Vascular health in subjects with rheumatoid arthritis: assessment of endothelial function indices and serum biomarkers of vascular damage.

BACKGROUND: The cardiovascular risk (CVD) in patients with rheumatoid arthritis (RA) is 1.5-2 times higher than that in individuals of the same age and sex. AIMS: To analyse the degree of endothelial dysfunction, the atherogenic immunoinflammatory serum background and the relationships among some vascular indices, cardiovascular comorbidities, and cognitive performance in subjects with RA. PATIENTS AND METHODS: All consecutive patients with a rheumatoid arthritis diagnosis admitted to the Rheumatology Ward of "Policlinico Paolo Giaccone" Hospital of Palermo were enrolled from July 2019 to September 2020. We evaluated our patients' cognitive functions by administering the Mini-Mental State Examination (MMSE). Reactive Hyperaemia Index (RHI) was evaluated for assessment of endothelial function. Serum levels of angiopoietin 2, osteopontin and pentraxin 3 were assessed by blood collection. RESULTS: Fifty-eight consecutive patients with RA and 40 control subjects were analysed. RA patients showed significantly lower mean RHI values, significantly higher mean Augmentation Index (AIX) values and significantly lower mean Mini-Mental State Examination (MMSE) score values than the control group. Patients with rheumatoid arthritis also showed higher mean serum values of pentraxin 3 and angiopoietin 2 than healthy controls. Multivariate logistic regression analysis showed a significant association between pentraxin 3 and angiopoietin 2 and the presence of RA. DISCUSSION: Angiopoietin 2 and pentraxin 3 could be considered surrogate biomarkers of endothelial activation and vascular disease, as they could play an essential role in the regulation of endothelial integrity and inflammation.

Glucocorticoid excess and COVID-19 disease.

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing's syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.

Multifunctional Carrier Based on Halloysite/Laponite Hybrid Hydrogel for Kartogenin Delivery.

A novel carrier system based on halloysite nanotubes (HNT), for the potential intraarticular delivery of kartogenin (KGN) by means laponite (Lap) hydrogel (HNT/KGN/Lap), is developed. The drug was first loaded into HNT, and the hybrid composite obtained was used as filler for laponite hydrogel. Both the filler and the hydrogel were thoroughly investigated by several techniques and the hydrogel morphology was imaged by transmission electron microscopy. Furthermore, the gelating ability of laponite in the presence of the filler and the rheological properties of the hybrid hydrogel were also investigated. The kinetic release of kartogenin from HNT and HNT/Lap hybrid hydrogel was studied both in physiological conditions and in ex vivo synovial fluid. In the last case, the kinetic results highlighted that HNT carrier can effectively release KGN in a sustained manner for at least 38 days. Finally, a preliminary biological assays showed that the HNT/KGN/Lap hybrid hydrogel did not exhibit any cytotoxic effect.

The Craniovertebral Junction in Rheumatoid Arthritis: State of the Art.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder, characterized by polyarticular inflammation causing progressive joint damage and disability. The mechanisms underlying its pathogenesis involve activation of innate and adaptive immunity, microvascular endothelial cell activation, and inflammatory infiltration of lymphocytes and monocytes into the synovium. Spinal involvement in RA is not typical; when it occurs, the main radiological features are (1) atlantoaxial subluxation (AAS), which is the most typical form of cervical spine involvement; (2) cranial settling-also known as basilar impression, atlantoaxial impaction or superior migration of the odontoid-which is the most severe form of associated spinal instability; and (3) subaxial subluxation. A combination of these alterations may occur. Synovitis is characterized by infiltration of innate and adaptive immune cells; joint destruction is a consequence of activation of synovial fibroblasts, which acquire aggressive, inflammatory, invasive features, associated with increased chondrocyte catabolism and synovial osteoclastogenesis.Neck pain is the most frequent symptom of spinal involvement in RA; it occurs in 40-80% of patients and is mostly localized at the craniocervical junction. Other symptoms-caused by compression of neural structures such as the greater occipital nerve (at C2), the nucleus of the spinal trigeminal tract and the greater auricular nerve-are occipital neuralgia, facial pain and ear pain, respectively. Irritation of the lesser occipital nerve (at C1) can cause pain in the suboccipital region. Sometimes patients may complain of a sensation of their head falling down with flexion, weakness, reduced endurance, loss of ability, gait alterations, paraesthesias or other symptoms due to cord and medullary compression, and upper or lower motor neuron signs, or both. Surgical management of RA remains a challenging field.

Role of Subclinical Gut Inflammation in the Pathogenesis of Spondyloarthritis.

Subclinical gut inflammation occurring in patients affected by spondyloarthritis (SpA) is correlated with the severity of spine inflammation. Several evidences indicate that dysbiosis occurs in SpA, and that may modulate intestinal permeability and intestinal immune responses. The presence of intestinal dysbiosis is accompanied in SpA patients with the presence of zonulin-dependent alterations of gut-epithelial and gut-vascular barriers. The leakage of epithelial and endothelial surface layers is followed by the translocation of bacterial products, such as lipopolysaccharide and intestinal fatty acid binding protein, in the systemic circulation. These bacterial products may downregulate the expression of CD14 on circulating monocytes leading to an "anergic" phenotype. In the gut, IL-23 may induce the expansion of innate immune cells such as mucosal-associated invariant T cells, γδ T cells, and innate lymphoid cells of group 3 that through the interaction with MAdCAM1 may recirculate form the gut to the sites of SpA active inflammation. On the basis of these findings, gut inflammation observed in SpA patient seems to be not only an epiphenomenon of the on going systemic inflammatory process but may also represent the base camp in which inflammatory cells are activated and from whom they shuttle.

CD3 immunohistochemistry is helpful in the diagnosis of giant cell arteritis.

OBJECTIVE: To evaluate whether CD3 staining performed routinely on temporal artery biopsy specimens might improve the sensitivity of temporal artery biopsy in patients with biopsy-negative GCA. METHODS: Two hundred and seventy biopsies were considered for this study, stained with haematoxylin and eosin and with an anti-CD3 antibody. RESULTS: The addition of CD3 staining modified the sensibility and the specificity of the histologic examination in 89.47 and 95.00%, respectively, with a positive and negative predictive values of 97.00 and 79.78% . CONCLUSION: The addition of CD3 immunostaining to the classic histologic evaluation is accompanied by a significant increase in the sensibility with a comparable specificity.

HLA-C1 ligands are associated with increased susceptibility to systemic lupus erythematosus.

Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR = 3.36; 95% CI = 1.46-7.74; p = .005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR = 6.47, 95% CI = 2.58-16.26; p < .0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR = 7.06, 95% CI = 0.07-2.19; p = .002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38 ±â€¯28.49 µmol/L) compared to SLE patients HLA-C1 negative (108.37 ±â€¯86.09 µmol/L) (p = .03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients.

New insights into the pathogenesis of giant cell arteritis.

Giant cell arteritis (GCA) is an inflammatory chronic disease occurring exclusively in elderly individuals. Until recently, the disease has been considered a unique disease resulting from the interaction in the walls of susceptible arteries, between an unknown infectious agents with local dendritic cells (DCs), activated CD4 T cells and effector macrophages. Recent evidence has shown that this view was too simplistic and has clarified many of the pathogenetic aspects of the disease. Many genetic studies recently published have identified different new genes, including cytokines, adhesion molecules and regulators of innate immunity, as crucial players in the development and progression of GCA. Recent evidence suggests that there is heterogeneity of histological lesions in GCA, that are correlated with different immunological Th9 and Th17 signature. The recent demonstration that Varicella-zoster virus (VZV) antigen is present in the 64% of GCA-negative TAs and in the 73% of GCA-positive TAs could represent an important point of arrival in the search for a causative agent in the pathogenesis of a metameric disease such as GCA. In this context, cytokines such as IL-32 and IL-33 that act as a danger signal following tissue damage and infection are over-expressed in GCA arteries. Artery tertiary lymphoid organs, present in up to 50% of GCA-positive arteries, could represent the sites were primary immune responses and T- and B-cell autoimmune responses against viral antigens are organized. The recently demonstrated disturbed distribution of B cells in GCA could be also relevant in the pathogenesis of the disease, possibly contributing to the enhanced IL-6 response. Altogether, these evidences may clarify many pathogenetic aspect of the disease, also suggesting complexity greater than first imagined.

Gut inflammation in spondyloarthritis.

Spondyloarthritis (SpA) is a group of related diseases sharing common etiopathogenic mechanisms and clinical manifestations supported by a complex genetic predisposition. Gut inflammation is present in patients with SpA including patients showing clinically evident intestinal inflammation in the form of Crohn's disease or ulcerative colitis and patients who despite the absence of signs and symptoms of intestinal inflammation display a subclinical gut inflammation. Emerging evidence suggests that subclinical gut inflammation in patients with SpA, apparently driven by intestinal dysbiosis, is not the consequence of the systemic inflammatory process but rather an important pathophysiological event actively participating in the pathogenesis of the disease. The dysregulation of intestinal epithelial barrier possibly modulated by intestinal dysbiosis and especially in HLA-B27 + patients modulates local and systemic inflammation possibly representing the occult mechanism of the disease. This review aims to summarise current data on the role of the gastrointestinal involvement and intestinal microbiota in the pathogenesis of systemic rheumatic disease.

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases.

Dysregulation of the intestinal epithelial barrier in genetically susceptible individuals may lead to both intestinal and extraintestinal autoimmune disorders. There is emerging literature on the role of microbiota changes in the pathogenesis of systemic rheumatic diseases such as rheumatoid arthritis, spondyloarthropathies, and connective tissue diseases. Although the role of the gastrointestinal tract in the pathogenesis of spondyloartropathies is well defined and many studies underline the importance of gastrointestinal inflammation in modulating local and systemic inflammation, the data are inconclusive regarding the effect of dysbiosis on rheumatoid arthritis and connective tissue diseases. This review aims to summarize current data on the role of the gastrointestinal involvement and intestinal microbiota in the pathogenesis of systemic rheumatic disease.

Endothelial progenitor cells: Are they displaying a function in autoimmune disorders?

Endothelial Progenitor Cells (EPCs) are bone marrow derived cells able to differentiate in mature endothelial cells (EC) contributing to the generation of new vessels, connecting to fibronectin, and forming colonies and/or colony forming units. Since circulating EPCs can be actively considered part of endothelial damage in several cardiovascular diseases and autoimmune disorders the possibility to have a measure for endothelium damage should be considered of interest to predict the patient out-come. At the same time the EPCs proliferative and regenerative role could be considered for therapeutic applications. Studies have been performed to elucidate the role of EPCs in Systemic Sclerosis and many review and articles published on this topic. In the present paper we aimed to review the role of EPCs in other autoimmune disorders.

Intestinal dysbiosis and innate immune responses in axial spondyloarthritis.

PURPOSE OF REVIEW: Inflammatory innate and adaptive immune cell responses to commensal bacteria underlie the pathogenesis of human chronic inflammatory diseases. Intestinal dysbiosis has been described in patients with spondyloarthritis (SpA) and seems to be correlated with histologic and immunologic alterations. Purpose of this review is to discuss the relationship occurring between intestinal dysbiosis and innate immune responses in patients with axial SpA. RECENT FINDINGS: Intestinal dysbiosis and differential activation of intestinal immune responses in patients with SpA have been demonstrated. Furthermore, innate cells that appear to be involved in the pathogenesis of SpA may control intestinal homeostasis through induction of apoptotic cell death and deletion of activated commensal bacteria-specific T cells. SUMMARY: Although the evidence shows that dysbiosis occurs in SpA, it is not clear the role of dysbiosis in regulating innate immune responses in SpA. Relationships between cause and effect remain to be answered. VIDEO ABSTRACT: http://links.lww.com/COR/A34.

Association of Renal Resistive Index with Markers of Extrarenal Vascular Changes in Patients with Systemic Lupus Erythematosus.

Recent data suggest that renal hemodynamic parameters obtained by duplex Doppler sonography, especially the intrarenal resistive index (RRI), may be associated with systemic vascular changes. We evaluated the relationships between RRI and arterial stiffness, assessed by aortic pulse wave velocity, and between RRI and subclinical atherosclerosis, assessed by measuring carotid intima-media thickness in patients with systemic lupus erythematosus. We enrolled 39 patients with systemic lupus erythematosus (mean age 39 y) compared with 19 healthy controls, matched for age and sex. Each participant underwent 24 h of ambulatory blood pressure, aortic pulse wave velocity, carotid intima-media thickness and RRI measurements. RRI correlated significantly with aortic pulse wave velocity (r = 0.44, p = 0.006), and with carotid intima-media thickness (r = 0.46, p = 0.003). Both correlations held (p = 0.01), even after correction for age, mean arterial pressure and glomerular filtration rate. Our results suggest that the RRI may be considered a marker of systemic vascular changes and probably a predictor of cardiovascular risk in patients with systemic lupus erythematosus.

Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis.

OBJECTIVE: To investigate the expression and tissue distribution of Th9-related cytokines in patients with psoriatic arthritis (PsA). METHODS: Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, HLA-B27-positive patients with ankylosing spondylitis (AS), patients with Crohn's disease (CD), and healthy controls. Expression and tissue distribution of interleukin-23 (IL-23), IL-17, IL-22, IL-9, and IL-9 receptor (IL-9R) were evaluated by immunohistochemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among peripheral blood, lamina propria, and synovial fluid mononuclear cells. The functional relevance of IL-9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells in synovial tissue from patients with PsA were also studied. RESULTS: Subclinical gut inflammation in PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune response. Unlike AS and CD, a strong and significant up-regulation of IL-9 was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules, and Paneth cells. IL-9-positive mononuclear cells were demonstrated to be in large part Th9 cells. IL-9 overexpression was accompanied by significant Paneth cell hyperplasia. Paneth cells strongly overexpressed IL-9R, and stimulation of epithelial cells, isolated from PsA patients, with IL-9 resulted in overexpression of α-defensin 5 and IL-23p19. Peripheral and synovial expansion of α4ß7+ Th9 cells was also observed in patients with PsA. Increased expression of IL-9 and IL-9R was also found in synovial tissue. CONCLUSION: Strong IL-9/Th9 polarization seems to be the predominant immunologic signature in patients in PsA.

Early Vascular Aging in Normotensive Patients With Systemic Lupus Erythematosus: Comparison With Young Patients Having Hypertension.

Connective tissue diseases, like systemic lupus erythematosus (SLE), are associated with early and accelerated atherosclerosis. Recently, the concept of "early vascular aging" (EVA) has been more widely accepted. Aortic stiffness is one of the important markers of EVA. We evaluated EVA and subclinical atherosclerosis, by measuring aortic pulse wave velocity (aPWV) and carotid intima-media thickness (cIMT), in 50 normotensive patients with SLE (mean age: 39 ± 12 years). We compared these participants with 50 age- and sex-matched patients with essential hypertension (EH) and 20 healthy controls. Each participant underwent 24-hour ambulatory blood pressure monitoring (ABPM), aPWV, and cIMT measurements. Clinic and 24-hour ABPM values were significantly lower in patients with SLE and controls when compared with the participants having EH (all P < .0001), but aPWV and cIMT were significantly lower in the control group when compared with patients having SLE and EH (all P < .001). Overall, patients with SLE and EH had similar cIMT and aPWV values (P = .31 and P = .47, respectively). Our results suggest that SLE has a similar deleterious impact on EVA as EH.

Rituximab modulates IL-17 expression in the salivary glands of patients with primary Sjögren's syndrome.

OBJECTIVE: The aim of this study was to evaluate the role of rituximab (RTX) in modulating the expression of the IL-17/IL-23 pathway in the salivary glands (SGs) of patients with primary SS (pSS). METHODS: Consecutive SG biopsies were obtained from 15 patients with pSS before and after 1 year of RTX therapy. The SG expression of IL-17, IL-23p19 and p-STAT3 was evaluated by immunohistochemistry at baseline and after RTX therapy. The role of mast cells in pSS patients in modulating the Th17 response and the immunologic effect of RTX on mast cells were also studied in in vitro experiments. RESULTS: IL-17 was overexpressed in the SGs of patients with pSS mainly by infiltrating T cells and mast cells. After RTX therapy, the SG expression of IL-17, but not of IL-23p19 and p-STAT3, was significantly reduced and was accompanied by the depletion of tissue mast cells. In in vitro experiments with heterologous peripheral lymphocytes RTX significantly induced the apoptosis of isolated mast cells. Finally, mast cells isolated from peripheral blood mononuclear cells of pSS patients in vitro significantly increased Th17 lymphocytes. CONCLUSION: RTX acts on pSS patients by globally reducing the expression of IL-17 and specifically inducing a pronounced apoptotic depletion of mast cells.

The role of innate and lymphoid IL-22-producing cells in the immunopathology of primary Sjögren's syndrome.

In primary Sjögren's syndrome (pSS) a complex of interconnections between epithelial barrier, innate and adaptive immunity occurs. IL-22 is a pleiotropic cytokine that in pSS may be placed at the intersection of the adaptive and innate branches of immunity. Some evidence suggests that, in pSS, IL-22 may play a prominent pro-inflammatory role driving the early phase of tissue and systemic inflammation and participating in the self-perpetuation of disease. Despite contradictory data in literature about the role of NK cells in pSS, recent data also suggest an important contribution of this subset of cells of the innate immune system in the development and perpetuation of inflammation. Here, we discuss the role of IL-22 in the pathogenesis of pSS and in epithelial barrier function.

No detection of occult HBV-DNA in patients with various rheumatic diseases treated with anti-TNF agents: a two-year prospective study.

OBJECTIVES: The widespread use of tumour necrosis factor (TNF)-targeted therapies in patients with rheumatic, digestive and dermatologic diseases has been associated with reports of reactivation of HBV replication and ensuing hepatitis flares both in asymptomatic HBsAg carriers and in subjects with occult HBV infection. The aim of our work was to investigate in a two-year prospective study the potential for HBV reactivation in patients with inflammatory joint diseases undergoing anti-TNF treatment from a southern Mediterranean area. METHODS: Fifty-seven consecutive outpatients attending the Academic Unit of Rheumatology at the University of Palermo (12 with rheumatoid arthritis, 17 with psoriatic arthritis and 28 with ankylosing spondylitis) were enrolled in the study. HBV-DNA was tested by a standard quantitative assay in HBsAg-positive subjects and by an ad hoc highly sensitive PCR in HBsAg-negative patients performed at baseline and then every six months on the anti-TNF agent. RESULTS: Occult HBV-DNA was never detected in the 54 HBsAg negative subjects, regardless of their anti HBs/HBc status. All HBsAg positive patients, who were started on prophylactic lamivudine, remained HBV-DNA undetectable throughout the anti-TNF treatment. CONCLUSIONS: Even in an area of previously high HBV endemicity, where occult HBV infection is likely to have a high prevalence, treatment of rheumatological patients with anti-TNF drugs is safe in terms of its potential to reactivate HBV. Prophylaxis with lamivudine is sufficient to prevent reactivation in HBsAg carriers.

Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome.

OBJECTIVES: In chronic inflammatory disorders, interleukin (IL)-22 may act either as a protective or as a pro-inflammatory cytokine. At mucosal sites, IL-22 is mainly produced by CD4(+) T cells and by a subset of mucosal natural killer (NK) cells expressing the receptor NKp44 (NKp44(+) NK cells). The aim of this study was to investigate the IL-22 expression in the salivary glands of patients with primary Sjögren's syndrome (pSS). METHODS: Minor salivary gland biopsies were obtained from 19 patients with pSS and 16 with non-specific chronic sialoadenitis. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-17, IL-22, IL-23 and STAT3 (signal transducer and activator of transcription) was performed on salivary glands from patients and controls. The cellular sources of IL-22 among infiltrating inflammatory cells were also determined by fluorescence-activated cell sorting analysis and immunohistochemistry. RESULTS: IL-22, IL-23 and IL-17 were significantly increased at both protein and mRNA levels in the inflamed salivary glands of patients with pSS. STAT3 mRNA and the tyrosine phosphorylated corresponding protein were also significantly increased in pSS. Th17 and NKp44(+) NK cells were the major cellular sources of IL-22 in patients with pSS. CONCLUSIONS: Our results suggest that, together with IL-17 and IL-23, IL-22 may play a pro-inflammatory role in the pathogenesis of pSS.

Successful intravenous immunoglobulin treatment for steroid-resistant eosinophilic enteritis in a patient with systemic lupus erythematosus.

Eosinophilic gastroenteritis is a rare condition of unknown etiology characterized by eosinophilic infiltration of the bowel. Corticosteroids are the mainstay of EG therapy. Although rare, steroid-resistant EG could be a life-threatening condition with tissue destructive evolution. Associations of eosinophilic gastroenteritis with systemic lupus erythematosus have rarely been reported. In this report we describe a case of successful IVIG treatment in a patient with systemic lupus erythematosus and steroid-refractory eosinophilic gastroenteritis.