Increased plasma levels of Gas6 and its soluble tyrosine kinase receptors Mer and Axl are associated with immunological activity and severity of lupus nephritis.

OBJECTIVES: Growth arrest-specific 6 (Gas6) and its receptors have been shown to play a crucial role in the homeostasis of the innate immune system by regulating apoptosis and inflammation. We aimed to verify whether an impairment of this system is associated with systemic lupus erythematosus (SLE) disease activity and with lupus nephritis (LN). METHODS: Plasma Gas6 and the soluble cleaved form of the receptors MerTK (sMer) and Axl (sAxl) concentrations were measured in n=59 SLE patients (n=44 with nephritis, 75%) and analysed in relationship to clinical and laboratory data. RESULTS: Patients with LN were characterised by higher Gas6 (19.0 ng/mL [16.8-24.5] vs. 16.5 ng/mL [13.89-18.91]; p=0.03) and sAxl plasma levels than those without LN (31.36 ng/mL [25.1-41.4] vs. 20.2 ng/mL [15.6-30.7]; p=0.03); conversely sMer plasma concentrations were similar between groups. All the three biomarkers studied were directly correlated to creatinine and daily proteinuria, being inversely related to creatinine clearance. 39 patients had a proteinuria level of <0.5 mg/day, 14 between 0.5 and 3.5 mg/day and 5 had ≥3.5 g/day; Gas6, sAxl and sMer plasma concentrations significantly increased for increasing degree of proteinuria (test for trend p=0.0002; p=0.02; p=0.009, respectively).These correlations were confirmed in multiple linear regression analysis models accounting for gender, age, disease duration and concomitant treatment. CONCLUSIONS: Plasma Gas6, sAxl and sMer concentrations are associated with the severity of LN in patients affected by SLE. The excess cleavage of TAM receptors might contribute to LN pathogenesis.

Nutritional Status and Bone Microarchitecture in a Cohort of Systemic Sclerosis Patients.

Systemic sclerosis (SSc) is a connective tissue disease characterized by initial microvascular damage, immune system activation and progressive fibrosis with insufficiency of internal organs. Gastrointestinal (GI) involvement is characterized by atrophy of the smooth muscle and small bowel hypomotility, mainly resulting from an autonomic nerve dysfunction. These modifications significantly affect gut transit and nutrient absorption, thus leading to malnutrition deficit induced by malabsorption. Nutritional deficit induced by malabsorption might also lead to bone alterations. This study aims to evaluate the relationship between malnutrition and bone status. Thirty-six postmenopausal female patients fulfilling the ACR 2013 criteria for SSc underwent dual-energy X-ray absorptiometry scan (DXA) to detect quantitative lumbar spine bone mineral density (BMD) and trabecular bone score (TBS) analysis to detect bone quality. Data from DXA also allow to assess body composition and provide several quantitative parameters, including free fat mass index (FFMI) that identifies the patient with malnutrition (values <15 kg/m2 in women and 17 kg/m2 in men), according to the ESPEN criteria. Body mass index (BMI) was calculated for all SSc patients and every patient completed a diary reporting GI symptoms. Two groups of SSc patients with or without diagnosed malnutrition according to FFMI parameter were identified. Malnourished SSc patients showed significantly lower weight (p = 0.01) and BMI (p = 0.001), as well as lower serum levels of hemoglobin (p = 0.009), albumin (p = 0.002), PTH (p = 0.02) and 25OH-vitamin D (p = 0.008). DXA analysis showed significantly lower lumbar L1-L4 T-score (p = 0.009) and BMD values (p = 0.029) in malnourished SSc patients. Consistently, TBS values were significantly lower in malnourished patients (p = 0.008) and correlated with BMD (at any site) and serum albumin levels (p = 0.02). In addition, FFMI positively correlated with bone parameters as well as with symptoms of intestinal impairment in malnourished SSc patients. Finally, GI symptoms significantly correlated with BMD but not with TBS. This pilot study shows that in malnourished SSc patients (2015 ESPEN criteria: FFMI<15 kg/m2), an altered bone status significantly correlates with GI involvement, in terms of symptoms being mainly due to intestinal involvement together with the presence of selected serum biomarkers of malnutrition.

Advanced microvascular damage associated with occurence of sarcopenia in systemic sclerosis patients: results from a retrospective cohort study.

OBJECTIVES: Systemic sclerosis (SSc) is characterised by microvascular inflammatory damage, loss of capillaries and progressive systemic fibrosis. Capillary rarefaction may precede sarcopenia, we therefore evaluated the body composition and occurrence of sarcopenia in SSc patients, in relation to the peripheral microcirculatory status, assessed and scored by nailfold videocapillaroscopy (NVC) patterns, including capillary number count and microangiopathy evolution score (MES). METHODS: Body composition and bone mineral density were assessed by Dual X-ray absorptiometry and a dedicated software (GE Lunar, USA) in 43 SSc patients (age 64.1 ± 11.2 yrs, 83.7% women) affected by limited or diffuse cutaneous (74.4%) according to the 2013 EULAR/ACR criteria and 43 age-matched healthy subjects (HS). Sarcopenia was checked as relative skeletal muscle index (RSMI). Clinical, laboratory, body composition and bone parameters were analysed according to the different NVC patterns and MES. Means were compared by the Student's t test or by one way analysis of variance; medians were compared by the Kruskall Wallis test; and frequencies by the chi square test. RESULTS: Sarcopenia was found in 23.26% of SSc patients with a prevalence significantly higher than age matched HS (4.65%; p = 0.03). Interestingly, SSc patients with "late" NVC pattern showed a significantly higher prevalence of sarcopenia (43.75%) compared to "early" (9.1%) and "active" (12.5%) NVC patterns (p<0.0002). In addition, capillary density was found significantly lower in sarcopenic versus non sarcopenic patients (4.4±1.8 vs. 5.8±2.2, p<0.05). Finally, MES showed significantly most severe score in sarcopenic SSc patients (p<0.001): peripheral blood flow analised in a sample of sarcopenic SSc patients by Laser speckle contrast analysis (LASCA) showed lowest values (p<0.05). Total mass (TM), lean mass (LM), fat mass (FM) and bone mineral content (BMC) values were found significantly lower in sarcopenic SSc patients (p<0.0001, p<0.001, p=0.004, p=0.04, respectively). CONCLUSIONS: SSc patients with sarcopenia and altered body composition were found affected by the most severe NVC pattern ("late"), a significantly reduced/altered number of capillaries and microvascular array (MES), suggesting a strong link between severity of local microvascular failure and associated muscle sufferance.

Lower urinary tract symptoms in systemic sclerosis: a detailed investigation.

OBJECTIVES: Urinary tract involvement is a seldom-reported manifestation of SSc that could compromise patients' quality of life. This study compares lower urinary tract symptoms (LUTS) in SSc patients and in healthy subjects and their association with clinical and diagnostic parameters. METHODS: LUTS were assessed through self-reported questionnaires in 42 SSc patients and 50 matched healthy subjects. Statistical analyses were performed to explore LUTS in the two populations and their association with SSc variables, including nailfold videocapillaroscopy patterns, SSc-related antibodies and DXA parameters. RESULTS: SSc patients showed significantly higher prevalence and severity of urinary incontinence (UI) and overactive bladder (OAB) than healthy controls (P < 0.005, P < 0.01). SSc was a strong predictor of LUTS, independent of demographic data, comorbidities and treatments (odds ratio 5.57, 95% CI 1.64-18.88). In SSc patients OAB positively correlated with sarcopenia (P < 0.001), and both OAB and UI significantly correlated with reduced BMD (P < 0.05, P = 0.001). UI positively correlated with Scl70 antibodies (P < 0.05) and ciclosporin treatment (P = 0.001) and negatively with RNA polymerase III antibodies (P < 0.05); OAB positively correlated with calcinosis (P < 0.005) and negatively with methotrexate treatment (P < 0.05). Nailfold videocapillaroscopy 'active' and 'late' patterns were predominant among SSc patients presenting urinary symptoms, although no statistical correlation was found. CONCLUSION: For the first time urinary tract involvement was found to be significantly higher in SSc patients than in healthy matched controls. In addition, sarcopenia, bone damage and calcinosis appeared significantly correlated with LUTS, suggesting a possible interplay.

Interactions between microbiota, diet/nutrients and immune/inflammatory response in rheumatic diseases: focus on rheumatoid arthritis.

Rheumatic and musculoskeletal diseases (RMDs) are chronic systemic immune/inflammatory conditions characterized by the interaction between gene predisposition, autoimmunity and environmental factors. A growing scientific interest has focused on the role of diet in RMDs, suggesting its significant contribution to the pathogenesis and prognosis of these diseases. It is now clear that diet can directly modulate the immune response by providing a wide range of nutrients, which interfere with multiple pathways at both the gastro-intestinal and systemic level. Moreover, diet critically shapes the human gut microbiota, which is recognized to have a central role in the modulation of the immune response and in RMD pathogenesis. We hereby provide an in-depth analysis on the role of the microbiota in RMDs and on nutritional intervention as an integral part of a multidisciplinary approach. Particular attention will be given to the Mediterranean diet, as the only diet proven to support substantial benefits in RMD management.