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Meta-Analysis
. 2016 Oct 4;10(10):CD002827.
doi: 10.1002/14651858.CD002827.pub4.

Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies

Michael Pt Lunn  1 , Eduardo Nobile-Orazio
Affiliations
Meta-Analysis

Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies

Michael Pt Lunn et al. Cochrane Database Syst Rev. .

Abstract

Background: Serum monoclonal anti-myelin-associated glycoprotein (anti-MAG) antibodies may be pathogenic in some people with immunoglobulin M (IgM) paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial. This is an update of a review first published in 2003 and previously updated in 2006 and 2012.

Objectives: To assess the effects of immunotherapy for IgM anti-MAG paraprotein-associated demyelinating peripheral neuropathy.

Search methods: On 1 February 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials (RCTs). We also checked trials registers and bibliographies, and contacted authors and experts in the field.

Selection criteria: We included randomised controlled trials (RCTs) or quasi-RCTs involving participants of any age treated with any type of immunotherapy for anti-MAG antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measures were numbers of participants improved in disability assessed with either or both of the Neuropathy Impairment Scale (NIS) or the modified Rankin Scale (mRS) at six months after randomisation. Secondary outcome measures were: mean improvement in disability, assessed with either the NIS or the mRS, 12 months after randomisation; change in impairment as measured by improvement in the 10-metre walk time, change in a validated linear disability measure such as the Rasch-built Overall Disability Scale (R-ODS) at six and 12 months after randomisation, change in subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; change in serum IgM paraprotein concentration or anti-MAG antibody titre at six months after randomisation; and adverse effects of treatments.

Data collection and analysis: We followed standard methodological procedures expected by Cochrane.

Main results: We identified eight eligible trials (236 participants), which tested intravenous immunoglobulin (IVIg), interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Two trials of IVIg (22 and 11 participants, including 20 with antibodies against MAG), had comparable interventions and outcomes, but both were short-term trials. We also included two trials of rituximab with comparable interventions and outcomes.There were very few clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial and more responsive outcomes are being developed. A well-performed trial of IVIg, which was at low risk of bias, showed a statistical benefit in terms of improvement in mRS at two weeks and 10-metre walk time at four weeks, but these short-term outcomes are of questionable clinical significance. Cyclophosphamide failed to show any benefit in the single trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified.Two trials of rituximab (80 participants) have been published, one of which (26 participants) was at high risk of bias. In the meta-analysis, although the data are of low quality, rituximab is beneficial in improving disability scales (Inflammatory Neuropathy Cause and Treatment (INCAT) improved at eight to 12 months (risk ratio (RR) 3.51, 95% confidence interval (CI) 1.30 to 9.45; 73 participants)) and significantly more participants improve in the global impression of change score (RR 1.86, 95% CI 1.27 to 2.71; 70 participants). Other measures did not improve significantly, but wide CIs do not preclude some effect. Reported adverse effects of rituximab were few, and mostly minor.There were few serious adverse events in the other trials.

Authors' conclusions: There is inadequate reliable evidence from trials of immunotherapies in anti-MAG paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. IVIg has a statistically but probably not clinically significant benefit in the short term. The meta-analysis of two trials of rituximab provides, however, low-quality evidence of a benefit from this agent. The conclusions of this meta-analysis await confirmation, as one of the two included studies is of very low quality. We require large well-designed randomised trials of at least 12 months' duration to assess existing or novel therapies, preferably employing unified, consistent, well-designed, responsive, and valid outcome measures.

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Conflict of interest statement

MPTL has published a pilot study of the use of fludarabine in IgM‐associated paraproteinaemic neuropathy (Wilson 1999) and was a blinded investigator in Comi 2002. He has received honoraria for consultation from Baxter Pharmaceuticals, CSL Behring, UCB and LFB and a travel support grant from CSL Behring and Grifols, all manufacturers of IVIg. He was a blinded Site Investigator on the FORCIDP study (fingolimod in CIDP (Novartis) who in August 2015 purchased ofatumumab (not included in this review). He is Joint Co‐ordinating Editor of Cochrane Neuromuscular. He did not have a role in editorial assessment or the decision to publish this updated review.

EN‐O has received honoraria from CSL Behring (Italy and USA), UCB (UK), and Kedrion (Italy) for Scientific Advisory Board participation and from Novartis (Switzerland) for being part of a Steering Committee for a trial with fingolimod on CIDP. He received compensation from Baxalta, Italy for preparing a teaching course on Multifocal Motor Neuropathy. He received compensation for lectures from Kedrion, Italy, CSL Behring, Italy and Baxter, USA. He received support for Meeting attendance from CSL Behring, Italy and Kedrion Italy. He has published a study of long‐term prognosis of IgM neuropathies and their immunotherapy (Nobile‐Orazio 2000) and was a member of the BIOMED INCAT Group which conducted the Comi 2002 study. He was the principal investigator in a RCT sponsored by Kedrion comparing the efficacy of intravenous corticosteroids with IVIg in CIDP. He is the Principal Investigator of a trial on IVIg in CIDP sponsored by LFB, France. He states that no part of the above‐mentioned financial support had any influence on his work in preparing this review.

Both review authors were investigators in Comi 2002. The Cochrane Neuromuscular Managing Editor carried out an independent risk of bias assessment and data extraction of outcome data for this study, and checked these against the data entered in the review.

This review was first published in 2003. One new trial, of rituximab, has been added at this update. Both review authors have declared financial remuneration for consultancy work relating to IVIg. The most recent trial of IVIg was published in 2002, the conclusion of the review being that the short‐term effects of this intervention are of doubtful clinical significance in this condition, a conclusion unchanged at this update.

Although the authorship of this updated review does not fully comply with the current Conflict of Interests policy, it did at the time of original publication. This has been discussed with the Funding Arbiters who have agreed that there is a low risk of significant bias resulting from the declared financial and academic interests.

Figures

1
1
PRISMA chart for searched to included studies of IgM paraproteinaemic neuropathy
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 3 Rituximab versus placebo, outcome: 3.1 Number of participants improved on INCAT score (see text) at 8‐12 months.
1.1
1.1. Analysis
Comparison 1 IVIg versus interferon alfa‐2a, Outcome 1 Change in Clinical Neuropathy Disability Score (CNDS) at six months.
1.2
1.2. Analysis
Comparison 1 IVIg versus interferon alfa‐2a, Outcome 2 Subjective score at six months.
1.3
1.3. Analysis
Comparison 1 IVIg versus interferon alfa‐2a, Outcome 3 Number of participants improved by at least 20% on NIS at 6 months.
2.1
2.1. Analysis
Comparison 2 Interferon alfa‐2a versus placebo, Outcome 1 Change in the CNDS at 6 months (maximum 93).
2.2
2.2. Analysis
Comparison 2 Interferon alfa‐2a versus placebo, Outcome 2 Number improved in CNDS by 20% at 6 months.
3.1
3.1. Analysis
Comparison 3 Rituximab versus placebo, Outcome 1 Number of participants improved on INCAT score (see text) at 8‐12 months.
3.2
3.2. Analysis
Comparison 3 Rituximab versus placebo, Outcome 2 Mean improvement in INCAT score (see text) at 8 ‐ 12 months.
3.3
3.3. Analysis
Comparison 3 Rituximab versus placebo, Outcome 3 Rituximab vs placebo. Mean improvement in INCAT score at 8 ‐ 9 months (post hoc data).
3.4
3.4. Analysis
Comparison 3 Rituximab versus placebo, Outcome 4 Mean improvement in NIS at 12 months.
3.5
3.5. Analysis
Comparison 3 Rituximab versus placebo, Outcome 5 Improvement in 10‐metre walk time at 8 ‐ 12 months.
3.6
3.6. Analysis
Comparison 3 Rituximab versus placebo, Outcome 6 Number improved in 10‐metre walk at 6 months.
3.7
3.7. Analysis
Comparison 3 Rituximab versus placebo, Outcome 7 Change in IgM level 8 months after treatment.
3.8
3.8. Analysis
Comparison 3 Rituximab versus placebo, Outcome 8 Change in IgM anti‐MAG titre at 8 ‐ 12 months.
3.9
3.9. Analysis
Comparison 3 Rituximab versus placebo, Outcome 9 Participant subjective impression of change stable or improved at 8 ‐ 12 months.
3.10
3.10. Analysis
Comparison 3 Rituximab versus placebo, Outcome 10 Participant subjective impression of change improved at 8 ‐ 12 months.
3.11
3.11. Analysis
Comparison 3 Rituximab versus placebo, Outcome 11 Mean change in SF36 physical subscores at 12 months.
3.12
3.12. Analysis
Comparison 3 Rituximab versus placebo, Outcome 12 Mean change in SF36 mental health subscores at 12 months.
3.13
3.13. Analysis
Comparison 3 Rituximab versus placebo, Outcome 13 Any adverse event.
3.14
3.14. Analysis
Comparison 3 Rituximab versus placebo, Outcome 14 Severe adverse event.
4.1
4.1. Analysis
Comparison 4 Cyclophosphamide and steroids versus placebo, Outcome 1 Improvement in modified Rankin Scale at 6 months.
4.2
4.2. Analysis
Comparison 4 Cyclophosphamide and steroids versus placebo, Outcome 2 Number of participants improved on modified Rankin Scale at 6 months.
4.3
4.3. Analysis
Comparison 4 Cyclophosphamide and steroids versus placebo, Outcome 3 Improvement in Rivermead Mobility Index (subjective participant score) at 6 months.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to other published versions of this review

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