CONTROVERSIAL ROLES OF MAST CELLS IN RHEUMATOID ARTHRITIS

Background Mast cells are tissue-resident cells of the innate immunity implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). In fact, they are present in synovia and their activation has been linked to the inflammatory responses driving the development of RA. However, their exact contribution to the development of RA is still unclear. In particular, their interactions with other immune cells at synovial levels and their correlation to disease outcomes have never been investigated in a systematic fashion. Objective Aim of this PhD project was to elucidate the role of mast cells in rheumatoid arthritis, by studying their cellular interaction at synovial levels, their influence on the activation of immune cells and, finally, their correlation with disease outcomes. Results In the synovia of RA patients, mast cells correlated with the degree of local inflammations and cellular infiltration. In particular, higher numbers of mast cells were associated with the presence of lymphoid aggregates, and mast cells were localized in close proximity of cellular aggregates of B and T cells. In vitro, mast cells were able to modulate the responses of immune cells, suppressing the pro-inflammatory activation of monocytes and supporting B cells survival, differentiation and antibody production. In patients with early RA, high numbers of synovial mast cells were associated with antibody positive disease and with systemic inflammatory markers. At the 12 months follow-up, baseline mast cells represented an independent predictor of radiographic progression. Conclusions Mast cells, as part of the inflammatory infiltrate in the synovia of RA patients, are able to induce both pro- and anti-inflammatory immune responses, which might explain the conflicting results obtained so far with experimental models not taking into account their tunable immunomodulatory properties. The ex vivo analysis performed in the synovia of early RA patients indicate that mast cell presence can be used to further dissect the disease heterogeneity, as mast cells clustered with antibody positivity and with a higher degree of local and system inflammation. Interestingly, independently from these associations, mast cell presence at baseline represented a predictor of radiographic progression at 1 year. Overall, our data suggest that mast cells play a multifaceted role in the pathogenesis of RA, warranting additional investigations to further assess their involvement in disease development, progression and response to therapy

How Well Can We Control Dyslipidemias Through Lifestyle Modifications?

The role for lifestyle modifications to correct dyslipidemia(s) is reviewed. Dietary composition is crucial. Replacing saturated fat with MUFA or n-6 PUFA lowers plasma low-density lipoproteins (LDL) cholesterol and ameliorates the LDL/HDL ratio. Replacing saturated fat with carbohydrates has diverging effects due to the heterogeneity of carbohydrate foods. Diets rich in refined carbohydrates increase fasting and postprandial triglycerides, whereas the consumption of fiber-rich, low GI foods lowers LDL cholesterol with no detrimental effects on triglycerides. The role of polyphenols is debated: available evidence suggests a lowering effect of polyphenol-rich foods on postprandial triglycerides. As for functional foods, health claims on a cholesterol lowering effect of psyllium, beta-glucans and phytosterols are accepted by regulatory agencies. The importance of alcohol intake, weight reduction, and physical activity is discussed. In conclusion, there is evidence that lifestyle affects plasma lipid. A multifactorial approach including multiple changes with additive effects is the best option. This may also ensure feasibility and durability. The traditional Mediterranean way of life can represent a useful model

Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA

Effects of wholegrain cereal foods on plasma short chain fatty acid concentrations in individuals with the metabolic syndrome

Short chain fatty acids (SCFAs) derived from dietary fiber fermentation by gut microbiota have been identified as one of the mechanisms behind the association between habitual whole-grain intake and a lower risk of cardiometabolic diseases. The aims of the present work are: (1) to evaluate whether a whole-grain wheat-based diet may increase SCFAs concentration, and (2) to identify possible associations between SCFAs and metabolic changes observed after the nutritional intervention

Effects of Polyurethane Foam Dressings as an Add-on Therapy in the Management of Digital Ulcers in Scleroderma Patients.

Digital ulcers (DUs) represent a severe and common complication occurring in patients affected by Systemic Sclerosis (SSc), with a consistent impact on the quality of life and often resulting in longer hospitalization than unaffected patients. Conventional treatment of SSc ulcers consists of both topical and systemic (oral or intravenous) pharmacological therapies. Several surgical options are also available, but there is overall a lack of official guidelines or recommendations. The aim of this study was to evaluate the efficacy of a novel local therapy based on polyurethane foam dressings, namely the Highly Hydrophilic Polyurethane Foam (HPF), in addition to the conventional pharmacological treatment, in a cohort of 41 SSc patients with at least one active ulcer. Our results showed that the addition of HPF to the conventional treatment based on systemic drugs induced i) a significant reduction in the number of active DUs (p=0.0034); ii) a significant reduction of the mean duration of ulcer-related hospitalization as compared with standard therapy (p=0.0001); iii) a significant improvement of patients' Quality of Life, as evaluated through the Scleroderma Health Assessment Questionnaire (SHAQ) (p=0.00011). Therefore, in our experience, the combined management of DUs can improve both the onset of new DUs and DU's healing thus leading to a better outcome