Javier Merayo-Chalico

Factors associated with mortality and infections in patients with systemic lupus erythematosus with diffuse alveolar hemorrhage.

Objective. To evaluate factors associated with mortality and infections in patients with systemic lupus erythematosus (SLE) and diffuse alveolar hemorrhage (DAH). Methods. A retrospective chart review was carried out for medical admissions of patients with a diagnosis of SLE and DAH in 9 hospitals. Clinical and laboratory data were recorded for each patient at DAH diagnosis. Results. We included 57 episodes of DAH of 50 patients (7 recurrences), 49 women (86%), 14 juvenile SLE (24.6%); 24 had died (42.1%). In the chart review we detected infection in 22 episodes (38.6%): 8 invasive fungal infections, 16 bacterial infections, and 2 patients had both types. In the bivariate analysis, factors associated with mortality were high Acute Physiology and Chronic Health Evaluation II scores, requirement of mechanical ventilation (OR 15.0, 95% CI 1.9 to 662.2), infections (fungal or bacterial; OR 3.2, CI 0.9 to 11.1), renal failure (OR 4.9, CI 1.4 to 18.0), and thrombocytopenia (OR 4.3, CI 1.2 to 15.6). We found similar mortality between children and adults. Infections were associated with treatment for SLE, requirement of mechanical ventilation, hypocomplementemia, and high levels of C-reactive protein. Conclusion. Infection is a frequent finding in patients with DAH and SLE; we found similar mortality between adult SLE and juvenile SLE. Factors that we describe associated with infections may influence the therapeutic selection for these patients.

Lymphopenia and autoimmunity: A double-edged sword.

Lymphopenia is strongly associated with autoimmune diseases. The molecular mechanisms that link both phenomena are still unclear, but certain key pathways have been described. Central tolerance is as important as peripheral. In the earlier, epithelial and dendritic cells play a crucial role in the selection of clones. In the latter, regulatory T cells (Tregs) rise as inductors of anergy in order to prevent the development of autoimmune pathology. In lymphopenic conditions, T cells develop the process of lymphopenia-induced proliferation (LIP). A complex interaction between the major histocompatibility complex (MHC) and the T cell receptor (TCR) makes this process possible. Furthermore, IL-7 can act synergistically or in an independent manner to promote LIP. A lack of Transforming Growth Factor-β (TGF-β) was recently described as the second hit needed to develop autoimmunity in a lymphopenic microenvironment, given its actions in Tregs and its interaction with CTLA-4. Regarding autoimmune clinical scenarios, lymphopenia is related to both, systemic and organ-specific diseases. Thus, the molecular study of such patients has been limited and needs to be widened to the pathways shown here to be involved in the development of lymphopenia and autoimmunity.

Clinical outcomes and risk factors for posterior reversible encephalopathy syndrome in systemic lupus erythematosus: a multicentric case–control study

Background Posterior reversible encephalopathy syndrome (PRES) is a well-known but rare complication in patients (<1%) with systemic lupus erythematosus (SLE). However, current epidemiological data are quite scant. The aim of the present study was to describe potentially unrecognised risk factors. Patients and methods We performed a multicentre, retrospective case–control study in Mexico between 1999 and 2014. We included a total of 168 patients who accounted for 77 episodes of PRES, as follows: SLE/PRES, 43 patients with 48 episodes; SLE without PRES, 96 patients; and PRES without SLE, 29 patients. SLE diagnosis was considered when patients fulfilled ≥4 American College of Rheumatology criteria. PRES was defined by reversible neurological manifestations and MRI changes. Results Patients with SLE/PRES were younger, presented with seizures as the most common manifestation (81%) and 18% had the typical occipital MRI finding. Hypertension (OR=16.3, 95% CI 4.03 to 65.8), renal dysfunction (OR=6.65, 95% CI 1.24 to 35.6), lymphopenia (OR=5.76, 95% CI 1.36 to 24.4), Systemic Lupus Erythematosus Activity Index ≥ 6 points (OR=1.11, 95% CI 1.01 to 1.22) and younger age (OR=0.86, 95% CI 0.81 to 0.91, p<0.001) were independent risk factors for development of PRES in SLE. Furthermore, dyslipidemia also characterised the association between PRES and SLE (OR=10.6, 95% CI 1.17 to 96.4). Conclusions This is the largest reported series of patients with SLE and PRES. We were able to corroborate the known risk factors for of PRES, and found two previously undescribed factors (lymphopenia and dyslipidemia), which suggests that endothelial dysfunction is a key element in PRES pathogenesis in lupus patients.

Renal Thrombotic Microangiopathy in Proliferative Lupus Nephritis: Risk Factors and Clinical Outcomes: A Case-Control Study.

BackgroundRenal thrombotic microangiopathy (TMA) may be associated with lupus nephritis. Its relationship to other disease factors and its specific effect on prognosis are not precisely known. Evidence regarding these aspects is controversial, and information focusing on kidney-limited TMA in systemic lupus erythematosus (SLE) patients is scarce. ObjectivesThe aims of this study were to identify risk factors for renal TMA in patients with lupus nephritis and to determine its impact on clinical outcomes. MethodsA case-control study was performed. We studied 245 renal biopsies from SLE patients. We included patients with renal TMA, as well as control subjects adjusted for glomerulonephritis class, estimated glomerular filtration rate, activity and chronicity indices, and follow-up time. Serological and clinical features were measured at the time of the biopsy and during follow-up. ResultsTwenty-three patients with renal TMA and 21 control subjects were included. There were no differences in Systemic Lupus Erythematosus Disease Activity Index score, end-stage renal disease, or mortality between groups during follow-up. After multivariate analysis, lymphopenia (odds ratio, 10.69; 95% CI, 1.35–84.74) and anti-Ro antibody positivity (odds ratio, 8.96; 95% CI, 1.49–53.57) remained significantly associated with renal TMA. ConclusionsLymphopenia and anti-Ro positivity are independent risk factors for renal TMA in SLE patients. This increased risk could be a consequence of the potential role of these factors in endothelial dysfunction and damage. Outcomes were similar for patients with the same estimated glomerular filtration rate and biopsy characteristics, regardless of the presence of TMA.

Risk Factors for Drug-resistant Bloodstream Infections in Patients with Systemic Lupus Erythematosus

Objective. To identify risk factors for developing drug-resistant bacterial infections in patients with systemic lupus erythematosus (SLE). Methods. A retrospective, case-control study was performed. Patients fulfilled American College of Rheumatology criteria for SLE and had an episode of bloodstream infection between 2001 and 2012. Cases were defined as those with bloodstream infection caused by drug-resistant bacteria (Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, or extended-spectrum-β-lactalamase-producing Escherichia coli); while controls had susceptible strains of S. aureus or E. coli. Differences between groups were analyzed by Student t test or Mann-Whitney U test. Association between variables was assessed by OR (CI 95%). Multivariate analysis was performed by binary logistic regression model. Results. Forty-four patients were included in each group. Variables associated with drug-resistant bloodstream infection were history of central nervous system activity; hematological activity, immunosuppressive treatment and prednisone dose at the time of the infection; and low C3 levels, antibiotic use, or hospitalization in the previous 3 months. In multivariate analysis, variables that remained significant were low C3 previous to infection (OR 3.12, CI 95% 1.91–8.22), previous hospitalization (OR 2.22, CI 95% 1.42–4.10), and prednisone dose at the time of infection (OR 1.10, CI 95% 1.04–1.22). Conclusion. Low C3 levels, recent hospitalization, and prednisone dose at time of infection are independent risk factors for acquiring drug-resistant bacteria in patients with SLE. Although the present data do not fully support a change in initial treatment-decision strategies, this information could lead to prospective studies designed to address this issue, which could determine the best approach in clinical practice.

Risk factors for systemic lupus erythematosus flares in patients with end-stage renal disease: a case–control study

OBJECTIVES The aim of this study was to recognize risk factors for extrarenal SLE flares in patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT). METHODS We performed a retrospective, case-control study in a tertiary care hospital in Mexico City from 1993 to 2014. Cases were lupus patients who had any extrarenal flare after RRT. Controls were SLE patients with ESRD but without flares. We recorded demographic features and clinical and immunological parameters. Differences between groups were analysed by Students t-test. Association was assessed by the odds ratio (OR) and 95% CI. Multivariate analysis was performed by binary logistic regression. RESULTS Eighty-eight patients were included: 38 cases (50 flares) and 50 controls. The proportion of men was higher in cases (24 vs 8%, P = 0.029). The most common flares were haematologic (42%), mucocutaneous (38%) and articular (30%). Independent risk factors for flares included age at RRT start [OR 0.92 (95% CI 0.88, 0.96), P < 0.001], history of haematologic activity [OR 3.79 (95% CI 1.05, 13.7), P = 0.04], anti-cardiolipin IgM [OR 4.39 (95% CI 1.32, 14.6), P = 0.02] and low C4 levels [OR 9.7 (95% CI 2.49, 39.12), P = 0.001]. CONCLUSION SLE patients continue to be at risk for extrarenal activity after RRT. The most common flare was haematologic, which correlated with the history of haematologic activity and anti-cardiolipin positivity as independent risk factors. Lower C4 levels and younger age at the beginning of RRT were also associated. Patients with these characteristics should have a closer follow-up in order to detect and treat SLE flares in a timely manner.

Guía de práctica clínica para el manejo del lupus eritematoso sistémico propuesta por el Colegio Mexicano de Reumatología

There are national and international clinical practice guidelines for systemic lupus erythematosus treatment. Nonetheless, most of them are not designed for the Mexican population or are devoted only to the treatment of certain disease manifestations, like lupus nephritis, or are designed for some physiological state like pregnancy. The Mexican College of Rheumatology aimed to create clinical practice guidelines that included the majority of the manifestations of systemic lupus erythematosus, and also incorporated guidelines in controversial situations like vaccination and the perioperative period. The present document introduces the «Clinical Practice Guidelines for the Treatment of Systemic Lupus Erythematosus» proposed by the Mexican College of Rheumatology, which could be useful mostly for non-rheumatologist physicians who need to treat patients with systemic lupus erythematosus without having the appropriate training in the field of rheumatology. In these guidelines, the reader will find recommendations on the management of general, articular, kidney, cardiovascular, pulmonary, neurological, hematologic and gastrointestinal manifestations, and recommendations on vaccination and treatment management during the perioperative period.

Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus

Objectives To assess if ubiquitinated proteins potentially present in neutrophil extracellular traps (NETs) can modify cellular responses and induce inflammatory mechanisms in patients with systemic lupus erythematosus (SLE) and healthy subjects. Materials and methods We studied 74 subjects with SLE and 77 healthy controls. Neutrophils and low-density granulocytes were isolated, and NETs were induced. Ubiquitin content was quantified in NETs by western blot analysis, ELISA and immunofluorescence microscopy, while ubiquitination of NET proteins was assessed by immunoprecipitation. Monocyte-derived macrophages from SLE and controls were isolated and stimulated with NETs or ubiquitin. Calcium flux and cytokine synthesis were measured following these stimuli. Results NETs contain ubiquitinated proteins, with a lower expression of polyubiquitinated proteins in subjects with SLE than in controls. Myeloperoxidase (MPO) is present in ubiquitinated form in NETs. Patients with SLE develop antiubiquitinated MPO antibodies, and titres positively correlate with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (P<0.01), and negatively correlate with complement components (P<0.01). Stimulation of monocyte-derived macrophages with NETs or with ubiquitin led to enhanced calcium flux. In addition, stimulation with NETs led to enhanced cytokine (tumour necrosis factor-α and interleukin-10) production in macrophages from patients with SLE when compared with controls, which was hampered by inhibition of NET internalisation by macrophages. Conclusion This is the first study to find ubiquitinated proteins in NETs, and evidence for adaptive immune responses directed towards ubiquitinated NET proteins in SLE. The distinct differences in ubiquitin species profile in NETs compared with healthy controls may contribute to dampened anti-inflammatory responses observed in SLE. These results also support a role for extracellular ubiquitin in inflammation in SLE.

Differential T cell subsets and cytokine profile between steady-state and G-CSF-primed bone marrow and its association with graft-versus-host disease

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). At our Institution, patients transplanted using G-CSF-primed bone marrow (G-BM), have a lower incidence of GVHD when compared to other sources. The objective of this study was to analyze and compare T cell subsets and cytokines in donor G-BM and steady-state BM (SS-BM). A prospective study was performed in 48 donor samples. Mononuclear cells were isolated by gradient density. T cell subsets and cytokine production in supernatants were analyzed by multiparametric flow cytometry. Six and 16 patients developed acute and chronic GVHD, respectively. Patients who developed GVHD were characterized by a predominant pro-inflammatory response (IL-17A (10.02 vs 0.43pg/mL, p=0.006), TNF-α (54.57 vs 0.81pg/mL, p=0.001)), in contrast to a deficient suppressor profile (IL-10 (7.87 vs 41.37pg/mL, p=0.003)) and Tregs (0.95% vs 1.52%, p=0.004). G-BM showed an enhanced suppressive phenotype (increased Th2 and Tregs) in comparison to SS-BM. GVHD is associated with an imbalance between pro-inflammatory and suppressor immune responses. G-BM showed a more favorable immunologic profile characterized by diminished pro-inflammatory cytokine production, which was associated with a lower frequency of GVHD in our cohort.