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Background and Objectives: Digital ulcers (DUs) are the most common complication in patients with Systemic Sclerosis (SSc). They cause pain with hand dysfunction and negatively impact activities of daily and working life. Our study aims to evaluate the efficacy of a combined treatment of manual therapy and ultrasound therapy in SSc patients with ischemic DU (IDU) compared to manual therapy alone. Materials and Methods: We conducted a before-and-after study (non-randomized study). We enrolled a consecutive series of IDU patients undergoing rehabilitation treatment and divided them into two groups: a treatment group consisting of patients undergoing a combination of manual therapy and US water immersion and a standard care group consisting of patients subjected to manual therapy alone. At the time of the first visit (T0) and at the end of the 4-week rehabilitation period (T1), we evaluated functional capacity, pain intensity, ulcer evolution, and quality of life. Results: In the treatment group, we observed a statistically significant improvement in the functional capacity of the hand (DHI: 28.15 ± 11.0 vs. 19.05 ± 8.83; p < 0.05), pain (NRS: 5.55 ± 1.2 vs. 2.9 ± 1.09; p < 0.05), and PSST score (24.4 ± 4.0 vs. 16.2 ± 2.36; p < 0.05). In the standard care group, we observed a statistically significant improvement only for the functional capacity of the hand (DHI: 28.85 ± 9.72 vs. 22.7 ± 7.68; p < 0.05). Finally, from the comparison between the treatment group and the standard care group, we observed statistically significant improvements in pain (2.9 ± 1.09 vs. 4.5 ± 1.07; p < 0.05) and in the PSST scale (16.2 ± 2.36 vs. 20.4 ± 4.02; p < 0.05). Furthermore, at the end of treatment in the treatment group, 15 ulcers (62.5%) were completely healed, while in the standard care group, only 3 ulcers were completely healed (14.3%). Conclusions: Combined treatment with manual therapy and ultrasound therapy appears to be useful in the management of IDU in patients with scleroderma.

– Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called “BAP1-related tumour predisposition syndrome”. Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients.

Background: Fibromyalgia (FM) patients report chronic widespread pain, fatigue, cognitive difficulties and sleep disturbances, often associated with anxiety and/or depression (1). FM syndrome more frequently affects women and many papers describe gender-related differences in the perception, description and expression of pain (2), but up to now, the impact of gender on the clinical severity of FM is still a controversial topic. Objectives: The aim of this study was to analyse the data from a web-based registry of FM patients in order to detect a relationship between gender and disease severity. Methods: Adult patients with FM, diagnosed on the basis of the 2010/2011 American College of Rheumatology (ACR) diagnostic criteria (3), were recruited at 19 Italian rheumatology centres between November 2018 and April 2019. Those affected by other conditions that could interfere with the assessment of FM, e.g. psychiatric disorders, were excluded from the study. The severity of the disease was evaluated by validated FM-specific questionnaires: the revised Fibromyalgia Impact Questionnaire (FIQR) (4), the modified Fibromyalgia Assessment Status (ModFAS) questionnaire (5), and the Polysymptomatic Distress Scale (PDS) (6). The data obtained were collected in the Italian Fibromyalgia Registry, an online registry created with the support of the Italian Society of Rheumatology (SIR). Results: We analyse data from 2.381 patients affected by FM, 2.184 females (91.7%) and 197 males. No significant differences in mean age, disease duration, or BMI between the two genders were reported. The women expressed greater disease burden as indicated by higher scores for each completed test: higher mean ModFAS score (25.23 ± 8.83 Vs 23.37 ± 9.22; p = 0.005), mean FIQR score (58.62 ± 23.22 Vs 51.68 ± 23.06; p

Fibromyalgia (FM) is a clinical syndrome characterized by chronic pain. FM patients complain hyperalgesia and allodynia and they are frequently affected by Non Celiac Wheat Sensitivity (NCWS), a condition where gastrointestinal and extraintestinal symptoms are triggered by gluten and/or wheat ingestion. The gluten-free diet (GFD) impact was evaluated on fibromyalgia-related and gastrointestinal symptoms, health-related quality of life and immune response of patients with both FM and NCWS in order to detect a possible pathogenetic role of wheat/gluten in the triggering of the inflammatory process. Peripheral blood from 8 FM patients, 10 FM and NCWS patients (FM+NCWS patients), 13 NCWS patients and 14 healthy subjects (HS) was taken before and after 8 weeks of GFD and used for cytofluorimetric analysis. In all FM+NCWS patients after GFD almost all the clinical parameters used to evaluate musculoskeletal and systemic symptoms related to FM were reduced as well as intestinal symptoms present before GFD. Moreover, pro-inflammatory cytokines production (IFN-γ, TNF- α, IL-17 and IL-22) by T helper (Th) cells of FM+NCWS patients was reduced after GFD. Our findings suggest that gluten/wheat could represent one of the triggering factors of the inflammatory condition playing an important role in the etiopathogenesis of both FM and NCWS.

Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients. © 2020

Hyperbaric oxygen therapy (HBOT) has been used as treatment for different clinical conditions, including fibromyalgia (FM). HBOT modulates brain activity, ameliorates chronic pain and modifies the ratio of immune cells. Clinical studies have provided evidence that FM is associated with immune system dysregulation. In the present study we aimed to evaluate the effect of HBOT on immune system and on the quality of life-style of FM patients.Patients with primary FM and controls were treated with HBOT. Physical, emotional and social assessment, quality of sleep, tender points, intensity score, WPI and symptom severity were evaluated before and after HBOT. Furthermore, a characterisation of CD4 T lymphocytes and their cytokine production was performed by flow cytometry. The expression of TNF-α, IFN-γ, IL-17, IL-9 and IL-22 was also assessed by RT-PCR. Finally, the serum levels of serotonin were evaluated by ELISA.Our results confirm the participation of immune system in the pathogenesis of FM and highlight the impact of HBOT treatment, with particular regard to the changes on proinflammatory cytokines production by CD4 T cells subsets.FM patients show a Th1 signature and the activation of this subset is modulated by HBOT.

OBJECTIVES: Vitamin D status influences the risk to develop autoimmune diseases affecting the percentage and/or functions of regulatory T cells (Tregs). Since low levels of 25 (OH) D have been decreased in patients with systemic sclerosis (SSc), we aimed to study the effect of Vitamin D3 (cholecalciferol) supplementation on Tregs frequencies and functions. METHODS: Peripheral blood and sera samples were obtained from 45 SSc patients and controls (HC). A number of eighteen SSc patients had consumed Cholecalciferol (orally) at the dose of 25.000 UI/month for 6 months at the time of enrollment. 25(OH)D serum levels were measured and VDR polymorphisms, were genotyped by polymerase chain reaction (PCR). Tregs isolated from peripheral blood mononuclear cells were in vitro expanded and a suppression assay was performed. Flow cytometry analysis was then carried out. Finally, IL-10 production was assayed by ELISA. RESULTS: Low serum levels of 25(OH)D were detected in SSc patients. The percentage of Tregs in SSc patients was similar to controls, but, among SSc patients, it was higher in those patients taking cholecalciferol. Tregs capability to suppress T cell proliferation was impaired in SSc patients and not restored after in vitro pre-treatment with the active form of Vitamin D (1,25(OH)2D3); but at the same time the production of IL-10 was increased in treated samples obtained from patients. The lack of response of Tregs from SSc patients to 1,25(OH)2D3 treatment in vitro was not due to altered Vitamin D/VDR signalling. CONCLUSIONS: Altogether, our results indicate that the increased production of IL-10 by 1,25(OH)2D3 -treated Tregs could provide a "suppressive" cytokine milieu able to modulate immune response but it is not sufficient to restore the immune suppressive functions of Tregs.

OBJECTIVES:It is accepted that the optimal management of patients with fibromyalgia (FM) requires a combination of non-pharmacological and pharmacological interventions. Our study aimed to analyse the effects of a supplemented physical program on the quality of life of FM patients.METHODS:We enrolled 60 patients, all female (mean age 49±5.7 years), with primary FM (mean years of disease 33±12 months). Patients who agreed to participate in this study met the proposed 1990 American College of Rheumatology classification criteria and the 2010 American College of Rheumatology preliminary diagnostic criteria and were recruited at Policlinico P. Giaccone, University Hospital of Palermo, Italy. Thirty patients undertook a physical program consisting by group exercises, laser and TENS treatment (Combi-group). The remaining 30 FM patients (Exonly-group) practiced only group exercise (Control group). Ten patients with mechanical pain were considered as unrelated control group disease. Fatigue, sleep dysfunction and pain were reported and evaluated before and after the treatment for each patient. Particularly, the Fibromyalgia Impact Questionnaire (FIQ), SF36 Questionnaire (SF36) and Visual analogic scale for pain and fatigue (VAS pain and fatigue) were administered at baseline (T0) and at the end of the treatment (T1) (after 40 rehabilitation sessions over 20-week).RESULTS:The combined treatment significantly improved the perception of pain and fatigue and the overall quality of life. In detail, the Combi-group experienced a statistically significant improvement in FIQ but not in the SF36 after the treatment. CONCLUSIONS:According to our results, an intense physical rehabilitation program could be considered a promising essential step in the management of FM patients.

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments. © 2018

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