Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

SYNOPSIS: The cause of most cases of small-fiber neuropathy is uncertain, but many patients have accompanying autoimmune biomarkers. In a carefully selected group of such patients, intravenous immunoglobulin treatment appears to provide benefit.

SOURCE: Liu X, Treister R, Lang M, Oaklander AL. IVIg for apparently autoimmune small-fiber polyneuropathy: First analysis of efficacy and safety. Ther Adv Neurol Disord 2018:11: 1756285617744484. doi: 10.1177/1756285617744484. eCollection 2018.

Affecting thinly myelinated A-δ and unmyelinated C-fibers, small fiber neuropathy (SFN) results in neuropathic pain and autonomic dysfunction. No etiology is found in 53% of cases. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus, glucose intolerance, and vitamin B12 deficiency are more prevalent compared to the general population, and 26.7% demonstrate additional underlying conditions, even when a known possible cause is present at screening. Alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and hemochromatosis are other associated conditions.¹ Autoimmunity may play a role, even absent a known diagnosis of autoimmune disease. Treatment remains symptomatic unless an underlying condition can be addressed. Does intravenous immunoglobulin (IVIG) have a therapeutic role in patients with apparently autoimmune SFN (aaSFN)?

aaSFN is a concept originating from reports of idiopathic SFN patients responding to corticosteroids or IVIG. It gained further traction with reports of improvement following IVIG in SFN patients with celiac disease, sarcoidosis, Sjögren’s syndrome, and eosinophilic granulomatosis with polyangiitis.

To gain further insight into the efficacy of IVIG for aaSFN, medical records of patients evaluated for SFN at Massachusetts General Hospital between 2007-2015 were reviewed, and those with definite SFN, defined as physician’s diagnosis confirmed with nerve biopsy or autonomic function testing (AFT), were selected. Inclusion criteria further required exclusion of other etiologies, including diabetes, thyroidopathy, Lyme disease, Sjögren’s syndrome, celiac disease, hepatitis, monoclonal gammopathies, and vitamin abnormalities. Evidence of dysimmunity also was required, comprising a systemic rheumatologic or specific autoimmune disorder affecting at least one organ system other than small nerve fibers. Patients with nerve-specific aaSFN also were included if their biopsies demonstrated inflammatory infiltrates or if blood studies documented unexplained inflammatory markers, including antinuclear antibody > 1:160, elevated erythrocyte sedimentation rate > 15 mm/h, low complement C3 or C4, or Sjögren’s antibodies. Lastly, inclusion required a trial of IVIG > 1 g/kg/4 weeks for at least three months. Primary outcome was pain severity rated on the standard 11-point scale and AFT, with secondary outcomes including safety and standard seven-point patient global impression of change. Statistical analysis comprised the Shapiro-Wilk, McNemar, and chi-square tests, with P < 0.025 required for statistical significance.

Among 55 eligible patients, 78% (n = 43) were female, and average age was 41 years. Overall, 74% of patients rated themselves improved, 77% of neurologists rated their patients as IVIG responders, and 16% remained in remission after IVIG withdrawal. More than 30% pain reduction was found in 31% of patients with baseline pain (10/32), and AFT improved in 31%. Adverse events included typical infusion reactions, such as headache, nausea, and flu-like symptoms, resulting in three patients discontinuing IVIG before three months, with two instances of venous thrombosis not requiring IVIG cessation and one instance of severe hemolytic anemia that resolved after IVIG discontinuation. IVIG is safe and appears effective for carefully selected aaSFN patients. Prospective trials are needed to support this class IV evidence.

COMMENTARY

Following infusion, IVIG requires three to five days to equilibrate between the intra- and extravascular systems. Essentially a collection of pooled antibodies, mainly of the immunoglobulin G (IgG) isotype, serum IgG rapidly declines during the first week because of a shift from the intravascular to the extravascular space, and more slowly thereafter, where the decline is due to catabolism, comprising a half-life of approximately three weeks. Numerous mechanisms have been proposed to explain the anti-inflammatory properties of IVIG, including, among others, Fc receptor blockade, complement inhibition, cytokine modulation, apoptosis enhancement, circulating IgG catabolism augmentation, IgG sialylation (attaching sialic acid to the Fc or Fab component of IgG), interruption of T-cell adhesion to the extracellular matrix, and modulating glucocorticoid receptors. Its potential benefit in treating apparently aaSFN is physiologically plausible. We await further evidence of its efficacy.

REFERENCE

1. De Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, et al. Associated conditions in small fiber neuropathy — a large cohort study and review of the literature. Eur J Neurol 2018;25:348-355.