Small fiber neuropathy (SFN) is a disorder of the thinly myelinated Aδ-fibers and the unmyelinated C-fibers, with a minimum prevalence of 53/100,000 [
1]. Patients suffer from neuropathic pain, usually according to a length-dependent pattern [
2]. In addition, they report autonomic symptoms such as palpitations, gastrointestinal disturbances, and orthostatic dizziness [
3,
4]. SFN interferes with daily functioning and may lead to a decrement in quality of life expectations [
5]. The diagnosis is based on SFN-related symptoms, without signs of large fiber involvement, in combination with an abnormal intraepidermal nerve fiber density (IENFD) in skin biopsy and/or abnormal temperature threshold levels in quantitative sensory testing [
3,
4]. Despite intensive search for underlying causes such as diabetes mellitus, impaired glucose tolerance, Fabry’s disease, hereditary disorders, celiac disease, sarcoidosis, HIV, and other systemic illnesses that may be potentially treatable [
3,
4], the proportion of patients with idiopathic SFN (I-SFN) remains substantial, ranging in different series from 24 % up to 93 % [
1,
6‐
8]. Conceivably, immunological mechanisms may play a role in patients with I-SFN, as several immune-mediated diseases such as sarcoidosis, Sjogren’s disease, and systemic lupus erythematosus are associated with SFN [
8‐
11]. Autoantibodies have also been reported in patients with SFN [
12‐
14]. Moreover, inflammatory changes in nerves have been found [
15,
16]. Elevated proinflammatory cytokines have been suggested to be involved in the pathophysiology of pain in SFN [
17]. In other immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy, treatment with intravenous immunoglobulin (IVIg) has proven to be efficacious [
18,
19]. Moreover, some immunomodulation therapies have shown efficacy in some open-label case studies in patients with SFN with chronic pain [
20‐
24]. Similar findings have been reported in erythromelalgia, a condition that is associated with SFN [
25,
26]. Pain reduction with IVIg treatment has been summarized recently [
23].
IVIg is a blood product with high doses of pooled IgG molecules, which are derived from thousands of donors. IgG antibodies are the primary mediators of protective humoral immunity against pathogens but can also be pathogenic [
27]. IVIg may be used either to boost the patients' immunological capabilities or, conversely, to blunt an immune response directed toward the patients’ own tissues [
28]. This dual IVIg-mediated effect on the immune system makes IVIg suitable for the treatment of several different diseases. When administered in high concentrations, IVIg has anti-inflammatory properties. How this anti-inflammatory effect is mediated has not been fully elucidated yet. Several mechanisms have been proposed, including toxin inactivation, stimulation of the leukocyte and serum bactericidal action, modulation of cytokine effect, and the modulation of the complement system [
28].
In SFN, current neuropathic pain treatment options are generally insufficient to relieve the pain substantially [
29,
30]. Therefore, a better treatment is warranted. IVIg appears to be a potential therapeutic option for pain alleviation in SFN. The aim of the current pilot study is to investigate the efficacy and safety of IVIg in patients with I-SFN in a randomized, double-blind, placebo-controlled, clinical trial.