Immune-Mediated Small Fiber Neuropathy With Trisulfated Heparin Disaccharide, Fibroblast Growth Factor Receptor 3, or Plexin D1 Antibodies: Presentation and Treatment With Intravenous Immunoglobulin

Abstract

Objectives:Up to 50% of small fiber neuropathy (SFN) cases are idiopathic, but novel antibodies to Trisulfated Heparin Disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been implicated in half of these cases; the role of anti-Plexin D1 is less clear. We aimed to clarify presentation and management of these patients. Methods:An 18-month retrospective analysis revealed 54 cases of cryptogenic SFN who had testing for the 3 autoantibodies. Demographics, clinical features, epidermal nerve fiber density, and Quantitative Sudomotor Axon Reflex Test results were analyzed. Intravenous immunoglobulin (IVIG) treatment response was assessed. Results:In total, 44.4% of patients had antibodies (62.5% TS-HDS, 29.2% FGFR-3, and 20.8% Plexin D1). Male patients were more likely to be FGFR-3 positive (P ¼ 0.014). Facial involvement was more common in seropositive patients (P ¼ 0.034), and patients with a higher Utah Early Neuropathy Scale score had a higher TS-HDS titer (P ¼ 0.0469), but other clinical features were not significantly different. Seropositive patients trended toward a higher SFN screening list score (P ¼ 0.16), abnormal Quantitative Sudomotor Axon Reflex Test (P ¼ 0.052), and prior erroneous diagnosis (P ¼ 0.19). In patients who completed IVIG, examinations and questionnaires improved and mean epidermal nerve fiber density increased by 297%.Conclusions: TS-HDS, FGFR-3, and Plexin D1 antibodies are present in a high proportion of cryptogenic SFN cases with more facial involvement, and greater disease severity is associated with higher antibody titers.They are often misdiagnosed but may respond subjectively and objectively to IVIG.

Anti–Plexin-D1 Seropositive Small Fiber Neuropathy: Clinical Phenotype, Demographics, and Literature Review

“…[13][14][15][16] However, the presentation and management of anti-plexin-D1 SFN remains unclear, with most studies to date having small study cohorts and/or being within animal models. 13,17 To allow for better management of anti-plexin-D1 SFN, there is a need to better define the demographics, symptoms, biopsy findings, and therapeutic interventions used within this subgroup of SFN patients. In this article, we present 11 patients of anti-plexin-D1 seropositive SFN and a brief review of the relevant literature on anti-plexin-D1 to provide clinicians and researchers with a better understanding of anti-plexin-D1 positive SFN presentation, demographics, symptoms, and management.…”

Intravenous immunoglobulin for immune‐mediated small fiber neuropathy with TS‐HDS and FGFR‐3 antibodies: The jury is still out

“…Looking at the individual biopsy sites, the calf specimens improved in four of six patients but worsened substantially in two of six patients; however, the lower thigh specimens improved dramatically in five of six patients, up to 1822% in one, and even by 252% in a patient who had worsened by 76% in the calf. 3 These latter data, although open label, suggest a high utility in checking proximal biopsy specimens to monitor for NLD improvement. Furthermore, a shorter duration of symptoms may lead to better treatment results with IVIg in immune SFN.…”

“…The SFN-SIQ has a sensitivity of 80% to 86% and a specificity of 70% to 81.8%. 6,7 These questionnaires improved post-IVIg treatment in the recent open-label study, 3 and will be used in NCT04153422.…”

“…1 Other studies have shown that 44% to 55% of cryptogenic cases may have TS-HDS and/or FGFR-3, along with plexin D1. 3 Anti-plexin D1 will be included in the upcoming trial (NCT04153422).…”

“…Given the overall high SFN incidence of 132 per 100 000, and the prevalence of autoimmunity in SFN, 3 immunotherapy may benefit many patients. Randomized trials are critical to determine treatment efficacy, but adequate study power, NLD biopsy analysis, higher IVIg dosing, and the use of SFN-specific questionnaires will also be critical to more accurately determine an efficacy signal and identify the need for larger multicenter trials to address this issue.…”