Relapsing-Remitting Immunotherapy Responsive Small-Fiber Neuropathy: Longitudinal Tracking Through 10 Years Including Pregnancies

Abstract

Objectives: To expand understanding of the pathogenesis, presentations, and treatment of initially idiopathic small fiber polyneuropathy (SFN).

Methods: We longitudinally readministered validated metrics to track disease course and treatment responses in a previously healthy woman with acute, postinfectious, skin biopsy-confirmed, idiopathic SFN.

Results: During 5 years, viral respiratory infections triggered 3 separated episodes of acute, disabling burning hand, foot, and face pain (erythromelalgia). The initial 2 resolved with high-dose prednisone, and the third responded to repeated immunoglobulin treatments. Pregnancy with miscarriage triggered a fourth exacerbation refractory to corticosteroids and cyclosporin. Immunoglobulins restored total remission for 2 months; then, 2 rituximab doses slightly improved later flaring. Subsequently, daratumumab initiated 100-day remission later maintained by belimumab, initiated to permit another pregnancy. Remission continued after gestational week 13 all-treatment withdrawal. A week 30 fifth flare responded to plasmapheresis, with healthy birth at week 40. At 11-week postpartum, as symptoms returned, restarting belimumab restored remission maintained during ≥19 months of breastfeeding.

Discussion: This decade of tracking characterizes a relapsing-remitting course of SFN with initially separated monophasic episodes becoming more confluent, as with multiple sclerosis. This tempo and responsiveness to 5 immunotherapies suggest dysimmune causality. Validated metrics helped define the course and track treatment efficacy, particularly during pregnancy and breastfeeding.

Classification of evidence: This is a single observational study without controls. This provides Class IV evidence.

Figure 1. Foot Erythromelalgia in Small Fiber Neuropathy

Photograph of patient's feet during second episode. Distal erythromelalgia (Gr; red, painful limb) was provoked by heated rooms, warm footwear, and physical activity. It was severe enough to limit walking. Erythromelalgia is a visible manifestation of the underlying triple flare response of Lewis caused by unprovoked, ectopic firing of damaged C-fiber axon terminals. C-fibers release paracrine inflammatory activators including histamine from their distal terminals, while they send electrical pain signals proximally. The neurogenic flare helps initiate the innate immune response to injury, including microvascular dilation to facilitate immunocyte diapedesis into the tissues. C-fiber activation becomes disabling if it persists chronically.

Figure 2. Total Scores on the Small Fiber Symptom Survey During Episodes 2–4

CyA = cyclosporin A, DARA = daratumumab, E1-6: episodes 1–6, IVIG = IV immunoglobulins, P = prednisone, PLEX = plasmapheresis, PGB = pregabalin, RTX = rituximab, SCIG = subcutaneous immunoglobulins, URI = upper respiratory infection. Scoring details: the Small Fiber Symptom Survey (SSS) is a validated patient-reported questionnaire that measures the presence and frequency of symptoms associated with small fiber neuropathy. The 32 items include 5 symptom clusters that cover pain, cardiovascular, gastrointestinal, sweating, and urinary/genital symptoms. Here, the scores for sleep disturbance and headache were excluded because sleep problems were caused by prednisone and headaches by IVIg/SCIg. Dosing details: October 26, 2017: prednisone 1 mg/kg/d for 28 days and then 10 mg/wk tapers. At 20 mg/d, tapering was slowed to 0.25 mg every 4-5 days with successful termination November 29, 2018. February 25, 2019: oral prednisone 1 mg/kg/d for 11 days and then 20 mg for 5 days. March 6, 2019: start of IVIG initial cycle 1.5 g/kg over 3 days and then 1g/kg/4 weeks until June 4, 2019. Doses then tapered to 15 g weekly at a very slow infusion rate due to severe, long-lasting meningeal headaches with nausea. June 12, 2019: SCIG 0.25 g/kg/wk (1 g/kg/4 weeks) until May 16, 2020. May 5, 2020: prednisone 0.5 mg/kg/d for 4 weeks and then taper by 5 mg every 2 weeks. Due to symptom return at 20 mg/d (during 1st pregnancy), prednisone was increased to 40 mg/d for a week, maintained at 25–30 mg/d until September 8, 2020, and then tapered until discontinuation on October 23, 2020. July 3, 2020: SCIG 0.25g/kg/wk until November 29, 2020. Higher single SCIG doses up to 30 g/1 d tried. September 25, 2020: oral methylprednisolone 1g/d pulse therapy for 5 days. August 31 and September 1, 2020: rituximab 1000 mg infusions. December 15, 2020: cyclosporin A initiated at 300 mg orally, then according to therapeutic drug monitoring until January 17, 2021. March 27, 2021: start of pregabalin at 25 mg/day and increase to max of 225 mg/d until June 10, 2021. March 19, April 9, and December 5, 2021: 3 doses of the mRNA anti–SARS-CoV-2 vaccine. May 5, 2021: subcutaneous daratumumab initiated at 1800 mg weekly over 2 months, then biweekly injections through August 3, 2021. October 17, 2021: subcutaneous (SC) belimumab weekly initiated at until April 1, 2022. January 7, 2022: IV infusion (to achieve high initial peak concentration) of daratumumab (16 mg/kg, January 7, 2022) followed by a SC daratumumab (1800 mg January 14, 2022) 7 days after. February. 9, 2022: GW 4 pregnancy confirmed through ultrasound. August 25, 2022: 7 plasmapheresis procedures through September 14, 2022. September 23, 2022: restart of SCIG 1g/kg/4 weeks (approximately) until December 8, 2022. December 9, 2022: restart of SC belimumab 200 mg weekly, continuing in December 2023.