Gabriela Medina

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.

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.

Bromocriptine during pregnancy in systemic lupus erythematosus: a pilot clinical trial.

Abstract:  Bromocriptine (BRC) prevents postpartum flare in lupus patients. However, its potential role in protecting lupus pregnancy from maternal–fetal complications has not been studied. The objective of the study was to explore the role of oral BRC during pregnancy in patients with systemic lupus erythematosus (SLE). Pregnant SLE patients were randomized into two groups: group 1 received BRC 2.5 mg/day and prednisone 10 mg/day; group 2 received prednisone 10 mg/day. These treatments were administered from 25 to 35 weeks of gestation. Prolactin (PRL) levels were determined at 25, 30, and 35 weeks. The SLE Pregnancy Disease Activity Index, maternal–fetal outcome including preterm birth, fetal loss, premature rupture of membrane (PRM), low birth weight, and preeclampsia/eclampsia were evaluated. We studied 20 patients (10 in each group). A significant decrease of PRL levels in group 1 compared to group 2 at week 30 and at week 35 was found. No patients in the BRC group had flares and three from group 2 had SLE activity. None of the patients in group 1 had PRM but three patients in group 2 did. Eighty percent of pregnancies ended in birth at term in group 1 and 50% in group 2. There was no fetal loss in both groups. Mean birth weight was higher in group 1 than in group 2 (P < NS). BRC was well tolerated. This is the first clinical trial of BRC in SLE pregnancy. Our pilot study suggests that BRC may play a role in the prevention of maternal–fetal complications, such as PRM, preterm birth, and active disease.

Clinical spectrum of males with primary antiphospholipid syndrome and systemic lupus erythematosus: a comparative study of 73 patients

The objective of this study was to compare the clinical findings, laboratory data, functional outcome and chronic damage in male patients with primary antiphospholipid syndrome (PAPS) and systemic lupus erythematosus (SLE). We studied 29 male patients with PAPS and 44 with SLE. Clinical findings, laboratory data, lupus damage index (SLICC/ACR DI), and functional outcome in PAPS, were analysed in each group. The mean age at diagnosiswas 29.8 + 10.4 years in patientswith PAPS and 26 + 10.1 years in SLE patients. The duration of disease was 4.5 + 2.6 versus 5.2 + 3.8 years in patients with PAPS and SLE, respectively(P NS). In patients with PAPS the most frequent clinical manifestations were venous thrombosis, thrombocytopenia, and pulmonary thromboembolism. Patients with SLE had joint, skin and renal involvement more frequently than those with PAPS (P 0.0001). All PAPS patients had anticardiolipin antibodies (aCL), and 14 patients (48%) had lupus anticoagulant (LA). All SLE patients had antinuclear antibodies (ANAs). Anti-dsDNA antibodies were positive in 39% of SLE patients. Five patients died: one with ‘catastrophic’ APS and four with SLE. SLICC/ACR-DI score in SLE patients was 1.9 (SD 1). In PAPS patients poor functional outcome was due to myocardial infarction, pulmonary thromboembolism, stroke and mesenteric thrombosis. Lupus nephritis was the principal organ damage in SLE. In conclusion, in male patients with PAPS and SLE, the clinical manifestations were significantly different. Arterial thrombosis was the major cause of functional impairment and permanent organ damage in PAPS. Renal involvement was the major cause of chronic damage in SLE.

The impact of gender on clinical manifestations of primary antiphospholipid syndrome

The objective of the study was to determine the clinical differences at diagnosis and during follow-up between male and female patients with primary antiphospholipid syndrome (PAPS). We analysed 68 patients, 30 males and 38 females diagnosed and followed between 1990 and 2003. Patients with antiphospholipid syndrome associated with systemic lupus erythematosus at onset and during follow-up were excluded. The mean age at diagnosis was 31.4 ± 11 years in males and 35.7 ± 11 years in females (NS). The follow-up after diagnosis was 8.7 ± 3.1 years in males and 9.2 ± 2.9 years in females (NS). We did not find significant differences between the two groups with respect to venous and arterial thrombosis. However, in female patients, stroke was more prevalent than in male patients (12/38 versus 3/30, P = 0.03). In contrast, we found a significant prevalence of severe gastrointestinal complications in male compared to female patients (7/30 versus 1/38, P = 0.009). One male patient died due to catastrophic antiphospholipid syndrome. This study suggests that clinical course in patients with PAPS may be different with significant prevalence of central nervous system involvement in females and gastrointestinal involvement in males. Factors such as accelerated atherosclerosis, hormones, related to gender could be the explanation of these findings.

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.

Is the immune neuroendocrine system the connection between epipharyngitis and chronic fatigue syndrome induced by HPV vaccine

An interesting study published in this issue of Immunologic Research, by Hotta et al. [1], analyzed forty-one patients who develop chronic fatigue syndrome (CFS) after HVP vaccine. All patients had at least two major criteria of the autoimmune/inflammatory syndrome induced by adjuvants or ASIA proposed by Shoenfeld et al. in 2011 [2], and all patients had severe chronic epipharyngitis. Sixteen patients were treated with abrasive ZnCl2 procedure on epipharynx mucosa, and the authors observed significant improvement of CFS symptoms in 81.2 %, with a complete cure in four patients (25 %). These findings are relevant, because at this time, CFS is an untreatable disease opening the door for a clinical trial. The authors proposed that the possible explanations of improvement of patients treated with abrasive ZnCl2 could be related to hypothalamic pituitary adrenal (HPA) axis normalization, which probably it was previously altered after HPV vaccine with the consequent development of CFS, suggesting an abnormal immune neuroendocrine interaction. In 1976, Besedovsky and Sorkin [3], in order to incorporate immune system to an integral response after antigen challenge, proposed an immune neuroendocrine network based on the existence of afferent and efferent pathways between the immune and neuroendocrine structures. This hypothesis has been confirmed and amplified by several investigators, and actually consider that the immune neuroendocrine system controls growth and cell differentiation, immune response, metabolism and human behavior. Hormones, such as estrogens, growth hormone, prolactin, thyroid hormones and insulin, stimulate the immune response. On the contrary, cortisol, corticotrophin releasing hormone, adrenocorticotropic hormone, androgens and progesterone decrease the innate and adaptive immune responses. On the other hand, proinflammatory and antiinflammatory cytokines released by the immune system cells stimulate or decrease the neuroendocrine system. All these actions are mediated by receptors for cytokines, hormones, neuropeptides and neurotransmitters present in the cells of the three systems, and the ability of these cells to synthesize these messengers. It has been proposed that the chronic stress triggers neuroendocrine hormones causing immune alterations, which may result in a risk factor for the development of autoimmune disease, by amplifying cytokine production. In human and experimental models, under stress situations, an integral response occurs, through the following stress axes: hypothalamic–pituitary–adrenal (HPA), hypothalamic–pituitary–gonadal (HPG), hypothalamic–pituitary–thyroid (HPT), prolactin–growth hormone & Luis J. Jara luis_jara_quezada@hotmail.com

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.