Idiopathic inflammatory myopathies (IIM) are characterized by muscle inflammation and weakness, myositis-specific autoantibodies (MSAs), and extramuscular organ damage. The role of neutrophil dysregulation and neutrophil extracellular traps (NETs) in IIM is unclear. We assessed whether pathogenic neutrophil subsets (low-density granulocytes [LDGs]) and NETs were elevated in IIM, associated with clinical presentation and MSAs, and their effect on skeletal myoblasts and myotubes. Circulating NETs and LDGs were quantified and correlated with clinical measures. Specific MSAs were tested for their ability to induce NETs. NETs and neutrophil gene expression were measured in IIM biopsies. Whether NETs damage skeletal myoblasts and myotubes was tested. Circulating LDGs and NETs were increased in IIM. IIM LDGs had an enhanced ability to form NETs. LDGs and NETs correlated with IIM disease activity and muscle damage. The serum MSA anti-MDA5 correlated with circulating and tissue NETs and directly enhanced NET formation. An enhanced neutrophil gene signature was present in IIM muscle and associated with muscle injury and tissue IFN gene signatures. IIM NETs decreased the viability of myotubes in a citrullinated histone-dependent manner. Dysregulated neutrophil pathways may play pathogenic roles in IIM through their ability to directly injure muscle cells and other affected tissues.

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages’ supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.

Skeletal muscle is one of the most abundant tissues of the human body and is responsible for the generation of movement. Muscle injuries can lead to severe disability. Skeletal muscle is characterized by an important regeneration capacity, which is possible due to the interaction between the myoblasts and immune cells. Neutrophils are fundamental as inducers of muscle damage and as promoters of the initial inflammatory response which eventually allows the muscle repair. The main functions of the neutrophils are phagocytosis, respiratory burst, degranulation, and the production of neutrophil extracellular traps (NETs). An overactivation of neutrophils after muscle injuries may lead to an expansion of the initial damage and can hamper the successful muscle repair. The importance of neutrophils as inducers of muscle damage extends beyond acute muscle injury and recently, neutrophils have become more relevant as part of the immunopathogenesis of chronic muscle diseases like idiopathic inflammatory myopathies (IIM). This heterogeneous group of systemic autoimmune diseases is characterized by the presence of muscle inflammation with a variable amount of extramuscular features. In IIM, neutrophils have been found to have a role as biomarkers of disease activity, and their expansion in peripheral blood is related to certain clinical features like interstitial lung disease (ILD) and cancer. On the other hand, low density granulocytes (LDG) are a distinctive subtype of neutrophils characterized by an enhanced production of NETs. These cells along with the NETs have also been related to disease activity and certain clinical features like ILD, vasculopathy, calcinosis, dermatosis, and cutaneous ulcers. The role of NETs in the immunopathogenesis of IIM is supported by an enhanced production and deficient degradation of NETs that have been observed in patients with dermatomyositis and anti-synthetase syndrome. Finally, new interest has arisen in the study of other phenotypes of LDG with a phenotype corresponding to myeloid-derived suppressor cells, which were also found to be expanded in patients with IIM and were related to disease activity. In this review, we discuss the role of neutrophils as both orchestrators of muscle repair and inducers of muscle damage, focusing on the immunopathogenesis of IIM.

Background: Most of the explanatory and prognostic models of COVID-19 lack of a comprehensive assessment of the wide COVID-19 spectrum of abnormalities. The aim of this study was to unveil novel biological features to explain COVID-19 severity and prognosis (death and disease progression).Methods: A predictive model for COVID-19 severity in 121 patients was constructed by ordinal logistic regression calculating odds ratio (OR) with 95% confidence intervals (95% CI) for a set of clinical, immunological, metabolomic, and other biological traits. The accuracy and calibration of the model was tested with the area under the curve (AUC), Somer’s D, and calibration plot. Hazard ratios with 95% CI for adverse outcomes were calculated with a Cox proportional-hazards model.Results: The explanatory variables for COVID-19 severity were the body mass index (BMI), hemoglobin, albumin, 3-Hydroxyisovaleric acid, CD8+ effector memory T cells, Th1 cells, low-density granulocytes, monocyte chemoattractant protein-1, plasma TRIM63, and circulating neutrophil extracellular traps. The model showed an outstanding performance with an optimism-adjusted AUC of 0.999, and Somer’s D of 0.999. The predictive variables for adverse outcomes in COVID-19 were severe and critical disease diagnosis, BMI, lactate dehydrogenase, Troponin I, neutrophil/lymphocyte ratio, serum levels of IP-10, malic acid, 3, 4 di-hydroxybutanoic acid, citric acid, myoinositol, and cystine.Conclusions: Herein, we unveil novel immunological and metabolomic features associated with COVID-19 severity and prognosis. Our models encompass the interplay among innate and adaptive immunity, inflammation-induced muscle atrophy and hypoxia as the main drivers of COVID-19 severity.

Background: Colchicine is an available, safe, and effective anti-inflammatory drug and has been suggested as a COVID-19 treatment, but its usefulness in hospitalized severe COVID-19 patients has not been thoroughly demonstrated. Objective: To address the safety and efficacy of colchicine in hospitalized patients with severe COVID-19. Design: We conducted a triple-blind parallel non-stratified placebo-controlled clinical trial. Participants: We recruited 116 hospitalized patients with severe COVID-19 in Mexico. Interventions: Patients were randomized to receive 1.5 mg of colchicine or placebo at the time of the recruitment in the study (baseline) and 0.5 mg BID PO to complete 10 days of treatment. Main Measures: The primary composite outcome was the progression to critical disease or death. Besides, we evaluated immunological features at baseline and after recovery or disease progression in 20 patients. Key Results: Fifty-six patients were allocated to colchicine and 60 patients received placebo. The study was suspended after the second interim analysis demonstrated colchicine had no effect on the primary outcome (OR 0.83, 95%CI 0.35–1.93, P = 0.67), nor in the days of ICU and hospital stays. Adverse events were similar between groups (OR 1.63, 95% CI 0.66–3.88, P = 0.37). After colchicine treatment, patients had higher BUN and lower serum levels of IL-8, IL-12p70, and IL-17A. Conclusions: Colchicine is safe but not effective in the treatment of severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04367168.

Objective.: The aim of this study was to describe the prevalence of erectile dysfunction (ED), as well as associated demographic and clinical features, in men with systemic lupus erythematosus (SLE), by means of a systematic, standardized evaluation.Methods.: We performed a transversal study in 8 tertiary care centers in Latin America. We included male patients ≥ 16 years who fulfilled ≥ 4 American College of Rheumatology criteria for SLE and had regular sexual activity, and evaluated them with the International Index of Erectile Function-5 questionnaire. Relevant demographic, clinical, and serological characteristics were recorded. We included 2 control groups: the first was made up of healthy men and the second of men with autoimmune diseases other than SLE (non-SLE group).Results.: We included 590 subjects (174 SLE, 55 non-SLE, and 361 healthy controls). The prevalence of ED in the SLE group was 69%. Mean age in that group was 36.3 ± 1.03 years. Among SLE patients with and without ED, these factors were significantly different: the presence of persistent lymphopenia (p = 0.006), prednisone dose (9.3 ± 1.2 vs 5.3 ± 1.3 mg, p = 0.026), and the Systemic Lupus International Collaborating Clinics damage score (1.25 ± 0.14 vs 0.8 ± 0.16 points, p = 0.042). Independent risk factors for ED in patients with SLE were persistent lymphopenia (OR 2.79, 95% CI 1.37–5.70, p = 0.001) and corticosteroid use in the previous year (OR 2.15, 95% CI 1.37–3.37, p = 0.001).Conclusion.: Regardless of comorbidities, treatment (excluding steroids), and type of disease activity, patients with SLE have a high prevalence of ED, especially considering that most patients are young. Recent corticosteroid use and persistent lymphopenia, which could be related to endothelial dysfunction, are risk factors for this complication in men with SLE.