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

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

Clinical Features of Diabetes Mellitus on Rheumatoid Arthritis: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group

Rheumatoid arthritis (RA) and diabetes mellitus (DM) are linked by underlying inflammation influencing their development and progression. Nevertheless, the profile of diabetic RA patients and the impact of DM on RA need to be elucidated. This cross-sectional study includes 1523 patients with RA and no episodes of cardiovascular events, followed up in 10 Italian University Rheumatologic Centers between 1 January and 31 December 2019 belonging to the “Cardiovascular Obesity and Rheumatic DISease (CORDIS)” Study Group of the Italian Society of Rheumatology. The demographic and clinical features of DM RA patients were compared to non-diabetic ones evaluating factors associated with increased risk of DM. Overall, 9.3% of the RA patients had DM, and DM type 2 was more common (90.2%). DM patients were significantly older (p &lt; 0.001), more frequently male (p = 0.017), with a significantly higher BMI and mean weight (p &lt; 0.001) compared to non-diabetic patients. DM patients were less likely to be on glucocorticoids (p &lt; 0.001), with a trend towards a more frequent use of b/ts DMARDs (p = 0.08), and demonstrated higher HAQ (p = 0.001). In around 42% of patients (n = 114), DM diagnosis preceded that of RA. Treatment lines were identical in diabetic and non-diabetic RA patients. DM is a comorbidity that may influence RA management and outcome. The association between DM and RA supports the theory of systemic inflammation as a condition underlying the development of both diseases. DM may not have a substantial impact on bDMARDs resistance, although further investigation is required to clarify the implications of biological therapy resistance in RA patients

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

Association between the response to B cell depletion therapy and the allele*2 of the HS1,2A enhancer in seropositive rheumatoid arthritis patients

Objective. Several studies underline the relevance of the genetic background for the response to therapy. We evaluated the relationship between the polymorphism of the HS1,2A enhancer, located in the 3' regulatory region of the heavy immunoglobulin chain (IgH), and the response to B cell depletion therapy (BCDT) with Rituximab (RTX). Methods. Fifty rheumatoid arthritis (RA) patients (42 women; disease duration 13.9±10.6 years) treated with RTX, not responsive to previous DMARDs and/or TNFα inhibitors therapies, and 220 healthy subjects were enrolled in the study. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described. Disease activity was assessed every three months according to the European League Against Rheumatism's (EULAR) criteria. Results. All RA patients were seropositive for at least one of the tested autoantibodies: rheumatoid factor (FR IgA, FR IgM e FR IgG), anti-cyclic citrullinated peptides (anti-CCP IgA, anti-CCP IgM e anti-CCP IgG) and anti-vimentin antibodies. RA patients had an increased frequency of the allele*2 (60.0%) of the HS1,2A enhancer compared to healthy subjects (42.0%; OR(95%ICs): 2.07 (1.33-3.22)). Patients with a good EULAR response at 6 months follow-up visit had an increased frequency of genotype 2/2 (47.1%) compared to poor-responders RA patients (genotype 2/2: 18.2%, OR(95%ICs): 4.00 (1.09-14.68)). All the patients with a good EULAR response had the allele*2, thus showing a possible association with the allele in this population. Conclusions. The presence of allele*2 seems to be related to a good response to BCDT with RTX in seropositive RA patients, thus highlighting the role of the HS1,2A enhancer in B cell maturation and class-switch recombination.Objective. Several studies underline the relevance of the genetic background for the response to therapy. We evaluated the relationship between the polymorphism of the HS1,2A enhancer, located in the 3' regulatory region of the heavy immunoglobulin chain (IgH), and the response to B cell depletion therapy (BCDT) with Rituximab (RTX). Methods. Fifty rheumatoid arthritis (RA) patients (42 women; disease duration 13.9±10.6 years) treated with RTX, not responsive to previous DMARDs and/or TNFα inhibitors therapies, and 220 healthy subjects were enrolled in the study. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described. Disease activity was assessed every three months according to the European League Against Rheumatism's (EULAR) criteria. Results. All RA patients were seropositive for at least one of the tested autoantibodies: rheumatoid factor (FR IgA, FR IgM e FR IgG), anti-cyclic citrullinated peptides (anti-CCP IgA, anti-CCP IgM e anti-CCP IgG) and anti-vimentin antibodies. RA patients had an increased frequency of the allele*2 (60.0%) of the HS1,2A enhancer compared to healthy subjects (42.0%; OR(95%ICs): 2.07 (1.33-3.22)). Patients with a good EULAR response at 6 months follow-up visit had an increased frequency of genotype 2/2 (47.1%) compared to poor-responders RA patients (genotype 2/2: 18.2%, OR(95%ICs): 4.00 (1.09-14.68)). All the patients with a good EULAR response had the allele*2, thus showing a possible association with the allele in this population. Conclusions. The presence of allele*2 seems to be related to a good response to BCDT with RTX in seropositive RA patients, thus highlighting the role of the HS1,2A enhancer in B cell maturation and class-switch recombination