Our systematic review aims to evaluate the efficacy of intravenous immunoglobulin therapy (IVIG) in patients with small fiber neuropathy (SFN).

SFN is characterized by neuropathic pain due to damaged unmyelinated C fibers. It often lacks an identifiable cause in over 50% of the cases (idiopathic SFN, I-SFN). Associations with immune-mediated disorders and the presence of autoantibodies suggest that immunologic support could be beneficial. IVIG has demonstrated efficacy in similar neuropathies, yet conclusive evidence from controlled trials supporting its use in I-SFN remains unclear.

We conducted a systematic review searching PubMed, Embase, and Cochrane Library. We included randomized clinical trials and cohort studies that assessed the efficacy of IVIG in patients with SFN. Conference abstracts, review articles, and duplicate publications were excluded.

Six studies were included, with two randomized controlled trials, with a total of 192 patients with SFN who were treated with IVIG. Nonrandomized studies showed significant improvements in nerve fiber density and reductions in various pain scores by up to 44%, particularly in non-length-dependent cases and Plexin D1-SFN, suggesting a disease-modifying role of IVIG in antibody-positive SFN. However, both double-blind, placebo-controlled trials found no statistically significant differences between IVIG and placebo in reducing pain, improving intra-epidermal nerve fiber density, or any other prespecified outcomes, such as general well-being, autonomic symptoms, and overall functioning and disability, in patients with SFN, including those with TS-HDS and FGFR-3 antibodies.

Overall, while IVIG may offer benefits for specific subtypes of antibody-positive SFN, its efficacy remains unclear in patients with idiopathic SFN. Further research should be conducted to define the specific patient groups that are most likely to benefit from this treatment.