Review question
What are the benefits and harms of immune treatments for peripheral neuropathy caused by an IgM paraprotein antibody that may bind to myelin-associated glycoprotein (MAG)?
Background
There are several types of antibodies in the human body. They are more or less specifically adapted to recognise a target, usually a 'foreign' protein such as a bit of a bacterium, virus or tumour. In some people too much of one type of antibody is made, called a paraprotein. Some of these paraproteins are of the IgM class (IgM antibodies are usually an 'early attack force' type of antibody). Some of these antibodies may react against myelin-associated glycoprotein, also known as MAG. MAG is a molecule on the insulating myelin sheath of nerves. The antibody probably results in damage to the nerve myelin to which it is bound and thus causes a specific type of damage to the nerves, known as a peripheral neuropathy. Anti-MAG paraprotein-associated peripheral neuropathy is a condition affecting more men than women, most commonly over the age of 60 years. It causes progressive sensory symptoms, unsteadiness and tremor, and sometimes some weakness of the feet and lower legs.
Treatments that act on the immune system such as plasma exchange (which removes circulating antibodies and replaces blood plasma with a clean plasma substitute), intravenous immunoglobulin (IVIg; antibodies that have been purified from donated blood), rituximab (which kills some of the cells that produce the antibody), corticosteroids, or anticancer drugs might be expected to reduce levels of these neuropathy-causing IgM antibodies and slow or prevent progression of the disease.
Study characteristics
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.
Results and quality of the evidence
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.
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.
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.
To assess the effects of immunotherapy for IgM anti-MAG paraprotein-associated demyelinating peripheral neuropathy.
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.
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.
We followed standard methodological procedures expected by Cochrane.
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.