Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model.

Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.

Clinical Manifestations and Long-Term Outcomes of Eosinophilic Granulomatosis With Polyangiitis in North America.

OBJECTIVE: To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. METHODS: Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied. RESULTS: The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow-up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow-up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow-up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow-up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores. CONCLUSION: This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long-term remission to limit the accrual of disease-related damage.

New-onset non-infectious pulmonary manifestations among patients with systemic lupus erythematosus in Sweden.

OBJECTIVE: The objective was to estimate the incidence of lung disease among patients with systemic lupus erythematosus (SLE). METHODS: Using Swedish register data, we identified patients with SLE and pulmonary diagnoses from the National Patient Register through ICD codes. We matched patients with SLE with individuals from the general population. Patients with SLE with a history of pulmonary disease were excluded. Incidence rates (IR) and 95% confidence intervals (CI) were calculated overall and by type of pulmonary disease for incident (2003-2013) and prevalent SLE separately. Hazard ratios (HR) and 95% CI of the association between SLE and pulmonary disease were estimated using adjusted Cox regression models. Sensitivity analyses using a semi-automated approach to quantitative probabilistic bias analysis accounted for potential bias due to unmeasured confounding by smoking. RESULTS: There were 3209 incident and 6908 prevalent cases of SLE identified. The IRs for pulmonary disease were similar in prevalent and incident SLE (∼14 cases per 1000 person-years). Patients with incident SLE had a nearly sixfold higher rate of pulmonary disease compared to the non-SLE population (HR 5.8 (95% CI 4.8-7.0)). Incident and prevalent SLE was associated with an increased rate of interstitial lung disease (HR 19.0 (95% CI 10.7-34.0) and 14.3 (95% CI 10.8-18.8), respectively). Bias due to unmeasured confounding by smoking was unlikely to explain our findings. CONCLUSION: Lung disease is relatively common in patients with SLE compared to the general population. Clinicians caring for patients with SLE should have heightened suspicion of lung disease, including interstitial lung disease, even early within the disease course or at the time of diagnosis of SLE.

Low prevalence of coeliac disease in patients with systemic sclerosis: a cross-sectional study of a registry cohort.

OBJECTIVES: Two prior studies suggested that coeliac disease (CD) has a higher prevalence rate (8%) in SSc than in the general population (1%), but these studies were limited by small numbers and the use of traditional coeliac screening antibody tests, where newer ones with improved accuracy have since emerged. Our aim was to determine the prevalence of CD in a larger SSc population using a more modern serological approach to coeliac testing and to correlate coeliac antibody status with gastrointestinal symptoms. METHODS: Stored sera from 72 SSc patients in the Scleroderma Registry at the Hospital for Special Surgery were tested for anti-tissue transglutaminase (traditional) and anti-deamidated gliadin peptide (novel) antibodies. If any of these antibodies were positive, anti-endomysial antibodies were tested and confirmatory small-bowel endoscopy and biopsy were obtained. Registry clinical data were used to determine whether antibody status correlated with gastrointestinal symptoms. RESULTS: The prevalence of coeliac antibodies in our SSc population was 3/72 (4%). No significant differences with respect to gastrointestinal symptoms were seen in the coeliac antibody-positive compared with -negative SSc patients. No cases of confirmed CD were seen in our cohort. CONCLUSION: Contrary to the only two previously published studies, the low prevalence of CD that we found does not suggest that concurrent CD is a common cause of gastrointestinal complaints in SSc patients.

The broad spectrum of urate crystal deposition: unusual presentations of gouty tophi.

OBJECTIVES: Gout is typically described as an inflammatory arthropathy that affects the peripheral joints. Our aim was to describe atypical and rare clinical presentations of gouty tophi to help increase physician awareness and aid in patient care. METHODS: The relevant English literature of unusual gout manifestations was searched using the keywords gout, toph*, monosodium urate, uric acid, unusual, and rare. Well-described case reports, case series, and review articles were evaluated and included, if relevant, in the literature review. RESULTS: Review of the literature revealed many unusual manifestations of gouty tophi involving the head and neck, skin, viscera, bones, tendons, ligaments, nerves, and axial skeleton. Transplant recipients, women, and elderly people are particularly susceptible to developing tophi. Furthermore, gout can cause diagnostic dilemmas, as it can be a great mimicker of and can coexist with infection, malignancy, and other connective tissue diseases. Imaging modalities can help detect tophi in atypical locations. CONCLUSIONS: Tophi can present in unexpected locations, even as the first sign of gout, and vigilance is required when unusual symptoms or signs occur in a patient with gout.