Dottorato in TECNOLOGIE INNOVATIVE NELLE MALATTIE DELLO SCHELETRO,
DELLA CUTE E DEL DISTRETTO ORO-CRANIO-FACCIALE

Titolo della tesi: How small fibre pathology influences somatosensory system function in patients with fibromyalgia

Study 1 : Small-fibre pathology has no impact on somatosensory system function in patients with fibromyalgia. A skin biopsy and voltage-gated sodium channel genotyping study. Study 2 : Comparison of Quantitative sensory testing profiling between fibromyalgia patients with and without small-fibre pathology and patients with small-fibre neuropathy. In a first study we aimed to investigate whether small-fibre pathology, a common skin biopsy finding in patients with fibromyalgia, implies clinically important abnormalities of somatosensory system function and verify whether it is associated with voltage-gated sodium channel variants. In 57 consecutively enrolled patients with fibromyalgia we used skin biopsy to distinguish patients with and without small-fibre pathology. In all patients, we assessed somatosensory system function using quantitative sensory testing and laser-evoked potentials and investigated voltage-gated sodium channel genotyping. We then compared these variables in patients with and without small-fibre pathology. We found that clinical measures, quantitative sensory testing, and laser-evoked potential variables did not differ between patients with and without small-fibre pathology. In most patients with small-fibre pathology, quantitative sensory testing and laser-evoked potential variables fell within normative ranges commonly used in clinical practice. Of the 57 patients, one patient without small-fibre pathology and two patients with small-fibre pathology had rare variants of voltage-gated sodium channels, namely SCN11A, SCN9A, and SCN1A variants. The SCN9A variant, found in a patient with small-fibre pathology, was an already profiled gain-of-function mutation, previously reported in small-fibre neuropathy. In a second study, after excluding patients with voltage-gated sodium channel mutations and recruiting other patients with fibromyalgia to increase the sample size, we performed a sensory profile allocation comparing three groups of patients (patients with fibromyalgia with and without small-fibre pathology, and patients with small-fibre neuropathy). In this study we aimed to verify whether patients with fibromyalgia and small-fibre neuropathy share similar sensory phenotypes and we aimed to detect the existence of a common pathological background between patients with FMG associated with small fibre pathology and patients with small fibre neuropathy, by comparing their QST sensory profiles. We enrolled 64 consecutively-diagnosed patients with fibromyalgia and 30 patients with a diagnosis of small-fibre neuropathy relied on BESTA criteria and associated with a definite aetiology (11 patients with amyloidosis, 8 with diabetes and 11 with systemic lupus). We compared the different clinical and quantitative sensory testing measures in patients with fibromyalgia with and without small-fibre pathology, and patients with small-fibre neuropathy. In the three groups of patients we defined four distinct sensory profiles clusters based on quantitative sensory testing in order to do a profile allocation. We found that patients with small-fibre neuropathy were slightly older and with a longer disease duration than fibromyalgia patients with and without small-fibre pathology. The mean variables of quantitative sensory testing of patients with fibromyalgia fell within normative ranges, with the exception of mechanical pain sensitivity. We showed that patients with fibromyalgia and small-fibre neuropathy have distinct sensory phenotypes. Specifically, we observed a predominantly gain of function phenotype in FMG patients with or without SFP, while SFN subgroup had a component of sensory loss. Our findings suggest that small-fibre pathology has a negligible impact on somatosensory system function in fibromyalgia. The genetic analysis suggests that patients with rare small-fibre neuropathy due to voltage-gated sodium channel variants may be misdiagnosed with fibromyalgia. The sensory profile results are in line with the hypothesis that small fibre pathology doesn’t lead to functional sensory deficits and indicate that the small-fibre damage is probably associated with different pathophysiological mechanisms in patients with fibromyalgia and small-fibre neuropathy.