Anti-MAG neuropathy: historical aspects, clinical-pathological correlations, and considerations for future therapeutical trials

Abstract

Background Patients with anti-MAG neuropathy present with distal demyelinating polyneuropathy, IgM monoclonal gammopathy, and elevated titers of anti-MAG antibodies.

Objective This paper reviews what is known about the clinical presentation, course, pathophysiology, and treatment of anti-MAG neuropathy, with considerations for the design of therapeutic trials.

Methods A literature review of the medical and scientific literature related to anti-MAG neuropathy, and the design of therapeutic clinical trials in peripheral neuropathy.

Results Anti-MAG neuropathy can remain indolent for many years but then enter a progressive phase. Highly elevated antibody titers are diagnostic, but intermediate titers can also occur in chronic inflammatory demyelinating polyneuropathy (CIDP). The peripheral nerves can become inexcitable, thereby masking the demyelinating abnormalities. There is good evidence that the anti-MAG antibodies cause neuropathy. Reduction of the autoantibody concentration by agents that target B-cells was reported to result in clinical improvement in case series and uncontrolled trials, but not in controlled clinical trials, probably due to inadequate trial design.

Conclusion We propose that therapeutic trials for anti-MAG neuropathy include patients with the typical presentation, some degree of weakness, highly elevated anti-MAG antibody titers, and at least one nerve exhibiting demyelinating range abnormalities. Treatment with one or a combination of anti-B-cell agents would aim at reducing the autoantibody concentration by at least 60%. A trial duration of 2 years may be required to show efficacy. The neuropathy impairment score of the lower extremities (NIS-LL) plus the Lower Limb Function (LLF) score would be a suitable primary outcome measure.

Resumo

Antecedentes Pacientes com neuropatia anti-MAG apresentam polineuropatia desmielinizante distal, gamopatia monoclonal IgM e títulos elevados de anticorpos anti-MAG.

Objetivo Este artigo revisa o que se sabe sobre a apresentação clínica, curso, fisiopatologia e tratamento da neuropatia anti-MAG, com considerações para o desenho de ensaios terapêuticos.

Métodos Revisão bibliográfica da literatura médica e científica relacionada à neuropatia anti-MAG e desenho de ensaios clínicos terapêuticos em neuropatia periférica.

Resultados A neuropatia anti-MAG pode permanecer indolente durante muitos anos, mas depois entra numa fase progressiva. Títulos de anticorpos altamente elevados são diagnósticos, mas títulos intermediários também podem ocorrer na polineuropatia desmielinizante inflamatória crônica (CIDP). Os nervos periféricos podem tornar-se inexcitáveis, mascarando, assim, as anomalias desmielinizantes. Há boas evidências de que os anticorpos anti-MAG causam a neuropatia. Foi relatado que a redução da concentração de autoanticorpos por agentes direcionados às células B resultou em melhora clínica em séries de casos e ensaios não controlados, mas não em ensaios clínicos controlados, provavelmente devido ao desenho inadequado dos ensaios.

Conclusão Propomos que os ensaios terapêuticos para neuropatia anti-MAG incluam pacientes com apresentação típica, algum grau de fraqueza, títulos de anticorpos anti-MAG altamente elevados e pelo menos um nervo exibindo anormalidades na faixa desmielinizante. O tratamento com um ou uma combinação de agentes anticélulas B teria como objetivo reduzir a concentração de autoanticorpos em pelo menos 60%. Pode ser necessária uma duração de ensaio de 2 anos para demonstrar eficácia. A pontuação de comprometimento da neuropatia das extremidades inferiores (NIS-LL) mais a pontuação da função dos membros inferiores (LLF) seria uma medida de resultado primário adequada.

Keywords

Demyelinating Diseases - Anti-MAG - Neuropathy

Palavras-chave

Doenças Desmielinizantes - Anti-MAG - Neuropatia

Authors' Contributions:

NL: is the main author and he reviewed the literature, planned the manuscript and selected the review topic, did selection of articles and data extraction, evaluated the quality of selected articles and wrote the first draft and the final version for the first submission; THBIII: did literature revision, selection of articles and data extraction, evaluated the quality of selected articles, helped with critical review and group discussion and wrote the final version for the first submission; HWS: did literature revision, selection of articles and data extraction, evaluated the quality of selected articles, helped with critical review and group discussion and wrote the final version for the first submission; FAAG: planned the manuscript and selected the review topic, did literature revision, selection of articles and data extraction, evaluated the quality of selected articles, helped with critical review and group discussion and wrote the final version for the first submission.

Publikationsverlauf

Eingereicht: 13. September 2023

Angenommen: 21. November 2023

Artikel online veröffentlicht:
07. Februar 2024

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