RR, the MD or the SMD, depending on the type of data.

IVIg versus methylprednisolone

Primary outcomes

One trial, including 45 participants, compared efficacy and tolerability of IVIg versus IVMP administered every month for a six-month period (Nobile-Orazio 2012). The primary outcome of the trial was the difference in the proportion of participants discontinuing treatment because of inefficacy, adverse events or intolerance. Lack of efficacy was defined as absence of improvement after two months of treatment, or worsening after 15 days. Three out of 24 participants (13%) discontinued IVIg, compared to 11 out of 21 participants (52%) treated with IVMP. Most participants discontinued treatment due to lack of efficacy. For the primary outcome of this meta-analysis, we analysed outcome at 15 days from original data provided by the authors.

Significant improvement in disability within six weeks of onset of treatment as determined and defined by the original authors (Analysis 4.1)

An improvement of one grade or more on the Overall Neuropathy Limitation Scale (ONLS) was reported in 5 out of 24 participants treated with IVIg compared to 3 out of 21 participants treated with IVMP. The proportion of participants improving on disability did not differ significantly between the two treatment arms (RR 1.46, 95% CI 0.4 to 5.38).

Improvement of one or more points on Rankin scale (Analysis 4.2)

An improvement of one grade or more on the modified Rankin scale was reported in 4 out of 24 participants treated with IVIg compared to 5 out of 21 participants treated with IVMP. The proportion of participants improving on the Rankin did not differ significantly between the two treatment arms (RR 0.70, 95% CI 0.22 to 2.27).

Secondary outcomes
Change in mean disability score on scale used in original study (Analysis 4.3)

Disability scores at 15 days were available in 43 participants (IVIg n = 24, IVMP n = 19). Mean improvement on disability score was 0.12 ± 1.3 grades after IVIg treatment compared to 0.16 ± 1.1 grades after IVMP treatment, resulting in a MD of -0.04 (95% CI -0.76 to 0.68).

Change in mean disability score on Rankin scale (Analysis 4.4)

Rankin scores at 15 days were available in 43 participants. Mean improvement on the Rankin scale was 0.08 ± 0.72 in the IVIg treated participants and 0.32 ± 0.58 after IVMP treatment. The MD was -0.24 (95% CI -0.63 to 0.15).

Change in mean MRC sum score (Analysis 4.5)

Mean MRC sum scores at 15 days were available for a total of 43 participants. After IVIg the MRC sum score improved on average by 1.63 ± 4.5 and after IVMP by 1.26 ± 3.5. The MD for change in mean MRC sum score was 0.37 (95% CI -2.00 to 2.74).

Change in the mean disability score at 24 weeks or more (Analysis 4.6)

The mean change in disability score at 24 weeks (or at an earlier end point if such occurred) was 0.63 ± 1.61 after IVIg treatment and 0.60 ± 1.57 after IVMP treatment, resulting in a MD of 0.03 (95% CI -0.91 to 0.97). Eleven out of 21 participants treated with IVIg who completed the 24-week period had an improvement of one grade or more on the ONLS disability scale, compared to 5 out of 9 participants treated with IVMP (data were missing for one participant treated with IVMP).

Serious side effects (Analysis 4.7) and any side effect (Analysis 4.8)

During the six months' follow-up, a total of 131 IVIg treatments were administered in 24 participants, compared to 82 IVMP treatments in 21 participants. Two serious side effects were reported in the IVIg group compared to none in the IVMP group, leading to a nonsignificant RR of 4.4 (95% CI 0.22 to 86.78). One participant died because of cardiac arrest one month after the last IVIg treatment, one participant died of respiratory failure three months after last IVIg treatment. Eleven out of 24 (46%) participants treated with IVIg reported at least one side effect compared to 14 out of 21 (67%) participants treated with IVMP. The proportion of participants developing any adverse event did not differ between the groups (RR 0.66, 95% CI 0.39 to 1.13).

Discussion

Eight RCTs including a total of 332 participants with CIDP were suitable for this systematic review. We did not find any other systematic review.

IVIg versus placebo

In the trials comparing IVIg with placebo a significantly higher proportion of participants improved in disability within six weeks after the onset of treatment with IVIg compared with placebo, RR 2.40 (95% CI 1.72 to 3.36) and an NNTB of 3.03 (95% CI 2.33 to 4.55) (Summary of findings for the main comparison). For the parallel design trials only, the RR was 2.14 (95% CI 1.48 to 3.09) and NNTB was 3.33 (95% CI 2.38 to 5.88). Whether all these improvements are equally clinically relevant cannot be derived from this analysis because each RCT used a different disability scale with a unique definition of a significant improvement. To overcome this problem an attempt was made to transform the various disability scales to the modified Rankin score. Again a significantly higher proportion of participants improved one point on the Rankin scale after IVIg treatment than after placebo (RR 2.40, 95% CI 0.98 to 5.83, NNTB 5.26, 95% CI 2.78 to 50.00).

The change in mean disability score on the scale used in the original studies and on the Rankin scale were in favour of IVIg. The change in MRC sum score was not significantly different between placebo and IVIg treated participants.

Disability scores at 24 weeks or more were only available from the largest trial, with 117 participants, in which an initial loading dose of 2 g/kg was followed by a maintenance dose of 1 g/kg every three weeks (Hughes 2008). After 24 weeks of treatment, disability improved with a mean change from baseline of 1.1 (SD 1.8) in the IVIg treatment group and 0.3 (SD) 1.3) in the placebo treatment group. The MD was 0.8 (95% CI 0.23 to 1.37) favouring IVIg. At the end of the first 24 weeks of treatment 32/59 (54%) participants in the IVIg group had a favourable response, whereas only 12/58 (21%) participants in the placebo group had improved. The absolute risk reduction (ARR) is thus 34% (95% CI 17.00 to 50.00), which gives a NNTB of 2.94 (95% CI 2.00 to 5.88). In the 24-week extension phase of the study most participants were re-randomised to IVIg or placebo. In the IVIg group, 37/43 (86%) participants had no relapse and remained clinically stable or improved, whereas 16/31 (52%) participants in the placebo group had no relapse; ARR 34% (95% CI 14.00 to 55.00) with a NNTB of 2.94 (95% CI 1.82 to 7.13). The results of the extension phase were not included in the analyses because this sample was largely biased. Similarly, due to treatment bias, a proof-of-principle study was excluded in which seven participants known to respond to IVIg therapy discontinued treatment and after deterioration were subsequently treated with IVIg or placebo in a double-blind, cross-over design. IVIg resulted in improvement in all participants, placebo in none (van Doorn 1990a).

IVIg versus plasma exchange

In the trial comparing IVIg versus plasma exchange, the primary and secondary outcomes of this systematic review, apart from the change in mean disability score, could not be assessed as these data were not available from the published report (Summary of findings 2). The other outcome measures used in this study revealed no significant difference between IVIg and plasma exchange and comparable effects when IVIg or plasma exchange was compared with assessment after a period of no treatment.

We excluded a single-blind parallel design trial that compared two doses of IVIg to a special plasma exchange system: low dose IVIg (0.5 g/kg/day in two days), high IVIg dose (1 g/kg/day in two days) and Excorim staphylococcal protein immunoadsorption plasma exchange (Zinman 2005). The advantage of this selective adsorption of immunoglobulin is that it reduces plasma protein and fluid loss caused by conventional plasma exchange. The study was of poor quality: from the 20 included participants only six participants from the high IVIg dose group and four participants from the immunoadsorption group completed the trial. Our primary outcome (proportion of participants with improvement within six weeks) could not be assessed as there were only two and six months assessments available. Furthermore, disability at six months could not be extracted from the paper as a composite of different outcomes was used to define clinical improvement. According to the paper three out of six participants treated with IVIg and all four participants treated with immunoadsorption improved. Considering the small number of participants larger trials will be needed to assess the efficacy and safety of immunoadsorption.

IVIg versus prednisolone

In the study comparing prednisolone with IVIg there were no significant differences between the two treatment arms for the primary outcomes of this systematic review (Summary of findings 3). Also, no significant difference in mean improvement on the disability scale was found at two weeks, six weeks and analysing the first treatment arm only between prednisolone and IVIg. On the Rankin scale participants improved equally. The other outcome measures revealed no significant differences between the two treatment arms. Disability scores at 24 weeks were not assessed or reported.

IVIg versus intravenous methylprednisolone

There were no differences between monthly IVIg and IVMP treatment in the primary and secondary outcomes of this meta-analysis (Summary of findings 4). However, the trial showed that IVIg is significantly less frequently discontinued than IVMP based on inefficacy, adverse events or intolerance which was the primary outcome of the study. Alternatively, 38% of the participants who improved after IVIg worsened within six months after stopping treatment, compared to none of the participants improving on IVMP.

Taken together these results show that IVIg treatment is superior to placebo in inducing an improvement in participants with CIDP regardless of whether this improvement is assessed by disability or impairment. However, the effect on disability was more pronounced and is, in our opinion, clinically far more relevant for the participant. Participants improved spontaneously in 30 out of 128 cases (23%), but treatment with IVIg increased their chance of improvement to 55% (78 out of 141 participants). The ARR is 32% which gives a NNTB of 3.03 (95% CI 2.33 to 4.55). In other words, if treated with IVIg one in every three participants will improve due to this treatment. However, if ten participants are treated with IVIg, three will improve due to the therapy, but approximately two participants will improve spontaneously and four participants will not improve and need additional treatment. Long-term results from the largest study shows an almost equal beneficial effect of IVIg treatment for up to 24 with an ARR of 34% and an NNTB of 2.94 (95% CI 2.00 to 5.88). Since only 3 out of 10 IVIg courses are expected to cause improvement and the costs of IVIg are high, cost-benefit studies are urgently needed to estimate the cost-effectiveness of this treatment.

IVIg appears to be equally as effective as plasma exchange, prednisolone and intravenous methylprednisolone, with some reservations. Firstly, the plasma exchange versus IVIg trial used an unusual dose and regimen of IVIg and had some major methodological shortcomings. Secondly, the prednisolone versus IVIg trial was terminated prematurely because trial medication expiry date was reached before all the intended 40 participants could be accrued. Moreover this trial was not designed and powered to detect equivalence between the two treatments. Furthermore, the regimen of prednisolone chosen was relatively short and not typical of clinical practice for the treatment of participants with CIDP. If prednisolone had been given in a more protracted regimen and had been compared with standard IVIg treatment, it might have been superior. Finally, in the trial comparing IVIg and IVMP, we used outcomes at 15 days as defined by our study protocol. Although in favour of IVIg, the proportion of participants improving on disability did not differ significantly between both groups, which was also the case when outcomes were assessed at two months (data not shown) and six months (Analysis 4.6). Participants with lack of improvement within two months were switched to the alternative treatment. Studies with a follow-up that is too short might underestimate the treatment effect, especially in participants treated with corticosteroids, as recent evidence has shown more than half of IVIg responders improve between three and six weeks (Latov 2010) while the median time to improvement in participants treated with pulsed oral dexamethasone was 17 weeks (van Schaik 2010). The dose of methylprednisolone in this study is high compared with doses used in previous studies of corticosteroids (Lopate 2005; Muley 2008; van Schaik 2010). The finding that the improvement in disability did not differ significantly between IVIg and IVMP could mean that higher dosing such as that used in this study is not necessary and will only lead to more adverse events. This could be an explanation for the high dropout rate at 15 days in the intravenous methylprednisolone group. Another problem might have been that more participants in the IVIg group were treated with IVIg previously and thus were known to be responsive to this treatment. Therefore, the design of the study could have overestimated the efficacy of IVIg.

One trial which has been excluded from analysis in this review for various reasons (see Characteristics of excluded studies), compared three different IVIg doses (0.25, 1.0 and 2.0 g/kg) in 59 participants with CIDP and multifocal motor neuropathy (MMN) (Kubori 1999). There was a beneficial treatment effect in respectively 15%, 21% and 60% of participants, illustrating that a lower dose of IVIg may not be effective.

Adverse events and safety

In two trials side effects were not mentioned (Analysis 1.9; Analysis 1.10). Headache, nausea, chills and fever are quite common but transient side effects with IVIg treatment and were reported to occur in 82 out of 167 (49%) IVIg treated participants, in 25 out of 141 (18%) placebo treated participants, and in 11 out of 27 (41%) prednisolone treated participants. Serious side effects were encountered in 10 out of 172 (6%) IVIg treated participants, in 10 out of 143 (7%) placebo treated participants, in 2 out of 27 (7%) prednisolone treated participants and in 2 out of 17 (12%) plasma exchange participants. These differences were not statistically significant.

Most side effects of IVIg are mild and transient and estimated to occur in 1% to 15% of infusions (Duhem 1994; Stiehm 1996). Rashes, chills, fever, mild hypo- or hypertension, nausea, malaise, headache and mild arthralgias seem to be the most frequent. Occasionally a short-lasting aseptic meningitis may occur without or with only minimal long-term sequelae. The most worrisome albeit rare complications are severe and potentially fatal anaphylactic shock, stroke, and temporary renal impairment, which is relatively common in those participants with pre-existing renal disease. The exact incidence of these severe side effects is unknown. In an ongoing postmarketing clinical pharmacovigilance study an adverse reaction rate of less than 0.5% for more than 26,000 participant infusions and less than 4% in 2554 participants was reported (Martin 2000).

In this review, mild and transient side effects were reported in 49% of IVIg-treated participants which is far more than has been reported in the 'non-randomised' literature (Duhem 1994; Stiehm 1996; Martin 2000). Headache was the most frequent side effect. As cumulative percentages of all side effects were not given, we used the percentage of headache as an estimate of any side effect. This figure probably underestimates the side effects of IVIg. RCTs are not suitable for determining the frequency of side effects. Serious side effects were encountered in six per cent of IVIg treated participants which is more in line with previously published figures. In comparison with plasma exchange and prednisolone there were no significant differences in the occurrence of minor or major side effects. However, it should be noted that the number of plasma exchange treated participants was small compared to the number of IVIg-treated participants, thus the reported frequency of side effects in IVIg participants will be more accurate than in plasma exchange treated participants. Furthermore, serious side effects known to occur after prolonged treatment with steroids were not seen due to the very short prednisolone regimen given in this particular trial.

The overall risk of bias in the trials was low. The allocation concealment was adequate in five (Vermeulen 1993; Hahn 1996; Mendell 2001; Hughes 2001; Hughes 2008) and unclear in two trials (Dyck 1994; Thompson 1996).

It is noteworthy that there is no agreement on the correct scale to assess participants with CIDP for clinical trials. Even the Neurological Disability Scale (NDS) (now known as the Neuropathy Impairment Scale), which was used twice, was modified in the second trial (Hahn 1996). The included trials used two types of NDS scales (Dyck 1992; Hahn 1996), the Hammersmith Motor Ability Score (Scott 1982), the functional disability score designed by Hughes (GBS study group 1985), the modified Rankin scale (de Haan 1993) and the INCAT disability score (Merkies 2000; Hughes 2001; Hughes 2008). A recent review showed great diversity in outcome measures used in immune-mediated neuropathies (van Nes 2008). There is a great need for standardisation of outcome measures used, to enable comparison of results between trials. To this end, an international database and The Peripheral Neuropathy Outcome Measures Standardisation (PeriNomS) study, has been initiated.

In clinical phase III trials, the primary outcome should be disability and not impairment as the primary question to be answered is whether a person with CIDP benefits from a particular treatment. Three studies (Dyck 1994; Hahn 1996; Thompson 1996), which included a total of 54 participants, did not use an appropriate scale to measure outcome adequately for this type of clinical trial.

CIDP is a chronic disease which can follow a chronic progressive or relapsing-remitting course. Outcomes were assessed at 14 days (Thompson 1996), at 15 days (Nobile-Orazio 2012), at 16 to 21 days (Vermeulen 1993), at 28 days (Hahn 1996) and at 42 days (Mendell 2001). Original INCAT disability scores and percentage of participants responding to treatment at six weeks were provided by the authors for this review (Hughes 2008). Of all these trials, only the most recent study had a longer follow-up period, up to 48 weeks. In a chronic disease, the number of participants maintaining remission for a longer periods is of major importance. Future trials should therefore use long-term rather than short-term outcomes.

We analysed the results from the cross-over trials as if they had come from a parallel group trial assuming that no carryover effect had occurred. Analysing cross-over trials in this way leads to a conservative estimate. In the case of dichotomous data, this is not statistically ideal but is unavoidable if an effort is made to assess efficacy from all available studies. To overcome this problem, individual patient data analysis of all studies should be carried out. These data have already been obtained from two studies and two other investigators have promised to supply us with the necessary information in due course. In the meantime, in the text of the review, the dichotomous outcome parameters have been given separately for all trials and for the parallel design trials. We also provided a GIV analysis for the cross-over trials where appropriate. In general the effect estimates were not far from the original analyses. For the interpretation of the overall effect of IVIg it did not make a great difference.

All cross-over trials used a predefined set of rules to determine the length of the washout period in which participants were crossed over if they remain stable, if they did not improve enough or if they deteriorated, depending on the scale used. Participants with significant improvements had to deteriorate below a predefined level before cross over could take place. Some participants who did not deteriorate again were not crossed over at all. Only one study (Hughes 2001) did a formal statistical test to exclude the possibility of a carry over effect. Nevertheless, we think it unlikely that a carry over effect accounts for the treatment effect found in this systematic review because of the extended washout periods used and the fact that the estimated treatment effects found in the various trials were all within the 95% CI of a funnel plot regardless of the design: parallel or cross-over (Figure 3). In the text, RRs are given separately for all studies and for the parallel design trials only (Vermeulen 1993; Thompson 1996). We have sent a request for individual patient data to the principal investigators of the other trials.

Figure 3.

Funnel plot of comparison: 1 IVIg versus placebo, outcome: 1.1 Significant improvement in disability score on scale used in original study.

We also planned to analyse other subgroups of interest because of their prognostic importance in previous prospective studies and trials (van Doorn 1991). One advantage of a systematic review is that data from an adequate number of participants might become available to detect significant differences between subgroups which were not apparent from individual trials. However, in none of the studies were enough data on subgroups available to allow such analyses.

Since IVIg, plasma exchange, prednisolone and IVMP seem to be equally effective in the treatment of people with CIDP, it is currently uncertain which of these should be the first choice. Costs, side effects, duration of treatment, dependency on regular hospital visits, and ease of administration all have a bearing on such a decision. Prednisolone treatment can be administered easily and is cheap. When compared to prednisolone treatment IVIg will be cost-effective only when one quality adjusted life year (QALY) is valued at over 250,000 Euro (McCrone 2003). However, adverse events due to long-term prednisolone treatment are not taken into account and would reduce the cost per QALY of IVIg treatment. Up to 70% of people with CIDP relapse when the dose of steroids is reduced and treatment schedules lasting two years have been recommended (Mehndiratta 2012; Lindenbaum 2001). The use of immunosuppressants and other immunomodulatory agents as adjuvant therapy have been advocated and the merits of these additional treatments have been discussed in detail in another systematic review (Mahdi-Rogers 2013). Only approximately 25% of people with CIDP do not need further steroid treatment because they have achieved a real clinical remission. Long-term treatment with prednisolone is accompanied by many serious side effects. Half-year treatment of corticosteroid pulses, which might reduce long-term side effects, might be sufficient in some people with CIDP (Nobile-Orazio 2012; van Schaik 2010). Plasma exchange is complicated, expensive and has no advantages over immunoglobulin treatment. Immunoglobulin treatment is expensive, usually needs a hospital setting to be administered, and must be repeated almost every month for many years to maintain the best possible functional status in people with CIDP.

Authors' conclusions

Implications for practice

The evidence from randomised controlled trials in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shows that intravenous immunoglobulin improves disability for up to 24 and possibly 48 weeks compared with placebo, with a number needed to treat of three. Short-term use of intravenous immunoglobulin (up to six weeks) has similar efficacy to plasma exchange and oral prednisolone. Since intravenous immunoglobulin, plasma exchange, prednisolone and pulsed intravenous methylprednisolone seem to be equally effective, it is currently uncertain which of these treatments should be the first choice. Cost, side effects, duration of treatment, dependency on regular hospital visits and ease of administration all have to be considered before such a decision can be made.

Implications for research

Further trials are needed to compare long-term benefit of intravenous immunoglobulin with that of plasma exchange or corticosteroids. Also, studies are needed to identify more appropriate outcome measures for trials in CIDP. Since intravenous immunoglobulin is expensive, cost-effectiveness studies comparing these treatments are needed.

Acknowledgements

We would like to thank Dr PP Choudhary, Dr AV Swan and Professor RAC Hughes for providing individual patient data and scoring their patients on the Rankin disability scale (Thompson 1996; Hughes 2001; Hughes 2008).

The Cochrane Neuromuscular Disease Group editorial base is supported by the MRC Centre for Neuromuscular Diseases.

Data and analyses

Download statistical data

Comparison 1. IVIg versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Significant improvement in disability score on scale used in original study5269Risk Ratio (M-H, Fixed, 95% CI)2.40 [1.72, 3.36]
1.1 Parallel design3198Risk Ratio (M-H, Fixed, 95% CI)2.14 [1.48, 3.09]
1.2 Cross-over design271Risk Ratio (M-H, Fixed, 95% CI)3.56 [1.59, 7.96]
2 Significant improvement in disability; GIV approach271RR (Fixed, 95% CI)3.52 [1.58, 7.87]
3 Improvement of 1 point or more on Rankin scale390Risk Ratio (M-H, Fixed, 95% CI)2.40 [0.98, 5.83]
3.1 Parallel design278Risk Ratio (M-H, Fixed, 95% CI)2.34 [0.92, 5.94]
3.2 Cross-over design112Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.15, 61.74]
4 Change in mean disability score on scale used in original study5247Std. Mean Difference (IV, Random, 95% CI)1.37 [0.22, 2.53]
4.1 Parallel design3183Std. Mean Difference (IV, Random, 95% CI)0.54 [0.24, 0.84]
4.2 Cross-over design264Std. Mean Difference (IV, Random, 95% CI)2.87 [-1.44, 7.19]
5 Change in mean disability score on scale used in study; GIV approach264SMD (Random, 95% CI)2.84 [-1.46, 7.13]
6 Change in mean disability score on Rankin scale390Mean Difference (IV, Fixed, 95% CI)0.26 [0.05, 0.48]
6.1 Parallel design278Mean Difference (IV, Fixed, 95% CI)0.33 [0.09, 0.57]
6.2 Cross-over design112Mean Difference (IV, Fixed, 95% CI)0.0 [-0.46, 0.46]
7 Change in mean MRC sum score242Mean Difference (IV, Fixed, 95% CI)0.78 [-1.04, 2.60]
7.1 Parallel128Mean Difference (IV, Fixed, 95% CI)0.29 [-2.11, 2.69]
7.2 Cross-over design114Mean Difference (IV, Fixed, 95% CI)1.43 [-1.35, 4.21]
8 Change in mean disability score at 24 weeks1117Mean Difference (IV, Fixed, 95% CI)0.80 [0.23, 1.37]
9 Serious side effects3315Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.36, 1.87]
9.1 Parallel design2258Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.30, 1.73]
9.2 Cross-over design157Risk Ratio (M-H, Fixed, 95% CI)2.71 [0.12, 63.84]
10 Any side effect3308Risk Ratio (M-H, Fixed, 95% CI)2.62 [1.81, 3.78]
10.1 Parallel design2258Risk Ratio (M-H, Fixed, 95% CI)2.61 [1.80, 3.78]
10.2 Cross-over design150Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 70.30]
Analysis 1.1.

Comparison 1 IVIg versus placebo, Outcome 1 Significant improvement in disability score on scale used in original study.

Analysis 1.2.

Comparison 1 IVIg versus placebo, Outcome 2 Significant improvement in disability; GIV approach.

Analysis 1.3.

Comparison 1 IVIg versus placebo, Outcome 3 Improvement of 1 point or more on Rankin scale.

Analysis 1.4.

Comparison 1 IVIg versus placebo, Outcome 4 Change in mean disability score on scale used in original study.

Analysis 1.5.

Comparison 1 IVIg versus placebo, Outcome 5 Change in mean disability score on scale used in study; GIV approach.

Analysis 1.6.

Comparison 1 IVIg versus placebo, Outcome 6 Change in mean disability score on Rankin scale.

Analysis 1.7.

Comparison 1 IVIg versus placebo, Outcome 7 Change in mean MRC sum score.

Analysis 1.8.

Comparison 1 IVIg versus placebo, Outcome 8 Change in mean disability score at 24 weeks.

Analysis 1.9.

Comparison 1 IVIg versus placebo, Outcome 9 Serious side effects.

Analysis 1.10.

Comparison 1 IVIg versus placebo, Outcome 10 Any side effect.

Comparison 2. IVIg versus plasma exchange
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in mean disability score on scale used in original study132Std. Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.76, 0.63]
Analysis 2.1.

Comparison 2 IVIg versus plasma exchange, Outcome 1 Change in mean disability score on scale used in original study.

Comparison 3. IVIg versus prednisolone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Significant improvement in disability score on scale used in original study129Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.50, 1.68]
2 Improvement of 1 point or more on Rankin scale131Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.42, 2.20]
3 Change in mean disability score on scale used in original study (primary analysis)148Mean Difference (IV, Fixed, 95% CI)0.13 [-0.50, 0.76]
4 Change in mean disability score on Rankin scale148Mean Difference (IV, Fixed, 95% CI)-0.21 [-0.61, 0.19]
5 Change in mean MRC sum score146Mean Difference (IV, Fixed, 95% CI)0.50 [-1.35, 2.35]
6 Serious side effects157Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.04, 4.69]
7 Any side effect157Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.86, 2.53]
Analysis 3.1.

Comparison 3 IVIg versus prednisolone, Outcome 1 Significant improvement in disability score on scale used in original study.

Analysis 3.2.

Comparison 3 IVIg versus prednisolone, Outcome 2 Improvement of 1 point or more on Rankin scale.

Analysis 3.3.

Comparison 3 IVIg versus prednisolone, Outcome 3 Change in mean disability score on scale used in original study (primary analysis).

Analysis 3.4.

Comparison 3 IVIg versus prednisolone, Outcome 4 Change in mean disability score on Rankin scale.

Analysis 3.5.

Comparison 3 IVIg versus prednisolone, Outcome 5 Change in mean MRC sum score.

Analysis 3.6.

Comparison 3 IVIg versus prednisolone, Outcome 6 Serious side effects.

Analysis 3.7.

Comparison 3 IVIg versus prednisolone, Outcome 7 Any side effect.

Comparison 4. IVIg versus methylprednisolone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Significant improvement in disability score on scale used in original study145Odds Ratio (M-H, Random, 95% CI)1.58 [0.33, 7.59]
2 Improvement of 1 point or more on Rankin scale145Risk Ratio (M-H, Fixed, 95% CI)0.7 [0.22, 2.27]
3 Change in mean disability score on scale used in original study143Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.76, 0.68]
4 Change in mean disability score on Rankin scale143Mean Difference (IV, Fixed, 95% CI)-0.24 [-0.63, 0.15]
5 Change in mean MRC sum score143Mean Difference (IV, Fixed, 95% CI)0.37 [0.00, 2.74]
6 Change in mean disability score at 24 weeks144Mean Difference (IV, Fixed, 95% CI)0.03 [-0.91, 0.97]
7 Serious side effects145Risk Ratio (M-H, Fixed, 95% CI)4.4 [0.22, 86.78]
8 Any side effect146Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.39, 1.13]
Analysis 4.1.

Comparison 4 IVIg versus methylprednisolone, Outcome 1 Significant improvement in disability score on scale used in original study.

Analysis 4.2.

Comparison 4 IVIg versus methylprednisolone, Outcome 2 Improvement of 1 point or more on Rankin scale.

Analysis 4.3.

Comparison 4 IVIg versus methylprednisolone, Outcome 3 Change in mean disability score on scale used in original study.

Analysis 4.4.

Comparison 4 IVIg versus methylprednisolone, Outcome 4 Change in mean disability score on Rankin scale.

Analysis 4.5.

Comparison 4 IVIg versus methylprednisolone, Outcome 5 Change in mean MRC sum score.

Analysis 4.6.

Comparison 4 IVIg versus methylprednisolone, Outcome 6 Change in mean disability score at 24 weeks.

Analysis 4.7.

Comparison 4 IVIg versus methylprednisolone, Outcome 7 Serious side effects.

Analysis 4.8.

Comparison 4 IVIg versus methylprednisolone, Outcome 8 Any side effect.

Appendices

Appendix 1. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to November Week 3 2012>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (342334)
2 controlled clinical trial.pt. (85694)
3 randomized.ab. (244919)
4 placebo.ab. (136550)
5 drug therapy.fs. (1588363)
6 randomly.ab. (175193)
7 trial.ab. (253825)
8 groups.ab. (1145730)
9 or/1-8 (2960405)
10 exp animals/ not humans.sh. (3812817)
11 9 not 10 (2515366)
12 (inflammatory adj3 demyelinating).tw. (3052)
13 (polyradiculoneuropath$3 or polyneuropath$3).tw. (10481)
14 polyneuropathies/ or Polyradiculoneuropathy/ (7525)
15 (polyneuritis or polyradiculoneuritis).tw. (1652)
16 13 or 14 or 15 (16128)
17 Chronic disease/ or "chronic disease".mp. (223294)
18 12 and 16 and 17 (327)
19 Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/ or (chronic adj3 inflammatory adj3 demyelinating adj3 polyradiculoneuropathy).tw. (1050)
20 cidp.tw. (962)
21 18 or 19 or 20 (1479)
22 exp immunoglobulins, intravenous/ (8970)
23 ((intravenous adj1 immunoglobulin$) or ivig).tw. (8289)
24 22 or 23 (12100)
25 11 and 21 and 24 (220)
26 25 and 20101101:20121201.(ed). (46)

Appendix 2. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2012 Week 48>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (35613)
2 double-blind procedure.sh. (112042)
3 single-blind procedure.sh. (16701)
4 randomized controlled trial.sh. (333315)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (915897)
6 trial.ti. (138124)
7 or/1-6 (1045481)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1224675)
9 animal/ or nonanimal/ or animal experiment/ (3336096)
10 9 not 8 (2761126)
11 7 not 10 (958693)
12 limit 11 to embase (745723)
13 (inflammatory adj3 demyelinating).tw. (4315)
14 (polyradiculoneuropath$3 or polyneuropath$3).tw. (14140)
15 polyneuropathies/ or Polyradiculoneuropathy/ (12776)
16 (polyneuritis or polyradiculoneuritis).tw. (1740)
17 or/14-16 (21128)
18 chronic disease.tw. or Chronic Disease/ (163494)
19 13 and 17 and 18 (127)
20 chronic inflammatory demyelinating polyneuropathy/ or (chronic adj3 inflammatory adj3 demyelinating adj3 polyradiculoneuropathy).tw. (1867)
21 cidp.mp. (1564)
22 19 or 20 or 21 (2508)
23 exp immunoglobulin/ (320221)
24 ((intravenous adj1 immunoglobulin$) or ivig).tw. (12899)
25 23 or 24 (321952)
26 12 and 22 and 25 (140)
27 remove duplicates from 26 (140)

Appendix 3. ISI search strategy

#1Topic=(Randomized Controlled Trial) OR Topic=(Clinical Trial) OR Topic=(Multicenter Study) OR Topic=(Controlled Study) OR Topic=(Crossover Procedure) OR Topic=(Double Blind Procedure) OR Topic=(Single Blind Procedure) OR Topic=(exp RANDOMIZATION) OR Topic=(Major Clinical Study) OR Topic=(PLACEBO) OR Topic=(Meta Analysis) OR Topic=(phase 2 clinical trial) OR Topic=(phase 3 clinical trial) OR Topic=(phase 4 clinical trial)
#2Topic=(human) OR Topic=(nonhuman)
#3#1 NOT #2
#4Topic=(human)
#5#1 AND #4
#6#3 OR #5
#7Topic=(chronic inflammatory demyelinating polyradiculoneuropathy) OR Topic=(CIDP) OR Topic=(chronic inflammatory demyelinating) OR Topic=(polyradiculoneuropath*) OR Topic=(polyneuropath) OR Topic=(polyneuritis) OR Topic=(polyradiculoneuritis) OR Topic=(Polyneuropathy) OR Topic=(polyradiculoneuropathy)
#8Topic=(Chronic disease) OR Topic=(inflammatory demyelinating)
#9Topic=(immunoglobulin) OR Topic=(intravenous immunoglobulin)
#10#7 AND #8
#11#6 AND #10 AND #9

Appendix 4. CENTRAL search strategy

#1 (inflammatory NEAR/3 demyelinating)
#2 polyradiculoneuropath* or polyneuropath* or polyneuritis or polyradiculoneuritis
#3 "chronic disease"
#4 (#1 AND #2 AND #3)
#5 MeSH descriptor Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, this term only
#6 (#1 AND #2 AND chronic)
#7 cidp
#8 (#4 OR #5 OR #6 OR #7)
#9 MeSH descriptor Immunoglobulins, Intravenous, this term only
#10 ivig
#11 (#9 OR #10)
#12 (#8 AND #11)

What's new

DateEventDescription
8 August 2013New citation required and conclusions have changed

One new study involving a new comparison included

Conclusions revised accordingly

4 December 2012New search has been performedAn updated search performed on 4 December 2012

History

Protocol first published: Issue 3, 1999
Review first published: Issue 2, 2002

DateEventDescription
10 November 2008New citation required and conclusions have changedA new randomised controlled trial was identified. The review conclusions have been updated to incorporate the results of this trial.
9 November 2008New search has been performedAn updated search of the Cochrane Neuromuscular Disease Group Trials Register was undertaken in May 2008. Supplementary searches of MEDLINE (January 1985 to May 2008), EMBASE (January 1985 to May 2008) and ISI (January 1985 to May 2008) were also undertaken. One new trial was identified which has been included.
30 September 2008AmendedConverted to new review format.
19 June 2008New citation required and conclusions have changedSubstantive amendment

Contributions of authors

INvS, JBW, MV, RdH were involved in all aspects of the development of the protocol. INvS and JBW assessed all the trials, extracted data and discussed and resolved any problems for the first version of the review. FE, JBW and INvS did this for the updates. FE, RdH and INvS calculated the effect sizes and did the meta-analysis. INvS wrote the first version of the review which was criticised and amended by all other authors. FE wrote the update which was criticised and amended by all other authors.

Declarations of interest

MV: has co-ordinated two RCTs of which one did not report a greater effect from IVIg than placebo.

FE: received an unrestricted grant (Baxter/PNS Fellowship 2012) and a travel grant to attend PNS meetings (2011, 2012 and 2013).

JBW's institution undertook an audit of IVIg side effects for which it received a grant from CSL-Behring for travel and computers for a research assistant. I have received a travel grant From CSL Behring to attend a meeting unrelated to this work.

RdH: none known.

INvS received departmental honoraria for serving on scientific advisory boards and a steering committee for CSL-Behring.

Sources of support

Internal sources

  • Academic Medical Center, University of Amsterdam, Dept of Neurology, Netherlands.

  • Dutch Cochrane Centre, Academic Medical Center, Netherlands.

  • Academic Medical Center, UVA, Dept of Biostatistics and Clinical Epidemiology, Netherlands.

  • Department of Neuroscience, University of Birmingham, UK.

External sources

  • No sources of support supplied

Differences between protocol and review

'Risk of bias' tables (Higgins 2008, updated Higgins 2011) and a 'Summary of findings' table have been added.

The search of ISI did not have additional value to other searches. We stopped searching the ISI database as of 2008.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dyck 1994

MethodsSingle-blind, cross-over design
ParticipantsCIDP according to Dyck 1993
n = 20; 15 IVIg; 17 plasma exchange
InterventionsIVIg 0.4 g/kg/week for 3 weeks, 0.2 g/kg/week for another 3 weeks versus PE 2/week for 3 weeks, 1/week for 3 weeks
Outcomes

Neuropathy Disability Score

Summated compound muscle action potential of median, ulnar and peroneal nerve (sumCMAP)

Summated sensory nerve action potentials of median and sural nerve (sumSNAP)
Vibration detection threshold great toe

NotesPredefined set of rules to determine length of wash-out
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe study did not contain adequate information to judge sequence generation; the study authors declined a request for additional information
Allocation concealment (selection bias)Unclear riskThe study did not contain adequate information to judge concealment; the study authors declined a request for additional information
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "The neuropathic evaluations were generally performed by the same examiner, who was blinded as to the treatment used. Each patient was instructed by the patient coordinator not to reveal treatment information to the examiner. Additionally, the examiner performed the neurological examination before questioning the patient about symptoms."

Comment: measures taken to assure blinding of the examiner seem to be adequate. Participants and treatment providers were not blinded for treatment, but this is unlikely to introduce bias

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOne participant withdrew during the first treatment period; neither treatment nor treatment effect stated.
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasUnclear riskNo intention-to-treat analysis was performed, one participant dropped out of the study during the first treatment period. Seven participants did not cross over to the second treatment

Hahn 1996

MethodsDouble-blind cross-over design
ParticipantsCIDP according to Ad hoc subcom 1991
n = 30; 25 IVIg; 25 placebo
InterventionsIVIg 0.4 g/kg/day for 5 days versus placebo (10% dextrose i.v.)
Outcomes

Modified Neurological Disability Scale
Clinical grading scale
Grip strength

Electrophysiological studies

NotesPredefined set of rules to determine length of wash-out
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Patients were randomly assigned to receive Ivlg in standard dose or placebo infusions (10% dextrose) on 5 consecutive days."

Comment: No details on randomisation procedure have been provided

Allocation concealment (selection bias)Low risk

Quote: "The code for individual patients was broken after completion of the second trial or at the time of trial analysis. Before the code was broken, study subjects and investigators were questioned regarding treatment effect and study phase assignments. However, a formal analysis of blinding was not performed."

Comment: measures taken to assure concealment of allocation seem to be adequate

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "The participating patients, the evaluating neurologist, the electromyographer and the nurses administering care and infusions were blinded to the nature of the treatment during the controlled portion of the trial.....To ensure that blinding was complete the infusions (Ivlg as well as placebo) were delivered from the transfusion services in identical opaque 600 ml transfer packs fitted with a sampling site coupler."

Comment: measures taken to assure blinding seem to be adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskDetailed data has been provided on 5 participants whose data were not used for analysis
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasUnclear risk

Participants were permitted to take part in the trial despite other treatments if these treatments were not altered just before or during the trial

Three participants did not cross over to the second treatment because of improvement during the first treatment period. All these participants were subsequently found to be on the active treatment

Hughes 2001

MethodsDouble-blind cross-over design
ParticipantsCIDP according to well defined criteria
n = 32; 24 IVIg; 24 prednisolone
InterventionsIVIg 1.0 g/kg/day for 2 days or 2.0 g/kg over 24 hours versus prednisolone 60 mg for 2 weeks, 40 mg for 1 week, 30 mg for 1 week, 20 mg for 1 week, 10 mg for 1 week
OutcomesINCAT disability scale
Timed 10-meters walk
9-hole pegboard test
MRC sum score
Maximum grip strength
Rotterdam Handicap scale
Rankin scale
SF-36 quality of life scale
Electrophysiological studies
NotesPredefined set of rules to determine length of wash out
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were randomly allocated to the treatment sequences, prednisolone followed by IVIg or IVIg followed by prednisolone. The sequences were stratified by center with a block size of 2 according to a sequence of random numbers provided by the trial statistician to the manufacturers who prepared the randomization packs."
Allocation concealment (selection bias)Low risk

Quote: "The block size was not revealed to the trialists. Each center was provided with coded packs containing either Sandoglobulin or placebo and tablets containing either placebo or prednisolone. Novartis prepared the coded packs from a random sequence generated by the trial statistician that was not revealed to the investigators except in an emergency."

Comment: measures taken to assure concealment of allocation seem to be adequate

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Placebo infusions contained albumin 6 mg/100 ml and were identical in appearance to the IVIg infusions. A neurologist who did not have access to laboratory data or the liberty to ask questions about adverse events assessed patients at entry and after 2, 4, and 6 weeks into each treatment period. A different neurologist applied a questionnaire about adverse events after 2, 4, and 6 weeks."

Comment: measures taken to assure blinding seem to be adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskResults from all participants whose data were not used for primary analysis have been addressed
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasUnclear riskNot all participants entered the cross-over phase. Primary analysis was performed only for participants completing both treatments

Hughes 2008

MethodsDouble-blind, response-conditional, cross-over design with extension phase
ParticipantsCIDP according to INCAT criteria
n = 117; 59 IVIg, 58 placebo
InterventionsIVIg 2.0 g/kg over 2 to 4 days and maintenance 1.0 g/kg over 1 to 2 days every 3 weeks for up to 24 weeks
OutcomesINCAT disability scale
Maximum grip strength
CMAP amplitude of the most severely affected motor nerve
Time to relapse
NotesFirst trial period is a parallel-group design with a conditional cross-over 'escape' for those participants who did not improve sufficiently
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Computer-generated random codes and treatment assignments were prepared by an independent group within the sponsor hierarchy and were distributed by the sponsor to the unblinded pharmacist at each centre."

Comment: we consider measures taken to assure adequate sequence generation to be adequate

Allocation concealment (selection bias)Low risk

Quote: "Eight randomisation numbers, in four blocks of two random numbers each, were initially assigned to each centre (block size was not disclosed to the centres). If a centre required additional random numbers, it received a set of eight numbers. The same procedure was used to generate separate random codes to assign patients to placebo or IGIV-C in the extension phase."

Comment: we consider measures taken to assure concealment of allocation to be adequate

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "During the study, unblinded monitors checked the drug batch log to ensure that the study medication was prepared and given as assigned. All other study team members were blinded to patient treatment during the study."

Comment: we consider measures taken to assure blinding to be adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasLow riskThe study appears to be free of other sources of bias

Mendell 2001

MethodsDouble-blind, parallel group RCT
ParticipantsCIDP according to Ad hoc subcom 1991
n = 50; 29 IVIg; 21 placebo
InterventionsIVIg 1.0 g/kg/day for 2 days versus placebo (5% albumin i.v.)
Outcomes

Hughes functional disability scale;

Average muscle score;
Forced vital capacity
Electrophysiological studies

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "A computer-generated randomization plan stratified subjects in blocks of four at each site'
Allocation concealment (selection bias)Low risk

Quote: 'To preserve the blind, all study medications were prepared by the pharmacy at each center and delivered to the infusion unit enclosed in amber IV bags. Potential decisions to break the code were based on a hierarchy of reporting with initial contacts to the clinical coordinating center at Ohio State University."

Comment: measures taken to assure concealment of allocation seem to be adequate

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "To preserve the blind, all study medications were prepared by the pharmacy at each center and delivered to the infusion unit enclosed in amber IV bags."

Comment: we consider measures taken to assure blinding to be adequate

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "In addition, no postinfusion efficacy data were available for two patients in the placebo group: one developed urticaria during the first infusion and the other dropped out after the first infusion because of personal preference. One patient treated with IVIg was dropped from the analysis before the unblinding because of an error in record documentation at the site."

Comment: No intention-to-treat analysis possible due to withdrawal of 3 participants

Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasUnclear riskThere was an imbalance in recruitment and a prestudy design for block randomisation by participating centres which accounted for the discrepancy in the number of participants in the groups

Nobile-Orazio 2012

Methods

Double-blind, parallel group RCT

Participants were treated every month or, in the case of worsening after an initial response, at the time of deterioration Participants worsening by at least 1 point in the INCAT limitation scale after the first treatment or not improving by the same score after the first two courses were shifted to the alternative treatment. After 6 months of treatment, participants were followed without treatment for another 6 months or until deterioration

Participants

CIDP according to INCAT criteria

25 IVIg, 21 IVMP

InterventionsIVIg (2 g/kg) and intravenous methylprednisolone (IVMP) placebo or IVMP (2 g) and IVIg placebo over four consecutive days, every month for 6 months
Outcomes

Primary outcome: proportion of participants discontinuing treatment due to inefficacy, intolerance or adverse events during a 6-month follow-up

Overall Neuropathy Limitation scale (ONLS, disability scale), Rankin score, MRC sum score, grip strength, INCAT sensory sum score, vibratory score, time on 10 m walk, Rotterdam score, SF-36 quality of life

NotesParticipants with lack of improvement within 2 months were switched to the alternative treatment
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Allocation to treatment was stratified by centre and centrally managed with a computer-generated 1:1 randomisation scheme with a sequential block size of four"
Allocation concealment (selection bias)Low riskQuote: "For each patient the treatment was prepared by a pharmacist or nurse, who had no further role in the study, in a different room or in the pharmacy of the hospital separate from where the patient was treated. Trial drugs were transferred in identical masked bottles marked with the patients' identification number to the trial nurse, who was masked to treatment allocation."
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Patients, their families, and investigators were masked to treatment assignment."

Comment: A large proportion of participants were not treatment naive for trial treatments, leading to possible unblinding due to adverse events if these were previously encountered

Incomplete outcome data (attrition bias)
All outcomes
Low riskData were available for all included participants
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasLow riskMinor imbalances in baseline characteristics in favour of IVIg

Thompson 1996

MethodsDouble-blind cross-over design
ParticipantsCIDP according to Ad hoc subcom 1991
n = 7; 7 IVIg; 7 placebo
InterventionsIVIg 0.4 g/kg/day for 5 days versus placebo (albumin solution)
OutcomesHammersmith Motor Ability Score
Ambulation index
10-m walk time
Expanded MRC sum score
Myometry
9-hole Peg Test
NotesPredefined set of rules to determine length of wash-out
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Patients were randomly treated with infusions of either IVIg"

Comment: No details on randomisation procedure have been provided

Allocation concealment (selection bias)Unclear riskComment: No details on allocation concealment have been provided
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: ''Patients were randomly treated with infusions of either IVIg....under double masked conditions".

Comment: Although no details on blinding are reported, blinding seems to be adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskData was available for all included participants
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasUnclear risk

Presence of an additional treatment was not mentioned

Primary outcome was assessed at two weeks which was considered not to be a clinically appropriate study duration

Vermeulen 1993

  1. a

    CIDP: chronic inflammatory demyelinating polyradiculopathy; MRC sum score: Medical Research Council sum score; INCAT: Inflammatory Neuropathy Cause and Treatment; i.v.: intravenous; IVIg: intravenous immunoglobulin; RCT: randomised controlled trial; wk: week.
    The first number under participants is the number of participants randomised in the particular study. In the case of cross-over design, the number of randomised participants does not equal the number of participants in the treatment arms. For an explanation of these discrepancies we refer the reader to the results section of this review.

MethodsDouble-blind, parallel group RCT
ParticipantsCIDP according to well defined criteria
n = 28; 15 IVIg; 13 placebo
InterventionsIVIg 0.4 g/kg/day for 5 days versus placebo (60 mg/ml albumin solution)
Outcomes

Rankin scale

MRC sum score
Electrophysiological studies

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "When a patient was eligible and after informed consent, the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service Amsterdam (CLB) was informed. The CLB supplied either bottles with immunoglobulin or placebo for a complete treatment course, according to a list based on a random number table, to the centre where the patient was admitted."
Comment: measures taken to assure concealment of allocation seem to be adequate
Allocation concealment (selection bias)Low risk

Quote: "The CLB supplied either bottles with immunoglobulin or placebo for a complete treatment course, according to a list based on a random number table, to the centre where the patient was admitted. Contents, size and labels of the bottles were not distinguishable."

Comment: measures taken to assure concealment of allocation seem to be adequate

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Contents, size and labels of the bottles were not distinguishable. The trial code was broken after the results of all patients had been recorded"

Comment: measures taken to assure blinding seem to be adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes stated in method section were available for all participants
Selective reporting (reporting bias)Low riskAll outcomes stated in method section were reported in results section
Other biasUnclear risk

Quote: "Patients eligible for this study were admitted with symptoms and signs of polyneuropathy in the absence of systemic disease, with an electrophysiological diagnosis of demyelinating polyneuropathy based on slowed nerve conduction velocities and or conduction blocks,increased CSF protein (more than 0.5 g/l) and progression of weakness exceeding eight weeks."

Comment: No electrophysiological criteria have are provided for the definition of a demyelinating polyneuropathy

The primary outcome was assessed between day 16 and 21 which was just below the cut-off level of 3 weeks which we have taken as the lower limit of a clinically appropriate study duration

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CIDP: chronic inflammatory demyelinating polyradiculopathy; IVIg: intravenous immunoglobulin; MMN: multifocal motor neuropathy

Baba 1996No randomisation procedure. Diagnostic criteria and outcome measures are not mentioned
Curro 1987No randomisation procedure
Dalakas 1996No definite or probable CIDP patients included
Hankey 1994n of 1 trial. Outcome measures did not include a disability scale
Kubori 1999Not properly randomised: lacking a placebo/control group. Patients were divided depending on clinical severity in three groups and treated with different dosages of IVIg. CIDP and MMN patients were not separated in the analysis
van Doorn 1990aSelection bias in only including patients that had responded to IVIg in the past. 'Proof of concept' study
Zinman 2005Assessments only at 2 and 6 months. Clinical improvement defined as improvement based on 2 out of 4 different outcome measures. Poor quality with only half of included patients assessed at 6 months

Characteristics of ongoing studies [ordered by study ID]

NCT01225276

  1. a

    CIDP: chronic inflammatory demyelinating polyradiculopathy; INCAT: Inflammatory Neuropathy Cause and Treatment; IVIg: intravenous immunoglobulin.

Trial name or titleSafety and efficacy study of three different dosages of NewGam in patients with chronic inflammatory demyelinating polyradiculoneuropathy
MethodsProspective, parallel group, double-blind, placebo-controlled, randomised trial
ParticipantsPatients diagnosed as having CIDP based on fulfilment of clinical criteria of the INCAT Group and the definite electrophysiological criteria for CIDP 
InterventionsDrug: IVIg (NewGam) 10%
OutcomesAdjusted INCAT disability score 
Starting dateOctober 2010
Contact informationStefan Wietek, stefan.wietek@octapharma.com
Notes 

Ancillary