Role of HLA-DRB1*04 in the susceptibility and HLA-DRB1*08 in the protection for development of rheumatoid arthritis in a population of Southern Mexico: brief report.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with an increased prevalence in Mexico. Although its etiology is unknown, its development can be influenced by environmental factors such as smoking and viral infections. But among the factors influencing susceptibility, it is the genetic factors that predominate, mainly the HLA-DRB1 genes, and specifically the alleles that have the shared epitope (SE). A transversal study was performed, in which 31 patients (28 women and 3 men) with RA, treated at the autoimmunity clinic of the High Specialty Hospital Ciudad Salud in Tapachula, Chiapas, southern México, were enrolled. Clinical, biochemical, and demographic data were analyzed; ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), RF (rheumatoid factor), and ACPA (anticitrullinated peptide antibody) were recorded. All patients had at least one positive RA biological marker. For HLA alleles frequencies comparison, we enrolled ethnically matched healthy controls in a ratio of 3:1 for 25 cases and 4:1 for 6 cases in order to guarantee the balance between groups regarding the mean of age and proportion of gender (males vs females). HLA-DRB1*04 was found to be significantly increased in patients compared with ethnically matched healthy controls (p 0.0007, OR: 2.8, 95% CI 1.5-5.1); contrarily, DRB1*08 showed a protective effect (p 0.005, OR 0.1). This paper confirmed the involvement of HLA genes on risk determination for RA in a population of Mexican Mestizos from Tapachula, Chiapas. Key Points • HLA-DRB1*04 confirms the increased risk of rheumatoid arthritis. • HLA-DRB1*08 showed a more definite protective effect in southern Mexicans mestizos, a population with more Amerindian ancestry.

Utility of neutrophil-to-lymphocyte ratio plus C-reactive protein for infection in systemic lupus erythematosus.

OBJECTIVE: To analyze the utility of neutrophil-to-lymphocyte ratio (NLR) plus C-reactive protein (CRP) to differentiate between infection and active disease in patients with SLE. METHODS: A cross-sectional study of a cohort of patients with SLE was carried out. Blood samples from four groups (patients without infection or active disease, patients with infection, patients with active disease, and patients with both infection and active disease) before therapeutic interventions were analyzed. We excluded patients with current malignancy, pregnancy, ischemic heart disease or use of antimicrobials during previous 7 days. Hematological cell count, CRP and cultures were obtained. We constructed receiver operating characteristic curves; sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Forty patients were included. NLR cut-off ≥6.3 had sensitivity 70%, specificity 85%, PPV 83% and NPV 74% to detect patients with non-viral infections. A CRP cut-off ≥7.5 mg/L had sensitivity 90%, specificity 75%, PPV 78% and NPV 88% to detect infections regardless of SLE activity. Combination of CRP plus NLR improves the specificity to 90% and PPV to 88%. Excluding the group with both infection and active disease, CRP plus NLR expands specificity to 95% and NPV to 90%. CONCLUSION: In our experience, levels of CRP, particularly CRP plus NLR, were useful in differentiating patients with SLE from those with suspected non-viral infection regardless of the activity of the disease.

Inflammatory biomarkers, disease activity index, and self-reported disability may be predictors of chronic arthritis after chikungunya infection: brief report.

The chikungunya virus (ChikV) is a reemerging mosquito-borne pathogen that causes disabling chronic arthritis. The relationship between clinical evolution and inflammatory biomarkers in patients with ChikV-induced arthritis has not been fully described. We performed a prospective case series to evaluate the association among joint involvement, self-reported disability, and inflammatory biomarkers. Patients with ChikV infection were followed for 1 year. Joint involvement and self-reported disability were evaluated with disease activity index 28 (DAS-28) and World Health Organization Disablement Assessment Schedule II (WHODAS-II). Interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were used as biomarkers. Ten patients with mean age 48 ±15.04 years were included. Symptoms at diagnosis were fever, arthralgias, myalgias, rash, arthritis, nausea, vomiting, and back pain. Polyarticular involvement was present in seven cases. At diagnosis, measures were as follows: DAS-28, 5.08±1.11; WHODAS-II score, 72.3±10.3 %; CRP, 5.09±7.23 mg/dL; ESR, 33.5±17.5 mm/h; RF, 64±21.7 IU/mL; and IL-6, 17.6±10.3 pg/mL. Six patients developed subacute and chronic symptoms. During follow-up, DAS-28 index, WHODAS-II score, ESR, and IL-6 were statistically different in patients with subacute and chronic symptoms compared to those who resolved in the acute phase (p < 0.05). DAS-28 index, WHODAS-II score, and IL-6 were related to chronicity of articular symptoms and could be used as predictors of ChikV-induced arthritis.

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.

Oxidative stress in Mexicans with diffuse cutaneous systemic sclerosis.

To compare oxidative stress (OS) biomarkers and antioxidant capacity of plasma (ACP) between dcSSc (diffuse cutaneous systemic sclerosis) and healthy Mexicans and their possible relationship with autoantibodies, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and uric acid (UA). We included 28 dcSSc and 28 healthy individuals. Patients were grouped in early and late dcSSc and were excluded if they had infections, neoplasias, comorbidity, or antioxidant treatment. Lipoperoxidation products (malondialdehyde), protein oxidation products (carbonyls, dityrosines), ACP, CRP, ESR, and UA were investigated. Age was 47.5 ± 10 in dcSSc versus 48 ± 7 years in controls. In dcSSc, OS was higher and ACP was decreased versus controls (p < 0.001). OS was similar in early and late dcSSc. Anti-Scl-70 (anti-topoisomerase I) was associated with a higher OS (p < 0.05). Eight dcSSc patients had hyperuricemia (28.5 %). A significant correlation between UA and malondialdehyde, dityrosines and carbonyls levels (r = 0.52, r = 0.78 and r = 0.69, p < 0.01) respectively, was found in dcSSc group. A high level of ESR was present in 71 % and CRP in 40 % of dcSSc patients. Mexican dcSSc patients had elevated lipid/protein OS with respect to healthy controls. These OS biomarkers have direct correlation with UA levels. ESR and CRP were elevated in a great number of dcSSc patients. These biochemical markers suggest that dcSSc patients have a continuous stimulus for endothelial dysfunction and accelerated atherogenesis.

Cerebral blood flow abnormalities in neurologically asymptomatic patients with primary antiphospholipid syndrome.

OBJECTIVE: To evaluate cerebral blood flow abnormalities in primary antiphospholipid syndrome (PAPS) patients without ongoing neurological manifestations. PATIENTS AND METHODS: We included 28 PAPS patients and 28 healthy controls. Carotid Doppler ultrasound, and echocardiographic evaluation were done. Transcranial Doppler ultrasonography measured mean flow velocity (MFV) in the carotid siphon, middle, anterior, posterior, intracranial vertebral arteries, and basilar artery (11 cerebral arteries). Results were considered abnormal when the MFV was out of the normal range according to age and/or flow asymmetry and/or more than four arterial segments affected. RESULTS: The mean age of patients was 41.4 ± 11.2 and 39.3 ± 8.6 years in controls. Disease duration was 11 ± 2.7 years. A significant increase in MFV in 7/11 cerebral arteries in PAPS patients, mainly in the middle and anterior cerebral arteries was found compared with controls. A significant association between lupus anticoagulant, history of stroke and obesity with a greater number of affected arteries was found. We did not find an association between MFV and abnormal echocardiography, arterial hypertension and carotid intima-media thickness. CONCLUSIONS: Asymptomatic patients with PAPS can have significantly increased MFVs. These alterations may be the consequence of accelerated atherosclerosis, PAPS vasculopathy or both. Whatever the cause, these findings can represent a risk for stroke in PAPS patients that needs the trial of other therapeutic options.

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.

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.

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 diagnosis was 29.8 +/- 10.4 years in patients with 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.

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 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.

[Evaluation of nopal capsules in diabetes mellitus]. / Evaluación de cápsulas de nopal en diabetes mellitus.

To find out if commercial capsules with dried nopal (prickle-pear cactus, Opuntia ficus indica may have a role in the management of diabetes mellitus, three experiments were performed: 30 capsules where given in fasting condition to 10 diabetic subjects and serum glucose was measured through out 3 hours; a control test was performed with 30 placebo capsules. OGTT with previous intake of 30 nopal or placebo capsules was performed in ten healthy individuals. In a crossover and single blinded study 14 diabetic patients withdrew the oral hypoglycemic treatment and received 10 nopal or placebo capsules t.i.d. during one week; serum glucose, cholesterol and tryglycerides levels were measured before and after each one-week period. Five healthy subjects were also studied in the same fashion. Opuntia capsules did not show acute hypoglycemic effect and did not influence OGTT. In diabetic patients serum glucose, cholesterol and tryglycerides levels did not change with Opuntia, but they increased with placebo (P < 0.01 glucose and cholesterol, P = NS triglycerides). In healthy individuals glycemia did not change with nopal, while cholesterol and triglycerides decreased (P < 0.01 vs. placebo). The intake of 30 Opuntia capsules daily in patients with diabetes mellitus had a discrete beneficial effect on glucose and cholesterol. However this dose is unpractical and at present it is not recommended in the management of diabetes mellitus.