Intravenous immunoglobulin for immune‐mediated small fiber neuropathy with TS‐HDS and FGFR‐3 antibodies: The jury is still out

I read with great interest the recent pilot study by Gibbons and colleagues regarding intravenous immunoglobulin (IVIg) in presumed immune-mediated small fiber neuropathy (SFN) with trisulfated heparin disaccharide Ido2SGlcNS-6S (TS-HDS) and fibroblast growth factor 3 (FGFR-3) autoantibodies. It was laudable in the midst of the COVID-19 pandemic that the authors recruited and carried out the study, and they should be congratulated. Their article does make some excellent points about the pitfalls of skin biopsy positivity in patients without clinical evidence of SFN, an uncritical approach regarding commercial biopsy testing results that have not been repeated, as well as the need for further research to clarify the pathogenicity of these novel antibodies. The authors also highlight that some patients with mild disease (likely excluded from the study) may improve without treatment. However, there are several problematic methodological factors that impact the study's conclusions, and its utility. One major issue is the study's power, as the authors stated, “This study was not powered to prove efficacy in most of the study endpoints. ” There was subject attrition due to the pandemic, and only 17 subjects completed the study out of the planned 20. However, in preparation for an upcoming similar clinical trial (NCT04153422), we completed a power analysis revealing that at least 20 subjects need to be enrolled (10 IVIg and 10 placebo) to yield a power of 80% and show a statistically significant difference in intraepidermal nerve fiber density (IENFD). Enrolling up to 26 patients to account for a potential 20% attrition rate is ideal to ensure adequate power. Thus, even the primary endpoint was underpowered in the Gibbons et al. investigation, and it is unclear whether there was consideration of extending the trial to enroll more subjects. Another critical issue recognized by the authors was that, “this study did not include patients with non-length dependent [NLD] neuropathy. ” The following are characteristic of autoimmune SFN (including patients with TS-HDS and FGFR-3), and hence potential IVIg responsiveness, “acute onset, coexisting autoimmune disease, persistent hand pain, younger age, and/or non-length dependent symptoms. ” A recent study looking at preand posttreatment composite IENFD scores in six patients with TS-HDS, FGFR-3, and plexin D1 antibodies treated with IVIg showed an average improvement of 297%. Looking at the individual biopsy sites, the calf specimens improved in four of six patients but worsened substantially in two of six patients; however, the lower thigh specimens improved dramatically in five of six patients, up to 1822% in one, and even by 252% in a patient who had worsened by 76% in the calf. These latter data, although open label, suggest a high utility in checking proximal biopsy specimens to monitor for NLD improvement. Furthermore, a shorter duration of symptoms may lead to better treatment results with IVIg in immune SFN. Gibbons et al. did not specifically address this issue, which may have affected the results. The symptom duration in their IVIg arm was several months longer than that in the placebo group (4.3 ± 5.6 vs. 3.7 ± 2.9 years). Also, the IVIg dosing may have been suboptimal. The typical ICE trial dosing of a 2-g/kg loading dose followed by a 1-g/kg maintenance dose was used, but a study on IVIg in Sjögren syndrome SFN using 2-g/kg dosing monthly for 6 months showed improved symptoms and autonomic testing. This higher dosing will be used in NCT04153422 and has also been shown to be safe and effective in chronic inflammatory demyelinating polyneuropathy. The authors’ rationale for using the 36-item Short Form questionnaire is also unclear, given that it has not been studied or validated specifically in SFN. SFN-specific questionnaires, including the SFN Symptom Inventory Questionnaire (SFN-SIQ) and the SFN Rasch-built Overall Disability Scale (SFN-RODS), are available and can be used to monitor treatment efficacy. The SFN-SIQ has a sensitivity of 80% to 86% and a specificity of 70% to 81.8%. These questionnaires improved post-IVIg treatment in the recent open-label study, and will be used in NCT04153422. Finally, a minor error was noted in the statement that the novel antibodies are “detected in up to 20% of patients with idiopathic SFN. ” Other studies have shown that 44% to 55% of cryptogenic cases may have TS-HDS and/or FGFR-3, along with plexin D1. Anti–plexin D1 will be included in the upcoming trial (NCT04153422). Given the overall high SFN incidence of 132 per 100 000, and the prevalence of autoimmunity in SFN, immunotherapy may benefit many patients. Randomized trials are critical to determine treatment efficacy, but adequate study power, NLD biopsy analysis, higher IVIg dosing, and the use of SFN-specific questionnaires will also be critical to more accurately determine an efficacy signal and identify the need for larger multicenter trials to address this issue. Received: 13 January 2023 Revised: 26 January 2023 Accepted: 7 March 2023