Apremilast as a target therapy for nail psoriasis: a real-life observational study proving its efficacy in restoring the nail unit.

PURPOSE: Psoriasis, Psoriatic Arthritis and Nail psoriasis are chronic diseases that share a common underlying etiology of immunity dysregulation, enhanced activation of inflammatory pathways and remitting-relapsing course. Although nails represent a small percentage of the body surface involvement of this site can lead to impaired quality of life, severe discomfort and even result in permanent disability. Current therapeutic options for nail psoriasis include a variety of topical and systemic treatments although they are often reported as unsatisfactory from patients either due to their poor effectiveness or disturbing side effects. Recently small molecule drugs such as the PDE4 inhibitors were introduced in clinical practice and specifically apremilast has shown to be an effective new treatment option for psoriasis and psoriatic arthritis. Considering either the specific mechanism of action of apremilast, we performed a real-life observational study of 24 weeks assessing apremilast role in nail psoriasis. MATHERIALS AND METHODS: Patients received apremilast 30mg bid, orally. Safety and efficacy were assessed at weeks 0, 4, 8, 12 and 24 using Dermatologic Life Quality Index (DLQI) and Nail Area Psoriasis Severity Index (NAPSI). At T0 we took a nail sample to investigate the presence of onychomycosis. Culture tests were performed in all the patients to search for fungi. RESULTS: We recruited a total of 15 patients with nail psoriasis. The analysis of variance (one-way ANOVA) showed the following results: DLQI (F.15.7; p-value < .00001) and NAPSI (F.9.4; p-value < .00001). Three patients (20%) presented also onychomycoses at the beginning of the treatment. CONCLUSIONS: Apremilast showed fast and sustained improvement of nail psoriasis over time and a complete resolution of life quality impairment due to the disease.

Association of fat mass and obesity-associated (FTO) gene rs9939609 with obesity-related traits and glucose intolerance in an indigenous population, the Xavante.

BACKGROUND AND AIMS: Common variants in fat mass and obesity-associated (FTO) gene have been implicated as a susceptibility locus for obesity and type 2 diabetes in different populations. Here, in an indigenous population-based study, we examined whether FTO rs9939609 has a role in susceptibility to glucose intolerance and obesity. METHODS: The study population comprised 949 full Xavante indigenous people (465 men) aged 18-99 years. The participants were submitted to clinical examination, anthropometrical measures and basal and 2-h post 75g oral glucose load capillary glucose measurements. FTO rs9939609 was genotyped and logistic regression was carried out to test the additive effect of the risk allele. RESULTS: The frequency of the minor allele of the FTO rs9939609 (0.06) was lower in Xavante than observed in some populations. A significant association between the variant and overweight was observed (OR = 1.56 (95% CI:1.06-2.29, p = 0.02), using an additive model of inheritance, adjusted by age and gender and considering the family structure. We found no associations with obesity or glucose intolerance. CONCLUSIONS: The FTO rs9939609 is associated with overweight, but not with obesity or glucose intolerance. The low frequency of the A allele suggests that it is not an important risk determinant for these conditions in Xavante indigenous people.

Incidence of cardiovascular risk factors in female patients with systemic lupus erythematosus: a 3-year follow-up cohort.

Objectives To evaluate the incidence and variability of traditional coronary artery disease (CAD) risk factors in a cohort of lupus patients and to investigate if prednisone use predicts an increase in the number of risk factors. Methods A total of 151 women, 37.8 ± 11.1 (mean ± SD) years old at baseline, were reevaluated after a median period of 39 (interquartile range 36.5-42.0) months. The cumulative incidence of traditional risk factors, the incidence rate (with 95% confidence interval) of hypertension, diabetes, dyslipidemia and hypertriglyceridemia, and the frequency of the risk factors' disappearance were calculated. Metabolic syndrome (MetS) and Framingham risk score (FRS) were computed. Logistic regression was used to investigate if maximum or cumulative prednisone dose used during follow-up predicted an increase in the cardiometabolic risk factors' number. Results The cumulative incidence of risk factors varied from 39.1% (abdominal obesity) to zero (smoking), and the incidence rate varied from 133.2 (87.8-178.6) per 1000 person-years (dyslipidemia) to 10.4 (1.3-19.5) per 1000 person-years (diabetes). The cumulative incidence for MetS was 18.8%, and 11.7% of 143 patients with low FRS at baseline (T1) were classified in the high-risk category at the end of the study (T2). Dyslipidemia was the most variable risk factor, with 43.5% disappearance at T2. The maximum prednisone dose used during follow-up was borderline ( p = 0.050) for prediction of an increase in the number of cardiometabolic risk factors in an adjusted model for antimalarial use, modified Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and age. Conclusion The authors described high incidence and variability of CAD risk factors in female lupus patients, with higher prednisone dose being borderline for an increase in the number of cardiometabolic risk factors.

Adipokines, tumor necrosis factor and its receptors in female patients with systemic lupus erythematosus.

OBJECTIVES: To analyze the association of adipokines and tumor necrosis factor α (TNFα) and its receptors with characteristics of systemic lupus erythematosus (SLE) and to investigate the correlation between adipokines and the TNF system. METHODS: One hundred and thirty-six SLE women, aged ≥18 years old, were assessed. TNFα, soluble TNFα receptors 1 (sTNFR1) and 2 (sTNFR2) and adipokines were analyzed by ELISA kits. RESULTS: The median (IQR) of age was 41.5 (33.0-49.7) years old and of disease duration 11.3 (7.8-15.8) years. The median (IQR) of disease activity was 0 (0-4) and of damage index was 2 (1-3). Higher levels of sTNFR1 and sTNFR2 were associated with nephritis (p < 0.001 for both), and sTNFR1 (p = 0.025) and TNFα (p = 0.014) were positively associated with arthritis. Higher sTNFR1 levels were found in participants that were not using antimalarial drugs (p = 0.04). Independent correlation was found between sTNFR1 (ß = 0.253; p = 0.003) and sTNFR2 (ß = 0.297; p < 0.001) levels and disease activity and damage index (sTNFR1: ß = 0.367; p < 0.001; sTNFR2: ß = 0.335; p < 0.001). Higher adiponectin levels were independently associated with nephritis (p = 0.009) and antimalarial drugs use (p = 0.015). There was a positive correlation between leptin and sTNFR2 levels (p = 0.002) and between resistin levels and sTNFR1 (p < 0.001) and sTNFR2 (p < 0.001). CONCLUSION: The correlation between adipokines and TNF system allows a better understanding of the role of adipokines in the inflammatory response in SLE patients.

The effects of NAMPT haplotypes and metabolic risk factors on circulating visfatin/NAMPT levels in childhood obesity.

OBJECTIVE: Polymorphisms in the NAMPT gene, which encodes the adipocytokine visfatin/nicotinamide phosphorybosil transferase (NAMPT), affect the circulating visfatin/NAMPT levels and are associated with obesity and cardiovascular diseases. However, no study has tested the hypothesis that NAMPT haplotypes could affect visfatin/NAMPT levels in case of childhood obesity. We investigated the effects of traditional metabolic risk factors (MRFs) and NAMPT polymorphisms T/C (rs1319501) and A/G (rs3801266) or haplotypes on visfatin/NAMPT levels in obese children and adolescents, and whether NAMPT polymorphisms and/or haplotypes are associated with susceptibility to childhood obesity. METHODS: We studied 175 control, 99 obese and 82 obese with ⩾ 3 MRFs children and adolescents. Genotypes were determined by a Taqman allele discrimination assay and real-time PCR. The plasma visfatin/NAMPT level was measured using an enzyme immunoassay. RESULTS: Obese children and adolescents with ⩾ 3 MRFs had higher plasma visfatin/NAMPT levels in comparison with control children and adolescents (P<0.05). Although positive associations were observed between visfatin/NAMPT and body mass index (rs = 0.157; P = 0.034) as well as visfatin/NAMPT and waist circumference (rs = 0.192; P = 0.011), visfatin/NAMPT and high-density lipoprotein cholesterol were inversely associated (rs = -0.162; P = 0.031). No significant differences in genotype, allele or haplotype frequency distributions for the studied polymorphisms were found when the three groups were compared. However, higher plasma visfatin/NAMPT levels were found in control and obese subjects carrying the GG genotype for the A/G (rs3801266) polymorphism (P<0.05) but not in obese children with ⩾ 3 MRFs. Moreover, control subjects carrying the 'T-G' haplotype showed higher plasma visfatin/NAMPT levels. NAMPT genotypes or haplotypes were not associated with childhood obesity. CONCLUSIONS: Obesity in children with ⩾ 3 MRFs increases plasma visfatin/NAMPT levels, and this marker was associated with body mass index and waist circumference. The A/G polymorphism and NAMPT haplotypes affect plasma visfatin/NAMPT levels in controls but not in obese children with ⩾ 3 MRFs. These results suggest that obesity and MRFs are more influential than genetic polymorphisms in the determination of visfatin/NAMPT levels in obese children. Further research is necessary to explain why the GG genotype is not associated with increased visfatin/NAMPT levels in obese children with ⩾ 3 MRFs.

The effects of endothelial nitric oxide synthase tagSNPs on nitrite levels and risk of hypertension and obesity in children and adolescents.

Obesity and the nitric oxide synthase 3 (NOS3) gene polymorphisms are associated with nitrite levels and hypertension. However, no study has tested the hypothesis that NOS3 tagSNPs rs3918226, rs3918188, rs743506 and rs7830 affect nitrite levels and are associated with hypertension in childhood obesity. We investigated the association of these NOS3 tagSNPs and the haplotypes formed by them with hypertension and with nitrite levels in children and adolescents with obesity and with obesity plus hypertension. We studied 355 subjects: 174 healthy (controls), 109 normotensive obese, and 72 obese children and adolescents with obesity plus hypertension. Genotypes were determined by Taqman allele discrimination assay and real-time PCR. We compared the distribution of NOS3 tagSNP genotypes, alleles and haplotypes in the three groups of subjects. Nitrite levels were determined by ozone-based chemiluminescence. Nitrite levels were affected by the rs3918226 polymorphism (P<0.05) but not by NOS3 haplotypes. There was no association between the tagSNPs studied and hypertension in children and adolescents. Our findings show that the NOS3 tagSNP rs3918226 is associated with NO production in children and adolescents, and suggest that this polymorphism may have an impact on cardiovascular health. Further studies are needed to better clarify the effects of this polymorphism on cardiovascular risk.

Adiponectin associates positively with nitrite levels in children and adolescents.

OBJECTIVE: To compare the circulating levels of adiponectin and nitric oxide (NO) bioavailability in eutrophic, eutrophic hypertensive, obese, and obese hypertensive children and adolescents, and to assess whether adiponectin is associated with increased NO bioavailability in these children and adolescents. METHODS: We studied 129 eutrophic, 8 eutrophic hypertensive, 91 obese, and 44 obese hypertensive children and adolescents in this cross-sectional study. Adiponectin concentrations were measured in plasma samples by enzyme-linked immunosorbent assay. To assess NO bioavailability, nitrite concentrations were measured in whole-blood samples by chemiluminescence. Multiple linear regression analysis was carried out to assess the effects of adiponectin on NO bioavailability. RESULTS: We found no significant differences in nitrite levels among groups (P>0.05). The obese hypertensive group had the lowest adiponectin levels among groups (P<0.05). Additionally, obese subjects had lower adiponectin levels than eutrophic individuals (P<0.05). A multiple linear regression analysis showed that NO bioavailability was positively associated with adiponectin concentrations (P<0.05). CONCLUSIONS: Our findings suggest that adiponectin increases NO bioavailability in children and adolescents. Further studies are needed to assess the cardiovascular protective role for this adipokine in childhood obesity.

Matrix metalloproteinase-9 genetic variations affect MMP-9 levels in obese children.

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) is involved in the atherosclerotic process and functional polymorphisms in the MMP-9 gene affect MMP-9 expression/activity, and are associated with cardiovascular diseases. However, no study has tested the hypothesis that functional MMP-9 polymorphisms could affect MMP-9 levels in obese children. We investigated whether three MMP-9 gene polymorphisms (C-1562T (rs3918242), 90(CA)((14-24)) (rs2234681) and Q279R (rs17576)), or haplotypes, affect MMP-9 levels in obese children. METHODS: We studied 175 healthy control children and 127 obese children. Plasma MMP-9, tissue inhibitor of MMPs (TIMP)-1 and adiponectin concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: We found similar MMP-9 genotypes, allelic and haplotypes distributions in the two study groups (P>0.05). However, we found lower plasma MMP-9 concentrations in obese subjects carrying the CC or the QQ genotypes for the C-1562T and the Q279R polymorphisms, respectively, in obese children compared with children with the other genotypes, or with non-obese children with the same genotypes (all P<0.05). Moreover, we found lower MMP-9 levels and lower MMP-9/TIMP-1 ratios (which reflect net MMP-9 activity) in obese children carrying the H2 haplotype (which combines the C, H and Q alleles for the three polymorphisms, respectively) when compared with obese children carrying the other haplotypes, or with non-obese children carrying the same haplotype (P<0.05). CONCLUSIONS: Our findings show that MMP-9 genotypes and haplotypes affect MMP-9 levels in obese children and adolescents, and suggest that genetic factors may modify relevant pathogenetic mechanisms involved in the development of cardiovascular complications associated with obesity in childhood.

eNOS haplotype associated with hypertension in obese children and adolescents.

OBJECTIVE: The aim of our study is to investigate whether genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (in the promoter region T(-786)C, in exon 7 (Glu298Asp) and in intron 4 (4b/4a)) or eNOS haplotypes are associated with hypertension in obese children and adolescents. METHODS: We genotyped 175 healthy (controls), 110 normotensive obese and 73 hypertensive obese children and adolescents. Genotypes were determined by Taqman allele discrimination assay and real-time PCR, and by PCR followed by fragment separation by electrophoresis. We compared the distribution of eNOS genotypes, alleles and haplotypes in the three study groups of subjects. We have also measured whole-blood nitrite concentrations. RESULTS: The 4a4a genotype for the intron 4 polymorphism was more common in normotensive obese and hypertensive obese (P<0.01). The AspAsp genotype for Glu298Asp polymorphism was less common in normotensive obese (P<0.02). No significant differences were found in allele distributions for the three eNOS polymorphisms. However, the haplotype combining the C, 4b and Glu variants for the three polymorphisms was more common in hypertensive obese than in normotensive obese or control children and adolescents (odds ratio=2.28 and 2.79, respectively; 95% confidence interval: 1.31-4.31 and 1.39-5.64, respectively; both P<0.00625). This haplotype was not associated with significantly different nitrite concentrations (P>0.05). CONCLUSIONS: Our findings suggest that the eNOS haplotype, C b Glu, is associated with hypertension in obese children and adolescents. Further studies examining the possible interactions of eNOS haplotypes with environmental factors and other genetic markers involved in the development of obesity and its complications are warranted.

Carotid atherosclerotic alterations in systemic lupus erythematosus patients treated at a Brazilian university setting.

To determine the frequency of carotid plaque and intima-media thickness (IMT) in patients with systemic lupus erythematosus (SLE) and their association with risk factors in a Brazilian university setting. Carotid plaque and IMT were identified and measured by ultrasonography. Traditional risk factors and lupus-related factors were analysed. One hundred and seventy-two patients (women = 96%, age = 38 +/- 11 years) were evaluated. The frequency of carotid plaque was 9.3%. The median (IR) IMT was 0.60 mm (0.54-0.71 mm). Age, family history (FH) of premature coronary disease, low-density cholesterol (LDL-c) >100 mg/dL, hypertriglyceridemia, diabetes, hypertension, smoking, postmenopause, number of risk factors, Framingham risk score, age at diagnosis, duration of lupus, mucocutaneous manifestations and duration of prednisone use were associated with plaque (P < 0.05), univariate analysis. Nephritis, immunosuppressive therapy, intravenous methylprednisolone and a higher average daily dose of prednisone were associated with the absence of plaque. Independent predictors of plaque were smoking (P = 0.004), LDL-c >100 mg/dL (P = 0.044), Framingham score (P = 0.006) and absence of immunosuppressive therapy (P = 0.032). There was an independent correlation between IMT and age (P < 0.001) and duration of prednisone use (P = 0.020). Subclinical atherosclerosis was associated with traditional risk and SLE-related factors, especially the absence of immunosuppressive therapy. The present study suggests that the levels of LDL-c should be kept under 100mg/dL in lupus.

Parathyroid hormone secretion in chronic human endogenous hypercortisolism.

Osteoporosis is a common manifestation of Cushing's syndrome, but the mechanisms responsible for this abnormality have not been defined. With the objective of analyzing parathyroid hormone (PTH) secretion in chronic hypercortisolism (CH), we evaluated 11 healthy subjects and 8 patients with CH, 6 with Cushing's disease and 2 with adrenal adenoma. These volunteers were submitted to tests of PTH stimulation through hypocalcemia (EDTA), PTH suppression through hypercalcemia (iv and oral calcium), and evaluation of bone mineral density (BMD) by DEXA. During the test of PTH stimulation, the calcium and magnesium concentrations of the normal and CH groups were similar. Patients with CH showed an increased PTH response to the hypocalcemic stimulus compared to controls. PTH values were significantly higher in the CH group at 70 (17.5 +/- 3.5 vs 10.2 +/- 1.3 pmol/l, P = 0.04), and 120 min (26.1 +/- 5.9 vs 11.3 +/- 1.9 pmol/l, P = 0.008) of EDTA infusion. The area under the curve for PTH during EDTA infusion was also significantly higher in patients with CH than in normal subjects (1867 +/- 453 and 805 +/- 148 pmol l(-1) 2 h(-1), P = 0.02). During the test of PTH suppression, calcium, magnesium and PTH levels of the patients with hypercortisolism and controls were similar. BMD was decreased in patients with hypercortisolism in the spine (0.977 +/- 0.052 vs 1.205 +/- 0.038 g/cm2 in controls, P<0.01). In conclusion, our results show that subjects with CH present decreased bone mass mainly in trabecular bone. The use of dynamic tests permitted the detection of increased PTH secretion in response to a hypocalcemic stimulus in CH patients that may probably be involved in the occurrence of osteoporosis in this state.

Parathyroid hormone secretion in chronic human endogenous hypercortisolism

Osteoporosis is a common manifestation of Cushing's syndrome, but the mechanisms responsible for this abnormality have not been defined. With the objective of analyzing parathyroid hormone (PTH) secretion in chronic hypercortisolism (CH), we evaluated 11 healthy subjects and 8 patients with CH, 6 with Cushing's disease and 2 with adrenal adenoma. These volunteers were submitted to tests of PTH stimulation through hypocalcemia (EDTA), PTH suppression through hypercalcemia (iv and oral calcium), and evaluation of bone mineral density (BMD) by DEXA. During the test of PTH stimulation, the calcium and magnesium concentrations of the normal and CH groups were similar. Patients with CH showed an increased PTH response to the hypocalcemic stimulus compared to controls. PTH values were significantly higher in the CH group at 70 (17.5 ± 3.5 vs 10.2 ± 1.3 pmol/l, P = 0.04), and 120 min (26.1 ± 5.9 vs 11.3 ± 1.9 pmol/l, P = 0.008) of EDTA infusion. The area under the curve for PTH during EDTA infusion was also significantly higher in patients with CH than in normal subjects (1867 ± 453 and 805 ± 148 pmol l-1 2 h-1, P = 0.02). During the test of PTH suppression, calcium, magnesium and PTH levels of the patients with hypercortisolism and controls were similar. BMD was decreased in patients with hypercortisolism in the spine (0.977 ± 0.052 vs 1.205 ± 0.038 g/cm² in controls, P<0.01). In conclusion, our results show that subjects with CH present decreased bone mass mainly in trabecular bone. The use of dynamic tests permitted the detection of increased PTH secretion in response to a hypocalcemic stimulus in CH patients that may probably be involved in the occurrence of osteoporosis in this state

Effect of metabolic control on parathyroid hormone secretion in diabetic patients

The metabolic derangement caused by diabetes mellitus may potentially affect bone mineral metabolism. In the present study we evaluated the effect of diabetes metabolic control on parathyroid hormone (PTH) secretion during stimulation with EDTA infusion. The study was conducted on 24 individuals, 8 of them normal subjects (group N: glycated hemoglobin - HbA1C = 4.2 + or - 0.2 percent; range = 3.5-5.0 percent), 8 patients with good and regular metabolic control (group G-R: HbA1C = 7.3 + or - 0.4 percent; range = 6.0-8.5 percent), and 8 patients with poor metabolic control (group P: HbA1C = 12.5 + or - 1.0 percent; range: 10.0-18.8 percent). Blood samples were collected at 10-min intervals throughout the study (a basal period of 30 min and a 2-h period of EDTA infusion, 30 mg/kg body weight) and used for the determination of ionized calcium, magnesium, glucose and intact PTH. Basal ionized calcium levels were slightly lower in group P (1.19 + or - 0.01 mmol/l) than in group N (1.21 + or - 0.01 mmol/l) and group G-R (1.22 + or - 0.01 mmol/l). After EDTA infusion, the three groups presented a significant fall in calcium, but with no significant difference among them at any time. Basal magnesium levels and levels determined during EDTA infusion were significantly lower (P<0.01) in group P than in group N. The induction of hypocalcemia caused an elevation in PTH which was similar in groups N and G-R but significantly higher than in group P throughout the infusion period (+110 min, N = 11.9 + or - 2.1 vs G-R = 13.7 + or - 1.6 vs P = 7.5 + or - 0.7 pmol/l; P<0.05 for P vs N and G-R). The present results show that PTH secretion is impaired in patients with poorly controlled diabetes

Effect of metabolic control on parathyroid hormone secretion in diabetic patients.

The metabolic derangement caused by diabetes mellitus may potentially affect bone mineral metabolism. In the present study we evaluated the effect of diabetes metabolic control on parathyroid hormone (PTH) secretion during stimulation with EDTA infusion. The study was conducted on 24 individuals, 8 of them normal subjects (group N: glycated hemoglobin - HbA1C = 4.2 +/- 0.2%; range = 3.5-5.0%), 8 patients with good and regular metabolic control (group G-R: HbA1C = 7.3 +/- 0.4%; range = 6.0-8.5%), and 8 patients with poor metabolic control (group P: HbA1C = 12.5 +/- 1.0%; range: 10.0-18.8%). Blood samples were collected at 10-min intervals throughout the study (a basal period of 30 min and a 2-h period of EDTA infusion, 30 mg/kg body weight) and used for the determination of ionized calcium, magnesium, glucose and intact PTH. Basal ionized calcium levels were slightly lower in group P (1.19 +/- 0.01 mmol/l) than in group N (1.21 +/- 0.01 mmol/l) and group G-R (1.22 +/- 0.01 mmol/l). After EDTA infusion, the three groups presented a significant fall in calcium, but with no significant difference among them at any time. Basal magnesium levels and levels determined during EDTA infusion were significantly lower (P<0.01) in group P than in group N. The induction of hypocalcemia caused an elevation in PTH which was similar in groups N and G-R but significantly higher than in group P throughout the infusion period (+110 min, N = 11.9 +/- 2.1 vs G-R = 13.7 +/- 1.6 vs P = 7.5 +/- 0.7 pmol/l; P<0.05 for P vs N and G-R). The present results show that PTH secretion is impaired in patients with poorly controlled diabetes.