Anti-myelin-associated-glycoprotein neuropathy successfully treated with tirabrutinib

Yasuda, Hajime; Tomizawa, Yuji; Harada, Shinji; Sasaki, Makoto; Komatsu, Norio; Ando, Jun

doi:10.1016/j.heliyon.2022.e10928

Cited by 8 publications

(7 citation statements)

References 14 publications

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“…There have been few case reports of anti‐MAG neuropathy; however, a case report of three patients with WM and mutated MYD88, who underwent bone marrow biopsy and were started on ibrutinib, showed that they had an early and subjective benefit, especially related to their sensory symptoms, as indicated by the inflammatory neuropathy cause and treatment sensory sum score, which was consistent with the objective improvement 45 . In another case report, tirabrutinib treatment of one rituximab‐refractory anti‐MAG neuropathy patient continued to give excellent disease control related to sensory nerve action potentials with no apparent adverse events at 11 months since initiation, and the patient remained free of plasmapheresis sessions, which were originally mandatory 46 …”

Section: Igm‐type Pansupporting

confidence: 70%

“…45 In another case report, tirabrutinib treatment of one rituximab-refractory anti-MAG neuropathy patient continued to give excellent disease control related to sensory nerve action potentials with no apparent adverse events at 11 months since initiation, and the patient remained free of plasmapheresis sessions, which were originally mandatory. 46…”

Section: Intravenous Immunoglobulin Therapymentioning

confidence: 99%

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Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

Nakajima

2024

Clinical & Exp Neuroim

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Paraproteinemia‐associated neuropathy (PAN) develops with paraproteinemia and is mainly caused by the monoclonal proliferation of mature B cells, especially monoclonal gammopathy of undetermined significance (MGUS). PAN tends to increase with age, and in a super‐aging society, its frequency is expected to increase. Among paraproteinemias, the immunoglobulin (Ig)G type is most common, but the frequency of PAN is reported to be higher for the IgM type. IgG/IgA‐type PAN includes MGUS, plasma cell myeloma, and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome. IgM‐type PAN includes anti‐myelin‐associated glycoprotein antibody‐associated neuropathy, chronic ataxic neuropathy with IgM antibody that recognizes disialosyl ganglioside and IgM‐type PAN without anti‐nerve antibodies. Light chain‐type PAN includes immunoglobulin‐related amyloidosis. PAN has the characteristics of a blood disease, as well as an immune‐mediated disease, and is treated by immunotherapy. As an example, anti‐myelin‐associated glycoprotein antibody‐associated neuropathy is treated with rituximab, plasmapheresis and intravenous immunoglobulin therapy, but their effectiveness has not been established. As novel treatments, lenalidomide, Bruton tyrosine kinase inhibitors, B‐cell lymphoma 2 inhibitors and mimetic human natural killer‐1 epitope polymers have been investigated. By analyzing the human natural killer‐1‐related sugar chain structure as an antigen, the selective removal of pathological antibodies might be a new therapeutic target.

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Section: Igm‐type Pansupporting

confidence: 70%

Section: Intravenous Immunoglobulin Therapymentioning

confidence: 99%

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

Nakajima

2024

Clinical & Exp Neuroim

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“…the need for chronic treatment and cumulative toxicities of the chemotherapeutic agents. 28 More recently, treatment with the anti-Bruton's tyrosine kinase (BTK) agents ibrutinib 57 or tirabrutinib, 58 or with venetoclax, an anti-B-cell lymphoma-2 (BLCl2) agent that promotes apoptosis, 59 have also been reported to be of benefit. A retrospective analysis of 50, mostly uncontrolled studies with 410 patients found that a relative reduction in the serum IgM anti-MAG antibody level is associated with a clinical response.…”

Section: Electrodiagnostic Studiesmentioning

confidence: 99%

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

Latov,

Brannagan,

Sander

et al. 2024

Arq Neuropsiquiatr

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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.

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“…Only patients with a MAG titer of over 10 000 BTU will be included. In addition, successful use of tirabrutinib, a third BTK inhibitor, has been demonstrated in a case of rituximab‐refractory anti‐MAG neuropathy 52 . No tirabrutinib trials are currently underway or planned.…”

Section: Current State Of Immunotherapeutic Researchmentioning

confidence: 99%

Anti–myelin‐associated glycoprotein neuropathy: Where do we stand?

Stino,

Elsheikh,

Allen

2023

Muscle and Nerve

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Myelin‐associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti‐MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off‐label immunotherapy is common, there are currently no proven effective disease‐modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti‐MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti‐MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti‐MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B‐cell–depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti‐MAG neuropathy patients.

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Anti-myelin-associated-glycoprotein neuropathy successfully treated with tirabrutinib

Cited by 8 publications

References 14 publications

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

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

Anti–myelin‐associated glycoprotein neuropathy: Where do we stand?

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