Luca Navarini

Leptin in immuno-rheumatological diseases

Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders.

International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.

Endocannabinoid system in systemic lupus erythematosus: First evidence for a deranged 2-arachidonoylglycerol metabolism

The endocannabinoid (eCB) system plays a key role in many physiological and pathological conditions and its dysregulation has been described in several rheumatological and autoimmune diseases. Yet, its possible alteration in systemic lupus erythematosus (SLE) has never been investigated. Here, we aimed filling this gap in plasma and peripheral blood mononuclear cells (PBMCs) of patients with SLE and age- and sex- matched healthy subjects (HS). Liquid chromatography-mass spectrometry quantitation of eCB levels highlighted that plasma levels of 2-arachidonoylglycerol (2-AG) were significantly increased in SLE patients compared to HS (p = 0.0059), and among SLE patients, highest 2-AG levels were associated with a lower disease activity. No differences were found in N-arachidonoylethanolamine (AEA) and its congeners N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) concentrations between the two groups. Moreover, gene expression analysis of metabolic enzymes and receptor targets of eCBs and investigation of functional activity and protein expression of selected components of eCB system disclosed a deranged 2-AG metabolism in patients with SLE. Indeed, expression and functional activity of 2-AG biosynthetic enzyme DAGL were selectively enhanced in PBMCs of SLE patients compared to HS. In conclusion, our results demonstrate, for the first time, an alteration of eCB system in SLE patients. They represents the first step toward the understanding of the role of eCB system in SLE that likely suggest DAGL and 2-AG as potential biomarkers of SLE in easily accessible blood samples. Our data provides proof-of-concept to the development of cannabis-based medicine as immune-modulating agents.

Angiogenic and angiostatic factors in renal scleroderma-associated vasculopathy

BACKGROUND The angiogenesis in systemic sclerosis (SSc) is impaired. An imbalance of pro-angiogenic factors and angiogenesis inhibitors has been implicated in the progression of peripheral microvascular damage, defective vascular repair and fibrosis. Intrarenal resistance index are considered markers of renal vasculopathy. The aim of the study is to evaluate angiogenic and angiostatic factors (VEGF and endostatin) in SSc patients and to correlate with intrarenal hemodynamic parameters. METHODS 91 SSc patients were enrolled in this study. Serum VEGF and endostatin levels were determined. All patients underwent a renal Doppler ultrasound RESULTS: A significant positive correlation was observed between endostatin and renal Doppler parameters (p<0.0001). A negative correlation was observed between serum levels of endostatin and eGFR (p<0.01). In SSc patients with high resistive index, serum levels of endostatin were significantly (p<0.01) higher than in SSc patients with normal resistive index. The serum levels of endostatin significantly increased with progression of nailfold videocapillaroscopy damage (p<0.01) and were significantly (p<0.05) higher in SSc patients with digital ulcers than in SSc patients without digital ulcers. CONCLUSION This is the first study that assess in SSc patients intrarenal hemodynamic parameters and endostatin. In SSc patients, endostatin represents a marker of renal scleroderma-associated vasculopathy.

Physical activity and sedentary behavior in patients with Systemic Lupus Erythematosus

Introduction The aim of this study was to evaluate the proportion of patients with Systemic Lupus Erythematosus (SLE) who did not met the WHO recommendations for physical activity and to evaluate the amount of time spent in sedentary behavior. Methods SLE patients were consecutively enrolled in a cross sectional study. The type and the time spent in physical activity and sedentary behavior were evaluated using the IPAQ short form questionnaire. The adequate physical activity was defined according to the 2010 WHO recommendations for health and the sedentary behavior according to the 2017 SBRN consensus. We also assessed quality of life using SF-36, mood disorders using BDI and HAM-H, fatigue using Facit-Fatigue and sleep disorders using PSQI scores. Results Physical activity was not sufficient to meet WHO recommendations in 56 of 93 SLE patients (60%). SLE patients spent a median (95% range) of 180 (0–600) minutes everyday in sedentary activities. The length of daily sedentary time was more than 6 hours in 25% of SLE patients. In multivariable analysis, the factors associated to the probability of not meeting WHO criteria was only the time of exposure to antimalarials (OR 0.88, p 0.03) and the factors related to the probability of being in the upper tertile of sedentary time (more than 270 minutes) were age (OR 1.04, p 0.02), disease activity expressed by SELENA-SLEDAI score (OR 1.2, p 0.01) and Facit-fatigue score (OR 0.94, p 0.04). Conclusion A relevant proportion of SLE patients were inadequately physically active. It is essential to improve the awareness of the importance of increase physical activity and reduce sedentary time. A better control of disease activity and fatigue and a prolonged use of antimalarials could help to reach this notable goal.

Performances of five risk algorithms in predicting cardiovascular events in patients with Psoriatic Arthritis: An Italian bicentric study

Introduction In patients with psoriatic arthritis (PsA) an increased cardiovascular (CV) risk has been observed. Recently, a EULAR taskforce suggested to use a multiplication by the factor of 1.5 of CV risk algorithms in patients with inflammatory arthritis. This study aims to evaluate the performance of five original and adapted according to EULAR recommendations CV risk algorithms in PsA: SCORE, CUORE, Framingham Risk Score (FRS), QRISK2, and Reynold’s Risk Score (RRS). Methods Prospectively collected data from two Italian cohorts were used. Discriminatory ability for CV risk prediction was evaluated by the area under the ROC curves. Calibration between predicted and observed events was assessed by Hosmer-Lemeshow (HL) tests. Sensibility and specificity were calculated for low-to-intermediate and intermediate-to-high risk cut-offs. Results One hundred fifty-five patients were enrolled with an observation of 1550 patient/years. Area under the ROC were 0.7679 (95% CI 0.64768 to 0.88812), 0.864 (95% CI 0.79675 to 0.93278), 0.7575 (95% CI 0.65784 to 0.85708), 0.8660 (95% CI 0.79428 to 0.93772), and 0.7183 (95% CI 0.57795 to 0.85862) for SCORE, CUORE, FRS, QRSIK2, and RRS, respectively. HL tests demonstrated poor model fit (p<0.05) for SCORE, CUORE, and RRS. Discriminative ability and calibration were not improved by adaption of the algorithms according to EULAR recommendations. Up to 80% of CV events occurred in patients at “low risk” and up to 93% of CV events in patients at “low-intermediate risk”. Conclusions Adaption of the CV risk algorithms according to EULAR indications did not provide improvement in discriminative ability and calibration in patients with PsA.

In systemic sclerosis, microvascular and hands digital arteries damage correlates with serum levels of endostatin

In SSc, vascular injury leads to endothelial dysfunction with reduced capillary blood flow and tissue hypoxia. In SSc, the angiogenesis is impaired and implicated in the microvascular damage. In severe vascular damage, VEGF is reduced and endostatin is increased. The aim of this study was to evaluate the correlation between endostatin serum levels and microvascular and digital arteries damage.

Female sexual dysfunction in systemic sclerosis: The role of endothelial growth factor and endostatin

Introduction: Since female sexual dysfunction in systemic sclerosis women is multifactorial, we can assume that vascular damage may play a role in pathogenesis. The aim of the study was to evaluate the clitoral blood flow, by Echo color Doppler, and to correlate it whit serum levels of vascular endothelial growth factor and endostatin. Methods: A total of 15 systemic sclerosis women and 10 healthy controls matched for sex and age were enrolled in this study. Serum VEGF165 and endostatin levels were determined in systemic sclerosis patients by commercial enzyme-linked immunosorbent assay kit. Clitoral blood flow was measured by Doppler indices of clitoral artery: pulsatile index, resistive index, and systolic/diastolic ratio were measured. Sexual dysfunction was assessed by Female Sexual Function Index. Results: Vascular endothelial growth factor (pg/mL) and endostatin (ng/mL) median values were significantly higher in systemic sclerosis women than healthy controls. Resistive index and systolic/diastolic ratio median values were significantly higher in systemic sclerosis women than healthy controls. Negative correlation exists between serum levels of vascular endothelial growth factor and resistive index (r = −0.55, p < 0.05). Positive correlation was observed between serum levels of endostatin and resistive index (r = 0.70, p < 0.01) and systolic/diastolic ratio (r = 0.77, p < 0.01). Discussion: We can suppose that clitoral blood flow in systemic sclerosis women is reduced not only for macro- and microvascular damage but also for impaired angiogenesis.

Serum level of endostatin and digital ulcers in systemic sclerosis patients

Patients with systemic sclerosis (SSc) are at a high risk of the development of ischaemic digital ulcers (DUs) that can be complicated with infections, gangrene, and osteomyelitis. The aim of this study is to evaluate the role of endostatin in scleroderma DUs.In total, 90 SSc patients were enrolled in this study. Serum endostatin levels and DU assessment were determined in all SSc patients. The serum levels of endostatin significantly increased with progression of capillaroscopic damage (P < .01). The serum levels of endostatin are significantly (P < .05) higher in SSc patients with new DUs than in SSc patients without new DUs (127 ± 31.1 ng/mL vs 116.3 ± 39.7 ng/mL). The Receiver Operating Characteristic (ROC) curves demonstrated good accuracy of new DU prediction for the serum level of endostatin (0.70, P < .01 [95% confidence interval (CI) 0.59‐0.81]). Using a cut‐off value of 116 ng/mL, the odds ratio was 2.609 (CI 1.075‐6.330, P < .05). The serum levels of endostatin are significantly (P < .01) higher in SSc patients with infected DUs than in SSc patients without infected DUs (139.2 [114.6‐340.91] ng/mL vs 117.5 [64.3‐163.9] ng/mL). Serum levels of endostatin are higher in patients with DUs, especially in those with infected DUs.

FRI0014 Low-dose aspirin may have a role as primary prophylaxis of cardiovascular events in rheumatoid arthritis: evidence from an italian multicentric retrospective study

Background Cardiovascular (CV) morbidity and mortality are significantly greater in Rheumatoid Arthritis (RA) patients than in the general population. Acetylsalicylic acid (ASA) is known to be associated with a significant decrease in the incidence of CV events in patients at high CV risk, as we have recently demonstrated in patients with Systemic Lupus Erythematosus, but its effectiveness as primary prophylaxis in RA patients has not yet been addressed. Objectives To investigate the role of ASA in reducing the incidence of CV events in an Italian multicentre RA cohort from the GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale). Methods The clinical charts of RA patients consecutively admitted to 4 GIRRCS centres for their 1 st visit from November 1 st 2000 to December 31 st 2015, who, at admission, satisfied 2010 ACR/EULAR criteria for RA and had not experienced any CV event, were analysed. The incidence of CV events during follow-up was recorded at December 2016. Kaplan Meier curve and log-rank test were used to investigate differences in event-free survival. Cox regression analysis served to identify factors associated with CV event occurrence. Results Seven hundred and forty-six consecutive RA patients were enrolled and followed up for a median of 5.6 years (range 2.9–8.9 years). The incidence rate (IR) of CV events was 7.8/1000 person-years (pys) in the overall cohort. Patients were subdivided into two groups, namely ASA- (242 patients) and non-ASA-treated (504 patients). The IR of CV events was significantly lower in the ASA-treated with respect to the non ASA-treated group (IR 1.7 vs 11.5/1000 pys;p=0.0002). Furthermore, the CV event-free rate was longer in ASA-treated than in non-ASA-treated patients (log-rank test 12.3;p=0.0004). Figure 1. At multivariate analysis hypertension and metabolic syndrome (HR 5.6, 95% CI:1.2–26.3;p 0.03 and HR 3.7, 95% CI:1.3–9.8;p 0.009) resulted to be the only positive predictors; ASA treatment (HR 0.04, 95% CI:0.06–0.33;p 0.02) the only negative one. Conclusions The incidence rate of CV events in our italian multicentric cohort was lower than that reported in other European and non European cohorts. Low-dose ASA may have a role in the primary prophylaxis of CV events in RA patients. References [1] del Rincón ID, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum2001;44(12):2737–45. [2] Fasano S, et al. Longterm Hydroxychloroquine Therapy and Low-dose Aspirin May Have an Additive Effectiveness in the Primary Prevention of Cardiovascular Events in Patients with Systemic Lupus Erythematosus. J Rheumatol2017;44(7):1032–1038. [3] Meek IL, et al. Cardiovascular case fatality in rheumatoid arthritis is decreasing; first prospective analysis of a current low disease activity rheumatoid arthritis cohort and review of the literature. BMC Musculoskelet Disord2014;15:142. Disclosure of Interest None declared