Luis J. Jara

Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases

Received October 16, 2004; revision received June 4, 2005; accepted June 7, 2005. Atherosclerosis is a multifactorial process that commences in childhood but manifests clinically later in life. Atherosclerosis is increasingly considered an immune system–mediated process of the vascular system. The presence of macrophages and activated lymphocytes within atherosclerotic plaques supports the concept of atherosclerosis as an immune system–mediated inflammatory disorder.1,2 Inflammation can aggravate atherosclerosis via different mechanisms secondary to autoimmunity, infectious diseases, and other proatherogenic changes that occur during the inflammatory state. Autoimmune rheumatic diseases (AIRDs) are associated with higher rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be attributed to traditional risk factors for atherosclerosis and use of specific drugs, such as corticosteroids, but also might be the result of other autoimmune and inflammatory mechanisms that are aggravated in AIRDs. Several AIRDs exhibit increased overt cardiovascular disease (CVD) prevalence as well as findings of advanced subclinical atherosclerosis, which may precede the appearance of a clinical disease and thus be a target of early identification and preventive therapy. Cells of the immune system can be found within atherosclerotic plaques, which suggests that they have a role in the atherogenic process. Their migration and activation within the plaques can be secondary to various stimuli, including infectious agents.3 These cells probably aggravate atherosclerosis, because CD4+ and CD8+ T-cell depletion reduced fatty streak formation in C57BL/6 mice. In addition, after crossing of apolipoprotein E (ApoE)-knockout mice with immunodeficient scid/scid mice, the offspring had a 73% reduction in aortic fatty streak lesions compared with the immunocompetent apoE mice. Moreover, when CD4+ T cells were transferred from the immunocompetent to the immunodeficient mice, they increased lesion area in the latter by 164%.4 It is therefore not surprising that as in autoimmune diseases, the cellular components …

Acute Abdomen in Systemic Lupus Erythematosus: The Importance of Early Laparotomy

BACKGROUND Acute abdomen (AA) in systemic lupus erythematosus (SLE) is a challenging diagnostic and therapeutic problem. Most patients are on steroid and/or immunosuppressive treatment and mortality is high. METHODS We assessed the relationship between the causes of AA in SLE and the SLE disease activity index (SLEDAI). RESULTS Of 51 patients with SLE and AA, 36 had active disease (Group 1) and 15 inactive disease (Group 2). Group 1 included 19 patients with vasculitis (mean SLEDAI 15.4, range 13 to 24). Three patients with intraabdominal thrombosis and high titers of anticardiolipin antibodies (mean SLEDAI 18.3) and 14 patients with non-SLE-related AA (SLEDAI 8.2, range 5 to 11). Group 2 consisted of 15 inactive SLE patients (mean SLEDAI 1.7, range 0 to 4). Mortality was high in the active group (14 patients) compared with inactive SLE (2 cases). A delay in surgical exploration (39.3 vs 178.6 hours) had a negative influence on the prognosis. CONCLUSIONS In SLE patients with AA, a SLEDAI score below 5 is indicative of non-SLE-related AA. Elevated aCL were found in patients with intraabdominal thrombosis. AA in inactive SLE is non-SLE-related and has low mortality, provided an appropriate surgical treatment is given. Early laparotomy influences positively the prognosis of SLE patients with AA.

Increased carotid artery intima-media thickness may be associated with stroke in primary antiphospholipid syndrome

Objective: To investigate the prevalence and clinical significance of carotid artery intima-media thickness (IMT) in patients with primary antiphospholipid syndrome (APS). Methods: 28 patients with primary APS with at least a five year follow up, and 28 healthy subjects, matched by age and sex, were included in the study. Colour Doppler with high resolution B mode carotid ultrasonography and spectral analysis were performed in patients and controls. Information on cardiovascular risk factors and the clinical course were collected. Results: The mean (SD) age of patients and controls (12 male, 16 female in each group) was 40 (8.5) years; the mean (SD) disease duration 7.7 (3) years. Carotid artery IMT was found in 23/28 patients (2.6 (1.14) mm) and 7/28 controls (1.2 (0.44)) (p=0.0001). A decrease in the lumen diameter was also found in 11/28 patients with primary APS without carotid atherosclerotic plaque, and 2/28 controls (p=0.004). Hyperlipidaemia, diabetes, smoking, obesity, and hypertension were not associated with carotid artery IMT. Patients with carotid artery IMT had arterial vascular disease more often than patients without: 9/23 v 0/5 (p<0.009). These patients had stroke (seven patients), myocardial infarction (one), and mesenteric thrombosis (one). Subjects with IMT had a threefold higher risk for stroke than those without IMT (95% CI 0.78 to 14.3). Conclusions: Patients with primary APS have a high prevalence of carotid artery IMT and a decreased lumen diameter. IMT in primary APS may be associated with stroke. Patients with primary APS with IMT must be considered as carriers of atherosclerosis.

Prolactin and autoimmunity.

Prolactin (PRL) is a versatile hormone that is produced by the anterior pituitary gland and various extrapituitary sites including immune cells. Furthermore, PRL has widespread influences on proliferation and differentiation of a variety of cells in the immune system and is, in effect, a cytokine. PRL-receptors (PRL-R) are distributed throughout the immune system and are included as members of the cytokine receptor superfamily. PRL-R signal transduction is mediated by a complex array of signaling molecules of which JAK2, Stat1 and Stat5 pathway have been well studied. In PRL-stimulated T cells, the transcription factor gene, interferon regulatory factor-1 provides a mechanism whereby PRL can regulate the immune response. The human PRL gene is situated on the short arm of chromosome 6 close to the major histocompatibility complex. Polymorphisms of the human PRL gene have implications for production of lymphocyte PRL in SLE. Mild and moderate hyperprolactinemia (HPRL) has been demonstrated in 20-30% of SLE patients and is associated with active disease. HPRL may have a role in lupus nephritis and central nervous system involvement of SLE patients. HPRL stimulated the production of autoantibodies. These evidences support the important role of PRL in autoimmunity and autoimmune diseases, mainly SLE.

Prolactin in human systemic lupus erythematosus.

In the last decade, evidence has accumulated to support the hypothesis that both mild and moderate elevations of serum prolactin (PRL) participate in the clinical expression and pathogenesis of systemic lupus erythematosus (SLE). Hyperprolactinemia (HPRL) has been found in 20–30% of patients with SLE. HPRL seems to be associated with clinical activity of SLE during pregnancy. Although the relationship between HPRL and active SLE in non-pregnant patients is controversial, recent clinical and experimental studies support the potential role of prolactin (PRL) as a promoter of clinical activity and severity of SLE. Mild elevations of serum PRL secondary to microadenoma could trigger the onset of SLE in a subset of patients. Elevated PRL and interleukin (IL)-6 have been found in the urine of patients with active lupus nephritis and in cerebrospinal fluid (CSF) of patients with active central nervous system (CNS) SLE. PRL may therefore participate in the pathogenesis of lupus nephritis and cerebritis, and the presence of PRL may reflect an abnormal communication between the immune system and the neuroendocrine system in active SLE. Lymphocytes from patients with active SLE produce increased amounts of PRL, and this extrapituitary PRL may participate in aberrant immune processes in SLE. There is exciting new evidence that HPRL in SLE may be explained by stimulation of pituitary PRL secretion by cytokines. In addition, defects in peptidergic modulators and dopamine metabolism have been described in patients with SLE. The interactions between PRL, cytoquines, autoantibodies and organ involvement suggest that PRL participates in local and generalized immune and inflammatory processes and acts as a bridge between the neuroendocrine and immune systems in SLE. Understanding the interactions between these systems in SLE will help us to understand and treat this important autoimmune disease.

Tolerogenic dendritic cells in autoimmune diseases: crucial players in induction and prevention of autoimmunity.

The immune system has evolved to coordinate responses against numerous invading pathogens and simultaneously remain silent facing self-antigens and those derived from commensal organisms. But, if both processes are not maintained in strict balance, a potential threat can emerge due to the risk of chronic inflammation and/or autoimmunity development. Therefore, there is a negative immune regulation where tolerogenic dendritic cells (tDCs) participate actively. Under steady-state conditions, tDC are notably involved in the elimination of autoreactive T cells at the thymus, and in the control of T cells specific to self and harmless antigens in the periphery. But in the presence of foreign antigens in an inflammatory milieu, dendritic cells (DCs) mature and induce T cells activation and their migration to B cell areas to assist in antibody production. Additionally, there are other factors such as infections, anti tumoral immune responses, trauma-mediated disruption, etc. that may induce alterations in the balance between tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases (ADs). Therefore, in recent years, DCs have emerged as therapeutic targets to control of ADs. Diverse strategies in vitro and/or in animal models of ADs have explored the tolerogenic functions of DCs and demonstrated their feasibility to prevent or control an autoimmune process, but still leaving a void in their application in clinical assays. The purpose of this paper is to give a general overview of the current literature on the significance of tDCs in tolerance maintenance to self and innocuous antigens, the most relevant alterations involved in the pathophysiology of ADs, the cellular and molecular mechanisms involved in their tolerogenic function and the current strategies used to exploit their tolerogenic potential.

Pulmonary hemorrhage in systemic lupus erythematosus

In order to assess the clinical characteristics and survival rate of pulmonary hemorrhage (PH) in systemic lupus erythematosus (SLE), we studied SLE patients who developed this complication. We found 34 patients within a total lupus cohort of 630 patients. A11 the patients had severe respiratory failure. We identified three different treatment regimens: (a) oral prednisone (1 mg/kg); (b) conventional methylprednisolone (3 g total dose) and (c) massive methylprednisolone ( > 4 g). The overall survival rate was 38.2% and it was correlated with the massive regimen and early treatment (within the first 48 h after the onset of the acute event).

Prolactin and Autoimmunity

The relationship between prolactin and the immune system has been demonstrated in the last two decades, opening new windows in the field of the immunoendocrinology. Prolactin has an important role in the innate and adaptive immune response. Increased prolactin levels have been described in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and systemic sclerosis among others. Hyperprolactinemia is associated with active disease and organ involvement in systemic lupus erythematosus. Therefore, prolactin is an integral member of the immunoneuroendocrinology network and seems to have a role in pathogenesis of autoimmune diseases. Few controlled studies of dopamine agonist treatment in humans with autoimmune disease have been conducted only in systemic lupus erythematosus patients, which support the potential efficacy of such agents even during pregnancy and postpartum. Further studies are necessary to elucidate the mechanisms by which prolactin affects autoimmune disease activity, increase the inflammatory mechanism, and determine the role of anti-prolactinemic drugs to regulate the immune/inflammatory process.

Systemic autoimmune diseases co‐existing with chronic hepatitis C virus infection (the HISPAMEC Registry): patterns of clinical and immunological expression in 180 cases

Objectives.  To describe the clinical and immunologic characteristics of a large series of patients with systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus (HCV) infection.

Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome): clinical and immunological spectrum.

An adjuvant is a substance that enhances the antigen-specific immune response, induces the release of inflammatory cytokines, and interacts with Toll-like receptors and the NALP3 inflammasome. The immunological consequence of these actions is to stimulate the innate and adaptive immune response. The activation of the immune system by adjuvants, a desirable effect, could trigger manifestations of autoimmunity or autoimmune disease. Recently, a new syndrome was introduced, autoimmune/inflammatory syndrome induced by adjuvants (ASIA), that includes postvaccination phenomena, macrophagic myofasciitis, Gulf War syndrome and siliconosis. This syndrome is characterized by nonspecific and specific manifestations of autoimmune disease. The main substances associated with ASIA are squalene (Gulf War syndrome), aluminum hydroxide (postvaccination phenomena, macrophagic myofasciitis) and silicone with siliconosis. Mineral oil, guaiacol and iodine gadital are also associated with ASIA. The following review describes the wide clinical spectrum and pathogenesis of ASIA including defined autoimmune diseases and nonspecific autoimmune manifestations, as well as the outlook of future research in this field.