Prevalence of Axonal Sensory Neuropathy With IgM Binding to Trisulfated Heparin Disaccharide in Patients With Fibromyalgia

Abstract

Objective:To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients. Methods:FM is a poorly understood pain disorder with several proposed pathophysiologic mechanisms. It is characterized by widespread pain, fatigue, and sleep abnormalities. Small fiber neuropathy (SFN) has been proposed as an underlying mechanism, and patients with FM have been shown to have a reduction in the intraepidermal nerve fiber density. An underlying inflammatory process that could be a result of autoimmune phenomena has also been suggested. Non-length-dependent SFN (NLDSFN) has been shown to have a higher incidence of autoimmune disease. Twenty-two patients with established diagnosis of FM underwent skin biopsy at 2 sites; 10 cm above the lateral malleolus and 10 cm above the patella. Serum IgM binding to TS-HDS was assayed using an ELISA method.Results: A total of 5/22 patients had positive TS-HDS antibodies; of these, 4 had NLDSFN (P ¼ 0.0393). Comparison with a control group at Washington University showed no significant difference in percentage with TS-HDS antibodies (P ¼ 0.41). When compared with Washington University database of skin biopsy, there was a trend for an increased percentage of NLDSFN in patients with FM (P ¼ 0.06). Conclusions:This study further supports the hypothesis that a subgroup of patients with FM has SFN. We suggest a correlation between the presence of NLDSFN and TS-HDS antibodies.

Clinical Features and Treatment Response in Immune-Mediated Small Fiber Neuropathy with Trisulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies

“…Also consistent with the previous article was substantially higher presences of acute onset in seropositive cases and a NLD-IENFD pathology. 4,15 The latter has been demonstrated clearly in autoimmune cases and is consistent with the inflammatory nature of these cases. 16 Symptom onset was also similar in our cohort to the previous paper, 4 in regards to the initial reported symptom of neuropathic pain and a high percentage having a widespread pain syndrome similar to fibromyalgia, with the odds ratio for both categories being significantly higher in the seropositive group.…”

Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy

“…Insensitivity (false-negative results) is the biggest concern, not only as a result of poor norms (particularly for young patients and female patients), but also from sampling error and the fact that axons typically degenerate later than symptoms appear. Second biopsies (eg, from the thigh for non–length-dependent neuropathic conditions, or from the foot) add sensitivity but also cost, and there are insufficient norms to recommend routine use. Immunofluorescence (Figure 1) visualizes twice as many fibers as conventional bright-field microscopy (Figure 3) and thus requires separate norms .…”

“…Passive transfer of human autoantibodies to contactin-associated protein-like 2 ( CASPR2 ) to mice causes pain hypersensitivity and enhanced dorsal-root ganglia cell excitability by reducing potassium-channel K v 1 function . Five of 8 children with isolated iiSFN had IgM autoantibodies against trisulfated disaccharide IdoA2S-GlcNS-6S, as did 5 in a study of 22 patients with fibromyalgia, with 86% of these patients (n = 19) having SFN-diagnostic skin biopsies . Following examples learned from autoimmune encephalitis may enable us to identify cellular and molecular mechanisms of apparently autoimmune SFN.…”

A role for pathogenic autoantibodies in small fiber neuropathy?

“…Trisulfated heparin disaccharide (TS-HDS) is a cell-surface protein expressed by peripheral nerves. It can bind extracellular proteins and is implicated in specific functions such as cell growth and angiogenesis ( Malik et al, 2019 ). Serum immunoglobulin M (IgM) binding to TS-HDS was first identified in a subset of patients with painful, distal axonal neuropathies ( Pestronk et al, 2003 ) and has more recently been linked with SFN.…”