Lansoprazole Increases Inorganic Pyrophosphate in Patients with Pseudoxanthoma Elasticum: A Double-Blind, Randomized, Placebo-Controlled Crossover Trial.

Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP). Lansoprazole is a partial inhibitor of TNAP. The aim was to investigate whether lansoprazole increases plasma PPi levels in subjects with PXE. We conducted a 2 × 2 randomized, double-blind, placebo-controlled crossover trial in patients with PXE. Patients were allocated 30 mg/day of lansoprazole or a placebo in two sequences of 8 weeks. The primary outcome was the differences in plasma PPi levels between the placebo and lansoprazole phases. 29 patients were included in the study. There were eight drop-outs due to the pandemic lockdown after the first visit and one due to gastric intolerance, so twenty patients completed the trial. A generalized linear mixed model was used to evaluate the effect of lansoprazole. Overall, lansoprazole increased plasma PPi levels from 0.34 ± 0.10 µM to 0.41 ± 0.16 µM (p = 0.0302), with no statistically significant changes in TNAP activity. There were no important adverse events. 30 mg/day of lansoprazole was able to significantly increase plasma PPi in patients with PXE; despite this, the study should be replicated with a large number of participants in a multicenter trial, with a clinical end point as the primary outcome.

Evidence for increased chylomicron remnants in rheumatoid arthritis.

BACKGROUND: Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis. METHODS: Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross-sectional study. Carotid intima-media thickness (cIMT) was measured as a surrogate for vascular damage. RESULTS: In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 ± 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 ± 5.16 and 5.22 ± 2.46, P < .001). Triglycerides levels were comparable with controls. In RA, apo B48 correlated positively with triglycerides (r = .645; P < .001) but not with cIMT. However, in RA subjects not using lipid or blood pressure lowering medication, a weak correlation was found with cIMT (r = .157; P = .014). RA patients in the highest apo B48 tertile were more often rheumatoid factor positive and anti-CCP positive compared to the lowest tertile. CONCLUSION: Rheumatoid arthritis patients have higher levels of apo B48 compared to controls with high CVD risk and healthy controls, with normal levels of triglycerides. This accumulation of atherogenic chylomicron remnants may contribute to the elevated CVD risk in RA patients.

Relationship between polyautoimmunity and sarcopenic obesity in rheumatoid arthritis patients.

OBJECTIVE: Sarcopenia is a major cause of morbidity in rheumatoid arthritis patients. Our purpose was to determine whether polyautoimmunity is associated with sarcopenia and alterations in whole body composition in patients with rheumatoid arthritis (RA). METHODS: We performed a cross-sectional observational study of a series of cases of RA. All patients were recruited consecutively from a rheumatology clinic. Body composition by dual-energy x-ray absorptiometry (DEXA) was assessed. The variables of interest were polyautoimmunity (RA associated with other autoimmune diseases), sarcopenia, fat mass, and body mass index (BMI). Other variables included were clinical-analytical and inflammatory cytokines and adipokines. The relationship between sarcopenic obesity and the presence of polyautoimmunity was studied using multivariate analysis. RESULTS: Of the 94 patients with RA included in the study, 15 (16%) had polyautoimmunity. A total of 23 patients with RA (24.5%) had sarcopenia, which was more prevalent in patients with polyautoimmunity than in patients without polyautoimmunity (46.7% vs 20.3%; p = .029). Sarcopenia was not associated with body fat content (p = .870) or with BMI (p = .998). The multivariate analysis showed the factors associated with polyautoimmunity in RA to be sarcopenia (odds ratio [95% CI], 4.80 [1.49-13.95]), BMI (1.18 [1.04-1.35]), and resistin (1.249 [1.01-1.53]). CONCLUSION: Sarcopenia and obesity were more prevalent in patients with RA and polyautoimmunity. Resistin values were also higher in this group than in patients with RA without polyautoimmunity.

Fractional excretion of phosphorus and vascular calcification in stage 3 chronic kidney disease.

The role of renal excretion of Pi in relation to vascular calcification (VC) in patients in the early stages of chronic kidney disease (CKD) is controversial. Thus, we determine the relation between fractional excretion of phosphorus (FEP) and VC, measured using two methods in a cross-sectional study of patients with stage 3 CKD. We recorded demographic data, anthropometry, comorbidities and active treatment. We measured 24-hour urine FEP and, in serum, measured fibroblast growth factor 23 (FGF23), α-Klotho, intact parathyroid hormone (iPTH), calcium and phosphorus. VC was measured by lateral abdominal radiography (Kauppila index (KI)) and CT of the abdominal aorta (measured in Agatston units). In 57% of subjects, abnormal VC was present when measured using CT, and in only 17% using lateral abdominal radiography. Factors associated with VC using CT were age, cardiovascular risk factors, vascular comorbidity, microalbuminuria and levels of FGF23, phosphorus and calcium x phosphorus product (CaxP); although only age (OR 1.25, 95% CI 1.11 to 1.41), smoking (OR 21.2, CI 4.4 to 100) and CaxP (OR 1.21, CI 1.06 to 1.37) maintained the association in a multivariate analysis. By contrast, only age (OR 1.35, 95% CI 1.07 to 1.74), CaxP (OR 1.14, CI 1.13 to 1.92) and FEP (OR 1.07,95% CI 1004 to 1.14) were associated with abnormal VC in the lateral abdominal radiography. In conclusion, in patients with stage 3 CKD, the detection of VC by abdominal CT is more sensitive than conventional X-rays. Moreover, CaxP is associated with cardiovascular risk factors and vascular comorbidity; quantification of FEPi in these patients provides additional clinical information in advanced VC detected by KI.

Plasma inorganic pyrophosphate and alkaline phosphatase in patients with pseudoxanthoma elasticum.

BACKGROUND: Inorganic pyrophosphate (PPi) plays a major role inhibiting dystrophic calcification. The aim was to analyze levels of PPi in patients having pseudoxanthoma elasticum (PXE), and controls as well as the enzymes who regulate the PPi plasma concentration. METHODS: We collected fasting blood samples from PXE patients and age- and sex-matched controls in ethylenediamine tetraacetic acid (EDTA) and citrate-theophylline-adenosine-dipyridamole (CTAD) containing tubes. We measured PPi, ENPP1 mass and activity, alkaline phosphatase (AP) and tissue non-specific alkaline phosphatase (TNAP), CD73 and Human Platelet Factor-4 (CXCL4). RESULTS: PPi in EDTA and CTAD samples were lower in PXE subjects than in controls (1.11±0.26 vs. 1.43±0.41 µM/L and 0.35±0.15 vs. 0.61±0.18 µM/L respectively, P<0.05). TNAP and liver TNAP activities were also higher in PXE than in controls (80.3±27.0 vs. 63.3±16.4 UI/L and 25.6±14.9 vs. 12.9±9.2 UI/L respectively, P<0.05). ENPP1 mass and activity as well as CD73 were almost identical. There was a weak but significant inverse correlation between TNAP activity and PPi levels (Pearson correlation -0.379, P<0.05) in both groups. CONCLUSIONS: High TNAP activity seems to contribute to low plasma levels of PPi in subjects with PXE, reinforcing the idea that pharmacological reduction of TNAP activity may help to reduce dystrophic calcification in PXE patients.

In vivo evidence for chylomicrons as mediators of postprandial inflammation.

BACKGROUND AND AIMS: The postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers. METHODS: Leukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h). RESULTS: Fasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 ± 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 ± 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression. CONCLUSION: This study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia.

Structural and functional brain changes in middle-aged type 2 diabetic patients: a cross-sectional study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an emerging risk factor for cognitive impairment. Whether this impairment is a direct effect of this metabolic disorder on brain function, a consequence of vascular disease, or both, remains unknown. Structural and functional neuroimaging studies in patients with T2DM could help to elucidate this question. OBJECTIVE: We designed a cross-sectional study comparing 25 T2DM patients with 25 age- and gender-matched healthy control participants. Clinical information, APOE genotype, lipid and glucose analysis, structural cerebral magnetic resonance imaging including voxel-based morphometry, and F-18 fluorodeoxyglucose positron emission tomography were obtained in all subjects. METHODS: Gray matter densities and metabolic differences between groups were analyzed using statistical parametric mapping. In addition to comparing the neuroimaging profiles of both groups, we correlated neuroimaging findings with HbA1c levels, duration of T2DM, and insulin resistance measurement (HOMA-IR) in the diabetic patients group. RESULTS: Patients with T2DM presented reduced gray matter densities and reduced cerebral glucose metabolism in several fronto-temporal brain regions after controlling for various vascular risk factors. Furthermore, within the T2DM group, longer disease duration, and higher HbA1c levels and HOMA-IR were associated with lower gray matter density and reduced cerebral glucose metabolism in fronto-temporal regions. CONCLUSION: In agreement with previous reports, our findings indicate that T2DM leads to structural and metabolic abnormalities in fronto-temporal areas. Furthermore, they suggest that these abnormalities are not entirely explained by the role of T2DM as a cardiovascular risk factor.