Role of BDNF-mediated neuroplasticity in patients affected by Fibromyalgia versus other chronic rheumatic diseases.

Background Fibromyalgia (FM) is still often viewed as a psychosomatic disorder. However, the increased pain sensitivity to stimuli in FM patients is not a phenomena of imagination, but the result of specific abnormalities in the central nervous system (CNS) pain matrix. Brain-derived neurotrophic factor (BDNF) is an endogenous protein involved in neuronal survival and synaptic plasticity of the central and peripheral nervous systems. Several lines of evidence converge to indicate that BDNF also participates in structural and functional plasticity of nociceptive pathways in the CNS and within the dorsal root ganglia and spinal cord. At these levels, release of BDNF appears to modulate or even mediate nociceptive sensory inputs and pain hypersensitivity. In the literature few studies evaluated BDNF levels in serum, plasma and cerebrospinal fluid samples of FM patients, finding increased levels of this neurotrophin compared to healthy controls. A number of studies also investigated BDNF levels in synovial fluid and plasma samples from patients affected by rheumatoid arthritis (RA), who are chronically subjected to pain, even though of inflammatory and autoimmune origin. No studies instead have been performed on patients affected by chronic fatigue syndrome (CFS), a condition that frequently overlaps with FM and whose etiopathogenesis, still unclear, is probably different from that of FM. Objectives The primary objective of the present PhD thesis project was therefore to investigate BDNF-mediated neuroplasticity, by detecting BDNF levels in FM patients, and therefore by comparing these levels to the ones found in CFS, RA and healthy volunteers. Secondary objectives were: (i) the relation between BDNF levels and clinical variables, including neurocognitive disorders, which were assessed in FM and CFS patients by means of a computerized system; (ii) the relation between BDNF levels and psychiatric comorbidity in FM and CFS patients; (iii) the relation between BDNF levels and inflammatory status in RA patients; (iv) serum and plasmatic BDNF levels in a subgroup of FM patients before, immediately after, and 3-months after thermal treatments. Materials and methods Among the patients recruited in the study, there were 68 FM, 45 CFS, and 46 RA together with 40 healthy controls. BDNF serum levels were determined by enzyme-linked immune-sorbent assay (Promega), and the differences among the various groups were observed. Demographic and clinical parameters were investigated in relation to BDNF levels. Moreover, a subgroup of FM patients (n=28) also participated to a clinical trial held at the Montecatini Thermal Baths, and another subgroup of FM patients (n=40), together with CFS patients, also completed a computerized test battery for the assessment of neurocognitive disorders. Results The main findings of the work can be summarized as follows: (i) the increased BDNF levels in sera of patients affected by FM, CFS and RA (but only those who were positive to rheumatoid factor of all isotypes), compared to healthy volunteers; (ii) the positive correlation between BDNF and rheumatoid factor (IgG and IgM isotypes), and the negative one with C-reactive protein; (iii) the lack of correlation between BDNF and neurocognitive disorders, assessed by the software CNS Vital Signs©; (iv) the higher prevalence of neurocognitive disorders in FM than in CFS patients, despite the more frequent complaint of CFS patients; (v) the tight relationship between neurocognitive impairments and chronic pain, which is independent of psychiatric comorbidity. Conclusions The conclusion reached by this study is that BDNF-mediated neuroplasticity in FM, CFS and RA could be interpreted as a protective mechanism against injuries, chronic pain and, more generally, against chronic stress conditions. This hypothesis could explain the elevated BDNF levels found in sera -but not in plasma- samples, and their decrease after thermal treatment. Although BDNF is not specific for FM or chronic pain -the difference here reported between BDNF levels of FM, CFS, RA patients compared to healthy controls are not strong enough to allow the use of BDNF in the diagnostic field- this work on one hand opens the way to new investigations on FM, CFS and RA etiopathogenesis, and on the other could suggest BDNF as a useful biomarker for FM/chronic pain therapy monitoring

Biomarkers in fibromyalgia: a review

Camillo Giacomelli,* Francesca Sernissi,* Alessandra Rossi, Stefano Bombardieri, Laura BazzichiRheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy *These authors contributed equally to the manuscript Abstract: Fibromyalgia is a common syndrome diagnosed by clinical criteria. The main symptom of fibromyalgia is pain, but patients frequently also complain about other nonspecific symptoms, such as headache, sleep disturbance, mood disorder, and cognitive impairment. In the light of the multifactorial origin of the disease and of the lack of objective diagnostic findings, several attempts have been made to find a reliable biomarker. For this reason, over the years, a number of patients and various biological samples have been studied, using many different approaches and techniques. Despite this, none of these studies has been able to find the proper biomarker. The aim of this review is to provide a critical overview of the current environment characterizing the search for fibromyalgia biomarkers. Keywords: genetics, proteomics, oxidative stress, fibromyalgi

Salivary gland ultrasonography: a highly specific tool for the early diagnosis of primary Sjögren's syndrome

INTRODUCTION:Recently, a great interest has arisen for salivary gland ultrasonography (SGUS) as a valuable tool for the assessment of major salivary gland involvement in primary Sjögren's syndrome (pSS. The aims of this study were to test the accuracy of SGUS for the early detection of pSSand to compare the diagnostic performance of SGUS with minor salivary gland biopsy (MSGB) and unstimulated salivary flow (USFR) in this context. METHOD:Patients with suspected pSS and symptoms duration of ≤5 years were consecutively enrolled in this study. The diagnosis of pSS was made according to the AECG criteria. SGUS was performed by two radiologists blinded to the diagnosis and a previously reported ultrasound scoring system (De Vita et al. 1992, cut-off ≥ 1) was used to grade the echostructure alterations of the salivary glands. Statistical analysis was performed using SPSS v16. RESULTS: This study included 50 pSS patients and 57 controls with no-SS sicca symptoms. The mean(SD) age of the pSS group was lower than non-SS group (47(13) vs 53(12)yrs, p = 0.006). No further differences between the two groups were observed. Patients with pSS showed a significantly higher SGUS score in comparison with controls (mean(SD) = 2.1(1.8) vs 0.0(0.4), p = 0.000). The SGUS cut-off ≥ 1 showed a sensitivity (SE) of 66 %, a specificity (SP) of 98 %, a positive predictive value (PPV) of 97 % and a negative predictive value (NPV) of 73 % for pSS diagnosis. The SGUS score correlated also with patients' MSGB/FS and USFR. CONCLUSIONS: This study confirmed the good performance of SGUS for the early non-invasive diagnosis of pSS. Further research in larger international cohort of patients is mandatory in order to assess the role of SGUS in the diagnostic algorithm of pSS

Salivary psoriasin (S100A7) correlates with diffusion capacity of carbon monoxide in a large cohort of systemic sclerosis patients

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive fibrosis of the skin and the internal organs. In a previous work we suggested a correlation between levels of salivary psoriasin (S100A7) and pulmonary involvement in SSc patients. The goals of this study are to determine the distribution characteristics of psoriasin in whole saliva (WS) of SSc and healthy donor populations and define its predictive value on diffusion capacity of carbon monoxide (DLCO), along with others clinical parameters. Methods: Salivary level of psoriasin was determined by ELISA kit in 134 SSc patients, 63 Raynaud syndrome patients, 40 patients affected by other connective diseases (non-case) and 74 healthy control subjects. Results: A significant increase of salivary psoriasin was observed in SSc patients when compared with other healthy and pathological controls. Moreover, we confirmed the efficacy of salivary psoriasin to correlate with DLCO in a large cohort of SSc patients. Conclusions: Overall our results suggest a rapid, non invasive and low costing method which can help clinicians in the evaluation of SSc pulmonary involvement

Gross Cystic Disease Fluid Protein-15(GCDFP-15)/Prolactin-Inducible Protein (PIP) as Functional Salivary Biomarker for Primary Sjögren's Syndrome

Gross cystic disease fluid protein-15(GCDFP-15)/prolactin-inducible protein (PIP) is a secretory acinar glycoprotein of 14 KDa which we have recently described as significantly lower in salivary samples of patients with primary Sjögren's syndrome (pSS) in comparison to healthy volunteers by proteomic analysis

A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a severe, systemic illness characterized by persistent, debilitating and medically unexplained fatigue. The etiology and pathophysiology of CFS remains obscure, and diagnosis is formulated through the patient’s history and exclusion of other medical causes. Thereby, the availability of biomarkers for CFS could be useful for clinical research. In the present study, we used a proteomic approach to evaluate the global changes in the salivary profile in a couple of monozygotic twins who were discordant for CFS. The aim was to evaluate differences of salivary protein expression in the CFS patient in respect to his healthy twin. METHODS: Saliva samples were submitted to two-dimensional electrophoresis (2DE). The gels were stained with Sypro, and a comparison between CFS subject and the healthy one was performed by the software Progenesis Same Spot including the Analysis of variance (ANOVA test). The proteins spot found with a ≥2-fold spot quantity change and p<0.05 were identified by Nano-liquid chromatography electrospray ionization tandem mass spectrometry. To validate the expression changes found with 2DE of 5 proteins (14-3-3 protein zeta/delta, cyclophilin A, Cystatin-C, Protein S100-A7, and zinc-alpha-2-glycoprotein), we used the western blot analysis. Moreover, proteins differentially expressed were functionally analyzed using the Ingenuity Pathways Analysis software with the aim to determine the predominant canonical pathways and the interaction network involved. RESULTS: The analysis of the protein profiles allowed us to find 13 proteins with a different expression in CFS in respect to control. Nine spots were up-regulated in CFS and 4 down-regulated. These proteins belong to different functional classes, such as inflammatory response, immune system and metabolism. In particular, as shown by the pathway analysis, the network built with our proteins highlights the involvement of inflammatory response in CFS pathogenesis. CONCLUSIONS: This study shows the presence of differentially expressed proteins in the saliva of the couple of monozygotic twins discordant for CFS, probably related to the disease. Consequently, we believe the proteomic approach could be useful both to define a panel of potential diagnostic biomarkers and to shed new light on the comprehension of the pathogenetic pathways of CFS