Placebo‐controlled trial of rituximab in IgM anti–myelin‐associated glycoprotein antibody demyelinating neuropathy

Dalakas, Marinos C.; Rakočević, Goran; Salajegheh, Mohammad; Dambrosia, James M.; Hahn, Angelika F.; Raju, Raghavan; McElroy, Beverly

doi:10.1002/ana.21577

Cited by 276 publications

(232 citation statements)

References 33 publications

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“…7,8 Moreover, even though no randomized controlled trials have provided evidence of improvement in primary outcome measures, several secondary outcomes were improved. 9,10 In WM and other indolent B-cell lymphomas, rituximab combined with nucleoside analogs or with nucleoside analogs plus alkylating agents, yields better responses than rituximab monotherapy. 4 Based on these results, we wondered whether patients with anti-MAG neuropathy might benefit more from rituximab plus chemotherapy (immunochemotherapy) than from rituximab alone (immunotherapy).…”

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confidence: 99%

Immunotherapy-based regimen in anti-MAG neuropathy: results in 45 patients

et al. 2013

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Immunotherapy-based regimen in anti-MAG neuropathy: results in 45 patientsThe prevalence of neuropathy in patients with immunoglobulin M (IgM) monoclonal gammopathies ranges from 5% to 31%.1 The most frequent neuropathy is associated with monoclonal IgM reacting with myelinassociated glycoprotein (MAG) and is usually a chronic demyelinating disorder that typically presents with progressive ataxia and painful paresthesias.2 The clinical features of neuropathies associated with Waldenstrom's macroglobulinemia (WM) and IgM-monoclonal gammopathy of unknown significance are similar.3 Treatment is only warranted in case of significant disability and should not be based on the IgM level or bone marrow infiltration. 4 Intravenous immunoglobulin (IVIg), interferon alpha, plasma exchange and immunosuppressive therapy have all been used, but there is no consensus treatment. 5More effective therapy is therefore needed as 30-40% of patients are disabled by severe, progressive neuropathies that undermine their quality of life.6 Several open-label trials of rituximab, a chimeric mouse-human monoclonal antibody directed against the B-cell surface protein CD20, have given encouraging results.7,8 Moreover, even though no randomized controlled trials have provided evidence of improvement in primary outcome measures, several secondary outcomes were improved.9,10 In WM and other indolent B-cell lymphomas, rituximab combined with nucleoside analogs or with nucleoside analogs plus alkylating agents, yields better responses than rituximab monotherapy.4 Based on these results, we wondered whether patients with anti-MAG neuropathy might benefit more from rituximab plus chemotherapy (immunochemotherapy) than from rituximab alone (immunotherapy).In this retrospective study, we therefore compared our experience with immunochemotherapy and rituximab monotherapy in 45 patients treated for anti-MAG neuropathy at Salpêtrière Hospital, Paris, France, from 1996 to 2011. Apart from symptomatic neuropathy, none of these patients met the criteria for treatment initiation defined by the second WM international workshop. The treatment choice was based on the aggressiveness of the neuropathy and its rate of progression. To evaluate the treatment response we used the Rankin Score (RS) that measures the degree of disability or dependence for daily activities. The scale ranges from 0 to 5, as described in Table 1. Improvement was defined as a 1 point or more decrease in the RS score, stabilization as an unchanged RS, and progression as a 1 point or more increase. -20). There was no difference in the median time to response between patients receiving first-line treatment (6 months, range 2-17) and previously treated patients (6.5 months, range 3-20). The base-line Rankin score was similar in the 3 groups. Because of the small size of the groups, however, it was difficult to assess the benefit of each combination individually. One patient relapsed after a median of 24 months. Three patients developed cytopenia requiring blood and platelet transfusion and o...

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Immunotherapy-based regimen in anti-MAG neuropathy: results in 45 patients

et al. 2013

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“…Efficacy of rituximab has been supported by uncontrolled studies [92][93][94][95]. In a first RCT conducted in 26 patients [96], intention-to-treat analysis showed improvement after 8 months in 4/13 patients treated with rituximab and none of the 13 patients on placebo (p=0.096) Excluding 1 patient randomized to the rituximab group who had a normal INCAT score on inclusion, and could not therefore improve, the results were significant (p=0.036). Another RCT, the rituximab versus placebo study in polyneuropathy associated with anti-MAG IgM monoclonal gammopathy (RIMAG study), involved 54 patients enrolled in 9 centers: 26 patients in the rituximab group (4 weekly infusions of rituximab 375 mg/m 2 ) and 28 patients in the placebo group [62].…”

Section: Anti-mag Neuropathymentioning

confidence: 98%

Immunotherapy in Peripheral Neuropathies

Léger¹,

Guimarães‐Costa²,

Muntean³

2016

Neurotherapeutics

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Immunotherapy has been investigated in a small subset of peripheral neuropathies, including an acute one, Guillain-Barré syndrome, and 3 chronic forms: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy associated with IgM anti-myelin-associated glycoprotein. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis. Either cell-mediated mechanisms or antibody responses to Schwann cell, compact myelin, or nodal antigens are considered to act together in an aberrant immune response to cause damage to peripheral nerves. Immunomodulatory treatments used in these neuropathies aim to act at various steps of this pathogenic process. However, there are many phenotypic variants and, consequently, there is a significant difference in the response to immunotherapy between these neuropathies, as well as a need to improve our knowledge and long-term management of chronic forms.

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“…Patients with anti-MAG neuropathy treated with rituximab saw clinical benefit, reduction of anti-IgM and anti-MAG antibodies, and upregulation of Tregs [77,78]. Further, patients with anti-MAG neuropathy show substantial clonal expansions of IgM memory B cells that recognized MAG antigen, while patients who experience clinical improvement after rituximab have lower numbers of anti-MAG memory B cells before and after therapy, and lower somatic hypermutation frequencies of IgM memory B cells [79].…”

Section: Autoimmune Polyneuropathiesmentioning

confidence: 99%

Section: Biomarkers Of Clinical Response To B-cell-depletion Therapiesmentioning

confidence: 99%

“…In many cases, treatment efficiency correlates with peripheral B-cell depletion and especially effective depletion of the CD20+CD27+ memory B cells [78]. In a small number of patients with anti-MAG neuropathy, following clinical improvement, reamplification of CD20+CD27 memory B-cell numbers appears to coincide with rising IgM levels [78]. In the same study, the patients showing no clinical improvement after rituximab were distinguished from the clinical responders by a higher load of clonal IgM memory B-cell expansions before and after therapy as well as by persistence of clonal expansions, despite efficient peripheral B-cell depletion, and by lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells [79].…”

Section: Biomarkers Of Clinical Response To B-cell-depletion Therapiesmentioning

confidence: 99%

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Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

2016

Self Cite

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B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurological disorders, acting as antibody-producing cells and, most importantly, as sensors, coordinators, and regulators of the immune response. B cells, among other functions, regulate the T-cell activation process through their participation in antigen presentation and production of cytokines. The availability of monoclonal antibodies or fusion proteins against B-cell surface molecules or Bcell trophic factors bestows a rational approach for treating autoimmune neurological disorders, even when T cells are the main effector cells. This review summarizes basic aspects of B-cell biology, discusses the role(s) of B cells in neurological autoimmunity, and presents anti-B-cell drugs that are either currently on the market or are expected to be available in the near future for treating neurological autoimmune disorders.

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Placebo‐controlled trial of rituximab in IgM anti–myelin‐associated glycoprotein antibody demyelinating neuropathy

Abstract: Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial.

Cited by 276 publications

References 33 publications

Immunotherapy-based regimen in anti-MAG neuropathy: results in 45 patients

Immunotherapy-based regimen in anti-MAG neuropathy: results in 45 patients

Immunotherapy in Peripheral Neuropathies

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

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