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.

Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry.

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.

Cutaneous and Vascular Deposits of 18F-NaF by PET/CT in the Follow-Up of Patients with Pseudoxanthoma Elasticum.

Active microcalcification of elastic fibers is a hallmark of pseudoxanthoma elasticum and it can be measured with the assessment of deposition of 18F-NaF using a PET/CT scan at the skin and vascular levels. It is not known whether this deposition changes over time in absence of specific therapy. We repeated in two years a PET/CT scan using 18F-NaF as a radiopharmaceutical in patients with the disease and compared the deposition at skin and vessel. Furthermore, calcium score values at the vessel wall were also assessed. Main results indicate in the vessel walls that calcification progressed in each patient; by contrast, the active microcalcification, measured and target-to-background ratio showed reduced active deposition. By contrast, at skin levels (neck and axillae) the uptake of the pharmaceutical remains unchanged. In conclusion, because calcification in the arterial wall is not specific for pseudoxanthoma elasticum condition, the measurement of the deposition of 18F-NaF in the neck might be potentially used as a surrogate marker in future trials for the disease.

IgG4-Related Disease Affecting Testicle and Myelodysplastic Syndrome: Just a Coincidence?

Immunoglobulin G4-related disease (IgG4-RD) is progressive immune-mediated fibrotic condition characterised by a tendency to form tumefactive lesions in different organs and by elevated IgG4 serum concentrations. Urological manifestations are rare and normally occur together with other systemic affections. Myelodysplastic syndromes (MDS) are hematopoietic stem cell neoplasms, with different subtypes based on the type of blood cells involved. MDS can be associated with other pathologies or medical treatments. We present an uncommon case of testicular manifestation associated with myelodysplastic syndrome here. LEARNING POINTS: Testicular inflammation is a manifestation of IgG4-related disease.Testicular inflammation and myelodysplastic syndrome can simultaneously present.

Skin and Arterial Wall Deposits of 18F-NaF and Severity of Disease in Patients with Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is a genetic disease characterized by the calcification of elastin fibers. Our aim was to quantify vascular calcification in the arteries and the deposition of 18F-sodium-fluoride (18F-NaF) in the skin and vessel walls with positron emission tomography/computed tomography. This was an observational study including 18 patients with PXE. Vascular calcification was measured in Agatston units, and deposition in the skin and vessel walls was shown using target-to-background ratio (TBR). Severity of the disease was scored by Phenodex. We found higher vascular calcification in the popliteal, femoral, and aortic arch vessels compared to other vascular regions; however, the uptake of radiotracer was the highest in the aorta and femoral arteries. In the skin, the highest uptake was observed in the neck and the axillae. There was no significant association between 18F-NaF deposition in the arteries or skin and the global Phenodex score. In contrast, the Phenodex score was significantly associated in univariate analyses with the averaged vascular calcium score (p < 0.01). In the neck, patients with higher skin Phenodex scores exhibited higher radiotracer uptake. As a conclusion, because vascular calcification is physiological, our data suggested that the detection of cutaneous (neck) 18F-NaF deposits might serve to monitor the calcification process in the short-term for patients with PXE.

The Effects of Parenteral K1 Administration in Pseudoxanthoma Elasticum Patients Versus Controls. A Pilot Study.

INTRODUCTION: Pseudoxanthoma elasticum (PXE) is a rare disease caused by mutations in the ABCC6 gene. Vitamin K1 is involved in the posttranslational carboxylation of some proteins related to inhibition of the calcification process. Our aim was to investigate, in patients affected by PXE, baseline levels of vitamin K1-dependent proteins and -metabolites and whether parenteral administration of phytomenadione was effective in modulating their levels. METHODS: We included eight PXE patients with typical clinical symptoms (skin, retina, and vascular calcification) and two ABCC6 causative mutations; 13 clinically unaffected first-degree patients' relatives (9 carrying one ABCC6 mutation and 4 non-carriers). We assessed urinary vitamin K1 metabolites and serum Glu- and Gla-OC, Gas6 and undercaboxylated prothrombin (PIVKA-II), at baseline and after 1 and 6 weeks after a single intramuscular injection of 10 mg vitamin K1. RESULTS: Comparison of PXE patients, heterozygous, and non-carriers revealed differences in baseline levels of serum MK-4 and of urinary vitamin K metabolites. The response to phytomenadione administration on vitamin K-dependent proteins was similar in all groups. CONCLUSION: The physiological axis between vitamin K1 and vitamin K-dependent proteins is preserved; however, differences in the concentration of vitamin K metabolites and of MK-4 suggest that vitamin K1 metabolism/catabolism could be altered in PXE patients.