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IgM MGUS and Waldenstrom-associated anti-MAG neuropathies display similar response to rituximab therapy
  1. Marta Campagnolo1,
  2. Renato Zambello2,
  3. Eduardo Nobile-Orazio3,
  4. Luana Benedetti4,
  5. Girolama Alessandra Marfia5,
  6. Nilo Riva6,
  7. Francesca Castellani1,
  8. Mariangela Bianco3,
  9. Alessandro Salvalaggio1,
  10. Martina Garnero4,
  11. Marta Ruiz1,
  12. Giorgia Mataluni5,
  13. Raffaella Fazio6,
  14. Mario Ermani1,
  15. Chiara Briani1
  1. 1 Department of Neurosciences, University of Padova, Padua, Italy
  2. 2 Medicine, Hematology and Clinical Immunology Unit, University of Padova, Padua, Italy
  3. 3 Second Neurology, Humanitas Clinical and Research Centre, Department of Medical Biotechnology and Translational Medicine, Milan University, Milan, Italy
  4. 4 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova and IRCCS AOU San Martino-IST, Genoa, Italy
  5. 5 Neurology COU, Department of Systems Medicine, University of Tor Vergata, Rome, Italy
  6. 6 Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
  1. Correspondence to Dr Chiara Briani, Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128 Padova - Italy; chiara.briani{at}

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No adequate immunotherapy has so far been shown to be effective in anti-myelin-associated glycoprotein (MAG) antibody neuropathy.1 Rituximab was assessed in two randomised controlled trials, both including only patients with monoclonal gammopathy of undetermined significance (MGUS), with Waldenstrom’s macroglobulinaemia (WM) being an exclusion criterion.2

The aim of our multicentre retrospective study was to assess whether the response to rituximab in patients with anti-MAG antibody neuropathy would differ according to the associated haematological condition.


We reviewed the clinical and laboratory features of 33 patients (21 men, mean age at time of therapy: 64.6±10.3, range: 41–87, mean neuropathy duration at time of therapy: 4.67 years±4.82, range: 0.5–17) with anti-MAG antibody neuropathy who underwent therapy with rituximab single agent in five Italian neurological centres. Twenty-five (73.5%) patients had Immunoglobulin M (IgM) MGUS and 8/33 had WM, according to bone marrow biopsy. The mean age was significantly different in the two groups (62.5±10.3 years in MGUS vs 70.5±7.9 years in WM, p=0.04). The mean neuropathy duration was 4.56±4.8 years in MGUS versus 5.6±5.1 years in WM (p=0.62, Mann-Whitney U test).

Anti-MAG antibodies were assayed by ELISA (Bühlmann Laboratories AG) (28 patients) or Western blot (5 patients). The median antibodies titre was 51 200 (range: 7500–800 000) in MGUS and 56 000 (range: 11 126–600 000) in patients with WM. Patients with low (<10 000 Bühlmann Titer Units) titre were included for clinical and neurophysiological features consistent with anti-MAG neuropathy. Antibody titres were not retrievable in two patients.

Twenty patients were therapy-naive, while 13 had previously undergone other therapies within a median time of 3 years before rituximab. No patients were previously treated with chemotherapy for WM. All patients had demyelinating features typical of anti-MAG neuropathy, and neuropathy was the only reason for therapy. Patients were treated with rituximab (375 mg/sqm/intravenously/week for four consecutive weeks). Patients were assessed before and 12 months after therapy with INCAT (Inflammatory Neuropathy Cause and Treatment) Disability Score, INCAT Sensory Sum Score (ISS) and Medical Research Council (MRC) sum score.3 4 Responders were considered those patients who improved by at least 1 point in two clinical scales. The patients’ characteristics are shown in table 1.

Table 1

Characteristics of patients with anti-MAG neuropathy treated with rituximab

The study was approved by the local ethics committees.

Statistical analysis

For normally distributed variables, t-test for independent group was performed. For ordinal variables Mann-Whitney U test or Wilcoxon test in case of repeated measures was performed. For categorical variables, Pearson’s χ2 test was used. Significance level was set at p<0.05.


Overall improvement following rituximab was present in 18/33 patients (54.5%). Patients with MGUS showed a significant improvement in all scales (p=0.03 for INCAT, p=0.0006 for ISS and p=0.012 for MRC). The greatest improvement occurred in the ISS scale, which is important considering the predominant sensory involvement of anti-MAG antibody neuropathy. The WM subgroup improved similarly in the three scales, but not with statistical significance likely for the low number of patients. In detail, 9/25 patients with neuropathy and MGUS (mean age: 62.5±10.3 years; mean disease duration: 4.56±4.8 years) improved (median pre-therapy INCAT: 3, ISS: 3, MRC score: 58; median post-therapy INCAT: 1, ISS: 1, MRC score: 60). Of the eight patients with WM (mean age: 70.5±7.9 years; mean disease duration: 5.6±5.1 years), three improved (median pretherapy INCAT: 3, ISS: 9, MRC score: 54; median post-therapy INCAT: 1, ISS: 6, MRC score: 60). All the other patients remained unchanged and none worsened after therapy.

Nine patients (7 MGUS, 2 WM) were treated twice at a variable time after the first cycle (from 1 to 7 years for patients with MGUS, and after 1 and 6 years for patients with WM) for worsening of ataxia and disability. Five re-treated patients with MGUS (median improvement in INCAT score of 2 points, ISS score of 3 points, MRS sum score of 2 points) and one patient with WM (improvement in INCAT score of 2 points, ISS score of 5 points, MRC sum score of 6 points) improved.

Mean age was inversely related to the response to therapy (68.1 years in no responders, 61.4 years in responders). Antibody titres significantly decreased 12 months after treatment in 60% of patients, regardless of the outcome. No association between response and antibody titres was found.

IgM serum levels were available in 67% of patients. In patients who improved, serum IgMs decreased after rituximab (3.22±2.5, range: 1.6–7.9 pre-therapy vs 1.9±1.9, range: 1.39–5.9 post-therapy in MGUS; 6.3 g/L pre-therapy vs 4.9 g/L post-therapy in WM). Patients who did not improve had instead similar IgM levels pre-therapy and post-therapy (MGUS pre-therapy: 3.3±1.8 g/L, range: 1.08–6 vs post-therapy: 3.2±1.3 g/L, range: 1.15–5.19; WM: 12.6±12.5 vs 12.2±15 g/L). The quality of life scale Short-Form 36 was assessed in 12/33 patients, disclosing subjective improvement after rituximab especially in items (3–6) regarding limitations in everyday functionality.


In this study we confirmed the significant response rate to rituximab in patients with anti-MAG antibody neuropathy with a similar percentage of responders in MGUS (56%) and WM (44%), the difference between the groups being not significant. Due to the low number of patients with WM, the improvement reached significance only for patients with MGUS.

Although the mean disease duration and antibody titres were comparable in the two subgroups, patients with WM had higher mean age compared with MGUS subgroup (p=0.04). Mean age was significantly correlated with response to therapy. Moreover, a longer disease duration seemed to be associated with poor response to rituximab (although not significantly, p=0.57), suggesting that early in the course of the disease the nerve damage may still be reversible. This pattern was independent of the underlying haematological disease.

Interestingly, six patients, who remained unchanged after the first treatment, improved after another rituximab cycle at recurrence of symptoms, leading to an additional 18% of response (reaching 72.5% for the whole population).

In conclusion, rituximab monotherapy retains a relevant role in anti-MAG neuropathy, likely being more effective in patients with shorter disease duration. A longitudinal prospective study with a larger and more balanced sample will help define possible predictors of response to rituximab. Nevertheless, more than one cycle of treatment was required in some patients, in line with the RIMAG follow-up study,5 suggesting that a more effective first-line combination therapy might be indicated to obtain a long-lasting response.



  • Contributors MC, AS, MR, FC and CB are the neurologists in charge of the patients at the University of Padova. LB and MG are the neurologists in charge of the patients at the University of Genova. ENO and MB are the neurologists in charge of the patients at the Humanitas Center in Rozzano, Milan. GAM and GM are the neurologists in charge of the patients at the University of Tor Vergata, Rome. NR and RF are the neurologists in charge of the patients at the San Raffaele Hospital, Milan. RZ is the haematologist in charge of most of the patients. ME is a neurologist, who did the statistical analysis. CB, MC and RZ are the persons who designed the study and wrote the draft of the manuscript.

    All the authors helped in the acquisition, analysis and interpretation of data, as well as in critically revising the manuscript for important intellectual content. All the authors have read and approved the final version of the manuscript.

  • Competing interests None declared.

  • Ethics approval Local ethics committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.