Objectives: Small-fiber polyneuropathy (SFPN) has various underlying causes, including associations with systemic autoimmune conditions. We have proposed a new cause; small-fiber-targeting autoimmune diseases akin to Guillain-Barré and chronic inflammatory demyelinating polyneuropathy (CIDP). There are no treatment studies yet for this 'apparently autoimmune SFPN' (aaSFPN), but intravenous immunoglobulin (IVIg), first-line for Guillain-Barré and CIDP, is prescribed off-label for aaSFPN despite very high cost. This project aimed to conduct the first systematic evaluation of IVIg's effectiveness for aaSFPN.
Methods: With IRB approval, we extracted all available paper and electronic medical records of qualifying patients. Inclusion required having objectively confirmed SFPN, autoimmune attribution and other potential causes excluded. IVIg needed to have been dosed at ⩾1 g/kg/4 weeks for ⩾3 months. We chose two primary outcomes - changes in composite autonomic function testing (AFT) reports of SFPN and in ratings of pain severity - to capture objective as well as patient-prioritized outcomes.
Results: Among all 55 eligible patients, SFPN had been confirmed by 3/3 nerve biopsies, 62% of skin biopsies, and 89% of composite AFT. Evidence of autoimmunity included 27% of patients having systemic autoimmune disorders, 20% having prior organ-specific autoimmune illnesses and 80% having ⩾1/5 abnormal blood-test markers associated with autoimmunity. A total of 73% had apparent small-fiber-restricted autoimmunity. IVIg treatment duration averaged 28 ± 25 months. The proportion of AFTs interpreted as indicating SFPN dropped from 89% at baseline to 55% (p ⩽ 0.001). Sweat production normalized (p = 0.039) and the other four domains all trended toward improvement. Among patients with pre-treatment pain ⩾3/10, severity averaging 6.3 ± 1.7 dropped to 5.2 ± 2.1 (p = 0.007). Overall, 74% of patients rated themselves 'improved' and their neurologists labeled 77% as 'IVIg responders'; 16% entered remissions that were sustained after IVIg withdrawal. All adverse events were expected; most were typical infusion reactions. The two moderate complications (3.6%) were vein thromboses not requiring discontinuation. The one severe event (1.8%), hemolytic anemia, remitted after IVIg discontinuation.
Conclusion: These results provide Class IV, real-world, proof-of-concept evidence suggesting that IVIg is safe and effective for rigorously selected SFPN patients with apparent autoimmune causality. They provide rationale for prospective trials, inform trial design and indirectly support the discovery of small-fiber-targeting autoimmune/inflammatory illnesses.
Keywords: autoimmune diseases; dysautonomia; immunotherapy; intravenous immunoglobulin; neuropathic pain; peripheral nervous system diseases.