Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy

Abstract

Small fiber neuropathy (SFN) is a subtype of sensory neuropathy with acral pain and normal findings in routine nerve conduction studies. Twenty-four patients with SFN and matched controls were prospectively studied in this case-control study. Patients were assessed clinically, with standardized pain and depression questionnaires, by neurophysiologic tests, and by quantitative sensory testing. All patients underwent skin punch biopsy in a clinically affected (distal calf) and a nonaffected area (proximal thigh). Blood samples were collected for systemic cytokine gene expression analysis. Patients with SFN had a 2-fold higher gene expression for interleukin (IL)-2 (p < 0.0001), IL-10 (p = 0.01), and transforming growth factor-beta1 (p = 0.001) in peripheral blood. Skin samples from affected areas showed increased IL-6 (7-fold; p = 0.001) and IL-8 (5-fold; p = 0.002) gene expression when compared to healthy controls. In 10/24 patients, SFN was termed length-dependent (LD) because of a > or =5-fold higher intraepidermal nerve fiber density in the proximal than in the distal skin. Patients with LD-SFN had higher gene expression in the affected distal skin than in nonaffected skin for tumor necrosis factor-alpha (2.6-fold; p = 0.04), IL-1beta (2-fold; p = 0.02), IL-6 (>200-fold; p = 0.01), and IL-8 (>500-fold; p = 0.046). Inflammatory cells were present in most SFN samples but their numbers were not correlated with cytokine levels. Elevated local proinflammatory cytokines may be involved in the pathophysiology of pain in length-dependent small fiber neuropathy. These findings suggest a potential therapeutic role of locally applied cytokine inhibitors.