Immunoglobulin Therapy in Patients with Painful Small Fiber Neuropathy: A Systematic Review

Small fiber neuropathy (SFN) affects pain and autonomic function, and there is increasing evidence that immune pathways are linked to its pathology. Intravenous immunoglobulin (IVIG) has been proposed as a treatment option for patients with painful SFN but has yielded mixed results. This review evaluates the effectiveness of IVIGs in the treatment of painful SFN.

According to PRISMA guidelines, a thorough literature search was conducted using five major electronic databases (PubMed, Google Scholar, Scopus, EMBASE, and Web of Science) up to August 17, 2023. Data extraction was performed independently by two reviewers, and quality assessments were performed using Joanna Briggs Institute tools. The PRISMA guidelines ensured the transparency of the review.

This systematic review included seven studies to evaluate the effectiveness of IVIG for the treatment of SFN. The review included 458 patients from various studies conducted between 2005 and 2023, covering various neuropathy subtypes such as idiopathic SFN, sarcoidosis-associated SFN, etc. Both double-blind RCTs reported no significant differences between IVIG and placebo in neuropathy severity or pain reduction. Retrospective cohort studies varied in quality and produced mixed results. Of note, some studies showed significant pain reduction with IVIG, while others did not. The effectiveness of IVIG on neuropathy severity and intraepidermal nerve fiber density was similarly variable, with some studies reporting efficacy and others indicate no significant changes. Overall, IVIG showed potential benefits, but the results were inconsistent across studies.

IVIG shows potential efficacy in select SFN subtypes, particularly autoimmuneassociated forms (e.g., TS-HDS/FGFR-3 positive), with some retrospective studies reporting pain and functional improvements. However, two high-quality RCTs found no significant benefit over placebo. Marked heterogeneity in study design, IVIG protocols, diagnostic criteria, and outcome measures limits comparability and generalizability. Adverse events, including infusion reactions were common. These findings highlight IVIG's possible role in immunologically mediated SFN but underscore the need for standardized protocols, biomarker-based patient selection, and large, wellcontrolled trials to establish definitive efficacy.

Some evidence suggests the potential benefit of IVIG therapy for certain subgroups of patients with SFN. However, the overall effectiveness is still unclear, and further studies are needed.