María Pilar Cruz-Domínguez

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.

Antioxidants decrease reperfusion induced arrhythmias in myocardial infarction with ST-elevation.

In myocardial infarctions with ST-segment elevation, ischemia followed by reperfusion (IR) leads to arrhythmia, myocardial stunning and endothelial dysfunction injury by reactive oxygen species (ROS). To determine the impact of ROS, we examined the effect of antioxidant vitamins on biochemical changes and arrhythmias induced by reperfusion before and after therapeutic thrombolysis (Actilyse). As compared with those receiving placebo, in individuals who received antioxidants, there was a significant decrease in premature ventricular beats (100% vs 38%), atrial fibrillation (44% vs 6%), ventricular tachycardia (31% vs 0%), first-degree atrial-ventricular block (44% vs 6%), plasma malondialdehyde at the first hour after initiation of thrombolysis (1.07 +/- 0.10 vs 0.53 +/- 0.10 nmols plasma malondialdehyde/mg protein) and circulating neutrophils after 24 hr after reperfusion. The antioxidant capacity of plasma was increased from 1.89 +/- 0.15 to 3.00 +/- 0.31 units/mg protein and paraoxonase-1 rose from 0.77 +/- 0.08 to 1.27 +/- 0.11 nmol/min/mg protein. These findings suggest that antioxidants might be useful as adjuvants in controlling reperfusion induced arrhythmias following therapeutic alteplase thrombolysis.

Antiphospholipid antibodies disappearance in primary antiphospholipid syndrome: Thrombosis recurrence

OBJECTIVE To evaluate the clinical outcome after aPL (antiphospholipid antibodies) disappearance in primary APS patients. METHODS From a cohort of 70 patients with primary APS, we selected patients with positive aPL determinations at onset and ≥2 subsequent negative aPL determinations during the last 5years. To corroborate the immunologic profile, we determined IgG/IgM aCL antibodies, IgG/IgM antiβ2GPl, anti-annexin A5 antibodies and lupus anticoagulant (LA). All patients continued treatment with oral anticoagulants. Clinical data and aPL determinations at onset/after disappearance were obtained. STATISTICAL ANALYSIS descriptive statistics and Kaplan-Meier analysis. RESULTS We found 24 patients with persistently negative aPL, including the last immunologic profile, 17 females, 7 males, mean age 51.7, disease evolution 16.3years, mean of 4 aPL previous positive determinations. aCL was positive at onset in 87.5%, 29% had double aPL positivity at onset (aCL/LA). Deep venous thrombosis (DVT) and ischemic stroke in 33% and pulmonary embolism in 12.5% were the most frequent manifestations at onset. INR range: 2-3. Time with aPL positive 109.4±80.7months. After 60months of follow-up since aPL disappearance, 45.8% of patients presented thrombosis recurrence, DVT in 9 patients, ischemic stroke in 1, pulmonary artery hypertension in 1. Other non-thrombotic APS manifestations were chronic ulcers in lower extremities and severe thrombocytopenia. CONCLUSIONS This study suggest, that in primary APS, persistent negative aPL profile is not an indication to interrupt oral anticoagulant therapy. However, there is a subset of patients that remained asymptomatic. Other studies are necessary in order to elucidate this controversy.

Metabolic syndrome, autoimmunity and rheumatic diseases

Graphical abstract Figure. No Caption available. &NA; Metabolic syndrome (MetS) is a cluster of metabolic and cardiovascular (CV) risk factors including obesity and visceral adiposity, insulin resistance, dyslipidemia and hypertension contributing to CV mortality. The interface between the metabolic and immune systems has been of great interest recently. These interactions are regulated through genetics, nutritional status, and the intestinal microbiome. Alterations in the immune‐metabolic cross‐talk contribute to the development of autoimmune diseases. Adipokines exert a variety of metabolic activities contributing to the ethiopathogenesis of MetS and are involved in the regulation of both inflammatory processes and autoimmunity occurring in rheumatic diseases. Patients with autoinflammatory disease such as gout and those with autoimmune rheumatic diseases (ARD), such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, ankylosing spondylitis and vasculitis among others, have increased prevalence of MetS. Despite recent advances in treatment of ARD, incidence of CVD remains high. MetS and altered secretion patterns of proinflammatory adipokines could be the link between CVDs and ARD. In addition, in ARD the activation of proinflammatory signalling pathways results in the induction of several biological markers of chronic inflammation contributing to CVD. In the present paper, we review recent evidences of the interactions between MetS and ARD, as well as novel therapeutic targets.

Effect of ezetimibe plus pravastatin on endothelial dysfunction in patients with systemic lupus erythematosus

Background Patients with systemic lupus erythematosus (SLE) have a higher risk for cardiovascular disease (CVD), not fully explained by the conventional risk factors. These patients have endothelial dysfunction (ED) as an early process of atherosclerosis, which can be reversed with therapy. Objective To determine the effect of ezetimibe plus pravastatin on endothelial function in patients with SLE after 12 months of treatment. Patients and methods An open study, before and after, which assessed the effect of ezetimibe plus pravastatin treatment, was performed. Twenty two patients (21 women and one man) with diagnosis of SLE were studied, with a mean age 40 ± 5 years. Endothelial dysfunction was evaluated using vascular ultrasound of the brachial artery in order to measure the flow-mediated vasodilation (FMV) basal and after 12 months of treatment with pravastatin 40 mg/day plus ezetimibe 10 mg/day. In addition, a lipid profile: total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and serum C-reactive protein (CRP), was done. Results We found a basal FMV of 7.58% and 18.22% after 12 months of treatment, with an improvement of 10.64 points 95% CI (7.58–13.58), p < 0.001. TC decreased from 201.3 ± 58.9 mg/dL to 158.06 ± 50.13 mg/dL (p < 0.01); LDL-C from 125.78 ± 44.4 mg/dL to 78.8 ± 32.9 mg/dL (p < 0.001); HDL-C increased from 49.0 ± 16.8 mg/dL to 52.2 ± 13.8 mg/dL (p = 0.077). The basal and final concentrations of CRP were 4.49 and 2.8, respectively, with a mean decrease of 2.11 mg/dL, 95% CI (0.908–3.32), p < 0.002. Both drugs were well tolerated. Conclusion Ezetimibe plus pravastatin significantly improved FMV in patients with SLE, decreasing ED and the lipid profile. This treatment ameliorated an early process of atherosclerosis and a risk factor for CVD.

Autoimmune/inflammatory syndrome induced by mineral oil: a health problem

Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) includes the following conditions: siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, and post-vaccination phenomena. Afterward, other syndromes have been recognized, such as in ASIA by mineral oil (ASIA-MO). These conditions are triggered by adjuvants and they are the result of the interplay of genetic and environmental factors. ASIA-MO is defined as the infiltration of oily type modeling substances for cosmetic purposes. It has been reported in many countries and used surreptitiously. Pathogenesis of ASIA-MO is not clear, but is characterized by chronic granulomatous inflammation, like the pristane model in mice, with increase of proinflammatory cytokines: type I interferons (IFNα and IFNß), systemic lupus erythematosus (SLE), and erosive arthritis. In humans, an increase of interleukin 1 (IL-1) has been found. Clinical spectrum of ASIA-MO is heterogeneous, varying from mild to severe and being local and systemic. The systemic manifestations can be non-specific and specific, meeting criteria for any autoimmune disease (AID), i.e., SLE, rheumatoid arthritis, and systemic sclerosis, among others. The areas of the body where the mineral oil is mostly applied include the following: buttocks (38–72%), breasts (12–16%), lower extremities (18–22%), and face (6–10%). The penis augmentation is also common. Treatment is focused on local and systemic manifestations and requires medical and surgical management representing a challenge for the physician.

Impact of intestinal mannitol on hyperammonemia, oxidative stress and severity of hepatic encephalopathy in the ED

ABSTRACT Hyperammonemia results from hepatic inability to remove nitrogenous products generated by protein metabolism of intestinal microbiota, which leads to hepatic encephalopathy (HE) in chronic liver disease (CLD). In ammonium neurotoxicity, oxidative stress (OxS) plays a pathogenic role. Our objective was to evaluate if intestinal mannitol is as effective and safe as conventional treatment for diminishing hyperammonemia, OxS, and HE in patients with CLD. Material and methods We included 30 patients with HE classified by “Haven Criteria for Hepatic Encephalopathy”. They were randomized into two groups: 1) Mannitol Group (MG) with mannitol 20% administered into the intestine by an enema, 2) conventional group (CG) with lactulose 40 g enema both substances were diluted in 800 mL of double distilled solution every 6 h; all patients received neomycin. We evaluated ammonia concentration, plasma oxidative stress, HE severity, intestinal discomfort and adverse effects. Results Hyperammonemia (171 ± 104 vs 79 ± 49 &mgr;mol ammonia/L, p < 0.01), and oxidative stress (MDA 29 vs 27%, formazan 15 vs 11%, carbonyls 16 vs 9% and dityrosines 10 vs 5%) were reduced in MG and CG respectively. The HE severity decreased by two degrees compared to baseline values in both groups. Intestinal discomfort and electrolyte plasma alterations were less frequent (p < 0.05) in MG than CG. Conclusions Intestinal mannitol is as effective and safe as conventional treatment for reducing hyperammonemia, oxidative stress, and hepatic encephalopathy of CLD patients in the emergency room. Likewise, mannitol is better tolerated than conventional treatment.

Cuestionario de funcionalidad para esclerosis sistémica (SySQ): validación en español del original en alemán y su relación con la enfermedad y la calidad de vida

OBJECTIVE Translation, transculturation and validity of the self-administered questionnaire for functionality (Systemic Sclerosis Questionnaires [SySQ]) for use in Spanish patients with systemic sclerosis and its relationship to the severity of the disease and to quality of life. PATIENTS AND METHODS We conducted an observational analytical study to perform a cross-cultural validation of the self-administered questionnaire on functionality in scleroderma. The validity of the form and content was evaluated by an expert panel. The method included: a) adaptation into Spanish of the construct for translation and back translation, and transculturation; b) internal consistency with the SySQ (Cronbachs alpha), and c) reproducibility was assessed taking into account all occasions in which the test was performed with Cohens kappa. Additionally, we calculated the Spearman correlation coefficient with the Medsger severity scale, Health Assessment Questionnaire score and SF-36 score. RESULTS We included 70 patients with systemic sclerosis: age 17-78 (51±12) years, 65 (93%) were women, diffuse/limited subtype 64/36%, disease duration of 0.5-40 years. Optimal internal consistency for all categories of the final version of SySQ (Cronbachs α of 0.961) and intraobserver reliability in 2 tests over a 2-week interval (Cohens kappa coefficient 0.618) and optimal interobserver reliability in 2 tests on the same day (Cohens kappa coefficient 0.911). Moderate correlation between functionality by SySQ and by Health Assessment Questionnaire (r=0.573, P<.0001). Inverse correlation between SySQ and quality of life mental health domain SF-36 (r=-0.435, P<.001) and physical domain SF-36 (r=-0.638, P<.001). Medsger severity scale (tendon, heart, lung, vascular) also showed significant correlation with SySQ. CONCLUSIONS SySQ in this validated Spanish version is a suitable instrument to measure functional status in patients with systemic sclerosis. Reduced functionality is related to greater tendon and peripheral vascular involvement and to a poorer quality of life.