Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications

Arthritis Rheumatol. 2014 Jul;66(7):1945-54. doi: 10.1002/art.38662.


Objective: A subset of patients with fibromyalgia (FM) exhibit a large fiber demyelinating peripheral polyneuropathy akin to that seen in chronic inflammatory demyelinating polyneuropathy (CIDP). It has been suggested that this demyelinating process is likely to be immune mediated. Because it is known that similar large fiber neuropathic lesions may be associated with a cutaneous small fiber neuropathy, we sought to determine the prevalence of small fiber neuropathy, as measured by epidermal nerve fiber density (ENFD), in a series of patients with FM and clinically healthy control subjects.

Methods: Forty-one consecutive patients with FM and 47 control subjects underwent a 3-mm punch skin biopsy at the proximal thigh and distal leg near the ankle, for analysis of the ENFD. Patients with FM who had clinical evidence of a disorder known to be associated with small fiber neuropathy were excluded. The patients with FM also underwent pinwheel testing and vibratory testing for hypesthesia and serologic testing for a series of cytokine, circulating immune complex, and complement measurements.

Results: All patients with FM had evidence of stocking hypesthesia. The ENFD of patients with FM was lower than that of control subjects at both the calf (mean ± SD 5.8 ± 2.8 versus 7.4 ± 1.9; P = 0.0002) and thigh (9.3 ± 3.2 versus 11.3 ± 2.0; P = 0.0007). There was an inverse correlation between calf ENFD and age at the time of skin biopsy in patients with FM (r = -0.29, P = 0.03) but not in control subjects; however, analysis of covariance showed that this relationship could not be explained by aging alone. Serologic evaluation showed an inverse correlation between calf ENFD in patients with FM and the interleukin-2 receptor (IL-2R) level (r = -0.28, P = 0.04). However, an inverse correlation between thigh ENFD and serum IL-2R levels did not reach significance (P = 0.08). Analysis of thigh-to-calf ENFD ratios suggested that the ENFD decline in FM is affected by both a diffuse and a length-dependent process.

Conclusion: The calf and thigh ENFD in patients with FM is significantly diminished compared with that in control subjects. Advancing age alone cannot explain this finding. Calf ENFD was inversely correlated, although weakly, with serum levels of IL-2R. These findings suggest that small fiber neuropathy is likely to contribute to the pain symptoms of FM; that pain in this disorder arises, in part, from a peripheral immune-mediated process; and that measurement of ENFD may be a useful clinical tool in FM.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biopsy
  • Epidermis / immunology
  • Epidermis / innervation*
  • Epidermis / pathology*
  • Erythromelalgia / immunology
  • Erythromelalgia / pathology
  • Female
  • Fibromyalgia / immunology*
  • Fibromyalgia / pathology*
  • Humans
  • Hypesthesia / immunology
  • Hypesthesia / pathology
  • Male
  • Middle Aged
  • Nerve Fibers / immunology
  • Nerve Fibers / pathology*
  • Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / immunology
  • Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / pathology
  • Receptors, Interleukin-2 / immunology
  • Young Adult


  • Receptors, Interleukin-2