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IgM paraprotein-associated peripheral neuropathy (PN) in patients without overt evidence of lymphoma is a recognised clinical entity of unknown aetiology. Interrogating the bone marrow B-cell or plasma cell clones underlying paraproteinemic neuropathies may improve our understanding of both pathogenesis and treatment options. This retrospective observational analysis of IgM paraprotein-associated PN identified five patients with small pathological MYD88 L265P and CD20-positive B-cell clones in their bone marrow using multi-parametric flow cytometry, who have shown durable neurological response to rituximab. We posit that multi-parametric flow cytometry may be instrumental in identifying the cellular source of the paraprotein in IgM paraprotein-associated PN, and thus directing appropriate immunomodulatory therapy. Further understanding of these small pathological B-cell clones may also provide additional insight into mechanisms of monoclonal gammopathy of clinical significance overall., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

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.

Background: Serum monoclonal anti-myelin-associated glycoprotein 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., Objectives: To assess the effects of immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy., Search Methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register 6 June 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. We also checked bibliographies and contacted authors and experts in the field., Selection Criteria: We included randomised or quasi-randomised controlled trials involving participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity.Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisation. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; 10-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-myelin-associated glycoprotein antibody titres at six months after randomisation; and adverse effects of treatments., Data Collection and Analysis: The two authors independently selected studies. Two authors independently assessed the risk of bias in included studies., Main Results: We identified seven eligible trials (182 participants), which tested intravenous immunoglobulin, alfa interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Only two trials, of intravenous immunoglobulin (with 33 participants, including 20 with antibodies against myelin-associated glycoprotein), had comparable interventions and outcomes, but both were short-term trials.There were no 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. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials., Authors' Conclusions: There is inadequate reliable evidence from trials of immunotherapies in anti-myelin-associated glycoprotein paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. Large well designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies, preferably employing unified, consistent, well designed, responsive and valid outcome measures.

Background: Serum monoclonal anti-myelin associated glycoprotein antibodies may be pathogenic in some people with IgM paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be beneficial., Objectives: To examine the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-myelin associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy., Search Strategy: We searched the Cochrane Neuromuscular Disease Group Register (March 2005), MEDLINE (January 1966 to March 2005) and EMBASE (January 1980 to March 2005) for controlled trials. We also checked bibliographies and contacted authors and experts in the field., Selection Criteria: We included randomised or quasi-randomised controlled trials of participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of any severity. Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at six months after randomisationSecondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomisation; ten-metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-myelin associated glycoprotein antibody titres at six months after randomisation and adverse effects of treatments., Data Collection and Analysis: We identified eight possible trials. Of these, five randomised controlled trials were included after discussion between the authors. One author extracted and the other checked the data. No missing data could be obtained from trial authors., Main Results: The five eligible trials (97 participants) tested intravenous immunoglobulin, interferon-alpha or plasma exchange. Only two, of intravenous immunoglobulin, had comparable interventions and outcomes but both were short-term. There were no significant benefits of the treatments used in the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed benefits in terms of improvement in Modified Rankin Scale at two weeks and 10-metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin are known to occur from observational studies but none were encountered in these trials., Authors' Conclusions: There is inadequate reliable evidence from trials of immunotherapies in anti-myelin associated glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous immunoglobulin is relatively safe and may produce some short-term benefit. Large well-designed randomised trials of at least six to 12 months duration are required to assess existing or novel therapies.

Background: Serum monoclonal anti-Myelin Associated Glycoprotein antibodies may be pathogenic in some patients with IgM paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be of benefit in the treatment of the neuropathy. Many potential therapies have been described in small trials, uncontrolled studies and case reports., Objectives: To examine the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-Myelin Associated Glycoprotein paraprotein-associated demyelinating peripheral neuropathy., Search Strategy: We searched the Cochrane Neuromuscular Disease Group register (August 2002) and MEDLINE (January 1966 - August 2002) and EMBASE (January 1980 - August 2002) for controlled trials, checked the bibliographies to identify other controlled trials and contacted authors and other experts in the field., Selection Criteria: Types of studies: randomised or quasi-randomised controlled trials., Types of Participants: patients of any age with anti-Myelin Associated Glycoprotein antibody associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of any severity. Types of interventions: any type of immunotherapy. Types of outcome measures: Primary: improvement in the Neuropathy Disability Score or Modified Rankin Scale six months after randomisation Secondary: Neuropathy Disability Score and/or the Modified Rankin Score 12 months after randomisation. Ten metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation. IgM paraprotein levels and anti-Myelin Associated Glycoprotein antibody titres six months after randomisation. Adverse effects of treatments., Data Collection and Analysis: We identified six randomised controlled trials of which five were included after discussion between the authors. One author extracted the data and the other checked them. No missing data could be obtained from authors., Main Results: The five eligible trials used four of the many available immunotherapy treatments. Only two had comparable interventions and outcomes but these were only short-term studies. There were no significant benefits of the treatments used in the predefined outcomes. However intravenous immunoglobulin showed benefits in terms of improved Modified Rankin Scale at two weeks and 10 metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin are known to occur from observational studies but none were encountered in these trials., Reviewer's Conclusions: There is inadequate reliable evidence from trials of immunotherapies in anti-Myelin Associated Glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous immunoglobulin is relatively safe and may produce some short-term benefit. Large well designed randomised trials are required to assess the efficacy of promising new therapies.

Monoclonal antibodies reactive with the HNK-1 epitope of myelin-associated glycoprotein (MAG) and the sulphate-3-glucuronyl paragloboside (SGPG)-like glycolipids are often found in the serum of patients with IgM paraprotein-associated demyelinating neuropathy. The presence of such antibodies in patients with chronic polyneuropathy has recently been associated with evidence of active cytomegalovirus (CMV) infection by the polymerase chain reaction. We wished to test these findings and examined sera from patients with MAG-reactive or MAG-nonreactive paraproteinemic neuropathy and patients with paraproteinemia only for the presence of CMV DNA and anti-CMV antibodies. CMV DNA was not detected in sera from any patient group. Furthermore, anti-CMV antibody prevalence was normal and similar in all 3 groups. We therefore report no evidence of an association between CMV infection and anti-MAG/SGPG antibodies associated with paraproteinemic peripheral neuropathy.

Objectives: To evaluate the response of four patients with IgM paraproteinaemic neuropathy to a novel therapy-pulsed intravenous fludarabine., Background: The peripheral neuropathy associated with IgM paraproteinaemia usually runs a chronic, slowly progressive course which may eventually cause severe disability. Treatment with conventional immunosuppressive regimens has been unsatisfactory. Fludarabine is a novel purine analogue which has recently been shown to be effective in low grade lymphoid malignancies., Methods: Four patients were treated with IgM paraproteinaemic neuropathy with intravenous pulses of fludarabine. Two of the four patients had antibodies to MAG and characteristic widely spaced myelin on nerve biopsy and a third had characteristic widely spaced myelin only. The fourth had an endoneurial lymphocytic infiltrate on nerve biopsy and a diagnosis of Waldenström's macroglobulinaemia., Results: In all cases subjective and objective clinical improvement occurred associated with a significant fall in the IgM paraprotein concentration in three cases. Neurophysiological parameters improved in the three patients examined. The treatment was well tolerated. All patients developed mild, reversible lymphopenia and 50% mild generalised myelosuppression, but there were no febrile episodes., Conclusion: Fludarabine should be considered as a possible treatment for patients with IgM MGUS paraproteinaemic neuropathy.