Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MD-P: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS.

In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age‐matched female controls. After screening for dry eye disease, corneal LC were counted and sub‐classified as dendritic (dLC) and non‐dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.

Objective.To investigate whether the expression of cytokine, nociception-associated ion channel, and axon guidance genes in patients with skin cell fibromyalgia syndrome (FMS) differs from healthy controls, potentially contributing to pain and small-fiber degeneration in FMS.Methods.We prospectively recruited 128 patients and 26 healthy controls. All study participants underwent neurological examination, and a skin punch biopsy was obtained from the lateral calf and thigh. Skin samples were processed to histologically determine intraepidermal nerve fiber density (IENFD) and for primary fibroblast and keratinocyte cell cultures. Gene expression of selected pro- and antiinflammatory cytokines, nociception-associated ion channels, and axon guidance cues was assessed with quantitative real-time PCR.Results.In fibroblasts, transforming growth factor–ß1 (TGF-ß1) gene expression was higher in patients with FMS compared to controls (calf and thigh: p < 0.001). Also, expression was higher in patients than in controls for these variables: hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (calf: p < 0.01), ephrin-A4 (EFNA4; calf: p < 0.05, thigh: p < 0.001), and ephrin receptor-A4 (EPHA4; thigh: p < 0.05). In keratinocytes, interleukin 10 gene expression was higher in patients with FMS than in controls (thigh: p < 0.05). While no intergroup difference was found for nociception-associated ion channels, EFNA4 and EPHA4 (calf: p < 0.01 each) expression was higher in patients with FMS than in controls. Axon guide expression did not correlate with IENFD.Conclusion.In FMS, skin cells may contribute to cutaneous nociception by differentially expressing membrane-bound and soluble pain mediators and axon pathfinders.

IntroductionWe characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. MethodsSkin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 μm each) were investigated for dermal nerve fiber length (DNFL). ResultsIn FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p<0.05). There were no differences for the other nerve fiber subtypes. DiscussionWe found less dermal nerve fibers in contact with blood vessels in FMS patients than in controls. The pathophysiological relevance of this finding is unclear, but we suggest the possibility of a relationship with impaired thermal tolerance commonly reported by FMS patients.

Background Coping strategies and their efficacy vary greatly in patients suffering from fibromyalgia syndrome (FMS). Objective We aimed to identify somatic and psychosocial factors that might contribute to different coping strategies and resilience levels in FMS. Subjects and methods Standardized questionnaires were used to assess coping, pain, and psychological variables in a cohort of 156 FMS patients. Quantitative real-time polymerase chain reaction (qRT-PCR) determined gene expression of selected cytokines in white blood cells of 136 FMS patients and 25 healthy controls. Data of skin innervation, functional and structural sensory profiles of peripheral nociceptive nerve fibers of a previous study were included into the statistics. An exploratory factor analysis was used to define variance explaining factors, which were then included into cluster analysis. Results 54.9% of the variance was explained by four factors which we termed (1) affective load, (2) coping, (3) pain, and (4) pro-inflammatory cytokines (p < 0.05). Considering differences in the emerged factors, coping strategies, cytokine profiles, and disability levels, 118 FMS patients could be categorized into four clusters which we named “maladaptive”, “adaptive”, “vulnerable”, and “resilient” (p < 0.05). The adaptive cluster had low scores in disability and in all symptom categories in contrast to the vulnerable cluster, which was characterized by high scores in catastrophizing and disability (p < 0.05). The resilient vs. the maladaptive cluster was characterized by better coping and a less pro-inflammatory cytokine pattern (p < 0.05). Conclusion Our data suggest that problem- and emotion-focused coping strategies and an anti-inflammatory cytokine pattern are associated with reduced disability and might promote resilience. Additional personal factors such as low anxiety scores, ability of acceptance, and persistence further favor a resilient phenotype. Individualized therapy should take these factors into account.