Cardiac involvement in systemic autoimmune diseases

The heart and the vascular system are frequent and characteristic targets of several systemic autoimmune diseases, in particular Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). In this chapter we review the classic cardiac abnormalities and the more recent data about cardiovascular involvement as part of a major disease complication determining a substantial morbidity and mortality. In addition to the classic cardiac abnormalities involving the heart structures, acute and chronic ischemic heart disease and cerebrovascular accidents are threatening clinical manifestations of SLE and RA associated to an early accelerated atherosclerosis. Immune-mediated inflammation is now recognized as an important factor involved in the pathogenesis of atherosclerosis. Ongoing clinical studies are being devised to find specific risk factors associated with systemic autoimmune diseases and/or treatment regimens. Hopefully, prophylactic measures should be available within the next few years.     

Cardiovascular disease in autoimmune rheumatic diseases

Various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis, spondyloarthritis, vasculitis and systemic lupus erythematosus, are associated with premature atherosclerosis. However, premature atherosclerosis has not been uniformly observed in systemic sclerosis. Furthermore, although experimental models of atherosclerosis support the role of antiphospholipid antibodies in atherosclerosis, there is no clear evidence of premature atherosclerosis in antiphospholipid syndrome (APA). Ischemic events in APA are more likely to be caused by pro-thrombotic state than by enhanced atherosclerosis.     

Cardiovascular involvement in systemic rheumatic diseases: An integrated view for the treating physicians

Systemic autoimmune diseases can affect various kinds of organs including the kidney, the skin, soft tissue and the bone. Among others, cardiovascular involvement in rheumatic diseases has been shown to affect myocardium, pericardium, cardiac vessels, conduction system and valves, eventually leading to increased mortality. In general, underlying chronic inflammation leads to premature atherosclerosis, but also other manifestations such as arrhythmia and heart failure may have a ‘silent’ progress. Traditional cardiovascular risk factors play a secondary role, while disease-specific factors (i.e. disease duration, severity, antibody positivity, persistent disease activity) can directly influence the cardiovascular system. Therefore, early diagnosis is critical to optimize management and to control inflammatory activity and recent data suggest that risk factors (i.e. hypercholesterolemia and hypertension) need intensive treatment as well. With the advent of immunosuppressive agents, most rheumatic diseases are well controlled on treatment, but information related to their cardioprotective efficacy is not well-defined. In this review, we focus on cardiovascular involvement in rheumatic diseases and highlight current evidence which should be of help for the treating physicians. Moreover, cardiotoxicity of immunosuppressive drugs is a rare issue and such potential adverse events will be briefly discussed.     

Intestinal fungi and systemic autoimmune diseases

Nearly 20 years of studies have shown that fungi and the human immune system (non-specific immunity and specific immunity) and bacterial––fungal interactions maintain a balance that can't lead to diseases. Fungi––microorganism that lives in human intestine––may play an important role in human health and disease. Population studies and animal models in some diseases have found the changes in the diversity and composition of fungi. The dysregulation of the fungi can disrupt the normal “running” of the immune system and bacteria, which triggers the development of inflammatory diseases. The latest studies of fungi in inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and type 1 diabetes mellitus were summarized. This review considers how the healthy host protect against the potential harm of intestinal fungi through the immune system and how fungal dysregulation alters host immunity.     

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

Heart involvement – often asymptomatic – 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.     

Prevalence of HHV-8 in systemic autoimmune diseases

BackgroundEpidemiological data suggest that some viruses may be linked to the development of autoimmunity.ObjectivesThe objective of this work was to determine the presence of HHV-8 viral DNA in whole blood from patients suffering from different systemic autoimmune diseases (SAD). We also aimed at testing the prevalence of patients showing antibodies against an HHV-8 orfK8.1 peptide.Study designTwo hundred and eighty SAD patients and 50 healthy blood donor controls were included. Molecular analyses were performed by nested PCR from DNA obtained from whole blood and an enzyme immunoassay was developed in order to test for the presence of antibodies directed against a synthetic peptide derived from the HHV-8 orfK8.1 protein.ResultsOnly 2 out of the 280 samples analyzed yielded the specific HHV-8 PCR product. Antibodies against orfK8.1 were detected in 2 SLE patients, 1 patient suffering from Sjögren's syndrome and 2 patients with vasculitis.ConclusionsWe conclude that HHV-8 is usually not present in blood neither from autoimmune patients nor from healthy controls. Furthermore, HHV-8 antibodies against the HHV-8 orfK8.1 peptide were rarely detected. It leads us to infer that HHV-8 is not involved on the development of these disorders. It does not rule out the possibility that other environmental and microbiological triggers may account for their etiopathogenesis.     

Vitamin D endocrine system involvement in autoimmune rheumatic diseases

Vitamin D is synthesized from cholesterol in the skin (80-90%) under the sunlight and then metabolized into an active D hormone in liver, kidney and peripheral immune/inflammatory cells. These endocrine-immune effects include also the coordinated activities of the vitamin D-activating enzyme, 1alpha-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) on cells of the immune system in mediating intracrine and paracrine actions. Vitamin D is implicated in prevention and protection from chronic infections (i.e. tubercolosis), cancer (i.e. breast cancer) and autoimmune rheumatic diseases since regulates both innate and adaptive immunity potentiating the innate response (monocytes/macrophages with antimicrobial activity and antigen presentation), but suppressing the adaptive immunity (T and B lymphocyte functions). Vitamin D has modulatory effects on B lymphocytes and Ig production and recent reports have demonstrated that 1,25(OH)2D3 does indeed exert direct effects on B cell homeostasis. A circannual rhythm of trough vitamin D levels in winter and peaks in summer time showed negative correlation with clinical status at least in rheumatoid arthritis and systemic lupus erythematosus. Recently, the onset of symptoms of early arthritis during winter or spring have been associated with greater radiographic evidence of disease progression at 12 months possibly are also related to seasonal lower vitamin D serum levels.     

Recent findings on genetics of systemic autoimmune diseases

Association studies of over 1 million SNPs capturing most of the human genome common variation became possible thanks to the information provided by the HapMap International project and the development of high-throughput genotyping technologies at accessible prices. Genome-wide scans analyzing thousands of individuals have now identified most if not all of the major genes involved in susceptibility for several systemic autoimmune diseases. In particular, results for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) are reviewed here. While most genes are shared between diseases, few seem to be unique reflecting that we still are long before knowing all genes, their interactions with other genes and the environment and their impact on biological functions.     

BAFF: a local and systemic target in autoimmune diseases

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF‐R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation‐inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)‐6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.     

Inflammation and atherosclerosis: Cardiovascular evaluation in patients with autoimmune diseases

Evidence now indicates that inflammation contributes considerably to the initiation and progression of atherosclerosis and active inflammatory processes may trigger plaque rupture and enhance the risk of coronary thrombosis leading to a clinical ischemic event. Interest in characterizing inflammatory markers that predict clinical events have dominated clinical investigation. Such markers include C-reactive protein, Fibrinogen and a number of interleukins.Human macrophages avidly phagocytize cholesterol crystals. These cholesterol crystals induce a dose-dependent secretion of mature Interleukin 1-beta (IL-1β) from human monocytes and macrophages (an NLRP3 inflammasome-mediated pathway). Since IL-1β production leads to increased levels of IL-6 and C-reactive protein, this could be a mechanistic link between early deposition of cholesterol crystals within the vessel wall to the macrophage–monocyte interactions that initiate fatty streaks and promote local atherosclerotic progression. We have entered a time where a pure anti-inflammatory drug without significant effects on lipids or any other traditional cardiovascular risk factor decreased cardiovascular events. Patients with autoimmune diseases are at increase cardiovascular risk. In this review we describe the link between inflammation and atherosclerosis. Furthermore we explore the data regarding primary prevention, cardiac imaging for risk stratification and the implications of targeting inflammation in patients with autoimmune disease.     

SARS-CoV-2 infection among patients with systemic autoimmune diseases

ObjectivesThis study aimed to evaluate the prevalence of clinically overt SARS-CoV-2 infection (COVID-19) among patients with systemic autoimmune diseases residing in Tuscany, and to compare it with that observed in the general Tuscan population.MethodsIn this cross-sectional study, Tuscan outpatients with systemic autoimmune diseases followed at a tertiary referral centre were telephonically interviewed between April 1st-14th 2020 to collect demographic and clinical data, information on ongoing immunomodulating/immunosuppressive treatments, and on the presence of symptoms suspected of SARS-CoV-2 or of a confirmed infection.Results458 patients were interviewed [74% female, median age 56 years (IQR 43–68)]; 56% of them were receiving corticosteroids, 44% traditional disease-modifying anti-rheumatic drugs (DMARDs), of whom 23% hydroxychloroquine, 5% colchicine, while 41% were on biologic DMARDs (of whom 9% on tocilizumab). Thirteen patients reported symptoms suggesting SARS-CoV-2 infection. Of them, 7 had undergone nasopharyngeal swab and only one was positive and developed severe SARS-CoV-2 complications. Within our cohort, the prevalence of SARS-CoV-2 infection was therefore 0.22% (0.01–1.21%), comparable to that observed in the general population of Tuscany [0.20% (0.20–0.21%), p = .597].ConclusionsPatients with systemic autoimmune diseases do not seem to carry an increased risk of SARS- CoV-2 infection as compared to the general population.     

Serum immunoglobulin free light chain levels in systemic autoimmune rheumatic diseases

Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)-related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti-phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still-unknown pathways.     

IL-17: A new actor in IFN-driven systemic autoimmune diseases

Systemic autoimmune diseases such as systemic lupus erythematosus are type I IFN-driven diseases with exaggerated B-cell responses and autoantibody production. Th17 cells, a T-helper-cell subset with high inflammatory capacity, was initially discovered and characterized in the context of experimental autoimmune encephalomyelitis - an animal model of multiple sclerosis. There is now emerging evidence that Th17 cells, and more generally IL-17 and IL-17-producing cells, may play a role in the pathogenesis of type I IFN-driven systemic autoimmune diseases such as lupus. Here, we review the different studies suggesting a role for IL-17 and IL-17-producing cells in systemic autoimmune diseases, both in humans and in animal models, and we consider the possible mechanisms by which these cells may contribute to disease. We also discuss the hypothesis that type I IFN and IL-17 act in concert to sustain and amplify autoimmune and inflammatory responses, making them a dangerous combination involved in the pathogenesis of systemic autoimmune diseases.     

Type I interferon in systemic lupus erythematosus and other autoimmune diseases

Different genetic alterations may lead to type I interferon (IFN) overproduction in human systemic lupus erythematosus (SLE). The increased bioavailability of type I IFN contributes to peripheral tolerance breakdown through the activation of immature myeloid dendritic cells (mDCs). IFN-matured mDCs activate autoreactive T cells. These cells, together with plasmacytoid DCs, help expand autoreactive B cells. IFN-matured DCs also activate cytotoxic CD8+ T cells, possibly increasing apoptotic cell availability. The capture of apoptotic cells by mDCs and of nucleic acid-containing immune complexes by plasmacytoid DCs and B cells amplifies the autoimmune reaction leading to disease manifestations. Genetic alterations in lineages other than B cells might explain other autoimmune syndromes where type I IFNs appear to be involved.