Androgens in rheumatoid arthritis: when are they effectors?

Neither hormone receptor genes nor plasma androgens seem significantly altered in female subjects before they became affected by rheumatoid arthritis (RA) and, therefore, do not seem to play a role as risk factors for its development. However, serum testosterone levels are inversely correlated with RA activity and dehydro-epiandrosterone sulfate (DHEAS) plasma levels are inversely correlated with both disease duration and clinical severity in patients already affected by active RA. In particular, gonadal and adrenal androgens (that is, testosterone and DHEAS) are significantly decreased in inflamed synovial tissue/fluids during active disease as a consequence of the inflammatory reaction, which supports a pro-inflammatory milieu in RA joints. Recently, male gender has been found to be a major predictor of remission in early RA

Glucocorticoids and chronotherapy in rheumatoid arthritis

It is evident that the morning symptoms of rheumatoid arthritis (RA) are linked to the circadian abnormal increase in night inflammation, favoured by inadequate cortisol secretion under conditions of active disease. Therefore, exogenous glucocorticoid treatment is recommended in RA at low doses since it may partially act like a \u2018replacement therapy\u2019. The prevention/treatment of the night upregulation of the immune/inflammatory reaction (and related flare of cytokine synthesis) has been shown to be more effective when exogenous glucocorticoid administration is obtained with a night-time-release formulation. Large-scale trials documented that modified-release prednisone has greater efficacy then morning prednisone for long-term low-dose glucocorticoid treatment in patients with RA, showing at least a more significant reduction in morning joint stiffness. Interestingly, despite a considerably higher cost than conventional prednisone, chronotherapy with night-time-release prednisone was recognised as a cost-effective option for patients with RA not on glucocorticoids who are eligible for therapy with biological disease-modifying antirheumatic drugs (DMARDs). Moreover, since different cell populations involved in the inflammatory process are particularly activated during the night, other therapeutical approaches used in RA, for example, conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs), should follow the same concepts of glucocorticoid chronotherapy. Indeed, bedtime methotrexate chronotherapy was found to improve RA symptoms compared to the current standard dosing methods, and several available NSAIDs (ie, indomethacin, aceclofenac, ketoprofen, flurbiporfen, lornoxicam) have been very recently modified in their formulation, in order to obtain chronotherapeutical effects in RA

INFLUENCE OF MEDITERRANEAN DIET ON INCIDENCE AND COURSE OF INFLAMMATORY RHEUMATIC DISEASES

Th e Greek “Father of Medicine” and physician Hippocrates, said around 400 B.C. “Let thy food be thy medicine and thy medicine be thy food” (Nikiphorou et al. 2018) Therefore, over the last decades we become increasingly aware and concerned about how nutrition affects our health and the field of nutrition have meet unprecedented interest and expansion. On the other hands, a number of dietary factors might act as environmental triggers in rheumatic and muskuloskeletal diseases (RMDs) development. Overall, a ‘Western’ type diet rich in energy intake, total and saturated fat, an unbalanced ratio of n-3 to n-6 fatty acids, high in sugar and low in fiber and antioxidants might increase the risk of RMDs both directly through increasing inflammation (Minihane et al. 2015) and indirectly through increasing insulin resistance, obesity and associated co-morbidities, with obesity being a known risk factor for RMDs (Qin et al. 2015). In detail, high consumption of foods characteristic of the ‘Western-type’ diet such as red meat, meat and meat products combined, or total protein have been shown to increase the risk of inflammatory polyarthritis suggesting a role of advanced glycation end products (AGEs) (Pattison et al. 2004). This is supported by findings of regular consumption of sugar-sweetened soda, but not diet soda, being associated with an increased risk of seropositive rheumatoid arthritis (RA) in women (Hu et al. 2014), and of high fructose corn-syrup sweetened soft drinks, fruit drinks and apple juice being associated with arthritis in young US adults (DeChristopher et al. 2016). It is hypothesized that regular consumption of excess free fructose and HFCS contributes to fructose reactivity in the gastrointestinal tract and intestinal in situ formation of enFruAGEs, which once absorbed, travel beyond the intestinal boundaries to other tissues and promote inflammation (DeChristopher et al. 2016). Individual biomarkers of antioxidant intake have also been previously investigated in relation to RA with some evidence that low serum levels of selenium and alpha tocopherol (Knekt et al. 2000) and beta carotene (Comstock et al. 1997) are associated with an increased disease risk. Interestingly, a meta-analysis also suggests that coffee consumption of ≥ four cups per day is associated with an elevated risk of seropositive RA but not seronegative RA (Lee et al. 2014). However, the results should be interpreted with caution due to other potential confounders. The same meta-analysis found no association between tea consumption and risk of RA (Lee et al. 2014). On the contrary, consumption of longchain omega-3 polyunsaturated fatty acids, derived from fish and fish oil, is associated with a reduced risk of inflammatory RMD like RA (Di et al. 2014) probably due to their anti-inflammatory properties. The Mediterranean diet (MD), rich in plant-based foods such as wholegrains, legumes, fruit, vegetables, extravirgin olive oil and low in red meat consumption, might have the potential to reduce the risk of RA. It has been shown that greater adherence to the MD is associated with lower concentrations of inflammatory biomarkers (Fung et al. 2005), while daily consumption of monounsaturated fatty acids from olive oil is thought to be the key factor in suppressing RA disease activity (Matsumoto et al. 2017). Other nutritional approaches like vegan, elemental or elimination diets did not showed any superiority to the MD (Ciccia et al 2018, Philippou et al. 2018) regarding the interference on RMDs. In addition, recent evidences suggest the diet pattern, by modifying the composition of intestinal microbiome, might influence the activation of innate immune pathways such as inflammasome and autophagy directly involved in the production of pro-inflammatory cytokines such as IL-1b and IL-18 with effects on RMDs Based on current research evidence, it is concluded that adherence to the MD with an increased consumption of fatty fish, reduced consumption of sugar-sweetened drinks and maintenance of a normal body weight, contributes to reducing the risk of RA. Interestingly, looking at the “chrononutrition” following the body circadian rhythms (Nobel Prize for Medicine 2017) it has been assessed that circadian misalignment, behavioral processes such as food intake or sleep occurring at inappropriate endogenous circadian times, commonly occurs during shift work (i.e. night shift workers) are associated with serious health problems over the time including RMDs (Cutolo 2018). In conclusion, both correct quality and timing in nutrition, are essential in prevention and/or co-management of RMD-

Macrocirculation versus microcirculation and digital ulcers in systemic sclerosis patients: Macro-microcirculation and scleroderma.

3nonemixedCUTOLO, MAURIZIO; RUARO, BARBARA; Smith, V.Cutolo, Maurizio; Ruaro, Barbara; Smith, V

Vitamin D, inflammation and immunity: review of literature and considerations on recent translational and clinical research developments

The most relevant and recent literature findings linking exposure to sunlight, Vitamin D (VD), inflammation and immune system in health and disease, are reviewed. Reduced sunlight exposure determined hypo-vitaminosis D to be common among patients or even healthy subjects, especially at higher latitudes. Numerous studies support the hypothesis that VD insufficiency could contribute to the higher autoimmune diseases incidence in the same geographic areas. In the present review, the ways in which VD was reported to influence immune system, contributing to organism homeostasis or disease development are addressed. In fact, some of the hormone activities were recognised to determine stimulation or inhibition of immune system components. Several diseases, where an association with VD deficiency was studied, are summarised. Finally, the rationale for optimization of substitutive/additive therapy with VD analogues and the last innovations regarding these drugs are mentioned

Capillaroscopy as an Outcome Measure for Clinical Trials on the Peripheral Vasculopathy in SSc—Is It Useful?

Peripheral microvascular impairment in systemic sclerosis (SSc) may be easily detected and scored in a safe noninvasive way by nailfold videocapillaroscopy (NVC). The paper highlights clinical conditions related to SSc in which NVC may represent an outcome measure of therapeutical interventions, by elaborating on their already assessed relationship with the NVC patterns and eventually scores. The 3 important biological/clinical conditions are: the positivity for SSc-specific serum autoantibodies, the presence of SSc skin digital ulcers (DUs) and of pulmonary arterial hypertension (PAH) SSc associated. In conclusion, to the question if capillaroscopy (NVC) may represent in SSc an outcome measure for clinical trials on the peripheral vasculopathy, based on the growing evidence and our detailed studies, the answer is positive. Recent therapeutic trials in SSc are confirming this role, and the experience is growing rapidly