Olga Vera-Lastra

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.

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.

Atherosclerosis and antiphospholipid syndrome.

Atherosclerosis is an autoimmune/inflammatory disease associated with infectious, inflammatory, and autoimmune factors. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions. Heat-shock protein (hsp), oxidized low-density lipoprotein (LDL), and β2-GPI have been reported to elicit humoral and cellular immune response in both experimental animals and humans. These autoantigens are expressed within atherosclerotic lesions. Immunization with the given autoantigens elicits an immune response that influences lesion progression. Atherosclerosis susceptibility can be transferred by autoantigen-sensitized lymphocytes from immunized animals. Patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have a high risk for atherosclerotic cardiovascular events. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS. Immunological alterations, such as antibodies to oxidized LDL, antiphospholipid antibodies (aPL), antibodies to β-2 Glycoprotein (anti-β2-GPL), anti-prothrombin antibodies, may play a role in premature atherosclerosis in SLE and APS. Paraoxonase (PON1) is an enzyme with antioxidant activity attached to the circulating high-density lipoprotein (HDL) in plasma. Its function is to prevent oxidation of LDL, thereby accounting for the antioxidant properties and the atherosclerotic protective effects of HDL. The relationship between PON1 and aPL has been recently suggested. IgG anti-HDL and IgG anti-β2-GPI antibodies were associated with reduced PON1 activity in patients with SLE and primary APS. The determination of classic and new factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis in SLE and PAPS. Therapeutic strategies, including early control of disease and other risk factors, are essential to reduce morbidity and mortality.

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.

Immune-Neuroendocrine Interactions and Autoimmune Diseases

The relationship between immune-neuroendocrine system is firmly established. The messengers of this connection are hormones, neuropeptides, neurotransmitters and cytokines. The immune-neuroendocrine system have the capacity to synthesize and release these molecules, which, in turn, can stimulate or suppress the activity of immune or neuroendocrine cells by binding to receptors. In fact, hormones, neuropeptides and neurotransmitters participate in innate and adaptive immune response. Autoimmune rheumatic diseases (ARD) are characterized by aberrant production of pro-inflammatory cytokines, which are a potent activator of the HPA axis. In consequence, high levels of pro-inflammatory hormones such as estrogens and prolactin, and low levels of glucocorticoids, an anti-inflammatory hormone, have been described in the active phase of ARD. In addition, high levels of pro-inflammatory hormones and cytokines have also been frequently detected in organ involvement of patients with ARD, suggesting an abnormal local neuroendocrine immune interaction. There is evidence that hormonal changes may appear before the symptomatic phase of the disease. Therefore, it is possible that a pro-inflammatory hormone favors the rupture of tolerance, which is a key feature of autoimmune diseases. The interactions between the immune-neuroendocrine system have a major impact on our understanding of the pathogenic mechanisms, diagnosis and therapy of ARD.

Human adjuvant disease induced by foreign substances: a new model of ASIA (Shoenfeld's syndrome)

Objective: To investigate the clinical, laboratory and histological manifestations of patients who received illegal injections of foreign substances for cosmetic purposes. Patients and methods: We studied patients who met the following inclusion criteria: 1) history of application of foreign substances for cosmetic purposes, 2) clinical data of autoimmune disease or non-specific autoimmune manifestation (i.e. arthralgias, myalgia, malaise, fever, and weight loss), 3) detection of autoantibodies in patients’ sera, 4) histological evidence of chronic inflammation and/or granulomatous reaction to foreign body. Results: Fifty female patients aged 44.4 ± 10 years were studied. The mean time between application of foreign substances and onset of symptoms was 4.5 ± 4.3 years. Patients were followed for 12 ± 7.5 years. Forty-one patients were injected with mineral oil, nine patients received other substances: three iodine gadital, one guayacol, one guayacol plus silicone fluid, two collagen, two silicone fluid. The sites of application were: buttocks (36), legs and/or thighs (11), breasts (eight) hands and face (one), face (two) (seven patients received an injection to more than one site). Thirty patients presented with non-specific autoimmune manifestations, whereas 20 patients fulfilled the criteria for a defined autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, overlap syndrome, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune hepatitis, and ulcerative colitis. Conclusions: Cases of human adjuvant disease following illegal injections of oil substances for cosmetic purposes are reported. Patients presented with defined autoimmune diseases as well as with non-specific autoimmune manifestations. Illegal injection of these substances could lead to serious local and systemic complications, even to death. These cases represent another model of Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA). The use of these substances should be prohibited.

Still’s disease, lupus-like syndrome, and silicone breast implants. A case of ‘ASIA’ (Shoenfeld’s syndrome)

In recent years, four conditions, siliconosis, Gulf War syndrome (GWS), macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena, were linked to a previous exposure to an adjuvant, suggesting a common denominator, and it has been proposed to incorporate comparable conditions under a common syndrome entitled Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA). We report a case of a female who at the age of 11 years was diagnosed with Still’s disease. At the age of 22 she underwent silicone breast implants and presented with a transient lupus-like syndrome. Then, at 25 years old she had a severe activation of Still’s disease in association with rupture of silicone breast implants. When the prostheses were removed, the clinical picture improved. This case fulfills the criteria for ASIA and complements seven previous reports of Still’s disease in association with silicone breast implants.

Implications in the difference of anti-Mi-2 and -p155/140 autoantibody prevalence in two dermatomyositis cohorts from Mexico City and Guadalajara

IntroductionAutoantibodies and clinical manifestations in polymyositis/dermatomyositis (PM/DM) are affected by both genetic and environmental factors. The high prevalence of DM and anti-Mi-2 in Central America is thought to be associated with the high UV index of the area. The prevalences of autoantibodies and the clinical manifestations of PM/DM were evaluated comparing two cohorts in Mexico.MethodsNinety-five Mexican patients with PM/DM (66 DM, 29 PM; 67 Mexico City, 28 Guadalajara) were studied. Autoantibodies were characterized by immunoprecipitation using 35S-methionine labeled K562 cell extract. Clinical information was obtained from medical records.ResultsDM represented 69% of PM/DM and anti-Mi-2 was the most common autoantibody (35%), followed by anti-p155/140 (11%); however, anti-Jo-1 was only 4%. The autoantibody profile in adult-onset DM in Mexico City versus Guadalajara showed striking differences: anti-Mi-2 was 59% versus 12% (P = 0.0012) whereas anti-p155/140 was 9% versus 35% (P = 0.02), respectively. A strong association of anti-Mi-2 with DM was confirmed and when clinical features of anti-Mi-2 (+) DM (n = 30) versus anti-Mi-2 (-) DM (n = 36) were compared, the shawl sign (86% versus 64%, P < 0.05) was more common in the anti-Mi-2 (+) group (P = 0.0001). Levels of creatine phosphokinase (CPK) were higher in those who were anti-Mi-2 (+) but they responded well to therapy.ConclusionsAnti-Mi-2 has a high prevalence in Mexican DM and is associated with the shawl sign and high CPK. The prevalence of anti-Mi-2 and anti-p155/140 was significantly different in Mexico City versus Guadalajara, which have a similar UV index. This suggests roles of factors other than UV in anti-Mi-2 antibody production.