Abstract: 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. 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.

Plain-language summary: Many of these therapies have been tried in non-randomised studies, but we found only eight small randomised controlled trials (RCTs), involving 236 participants, that met our criteria for inclusion. Two trials with 22 and 11 participants (20 with antibodies against MAG) suggest that IVIg may sometimes produce short-term measurable benefit and is relatively safe, but the benefit is of doubtful clinical significance. No severe adverse effects related to IVIg were reported in these trials. A trial of cyclophosphamide and corticosteroids showed some mild benefit. Two trials of rituximab demonstrated a positive benefit of rituximab, but this evidence was of low quality because of small numbers of participants and concerns about the design of one of the two studies. Reported adverse effects of rituximab were few, and mostly minor. Other trials did not allow us to draw conclusions about the efficacy of other agents and reported few serious adverse events. We need large, well-designed RCTs to assess the efficacy of the existing and new therapies, and better ways for doctors and researchers to detect changes that people report in response to treatments. The evidence is up to date to February 2016.