By Alexander Chamessian, MD PhD
Washington University, St. Louis
Small fiber neuropathy (SFN) is a neurological disorder involving widespread damage to the small-diameter somatic and autonomic unmyelinated C-fibers and/or thinly myelinated A-delta fibers.1 Patients often experience pins-and-needles or burning pain sensations. Damage to the autonomic small fibers can cause dysfunction in key systems controlling blood pressure, heart rate and gastrointestinal motility2.
There are several and varied causes of SFN, but in up to half of patients, no definitive cause is found. This has prompted physicians and researchers to search for new causes. Work in the Pestronk laboratory at Washington University in St. Louis turned up evidence that the immune system is the culprit in some cases. In their studies, patients with SFN were more likely to have specific autoantibodies in their blood3,4.
What Are Autoantibodies and What Is Their Role in Neuropathy?
Your body’s immune system makes antibodies to neutralize invading pathogens such as bacteria and viruses. Normally, we only make antibodies that recognize foreign, or non-self, targets. However, sometimes things go awry, and antibodies are produced that also react to molecules on some of the body’s own cells. Self-directed antibodies are called autoantibodies. They are common in autoimmune diseases where the immune system improperly targets healthy host cells such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome5.
Autoantibodies are present in many neuropathies including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP)6, and multifocal motor neuropathy7.These autoantibodies target molecules expressed by nerve cells, and damage the cells to cause neuropathy. In these conditions, the autoantibodies have been demonstrated to directly cause the neuropathy, and treatment with immune-modifying therapy typically improves neuropathy symptoms.
Distinct antibodies discovered in some patients with SFN are named for their molecular targets. They include the Fibroblast Growth Factor Receptor 3 (FGFR3) and Trisulfated Heparin Disaccharide (TS-HDS) antibodies.
Fibroblast Growth Factor Receptor 3 (FGFR3)
In 2015, French scientists investigated possible immune-related causes of sensory neuropathy, including small fiber neuropathy, in patients with no other known causes8. Their search uncovered a highly specific autoantibody to FGFR3. They corroborated this finding in a larger prospective, multi-center study in 2019 in France and Brazil9. In both studies, the researchers detected FGFR3 autoantibodies in fifteen percent of patients with unexplained sensory neuropathy. A study in the United States also reported the presence of FGFR3 antibodies in a similar proportion of patients with biopsy-verified small fiber neuropathy3.
Trisulfated Heparin Disaccharide (TS-HDS)
TS-HDS is a type of complex sugar found on cell surfaces, including on some nerve cells. In 2003, Pestronk and colleagues discovered that some patients with unexplained small fiber neuropathy have high levels of TS-HDS autoantibodies4. More recently, they demonstrated that more than 1/3 of SFN patients have TS-HDS autoantibodies, and that 92 percent of people with acute-onset SFN have these antibodies3.
What Do These SFN-Associated Antibodies Mean?
The significance of these autoantibodies is still uncertain. Not all autoantibodies are pathological, but many are. For FGFR3, the initial paper by Antoine demonstrated that among 65 healthy people without neuropathy, none possessed FGFR3 autoantibodies. This suggests that FGFR3 autoantibodies arise from an abnormal immune process in those who possess them. The same is likely true of TS-HDS autoantibodies. However, studies have not been done to determine if healthy people have TS-HDS antibodies, so we can only guess that if someone with SFN has these autoantibodies, the two are related.
This leaves many important questions unanswered. Do the autoantibodies themselves cause SFN, or does some other aspect of aberrant immunity damage the small fibers? Studies are underway to address these and related questions, and hopefully will shed light on the role and significance of these and other autoantibodies in SFN.
Even if we do not yet know what role, if any, FGFR3 or TS-HDS autoantibodies play in SFN, they can serve as objective and quantifiable markers of what is otherwise a subjective experience of pain and disability. For many patients with small-fiber and other neuropathies, all the generally-used diagnostic tests return normal results, and no cause is ever identified. This frustrates patients and physicians alike. Detecting high levels of an SFN-associated autoantibody can provide demonstrable evidence that something is wrong, and that the problem lies in the immune system. This has implications for potential treatments for patients who have FGFR3 or TS-HDS autoantibodies.
Clinical Trials for Patients with TS-HDS and FGFR3 Autoantibodies
A goal of diagnostic testing for autoantibodies such as FGFR3 or TS-HDS is to use their presence or absence to guide treatment. Right now, there are no specific treatments for patients who have either autoantibody. However, given that their presence suggests dysfunctional immunity, it follows that immune system modulating therapies might offer benefit, as they do for other autoimmune neuropathies such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy.
Indeed, this is the rationale for an ongoing clinical trial in Boston that aims to determine whether a specific immunomodulatory therapy called Intravenous Immunoglobulin (IVIg) can help patients with SFN and TS-HDS or FGFR3 autoantibodies. According to the trial’s website, the investigators are still recruiting patients to participate. The investigators say, “The results of this study will establish a rationale, with an appropriate screening test, for the use of immune globulin for the treatment of small fiber neuropathy.”
More studies will be needed to understand the role and significance of the known SFN-associated antibodies and to discover new ones. Clinical trials are also needed to identify how best to treat patients with SFN-associated autoantibodies.
1. Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review.
Oaklander A, Nolano M.
JAMA Neurology 2019;76(10):1240–1251.
2. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes.
Terkelsen A, Karlsson P, Lauria G, Freeman R, Finnerup N, Jensen T.
The Lancet Neurology 2017;16(11):934-944.
3. Cryptogenic small‐fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor‐3.
Levine T, Kafaie J, Zeidman L, Saperstein D, Massaquoi R, Bland R, Pestronk A.
Muscle & Nerve 2019;61(4).
4. Sensory neuropathy with monoclonal IgM binding to a trisulfated heparin disaccharide.
Pestronk A, Choksi R, Logigian E, Al-Lozi M. (2003).
Muscle & Nerve 2003;27(2):188–195.
5. Primary Sjögren’s Syndrome.
Lefaucheur J-P, Sène D, and Oaklander AL.
The New England Journal of Medicine. 2018 Jul 5;379(1):96.
6. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews.
Oaklander AL, Lunn MP, Hughes RA, van Schaik IN, Frost C, Chalk CH.
Cochrane Database Syst Rev. 2017 Jan 13;1:CD010369.
7. Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications..
Querol L, Devaux J, Rojas-Garcia R, Illa I.
Nature Reviews Neurology 2017;13(9):533–547.
8. Antifibroblast growth factor receptor 3 antibodies identify a subgroup of patients with sensory neuropathy.
Antoine J, Boutahar N, Lassabliere F, Reynaud E, Ferraud K, Rogemond V, Paul S, Honnorat J, Camdessanche J.
J Neurol Neurosurg Psychiatry 2015;86(12):1347-1355.
9. Clinical characterisation of sensory neuropathy with anti-FGFR3 autoantibodies. Journal of neurology, neurosurgery, and psychiatry Group a.
Tholance Y, Moritz C, Rosier C, Ferraud K, Lassablière F, Reynaud-Federspiel E, França M, Martinez A, Camdessanché J, Antoine J.
J Neurol Neurosurg Psychiatry 2019;Jan;91(1):49-57.
Getting Tested: Recommended Blood Tests for Small Fiber Neuropathy
Overview of Autoimmune Neuropathies – a slide show by Dr. Chafic Karam
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