IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality

Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy are umbrella terms for a number of pathologically distinct diseases involving disabling, immune-mediated injury to peripheral nerves. Current treatments involve non-specific immunomodulation. Prospective identification of patients with specific disease mechanisms should increasingly inform the use of more targeted disease modifying therapies and may lead to improved outcomes. In this cohort study, we tested serum for antibodies directed against nodal/paranodal protein antigens. The clinical characteristics of antibody positive and seronegative patients were then compared. Eight patients with IgG1-subclass antibodies directed against both isoforms of the nodal/paranodal cell-adhesion molecule neurofascin were identified. All developed rapidly progressive tetraplegia. Cranial nerve deficits (100% versus 26%), autonomic dysfunction (75% versus 13%) and respiratory involvement (88% versus 14%) were more common than in seronegative patients. The response to intravenous immunoglobulin, steroids and/or plasmapheresis was poor. Four patients received the B-cell-depleting therapy rituximab. After several weeks, these patients began to show progressive functional improvements, became seronegative, and were ultimately discharged home. Four patients who did not receive rituximab did not improve and died following the development of infectious complications and/or withdrawal of intensive care support. IgG1 panneurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically-classified patient group. ### Competing Interest Statement JF has received research grants from the Guarantors of Brain and GBS|CIDP Foundation International. TL has received speaker's honoraria from CSL Behring and Akcea. AJD, RJW, RK, AMR, TM, ND, RR, DB, and GL report no disclosures or conflicts of interest. SR has received has received speaker's honoraria from Fresenius, Alnylam and Excemed, and payments to provide expert medicolegal advice on inflammatory neuropathies and their treatment. He has received complimentary registration and prize money from the Peripheral Nerve Society, and a travel bursary from the European School of Neuroimmunology. He is a member of the GBS and Associated Inflammatory Neuropathies (GAIN) patient charity medical advisory board. He runs a not-for-profit nodal/paranodal antibody testing service at the Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK, in partnership with Clinical Laboratory Immunology of Oxford University Hospitals. ### Funding Statement We acknowledge funding support from the GBS/CIDP Foundation International (Benson Fellowship awarded to JF) and the Medical Research Council (UK) (grant MR/P008399/1 supports SR and AJD). The funders had no role in the design of this study or in the interpretation or presentation of its results. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the NHS National Research Ethics Service Committee (South Central Oxford A, 14/SC/0280). The use of de-identified clinical data from other patients to audit the relative value of available and novel methods to determine autoantibodies, based on the gold standard of immune-mediated clinical phenotypes, was approved by the Oxford University Hospitals NHS Trust clinical audit leads (ID 5106). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available from the corresponding author, upon reasonable request. * Caspr : contactin-associated protein (1) CBA : cell-based assay CIDP : chronic inflammatory demyelinating polyneuropathy ELISA : enzyme-linked immunosorbent assay GBS : Guillain-Barré syndrome Ig : immunoglobulin IVIg : intravenous immunoglobulin NF : neurofascin OR : odds ratio CI : confidence interval PLEx : plasma exchange