title: Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study.
abstract: OBJECTIVE
  Fibromyalgia (FM) is one of the most common chronic pain syndromes. Various pathogenetic mechanisms have been implicated but none is proven. Our scope was to determine if Intraepidermal Nerve Fiber Density (IENFD) is reduced in the skin of FM patients, as observed in patients with painful small fiber sensory neuropathy (SFSN).
  
  
  METHODS
  We prospectively studied 46 FM patients (5 men and 41 women), aged 29 to 76 (mean: 52.5) years, diagnosed according to the ACR 2010 criteria, and 34 controls (18 women and 16 men) aged 19 to 84 (mean: 31.7) years. IENFD was measured using published guidelines and immune markers were sought immunocytochemically. In 30 FM patients, pain intensity was assessed with the Neuropathic Pain Symptom Inventory (NPSI), a scale validated for neuropathic pain.
  
  
  RESULTS
  15 of 46 (32.6%) FM patients had reduced IENFD [range: 0.6-12.5 fibers/mm (mean: 4.83 SD: 2.5)], compared to healthy controls [2.8-11.5 fibers/mm (mean: 7.35, SD: 1.85)] (p<0.0001). No significant correlation was noticed between NPSI scores and IENFD. No difference in the Langerhans cells, the major Antigen Presenting Cells (APCs) in the epidermis, or in IL-6 staining, was noted between FM and controls. IENFD was equally reduced in a subset of FM patients who also had another autoimmune disease.
  
  
  CONCLUSIONS
  This is one of the largest series of FM patients demonstrating a significant reduction of IENFD in their skin biopsies. The findings indicate that in a subset of FM patients, the pain syndrome is, at least partially, of neuropathic origin. Skin biopsy may prove a useful tool and a potential biomarker in future studies of FM patients.
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Michalis L
authors.initials: ML
authors.lastname: Kosmidis
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Loukia
authors.initials: L
authors.lastname: Koutsogeorgopoulou
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Harry
authors.initials: H
authors.lastname: Alexopoulos
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Mamali
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Panagiotis G
authors.initials: PG
authors.lastname: Vlachoyiannopoulos
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Michalis
authors.initials: M
authors.lastname: Voulgarelis
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Haralampos M
authors.initials: HM
authors.lastname: Moutsopoulos
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Tzioufas
authors.affiliation: Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: mdalakas@med.uoa.gr.
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D004817:Epidermis / Q000294:innervation; D005260:Female; D005356:Fibromyalgia / Q000175:diagnosis* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology*; D009437:Neuralgia / Q000175:diagnosis / Q000473:pathology*; D011446:Prospective Studies; D012867:Skin / Q000294:innervation*; D055815:Young Adult
keywords: Autoimmunity; Fibromyalgia; Langerhans cells; Pain; Skin biopsy; Small fiber neuropathy