Risk factors for hospitalization in Mexican patients with systemic lupus erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease that often requires hospitalization. Most hospitalizations are due to infections and/or disease activity, for which several risk factors have been described in non-Mestizo patients. OBJECTIVE: To identify risk factors for hospitalization in patients with systemic lupus erythematosus (SLE). METHODS: This was an observational case-control study of patients with SLE in San Luis Potosí, Mexico, evaluated from January 2019 to October 2020. We compared hospitalized lupus patients with non-hospitalized lupus patients. We used descriptive statistics and logistic regression to describe potential risk factors. RESULTS: Of a total of 202 patients, 89 (45.1%) were hospitalized; these patients were younger, had shorter disease duration, higher disease activity scores (systemic lupus erythematosus disease activity index-SLEDAI), and more accumulated damage than non-hospitalized patients. The primary reasons for hospitalization were disease activity (60.7%), kidney disease, infection, and drug toxicity (5.6%). Multivariate analysis revealed several risk factors associated with hospitalization, including elevated creatinine, C-reactive protein, neutrophil levels, and constitutional symptoms, while prolonged international normalized ratio (INR), longer stay in the intensive care unit (ICU), and vasopressor use were associated with mortality. The use of antimalarials was a protective factor against hospitalization. Survival analysis revealed that patients with hospital-acquired infections had a lower probability of survival. CONCLUSIONS: Disease activity was the most common reason for hospitalization; kidney, constitutional, and hematological factors were associated with hospitalization; and the use of antimalarial was a protective factor for hospitalization.

Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low-dose methotrexate in patients recently diagnosed with rheumatoid arthritis.

Low-dose methotrexate can be challenging to treat rheumatoid arthritis due to side effects, lack of adherence and risk of medication errors. The aim of this study was to explore the safety and efficacy of low-dose methotrexate administered daily or weekly in patients with rheumatoid arthritis. Patients were randomized according to a total oral dose of 12.5 mg of methotrexate administered: (A) divided in 5 days/week and (B) once per week. Patients were assessed along 24 weeks after starting treatment. Polyglutamates of methotrexate were quantified by ultrahigh-performance liquid chromatography coupled to tandem mass spectrometer. Patients from groups A and B showed a good response to methotrexate treatment in 29% and 25.5%, respectively, and a global frequency of adverse events of 37%. Methotrexate polyglutamate 3 concentrations were higher in normal weight (body mass index 18.5-24.9 kg/m2 ) than in obese (body mass index 30 kg/m2 ) patients with a median (interquartile range) of 28 (17.95-45.15) and 10.35 (5.22-30.88) nM without differences between dosage groups. Daily dosage regimen represents a therapeutic alternative without compromising the efficacy and safety of methotrexate treatment and with similar adherence patterns than weekly dosage regimen; further, methotrexate polyglutamate 3 concentrations could be a useful tool for therapeutic drug monitoring purposes.

Methotrexate Triglutamate as a Determinant of Clinical Response in Mexican Patients With Rheumatoid Arthritis: Pharmacokinetics and Dose Recommendation.

Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low-dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra-performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real-time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed-effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1-compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m2 ) * (red blood cells/4.6 × 106 cells/µL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.

Urinary Metabolomic Profile of Neonates Born to Women with Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is one of the most frequent pregnancy complications with potential adverse outcomes for mothers and newborns. Its effects on the newborn appear during the neonatal period or early childhood. Therefore, an early diagnosis is crucial to prevent the development of chronic diseases later in adult life. In this study, the urinary metabolome of babies born to GDM mothers was characterized. In total, 144 neonatal and maternal (second and third trimesters of pregnancy) urinary samples were analyzed using targeted metabolomics, combining liquid chromatographic mass spectrometry (LC-MS/MS) and flow injection analysis mass spectrometry (FIA-MS/MS) techniques. We provide here the neonatal urinary concentration values of 101 metabolites for 26 newborns born to GDM mothers and 22 newborns born to healthy mothers. The univariate analysis of these metabolites revealed statistical differences in 11 metabolites. Multivariate analyses revealed a differential metabolic profile in newborns of GDM mothers characterized by dysregulation of acylcarnitines, amino acids, and polyamine metabolism. Levels of hexadecenoylcarnitine (C16:1) and spermine were also higher in newborns of GDM mothers. The maternal urinary metabolome revealed significant differences in butyric, isobutyric, and uric acid in the second and third trimesters of pregnancy. These metabolic alterations point to the impact of GDM in the neonatal period.

Placental exosomes viewed from an 'omics' perspective: implications for gestational diabetes biomarkers identification.

Exosomes are defined as extracellular vesicles that are released from cells upon fusion of an intermediate endocytic compartment - the multivesicular body - with the plasma membrane. Recently, placenta-derived exosomes have gained special attention, since they play a crucial role in the communication between the mother and fetus. It is known that the concentration of placenta-derived exosomes in the maternal bloodstream is higher in patients with preeclampsia or gestational diabetes mellitus. However, their composition in terms of the content of proteins, nucleic acids or lipids is uncertain. In this work, we reviewed the recent advances in placental exosomes characterization through omics-based methods, and their potential to predict gestational diabetes mellitus.

IgG4 deposits in pure and combined membranous lupus nephritis.

The aim of this study is to determine the frequency and prognosis of IgG4 deposits in renal biopsy of patients with membranous lupus nephritis (MLN). This is a retrospective cohort study in which we included patients with class V alone or combined (III/V or IV/V) of lupus nephritis according to the 2004 ISN/RPS. All the patients included must have availability of renal tissue for immunohistochemistry analyses. We excluded other classes of lupus nephritis. The renal tissue was examined by a nephro-pathologist. We included 65 patients with MLN; of these, 24 (37 %) were class V, and the other had proliferative concomitant with membranous patterns. Seven renal specimens had IgG4 deposits (10 %). Patients with IgG4 deposits had higher levels of eosinophils in serum. All of the patients with IgG4 had renal involvement as first manifestations of systemic lupus erythematosus. The rate of renal failure was 42 and 43 % in IgG4 positive and negative, respectively, 28 % of IgG4 required renal replacement therapy. From a histological view, 42 % of IgG4 had evidence of arteriolar vasculitis in renal biopsies. Lupus patients with IgG4 deposits were more likely to have renal involvement as a first manifestation of systemic lupus erythematosus, and they course with a worse prognosis since they required more dialysis. Also, they have more probability of vascular inflammation on the renal biopsy.

IgG4-related disease, retrospective histopathological diagnosis. Prevalence in a University Hospital.

INTRODUCTION: IgG4 related diseases (IgG4-RD) are characterized mainly by organic dysfunction and inflammation with lymphoplasmacytic cells infiltration. METHODS: We conducted a retrospective study. We analyzed patients with a diagnosis of IgG4-RD through histopathologic registries. We divided the study into three phases: (i)extraction of data from the registries of the Pathology Department, including specimens reported with: non-specific inflammation with plasmatic cell infiltration, inflammatory pseudo-tumors and storiform fibrosis, and excluding any report of cancer or infection; (ii)from the selected specimens, three pathologists microscopically re-analyzed these biopsies and included only those who had at least two of the inclusion criteria cited above; (iii)finally, immunostaining was performed in the specimens selected in the second phase. The selected biopsies were catalogued as compatible for IgG4-RD if they had at least 3 inclusion criteria and as probable if they had 2 inclusion criteria. RESULTS: On the first phase of the study we analyzed 23,720 biopsies, from which we included 71 and excluded 29 specimens; the rest of the specimens (n=41) underwent immunostaining. From the biopsies included, 41.4% (n=17/71) were positive to IgG4, with the most common histological diagnosis for the positive specimens being granulomatous mastitis, which represented 12.1% of the specimens catalogued initially as probable. The rest of the positive biopsies were from aortitis, dacrioadenitis and/or sialoadenitis, lung pseudo-inflammatory tumor, pericarditis and chronic pancreatitis. CONCLUSIONS: The suspicion of IgG4 related disease should not be based solely on clinical manifestations or serology. In the present study we confirm the characteristic changes of IgG4-RD in patients without initial clinical suspicion.

Antinuclear antibodies recognize cellular autoantigens driven by apoptosis.

OBJECTIVE: Present study addresses the issue whether cellular antigens recognised by antinuclear autoantibodies are driven by apoptosis. MATERIALS AND METHODS: HEp-2 cells were committed to apoptosis by camptothecin; DNA fragmentation and FasL and Bax expression monitored apoptosis. Autoantigens were probed by indirect immunofluorescence and Western blot with autoantibodies or monoclonals against: DNA, Ro60, La, U1-RNP, CENP-B, DNA Topoisomerase I, Jo-1 and NuMA. A comparison of antinuclear antibody reactivity between living and apoptotic cells was performed by ELISA. RESULTS: Apoptotic changes such as chromatin fragmentation, blebs and apoptotic bodies were induced with 20 mM camptothecin. Autoantigens were better detected in apoptotic cells. U1-RNP, Jo1, DNA-Topoisomerase I, CENP-B and NuMA exhibited fragmentation and redistribution as a consequence of apoptosis; in contrast, Ro60 and La ribonucleoproteins did not show proteolysis. Additionally the ELISA titers of antinuclear antibodies were higher in apoptotic cells than in normal cells. CONCLUSION: Apoptosis induces molecular changes in different autoantigens, this modification increases the antigen-driven response of autoantibodies such as anti-RNP, anti-DNA Topoisomerase I, anti-CENP-B and anti-Jo1. Apoptotic changes would contribute to break down the tolerance in autoimmune connective tissue disease.

Invasive fungal infections in patients with systemic lupus erythematosus.

OBJECTIVE: Invasive fungal infections (IFI) are catastrophic diseases associated with a high mortality. Relatively few cases of IFI have been described in systemic lupus erythematosus (SLE) and their related factors have not been completely explored. We evaluated factors associated with IFI in patients with SLE. METHODS: All patients with both IFI and SLE admitted to our hospital in the last 7 years were evaluated and each was compared with 5 hospitalized patients with SLE (controls). Demographic factors, duration of SLE, and treatment in the previous month were compared. RESULTS: Sixty patients with SLE were evaluated (10 with IFI and 50 controls). Median age was 29 years. High C-reactive protein levels were associated with IFI, along with other factors such as high disease activity, mechanical ventilation, treatment with antibiotics, hemodialysis, high doses of glucocorticoids (GC), and treatment with mycophenolate mofetil. Mortality was 4 times more frequent in patients with IFI than in SLE patients without the deep fungal infection. CONCLUSION: IFI is a rare infection observed in patients with rheumatic diseases. We describe factors associated with IFI in patients with SLE. IFI is associated with elevated morbidity and mortality. Early diagnosis and treatment are desirable.