Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy

Geerts, Margot; Greef, Bianca T A de; Sopacua, Maurice; Kuijk, Sander M J van; Hoeijmakers, Janneke G. J.; Faber, Catharina G.; Merkies, Ingemar S. J.

doi:10.1212/wnl.0000000000011919

Cited by 45 publications

(61 citation statements)

References 53 publications

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“…A recent randomized, double-blind, controlled trial of patients with painful idiopathic SFN showed that IVIG treatment has no significant effect on pain. 11 Effective pain control remains a challenge for many patients with SFN, especially if there is no known underlying disease or the underlying disease is not treatable. Further study with more participants and standardized data collection is necessary to evaluate treatment efficacy and long-term outcome.…”

Section: Etiologymentioning

confidence: 99%

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Small fiber neuropathy: Swiss cohort characterization

2021

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Introduction/Aim: There is currently insufficient clinical and epidemiological data concerning small fiber neuropathy (SFN). This research analyzes data from medical records to determine epidemiology, demographics, clinical characteristics and etiology of SFN.Methods: This is a retrospective, observational study of sequential patients diagnosed with definite SFN (typical clinical features, normal nerve conduction studies, abnormal epidermal nerve fiber density) from the end of November 2016 to the middle of July 2019 at the Cantonal Hospital Lucerne, central Switzerland.Results: A total of 84 patients (64.3% female) with a mean age of 54.7 y were analyzed.Symptoms had been present in patients for an average of 4.8 y when entering the study.A length dependent clinical pattern was seen in 79.8%. All patients had sensory discomfort.Etiology could not be determined in 35.7% of patients, who were diagnosed with idiopathic SFN; 34.5% of patients had an apparently autoimmune SFN, followed by14.3% of patients with metabolic causes. The estimated incidence was at least 4.4 cases/100.000 inhabitants/y. The minimum prevalence was 131.5 cases/100.000 inhabitants.Discussion: This study indicates significant incidence and prevalence rates of SFN in Switzerland. SFN can vary greatly in its symptoms and severity. Extensive work-up resulted in two thirds of the patients being assigned an etiological association. The largest group of patients could not be etiologically defined, underlining the importance of further research on etiologic identification. We expect increased awareness of the developing field of SFN.

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Section: Etiologymentioning

confidence: 99%

“… 10 In contrast, a recent randomized, double‐blind, controlled trial found that IVIG treatment had no significant effect on pain in patients with painful idiopathic SFN. 11 …”

Section: Introductionmentioning

confidence: 99%

Small fiber neuropathy: Swiss cohort characterization

2021

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“…However, prior studies were retrospective and descriptive small case series or reports, and quality evidence is lacking. To date, the only double‐blinded, randomized controlled trial performed on iSFN patients contradicts this, showing a statistically nonsignificant improvement of neuropathic pain in 40% of iSFN patients treated with IVIg, compared to 30% with placebo 11 . Improvement of neuropathic pain was defined as a 1‐point improvement on the Pain Intensity Numerical Rating Scale score 11 .…”

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confidence: 99%

Novel Autoantibodies in Idiopathic Small Fiber Neuropathy

Chan

Wong

Chong

et al. 2021

Annals of Neurology

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Objective: Small fiber neuropathy (SFN) is clinically and etiologically heterogeneous. Although autoimmunity has been postulated to be pathophysiologically important in SFN, few autoantibodies have been described. We aimed to identify autoantibodies associated with idiopathic SFN (iSFN) by a novel high-throughput protein microarray platform that captures autoantibodies expressed in the native conformational state. Methods: Sera from 58 SFN patients and 20 age-and gender-matched healthy controls (HCs) were screened against >1,600 immune-related antigens. Fluorescent unit readout and postassay imaging were performed, followed by composite data normalization and protein fold change (pFC) analysis. Analysis of an independent validation cohort of 33 SFN patients against the same 20 HCs was conducted to identify reproducible proteins in both cohorts. Results: Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC = 2.99 and 3.07, respectively, p = 0.003, q = 0.076), DBNL (FC = 2.11 and 2.16, respectively, p = 0.009, q < 0.003), and KRT8 (FC = 1.65 and 1.70, respectively, p = 0.043, q < 0.003). Further subgroup analysis into iSFN and SFN by secondary causes (secondary SFN) in the main cohort showed that MX1 is higher in iSFN compared to secondary SFN (FC = 1.61 vs 0.106, p = 0.009). Interpretation: Novel autoantibodies MX1, DBNL, and KRT8 are found in iSFN. MX1 may allow diagnostic subtyping of iSFN patients.

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“…Two non-specific autoantibodies, one against trisulfated heparin disaccharide (TS-HDS) and another against fibroblast growth factor-3 (FGFR3), have been detected more frequently than in controls [129]. A small placebo-controlled trial of IVIg in 60 SFSN patients without underlying autoimmune conditions [130] showed that after 3 months, the pain improved in 40% of IVIg-recipients compared to 30% of the placebo, concluding no clinically relevant benefit. The study was however centered on the economics of IVIg, not taking into consideration the economics of disability induced by SFSN or patient subsets with immune etiologies that can benefit from IVIg for some time period.…”

Section: Neuropathic Pain Syndromes: Possibly-autoimmune Small Fibre Sensory Neuropathy (Sfsn) Reflex Sympathetic Dystrophy (Rsd) and Commentioning

confidence: 99%

Update on Intravenous Immunoglobulin in Neurology: Modulating Neuro-autoimmunity, Evolving Factors on Efficacy and Dosing and Challenges on Stopping Chronic IVIg Therapy

Dalakas

2021

Neurotherapeutics

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In the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune neurological disorders. Derived from thousands of healthy donors, IVIg contains IgG1 isotypes of idiotypic antibodies that have the potential to bind pathogenic autoantibodies or cross-react with various antigenic peptides, including proteins conserved among the “common cold”-pre-pandemic coronaviruses; as a result, after IVIg infusions, some of the patients’ sera may transiently become positive for various neuronal antibodies, even for anti-SARS-CoV-2, necessitating caution in separating antibodies derived from the infused IVIg or acquired humoral immunity. IVIg exerts multiple effects on the immunoregulatory network by variably affecting autoantibodies, complement activation, FcRn saturation, FcγRIIb receptors, cytokines, and inflammatory mediators. Based on randomized controlled trials, IVIg is approved for the treatment of GBS, CIDP, MMN and dermatomyositis; has been effective in, myasthenia gravis exacerbations, and stiff-person syndrome; and exhibits convincing efficacy in autoimmune epilepsy, neuromyelitis, and autoimmune encephalitis. Recent evidence suggests that polymorphisms in the genes encoding FcRn and FcγRIIB may influence the catabolism of infused IgG or its anti-inflammatory effects, impacting on individualized dosing or efficacy. For chronic maintenance therapy, IVIg and subcutaneous IgG are effective in controlled studies only in CIDP and MMN preventing relapses and axonal loss up to 48 weeks; in practice, however, IVIg is continuously used for years in all the aforementioned neurological conditions, like is a “forever necessary therapy” for maintaining stability, generating challenges on when and how to stop it. Because about 35-40% of patients on chronic therapy do not exhibit objective neurological signs of worsening after stopping IVIg but express subjective symptoms of fatigue, pains, spasms, or a feeling of generalized weakness, a conditioning effect combined with fear that discontinuing chronic therapy may destabilize a multi-year stability status is likely. The dilemmas of continuing chronic therapy, the importance of adjusting dosing and scheduling or periodically stopping IVIg to objectively assess necessity, and concerns in accurately interpreting IVIg-dependency are discussed. Finally, the merit of subcutaneous IgG, the ineffectiveness of IVIg in IgG4-neurological autoimmunities, and genetic factors affecting IVIg dosing and efficacy are addressed.

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Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy

Cited by 45 publications

References 53 publications

Small fiber neuropathy: Swiss cohort characterization

Small fiber neuropathy: Swiss cohort characterization

Novel Autoantibodies in Idiopathic Small Fiber Neuropathy

Update on Intravenous Immunoglobulin in Neurology: Modulating Neuro-autoimmunity, Evolving Factors on Efficacy and Dosing and Challenges on Stopping Chronic IVIg Therapy

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