Adiposity, joint and systemic inflammation: the additional risk of having a metabolic syndrome in rheumatoid arthritis.

Summary Adiposity is a predisposing condition to atherosclerosis, and rheumatoid arthritis (RA) also predisposes to accelerated atherosclerosis. Adiposity is one of the key features of the metabolic syndrome (MetS) and it is well recognised that a metabolic syndrome (and fat tissue) is a major player in this complex network. Endothelial dysfunction and carotid intima-media thickness, early pre-clinical markers of atherosclerosis which are the main determinants of cardiovascular (CV) morbidity and mortality, occur early on in RA. RA patients have an incidence of CV diseases at least two times higher than the general population. MetS and RA have a low and a severe-moderate degree of inflammation in common, respectively. Adipose tissue has emerged as a dynamic organ that releases several inflammatory and immune mediators (adipokines). In addition, fat has been recognised as a producer of B cell activating factor (BAFF) and of chemerin, an inducer at the chondrocyte level of IL1β, TNFα, IL6, IL8 and MMP13, thus possibly contributing to cartilage damage. Since fat produces inflammation, to obtain a full control of the CV risk in RA, data suggest that it is therefore mandatory to have a "tight control" of both RA and MetS-related inflammation, especially if RA presents MetS as a co-morbidity

Microvascular heart involvement in systemic autoimmune diseases: The purinergic pathway and therapeutic insights from the biology of the diseases

Heart involvement \u2013 often asymptomatic \u2013 is largely underestimated in patients with systemic autoimmune diseases (SADs). Cardiovascular events are more frequent in patients with SADs compared to the general population, owing to the consequences of inflammation and autoimmunity and to the high prevalence of traditional risk factors. Coronary microvascular disease (CMD) is a form of cardiac involvement that is increasingly recognised yet still largely neglected. CMD, the incapacity of the coronary microvascular tree to dilate when myocardial oxygen demand increases or when there is a microvascular spasm (or subclinical myocarditis), is increasingly reported because of the widespread use of new cardiac imaging tools, even in a subclinical phase. The assessment of myocardial coronary flow reserve (CFR) emerged as the most effective clinical tool to detect microvascular damage. The potential causes of microvascular damage, molecular and cellular inflammation along with a pathological CD39-CD73 axis, need always to be considered because data show that they play a role in the occurrence of acute coronary syndromes, heart failure and arrhythmias, even in the early asymptomatic stage. Data suggest that controlling disease activity by means of methotrexate, biologic drugs, antimalarial medications, statins and aspirin, according to indication, might reduce the cardiovascular risk related to macrovascular and microvascular damage in most patients with SADs, provided that they are used early and timely to control diseases. The need of new biomarkers and a careful assessment of myocardial CFR emerged as the most effective clinical tool to detect microvascular damage

Proton pump inhibitors in rheumatic diseases: clinical practice, drug interactions, bone fractures and risk of infections.

Patients affected by acute coronary syndrome (ACS) or by chronic inflammatory musculoskeletal and connective tissue diseases (i.e. systemic sclerosis), often need antiaggregant therapy (ASA or Clopidogrel). The concomitant use of proton pump inhibitors (PPIs) is suggested to reduce the risk of haemorrhage. Clopidogrel is a prodrug activated by cytocrome P 450. PPIs too have a CYP P450 metabolism, and a drug interaction has been observed between PPIs and clopidogrel. 25% of nonresponsiveness to clopidogrel is due to this drug interaction (1). Some studies have demonstrated that the use of PPIs is associated with an increased risk of bone fractures and Clostridium difficile infection

Bosentan Does Not Affect Renal Resistive Index in Scleroderma/Systemic Sclerosis Patients

Introduction: If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. Methods: Twenty-one patients (age 57 ± 9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean arterial pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. Results: Bosentan treatment for 16 weeks did not change RRI (0.731 ± 0.049-0.730 ± 0.054, p = 0.925), but increased urine endothelin-1 to creatinine ratio (0.27 ± 0.15-0.49 ± 0.57 pg/mg, p = 0.032) and reduced MAP (123 ± 10-101 ± 11 mm Hg, p < 0.001), PP (76 ± 11-68 ± 10 mm Hg, p = 0.003), D/S ratio (0.563 ± 0.044-0.538 ± 0.031, p = 0.006), and eGFR (92 ± 20-84 ± 24 mL/min/1.73 m2, p = 0.003). Discussion/Conclusion: In conclusion, in patients with SSc complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function

SAT0092 CARDIOVASCULAR RISK ASSESSMENT IN PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASES: AN ITALIAN RHEUMATOLOGISTS' SURVEY

Background:Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with inflammatory arthritis. The growing attention to the CV risk characterizing patients with autoimmune inflammatory disease led EULAR to provide recommendations on CV risk management (1). To date, there are no data on the adherence to EULAR recommendation among Italian rheumatologists.Objectives:Our objective was to measure the level of awareness and the attitude to manage CV risk.Methods:Italian rheumatologists were invited to anonymously answer a web-based questionnaire designed by the steering committee of the Cardiovascualr and Obesity in Rheumatic Diseases (CORDIS) study group of the Italian Society of Rheumatology. The first part of the questionnaire concerned demographic information; the subsequent questions concerned the attitude to assess CV risk and the limitations for not assessing, the specific CV risks considered in the clinical practice and their management. Data are presented using standard summary statistics and were expressed as mean+/-standard deviation or median (interquartile range) according to variables' distribution.Results:One thousand-three hundred rheumatologists (of whom 500 are under 40 and 100 over 70 years of age) have been invited by email to complete the survey. The questionnaire has been filled by 102 rheumatologists (7.85%) (53 females and 49 males) with a median age of 38 years (32-48) and a median of 4 (0-15) years of specialization. Most of the physician who answered the questionnaire works in University Hospitals (67/102; 65.7%), 22 out of 102 (21.6%) in non-academic Hospitals, and the remaining 12,7% in territorial outpatient clinics.When asked if they usually evaluate CV risk in patients with autoimmune rheumatic diseases, 67/102 (67.2%) answered positively, 18 no (17.6%) and 7 did not answer the question; 82% of those who routinely assess the CV do it by themselves. The barriers limiting the assessment of CV risk included: i) lack of time (79%); ii) complex management (12%); inadequate training (9%).As for the CV risk factors, lipid profile, hypertension and diabetes are assessed by most of the rheumatologists (90%, 89% and 88%, respectively), family history by 78% and body mass index by 75.3% and waist circumference only by 25% of those who completed the survey.Finally, only 18.6% stated that they manage by themselves CV risk in patients with autoimmune rheumatic diseases while 50% refer patients to other specialists and 23.4% to general practitioner.Conclusion:Despite the growing awareness on the CV risk characterizing patients with autoimmune rheumatic disease, about one third of young Italian rheumatologists does not strictly adhere to the EULAR recommendations on CV management, mostly due to insufficient time during the routine care visits.References:[1] Agca R et al. Ann Rheum Dis 2017; 76: 17-28.Disclosure of Interests:Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, Fabio Cacciapaglia Speakers bureau: BMS; Roche; Pfizer; Abbvie, Fabiola Atzeni: None declared, Gianluca Erre: None declared, Andreina Manfredi: None declared, Elena Bartoloni Bocci: None declared, Matteo Piga: None declared, Garifallia Sakellariou Speakers bureau: Abbvie, Novartis, MSD, Ombretta Viapiana: None declared, Elisa Gremese Speakers bureau: Abbvie, BMS, Celgene, Jannsen, Lilly, MSD, Novartis, Pfizer, Sandoz, UC

JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy

Methotrexate (MTX) is recognized as the anchor drug in the algorithm treating chronic arthritis (RA, psoriatic arthritis), as well as a steroid sparing agent in other inflammatory conditions (polymyalgia rheumatica, vasculitis, scleroderma). Its main mechanism of action has been related to the increase in extracellular adenosine, which leads to the effects of A2A receptor in M1 macrophages that dampens TNFα and IL12 production and increases IL1Ra and TNFRp75. By acting on A2B receptor on M2 macrophages it enhances IL10 synthesis and inhibits NF‐kB signaling. MTX has also been shown to exert JAK inhibition of JAK2 and JAK1 when tested in Drosophila melanogaster as a model of kinase activity and in human cell lines (nodular sclerosis Hodgkin's lymphoma and acute myeloid leukemia cell lines). These effects may explain why MTX leads to clinical effects similar to anti‐TNFα biologics in monotherapy, but is less effective when compared to anti‐IL6R in monotherapy, which acting upstream exerts major effects downstream on the JAK1‐STAT3 pathway. The MTX effects on JAK1/JAK2 inhibition also allows to understand why the combination of MTX with Leflunomide, or JAK1/JAK3 inhibitor leads to better clinical outcomes than monotherapy, while the combination with JAK1/JAK2 or JAK1 specific inhibitors does not seem to exert additive clinical benefit

analysis of the kinetic of expression of tristetraprolin and hur by rheumatoid arthritis patients pheripheral blood mononuclear cells stimulated with lipopolysaccharide

Objective. Given the role of TNF-α in Rheumatoid Arthritis (RA) we decided to define the characteristics of the TNF- α synthesis by peripheral blood mononuclear cells (PBMNCs) obtained from active-aggressive RA patients giving a particular attention to the modulation of the expression of two fundamental proteins in TNF-α mRNA stability regulation, Tristetraprolin (TTP) and HuR. Methods. 11 RA patients with active disease were enrolled in the study before their entry in 2 double blind protocols: Infliximab versus MTX and Etanercept versus MTX. 9 healthy blood donors were taken as controls. PBMNCs obtained by Ficoll centrifugation and plastic adherence were stimulated with lipopolysaccharide (LPS) and TNF-α was measured in the supernatant during 8 hours by ELISA. At each time point the cells were harvested and analysed for TNF- α, TTP and HuR mRNA expression by semi-quantitative PCR. Results. MNCs TNF-α secretion after LPS stimulation did not differ significantly between RA and control subjects, even if a tendency towards a more prompt response was observed in the patients. More importantly only the DMARDs responsive patients (DAS <3.7 at the 6th month, with a minimal reduction of 1.2 points) disclosed precociously (at the first month) a significant change in the profile of TNF-α secretion and maintained it until the 6th month. The "normalization" of the synthetic behaviour was accompanied by the resetting in the regulation of the expression of the TTP, that appeared significantly different in the patients before and after therapy. Conclusions. Independently from the type of therapy, responsive patients demonstrate a rapid change in the cellular biology at the systemic level that might drive the resolution of the phlogistic process at the synovial level

RAASI, NSAIDs, antidiabetics, and anticoagulants: More data needed to be labeled as harmful or neutral in SARS-CoV-2 infection

Not applicabl

Treatment strategy introducing immunosuppressive drugs with glucocorticoids ab initio or very early in giant cell arteritis: A multicenter retrospective controlled study

Objective: Glucocorticoids (GC) are associated with side effects in giant cell arteritis (GCA). Immunosuppressive therapies (ITs) have given conflicting results in GCA, regarding GC sparing effect. Primary endpoint is to evaluate whether very early introduction of ITs in GCA minimize the rate of GC-induced adverse events, in terms of infections, new onset systemic arterial hypertension, GC-induced diabetes and osteoporotic fractures. Methods: A multicenter retrospective case-control study included 165 patients. One group included 114 patients who were treated with at least one IT given at diagnosis or within 3 months from the start of GC. A second group included 51 GCA who received only GC or an IT more than 3 months later. Results: The most frequently used ITs were: methotrexate (138 patients), cyclophosphamide (48 patients) and tocilizumab (27 patients). No difference was observed as concerns the follow-up time between groups [48.5 (IQR 26\u201372) vs 40 (IQR 24\u201369), p \u200b= \u200b0.3)]. The first group showed a significantly lower incidence of steroid-induced diabetes (8/114, 7% vs 12/51, 23.5%; p \u200b= \u200b0.003) and no differences for the rate of infections (p \u200b= \u200b0.64). The group was also exposed to lower doses of GC at first (p \u200b< \u200b0.0001) and third (p \u200b< \u200b0.0001, rank-sum test) month. Forty-four patients in the first group (38.6%) compared with 34 in the second one (66.7%) experienced at least one relapse (p \u200b= \u200b0.001). Conclusion: Very early introduction of IT in GCA lowered the incidence of steroid-induced diabetes, possibly due to the lower doses of GC in the first three months. Relapse rate was even lower

FRI0216 STEROID SPARING EFFECT, LOWER INCIDENCE OF DISEASE RELAPSE AND DIABETES IN GIANT CELL ARTERITIS TREATED WITH IMMUNOSUPPRESSORS AB INITIO OR VERY EARLY: A MULTICENTER RETROSPECTIVE CASE-CONTROL STUDY

Background:Glucocorticoids (GC) are associated with serious side effects in giant cell arteritis (GCA). Immunosuppressive therapies (IT) gave conflicting results in GCA, regarding GC sparing effect. Recently, tocilizumab by blocking IL-6, has been licensed as first biologic treatment for GCA, being clinically effective and saving GC (1).Objectives:To evaluate the usefulness of IT for GCA in: 1) minimizing the rate of GC-induced adverse events (AEs) and 2) reducing the risk of relapse.Methods:A multicenter retrospective case-control study included 165 GCA was performed. The first group of patients (GCA-IT) included 114 patients who were treated with at least one IT given ab initio or within 3 months from the start of GC. The control group included 51 GCA who received only GC or an IT later than 3 months (GCA-steroid). The primary endpoints were the rate of GC-related side effects: infections, hospitalized infections, new onset systemic arterial hypertension, GC-induced diabetes and osteoporotic fractures.Results:Methotrexate up to 20 mg/week (138 patients), followed by cyclophosphamide (48 patients) and tocilizumab (27 patients) were the most frequently used IT. No difference was observed as concerns the follow-up time between the two groups [48.5 (IQR 26-72) vs 40 (IQR 24-69), p=0,3, rank-sum test)]. The two groups were similar as concerns sex (p=0,13), while the first group (69±8 yrs) was slightly younger than the second one (72±7 yrs) (p=0,005). Comorbidity was similar between groups. Patients in the GCA-IT group showed a significant lower incidence of GC-induced diabetes (8/114, 7% vs 12/51, 23,5%; p=0,003, chi-square test), while no differences were documented for rate of infections (p=0,64), including hospitalized infections (p=0,44), new onset systemic arterial hypertension (p=0,68), or osteoporotic fractures (p=0,32). Forty-four patients in the GCA-IT group (38,6%), while 34 patients in the GCA-steroid group (66,7%) experienced at least one relapse (p=0,001, chi square test). There was no difference in terms of time to first relapse between the two groups (p=0,53, log-rank test). GCA-IT group was exposed to lower dose of GC at first (p<0,0001, rank-sum test) and third (p<0,0001, rank-sum test) month, while no differences were recorded at the other time points. Clinical outcomes were similar between the two groups.Conclusion:Very early introduction of IT in GCA provided a greater steroid sparing in the first 3 months of treatment, leading to a lower incidence of diabetes. Relapse rate was even lower. IT was usually well tolerated without an increase incidence of infections. A randomized prospective trial is required to support this strategy in the management of GCA.References:[1]Hellmich B, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79:19-30.Disclosure of Interests:Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer, Miriam Isola: None declared, Dario Bruno: None declared, Elena Treppo: None declared, Laura Gigante: None declared, Francesca Angelotti: None declared, Riccardo Capecchi: None declared, Gianfranco Vitiello: None declared, Elena Cavallaro: None declared, Antonio Tavoni: None declared, Silvia Laura Bosello: None declared, Daniele Cammelli: None declared, Salvatore De Vita Consultant of: Roche, GSK, Speakers bureau: Roche, GSK, Novartis, Elisa Gremese Speakers bureau: Abbvie, BMS, Celgene, Jannsen, Lilly, MSD, Novartis, Pfizer, Sandoz, UC