Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

Amaador, Karima; Koel-Simmelink, Marleen; Kamp, A; Jongerius, Ilse; Heer, Koen de; Teunissen, Charlotte E.; Minnema, Monique C.; Notermans, Nicolette C.; Eftimov, Filip; Kersten, Marie José; Vos, Josephine M.I.

doi:10.1007/s00415-022-10993-4

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…In one study of 24 treatment-naive anti-MAG patients, serum NFL levels were similar to those of non-neuropathy controls. 43 Levels of contactin-1 protein, a potential marker of paranodal damage, were also similar to those of control patients. The findings suggest that NFL and contactin-1 protein may not be useful disease activity biomarkers in anti-MAG neuropathy.…”

Section: What Other Biomarkers Have Been Explored In Anti-mag Neuropa...supporting

confidence: 52%

“…Neurofilament light chain (NFL), a neuronal cytoplasmic protein highly expressed in myelinated axons, has been shown to reflect axonal injury in a number of central and peripheral nervous system disorders. In one study of 24 treatment‐naive anti‐MAG patients, serum NFL levels were similar to those of non‐neuropathy controls 43 . Levels of contactin‐1 protein, a potential marker of paranodal damage, were also similar to those of control patients.…”

Section: What Other Biomarkers Have Been Explored In Anti‐mag Neuropa...mentioning

confidence: 82%

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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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Section: What Other Biomarkers Have Been Explored In Anti-mag Neuropa...supporting

confidence: 52%

Section: What Other Biomarkers Have Been Explored In Anti‐mag Neuropa...mentioning

confidence: 82%

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

Stino,

Elsheikh,

Allen

2023

Muscle and Nerve

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“…There is an unmet need for reliable biomarkers for diagnosis, appropriate selection of patients for treatment and monitoring response 59 . There is a lack of prospective clinical trials to optimise treatment options.…”

Section: Treatmentmentioning

confidence: 99%

“…There is an unmet need for reliable biomarkers for diagnosis, appropriate selection of patients for treatment and criteria for monitoring response. 59 There is a lack of prospective clinical trials to optimize treatment options. A phase II clinical trial, MAGNAZ, of the oral BTK inhibitor zanubrutinib in anti-MAG peripheral neuropathies is underway.…”

Section: Igm-related Neuropathiesmentioning

confidence: 99%

IgM monoclonal gammopathies of clinical significance: diagnosis and management

et al. 2022

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IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenstrom Macroglobulinaemia (WM) and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/l with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or more recently Monoclonal Gammopathy of Clinical Significance (MGCS). Treatment indication in these patients is dictated by the pathological characteristics of the circulating IgM rather than the tumour itself. The clinical workup and treatment options vary widely and differ from the regular treatment for WM. The aim of this review is to alert clinicians to IgM MGCS and to provide practical guidance of when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: Cold agglutinin disease, type I and II cryoglobulinemia, IgMassociated peripheral neuropathy (PN), Schnitzler syndrome and IgM-associated AL Amyloidosis. The inhibition of the pathogenetic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centred on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and PN are the least well developed. A multidisciplinary approach is required particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel clone directed agents and pathogenetic IgM-directed therapies is welcomed.

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“…Studies of NfL have also been conducted in different axonal and demyelinating polyneuropathies. 15,16 This study was undertaken to determine if there are significant detectable sonographic and serum NfL changes in individuals with DPN compared with healthy controls.…”

mentioning

confidence: 99%

Evaluation of Serum Neurofilament Light Chain and Nerve Ultrasound in Diabetic Neuropathy

Nasr‐Eldin,

Cartwright,

Hamed

et al. 2023

J of Ultrasound Medicine

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ObjectiveTo assess the role of serum neurofilament light chain (NfL) levels in individuals with diabetic polyneuropathy (DPN) compared with controls, as well as to highlight the different sonographic changes in DPN and determine if NfL correlates with sonographic, clinical, and functional parameters.MethodsDiabetic individuals with signs or symptoms consistent with peripheral nerve involvement were recruited. They were evaluated by examination, functional neuropathy severity scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was performed of the bilateral median, ulnar, tibial, fibular, sural, and vagus nerves, and cervical roots 5 and 6. Results were compared with age, sex, and body mass index matched healthy controls.ResultsA total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with diabetes with a mean and standard deviation of 6.95 ± 2.95 pg/mL in the diabetic group and 2.83 ± 0.77 pg/mL in controls (P < .001). Nerve cross‐sectional area and serum NfL levels correlated significantly with clinical and functional parameters and with each other (P < .05).ConclusionIndividuals with DPN have significantly higher NfL levels than healthy controls, and NfL levels correlate with ultrasonographic parameters. These findings may be useful for the diagnosis, prognosis, and disease monitoring of those with DPN, though further exploration is needed.

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Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

Cited by 9 publications

References 22 publications

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

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

IgM monoclonal gammopathies of clinical significance: diagnosis and management

Evaluation of Serum Neurofilament Light Chain and Nerve Ultrasound in Diabetic Neuropathy

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