Abstract Background Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) events and CV mortality. Subclinical carotid atherosclerosis is independently associated with ...rates of incident CV events among patients with RA. The complement system has been related to both the etiopathogenesis of RA and CV disease. In this study, we aimed to evaluate the association between a comprehensive assessment of the complement system and carotid intima media thickness and carotid plaque in patients with RA. Methods 430 patients with RA were recruited. Functional assays of the three pathways of the complement system, utilizing new-generation techniques, were assessed. Additionally, serum levels of individual components of the complement system belonging to the three pathways were measured: C1q (classical), lectin (lectin), C2, C4, and C4b (classical and lectin), factor D and properdin (alternative), C3 and C3a (common), C5, C5a, and C9 (terminal), as well as regulators factor I and C1-inhibitor. Subclinical carotid atherosclerosis was evaluated by ultrasonography. Multivariable linear regression analysis was conducted to investigate the association between the complement system and carotid intima media thickness and carotid plaque. Results After multivariable adjustment, which included traditional CV risk factors and disease-related data, C3a and C5a exhibited significant positive correlations with carotid intima media thickness. Additionally, higher values of C1-inhibitor, properdin, C3, C5, and C5a were independently associated with the presence of carotid plaque. Conclusion The complement system and subclinical carotid atherosclerosis are linked in patients with RA.
Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and ...chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders.
Progranulin (PGRN) is a recently identified adipokine that is supposed to have anti-inflammatory actions. The proinflammatory cytokine interleukin-1β (IL1β) stimulates several mediators of cartilage ...degradation. Toll like receptor-4 (TLR4) can bind to various damage-associated molecular patterns, leading to inflammatory condition. So far, no data exist of PGRN effects in inflammatory conditions induced by IL1β or lipopolysaccharide (LPS). Here, we investigated the anti-inflammatory potential of PGRN in IL1β- or LPS-induced inflammatory responses of chondrocytes. Human osteoarthritic chondrocytes and ATDC-5 cells were treated with PGRN in presence or not of IL1β or LPS. First, we showed that recombinant PGRN had no effects on cell viability. We present evidence that PGRN expression was increased during the differentiation of ATDC-5 cell line. Moreover, PGRN mRNA and protein expression is increased in cartilage, synovial and infrapatellar fat pad tissue samples from OA patients. PGRN mRNA levels are upregulated under TNFα and IL1β stimulation. Our data showed that PGRN is able to significantly counteract the IL1β-induced expression of NOS2, COX2, MMP13 and VCAM-1. LPS-induced expression of NOS2 is also decreased by PGRN. These effects are mediated, at least in part, through TNFR1. Taken together, our results suggest that PGRN has a clear anti-inflammatory function.
Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical ...specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.
Background and Purpose
Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc), and current therapies available are of low efficacy or high toxicity. Thus, the ...identification of innovative less toxic and high efficacy therapeutic approaches to ILD treatment is an urgent need. The interaction of P‐selectin glycoprotein ligand‐1 (PSGL‐1) with P‐selectin initiates leukocyte extravasation and deletion of the corresponding gene (Selplg) induces a SSc‐like syndrome with high incidence of ILD in aged mice.
Experimental Approach
Aged PSGL‐1 KO (Selplg‐/‐) mice were used to assess the therapeutic effects of nanotherapy with everolimus, included in liposomes decorated with high MW hyaluronic acid (LipHA+Ev) and administered intratracheally to specifically target CD44‐expressing lung cells.
Key Results
PSGL‐1 KO mice had increased numbers of CD45+ and CD45− cells, including alveolar and interstitial macrophages, eosinophils, granulocytes and NK cells, and myofibroblasts in bronchoalveolar lavage (BAL). CD45+ and CD45− cells expressing pro‐inflammatory and pro‐fibrotic cytokines were also increased. Lungs from PSGL‐1 KO mice showed increased immune cell infiltration and apoptosis and exacerbated interstitial and peribronchial fibrosis. Targeted nanotherapy with LipHA+Ev decreased the myofibroblasts in BAL, cells producing proinflammatory and profibrotic cytokines, and the degree of lung inflammation at histology. LipHA+Ev treatment also decreased the severity of peribronchial and interstitial lung fibrosis, from moderate to mild levels.
Conclusions and Implications
In PSGL‐1 KO mice, targeted nanotherapy with LipHA+Ev was an effective treatment for SSc‐ILD, reducing the number of inflammatory and fibrotic cells in BAL and reducing inflammation and fibrosis in lungs.
ObjectiveAdverse events during pregnancy are common in systemic lupus erythematosus (SLE). For this reason, EULAR recommends its management in specialized pregnancy clinics. Our aim is to report the ...10-year experience of a pregnancy clinic in a tertiary center in Spain.MethodsRetrospective study of patients with SLE followed up in a specialized pregnancy clinic at a tertiary center in Madrid, Spain, who attended the clinic from December 2012 to January 2023. Categorical variables were described as proportions and/or percentages, while continuous variables were shown as mean and standard deviation (SD) or median and interquartile range (IQR) when appropriate.Results56 cases of pregnancy counselling’s in 38 patients with SLE were included. The main characteristics are reported in table 1. Preconception consultation was performed in 57.1% (32/56) of the cases since 42.9% (24/56) were already pregnant in the 1st visit; 58.3% (14/24) of pregnant patients were referred from services other than Rheumatology. Before 1st visit, only 48.2% (27/56) of SLE patients had been treated with hydroxychloroquine (HCQ) and 33.3% (5/15) of patients treated with corticosteroids had doses ≥ 10 mg/day. At the first visit, treatment adjustment was recommended to 46.9% (15/32) of patients being the introduction of HCQ was the most frequent. The pregnancy rate was 80.4% (45/56) and 6 (13.3%) ended in spontaneous abortion. 80% (36/45) pregnancies ended with a live birth, 6/36 (16.7%) flared. During pregnancy the use of corticosteroids continued to be around 33.3% (n=12/36), median dose 6.9 mg/day (IQR 3.1–10.0). The most frequent delivery was eutocic 27/36 (75%) at a median of 39.2 GW (IQR 37.6–40.1). An adverse pregnancy outcome occurred in 44.4% (n=16/36) of the pregnancies, being gestational diabetes and premature rupture of membranes the most frequent ones. Preeclampsia was found in 5.6% (n=2/36) of the pregnancies and 12.1% (n=4/36) of the neonates had low birth weight.ConclusionsBesides high rates of pregnancy at 1st visit there was a low rate of flares and adverse outcomes. Pregnancy planning should be carried out to minimize the risk of adverse events during pregnancy. It is advisable to closely monitor pregnancies in patients with SLE in specialized clinics.Abstract P140 Table 1Demographic and clinical characteristicsCases, n (%) 56 (100) Age at 1st visit, mean (SD), years 35.6 (4.5) BMI, mean (SD) 23.1 (4.1) Smoke, n (%)neveractiveprevious smoker 39 (69.7)6 (10.7)11 (19.6) Hypertension, n (%) 3 (5.4) Diabetes, n (%) 0 (0) Dyslipidemia, n (%) 1 (1.8) Previous nephritis, n (%) 9 (16.1) Disease duration, days, median (IQR) 2845 (998.0–5325.0) ART, n (%) 13 (23.2) anti-Ro positive, n (%) 12 (21.4) APL positive, n (%) 25 (46.3) APS associated, n (%) 6 (10.7) Never pregnant, n (%)Previous newborn, n (%)Previous abortion, n (%) 23 (41.1)33 (59)23 (41.1) High pregnancy risk, n (%) 54 (96.4) Preconceptional counsellingPregnant at 1st visit, n (%)Treatment adjustment, n (%)Contraindicated pregnancy, n (%)Not adjustment needed, n (%) 24 (29.3)15 (26.8)2 (3.6)15 (40.3) Corticosteroid use at 1st visit, n (%) 15 (26.8) Corticosteroid daily at 1st visit, mg/day, median (IQR) 5 (2.5–15.0) cDMARDS at 1st visit, n (%) 11 (19.6) bDMARDs at 1st visit, n (%) 2 (3.6) Hydroxychloroquine at 1st visit, n (%) 29 (51.8) Aspirin at 1st visit, n (%)Anticoagulation at 1st visit, n(%) 16 (28.6)4 (7.1) Pregnancy, n (%) 45 (80.4) ART (additional reproductive therapies), APL (antiphospholipid antibodies), APS (antiphospholipid syndrome), bDMARDS (biological disease-modifying antirheumatic drugs), BMI (Body Mass Index), RA (rheumatoid arthritis), cDMARDS (conventional disease-modifying antirheumatic drugs).
Abstract
Interleukin (IL) 1, and its family member, IL-1 receptor antagonist (IL-1ra), are involved in the pathogenesis and inflammation perpetuation of patients with rheumatoid arthritis (RA). ...Besides, IL-1 has been linked to an increased risk and greater severity of cardiovascular (CV) disease. We aimed to study if IL-1ra is related to the CV manifestations—including lipid pattern and insulin resistance or subclinical atherosclerosis—that accompanies the disease in a large series of patients with RA. Cross-sectional study that encompassed 430 patients with RA. Serum IL-1ra levels were assessed. A multivariable analysis was performed to analyze the relation of IL-1ra to subclinical carotid atherosclerosis, and to traditional CV factors including a complete lipid molecules profile and insulin resistance or beta cell function indices. Body mass index, abdominal circumference, and the presence of obesity were significantly and positively associated with circulating IL-1ra. Similarly, erythrocyte sedimentation rate, and disease activity scores were significantly related to higher IL-1ra serum levels after adjustment for confounders. Neither carotid intima-media thickness nor the presence of carotid plaque were associated with serum levels of IL-1ra. However, after multivariable analysis circulating IL-1ra was independently and positively associated with higher serum levels of total cholesterol, triglycerides, and apolipoproteins B and C-III. Similarly, IL-1ra was related to higher levels of beta-cell function in the univariable analysis, although, in this case, significance was lost after adjustment. Among patients with RA, IL-1ra is associated with both disease activity and several traditional CV risk factors such as obesity and the presence of higher lipid levels. Our findings suggest that IL-1ra can represent a link between the inflammation and the CV disease risk that are present in patients with RA.
Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a ...central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.
Intervertebral disc degeneration (IVDD) is a chronic, expensive, and high-incidence musculoskeletal disorder largely responsible for back/neck and radicular-related pain. It is characterized by ...progressive degenerative damage of intervertebral tissues along with metabolic alterations of all other vertebral tissues. Despite the high socio-economic impact of IVDD, little is known about its etiology and pathogenesis, and currently, no cure or specific treatments are available. Recent evidence indicates that besides abnormal and excessive mechanical loading, inflammation may be a crucial player in IVDD. Furthermore, obese adipose tissue is characterized by a persistent and low-grade production of systemic pro-inflammatory factors. In this context, chronic low-grade inflammation associated with obesity has been hypothesized as an important contributor to IVDD through different, but still unknown, mechanisms. Adipokines, such as leptin, produced prevalently by white adipose tissues, but also by other cells of mesenchymal origin, particularly cartilage and bone, are cytokine-like hormones involved in important physiologic and pathophysiological processes. Although initially restricted to metabolic functions, adipokines are now viewed as key players of the innate and adaptative immune system and active modulators of the acute and chronic inflammatory response. The goal of this review is to summarize the most recent findings regarding the interrelationships among inflammation, obesity and the pathogenic mechanisms involved in the IVDD, with particular emphasis on the contribution of adipokines and their potential as future therapeutic targets.
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