Cryptogenic small‐fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor‐3

Abstract

Introduction Causes of small‐fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor‐3 (FGFR‐3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS‐HDS) in cryptogenic SFN. Methods One hundred fifty‐five patients with biopsy‐proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS‐HDS and IgG vs FGFR‐3. Results Forty‐eight percent of SFN patients had serum antibodies, 37% with IgM vs TS‐HDS and 15% with IgG vs FGFR‐3. TS‐HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non–length‐dependent nerve pathology. Nintey‐two percent of patients with acute‐onset SFN had serum IgM vs TS‐HDS. Discussion Autoantibodies directed against TS‐HDS and FGFR‐3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS‐HDS may be a marker for SFN with an acute onset.

Green shoots but deep roots: New antibodies in small fiber neuropathy

“…The association of immunologic mechanisms with large fiber demyelinating neuropathy is well established . The identification of a primary autoimmune etiology for cryptogenic SFN, which is implied in this recent report by Levine and colleagues, carries with it unique challenges if immunomodulatory therapy is to be considered. Large fiber demyelinating neuropathies include electrophysiologic and cerebrospinal fluid biomarkers in addition to more objective clinical metrics that can be followed to gauge therapeutic efficacy and designate a stopping point for therapy.…”

“…Variability in specific criteria used to define SFN reflect not only diagnostic challenges but also difficulties in following progression and gauging therapeutic response. This is compounded by the lack of widespread availability and use of the principal diagnostic tools—QST, QSART, and HRV …”

“…In this issue of Muscle and Nerve , Levine and colleagues extend the body of literature in which serum immunoglobulin (Ig) M targeting of specific antigens is associated with peripheral neuropathy and, in particular, IgM antibodies to trisulfated heparin disaccharide (TS‐HDS) and fibroblast growth factor‐3 (FGFR3). These antibodies have been described in the past in association with both sensorimotor neuropathies, sensory predominant large fiber neuropathies and neuronopathies .…”

“…These antibodies have been described in the past in association with both sensorimotor neuropathies, sensory predominant large fiber neuropathies and neuronopathies . In the Levine and colleagues series, 155 patients were enrolled in the retrospective review. All patients met clinical and skin biopsy criteria for small fiber neuropathy.…”

“…Given the variability in diagnostic criteria, an objective metric of clinical improvement that does not rely solely on psychophysical data is difficult to isolate. Levine and colleagues acknowledge that “An association of SFN with serum IgM vs TS‐HDS could have treatment implications.” While they also raise concerns that this may represent a treatment refractory form of autoimmune SFN, the association certainly begs the question of whether immunomodulation may come to the forefront of management considerations in SFN. Indeed, at least one randomized controlled, double blind, placebo‐controlled clinical trial of the efficacy and safety of intravenous immunoglobulin in idiopathic SFN is currently underway …”