Antibodies to Malondialdehyde-Acetaldehyde Adduct Are Associated with Prevalent and Incident Rheumatoid Arthritis-Associated Interstitial Lung Disease in U.S. Veterans.

OBJECTIVE: To determine the associations of protein-specific anti-malondialdehyde acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis-interstitial lung disease (RA-ILD). METHODS: Within a multicenter, prospective cohort of U.S. Veterans with RA, RA-ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA-albumin, MAA-collagen, MAA-fibrinogen, and MAA-vimentin (IgA, IgM, and IgG) were measured by a standardized ELISA. Associations of anti-MAA antibodies with prevalent and incident RA-ILD were assessed using multivariable regression models adjusting for established RA-ILD risk factors. RESULTS: Among 2,739 RA participants (88% male, mean age 64 years), there were 114 prevalent and 136 incident RA-ILD cases (average time to diagnosis: 6.6 years). Higher IgM anti-MAA-collagen (per 1 SD: aOR 1.28 [1.02-1.61]), IgA anti-MAA-fibrinogen (aOR 1.48 [1.14-1.92]), and IgA (aOR 1.78 [1.34-2.37]) and IgG (aOR 1.48 [1.14-1.92]) anti-MAA-vimentin antibodies were associated with prevalent RA-ILD. In incident analyses, higher IgA (per 1 SD: aHR 1.40 [1.11-1.76]) and IgM (aHR 1.29 [1.04-1.60]) anti-MAA-albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13 [1.16-3.90]) or IgM (aHR 1.98 [1.08-3.64]) anti-MAA-albumin antibody concentrations in the highest quartile had an approximate 2-fold increased risk of incident RA-ILD. Across all isotypes, anti-MAA-fibrinogen, -collagen, and -vimentin antibodies were not significantly associated with incident RA-ILD. CONCLUSIONS: Protein-specific anti-MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA-ILD. IgA and IgM anti-MAA-albumin antibodies were associated with a higher risk of incident RA-ILD. These findings suggest that MAA-modifications and resultant immune responses may contribute to RA-ILD pathogenesis.

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival.

Background: Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA validation in multiple IPF lung compartments and cohorts we explored novel markers of IPF survival. Methods: In our discovery analysis, agnostic label-free quantitative proteomics differentiated lung tissue protein expression based on survival trajectory (n=10). Following selection of the candidate pathway (neutrophil extracellular trap (NET) formation), we subsequently validated the presence of NETs in the IPF lung microenvironment using fully quantitative assays of known NET remnants in separate IPF cohorts (n=156 and n=52) with bronchoalveolar lavage fluid. We then assessed the correlation of these markers with baseline pulmonary function and survival. Results: Discovery lung tissue proteomics identified NET formation as significantly associated with poor IPF survival. Using fully quantitative confirmatory tests for reproducibility we confirmed the presence of NET markers in IPF BALF and found significant correlations with worse pulmonary function in both cohorts (p<0.03 and p = 0.04 respectively). In the survival cohort, higher levels of NET markers predicted worse survival after adjusting for gender, age, and baseline physiologic severity (hazard ratio range: 1.79-2.19). Conclusions: NET markers were associated with disease severity and worse survival in IPF. These findings suggest NET formation contributes to lung injury and decreased survival in IPF and may represent a potential therapeutic target.

Connective Tissue Disease Associated Interstitial Lung Disease.

Connective tissue disease associated interstitial lung disease (CTD-ILD) is a heterogenous collection of conditions with a diverse spectrum of interstitial lung disease (ILD) manifestations. Currently, clinical practice of lung-directed immunosuppression in CTD-ILD is supported by several randomized, placebo-controlled trials (RCTs) in patients with scleroderma and several observational, retrospective studies in other autoimmune conditions. However, given the harm of immunosuppression in idiopathic pulmonary fibrosis, there is an urgent need for RCTs of immunosuppression and antifibrotic agents in fibrotic CTD-ILD populations as well as the study of intervention in patients with subclinical CTD-ILD.

Treatment Outcomes for Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Real-World, Multisite Study of the Impact of Immunosuppression on Pulmonary Function Trajectory.

BACKGROUND: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is common in patients with RA and leads to significant morbidity and mortality. No randomized, placebo-controlled data are available that support the role of immunosuppression to treat RA-associated ILD, despite being widely used in clinical practice. RESEARCH QUESTION: How does immunosuppression impact pulmonary function trajectory in a multisite retrospective cohort of patients with RA-associated ILD? STUDY DESIGN AND METHODS: Patients with RA who started treatment for ILD with mycophenolate, azathioprine, or rituximab were identified retrospectively from five ILD centers. Change in lung function before and after treatment was analyzed using a linear spline mixed-effect model with random intercept. Prespecified secondary analyses examined the impact of radiologic pattern of ILD (ie, usual interstitial pneumonia [UIP] vs non-UIP) on treatment trajectory. RESULTS: Two hundred twelve patients were included in the analysis: 92 patients (43.4%) were treated with azathioprine, 77 patients (36.3%) were treated with mycophenolate mofetil, and 43 patients (20.3%) were treated with rituximab. In the combined analysis of all three agents, an improvement in FVC % predicted was found after 12 months of treatment compared with the potential 12-month response without treatment (+3.90%; P ≤ .001; 95% CI, 1.95-5.84). Diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted also improved at 12 months (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Neither the UIP pattern of ILD nor choice of immunosuppressive agent significantly impacted the pulmonary function trajectory on immunosuppression. INTERPRETATION: Immunosuppression was associated with an improved trajectory in FVC and Dlco compared with the pretreatment pulmonary function trajectory. Prospective, randomized trials are required to validate these findings.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Airway Disease in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a common condition affecting approximately 1% of the general population. RA is a multisystem disorder that causes progressive articular destruction through synovial inflammation. One of the most common extraarticular manifestations of RA is pulmonary involvement, where all compartments of the pulmonary system can be impacted (e.g., pulmonary vasculature, pleura, parenchyma, and the airways). Although it has been known for decades that a portion of patients with RA develop interstitial lung disease, and recent advancements in understanding the genetic risk and treatment for RA-interstitial lung disease have drawn attention, more recent data have begun to highlight the significance of airway disease in patients with RA. Yet, little is known about the underlying pathogenesis, clinical impact, or optimal treatment strategies for airway disease in RA. This review will focus on airway disease involvement in patients with RA by highlighting areas of clinical inquiry for pulmonologists and rheumatologists and discuss areas for future research. Finally, we discuss a potential screening algorithm for providers when approaching patients with RA with respiratory complaints.

Essential Components of an Interstitial Lung Disease Clinic: Results From a Delphi Survey and Patient Focus Group Analysis.

BACKGROUND: Management of patients with interstitial lung disease (ILD) requires subspecialized, comprehensive, multidisciplinary care. The Pulmonary Fibrosis Foundation established the Care Center Network (CCN) in 2013 with identified criteria to become a designated CCN site. Despite these criteria, the essential components of an ILD clinic remain unknown. RESEARCH QUESTIONS: How are ILD clinics within the CCN structured? What are the essential components of an ILD clinic according to ILD physician experts, patients, and caregivers? STUDY DESIGN AND METHODS: This study had three components. First, all 68 CCN sites were surveyed to determine the characteristics of their current ILD clinics. Second, an online, three-round modified Delphi survey was conducted between October and December 2019 with 48 ILD experts participating in total. Items for round 1 were generated using expert interviews. During rounds 1 and 2, experts rated the importance of each item on a 5-point Likert scale. The a priori threshold for consensus was more than 75% of experts rating an item as important or very important. In round 3, experts graded items that met consensus and ranked items deemed essential for an ILD clinic. Third, ILD patient and caregiver focus groups were conducted and analyzed for content to determine their perspectives of an ideal ILD clinic. RESULTS: Forty items across four categories (members, infrastructure, resources, and multidisciplinary conference) achieved consensus as essential to an ILD clinic. Patient and caregiver focus groups identified three major themes: comprehensive, patient-centered medical care; expanded access to care; and comprehensive support for living and coping with ILD. INTERPRETATION: The essential components of an ILD clinic are well-aligned between physician experts and patients. Future research can use these findings to evaluate the impact of these components on patient outcomes and to inform best practices for ILD clinics throughout the world.

Two sides of the same coin? A review of the similarities and differences between idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) are distinct diseases; however, they share several clinical, radiographic and genetic features. For instance, usual interstitial pneumonia (UIP), which is an ILD pattern required for a diagnosis of IPF, is also the most common ILD pattern in RA-ILD. The presence of UIP in RA-ILD is a poor prognostic sign with outcomes similar to those seen in IPF. The recent finding of a shared genetic susceptibility between IPF and RA-ILD has sparked additional interest in this relationship. This review outlines these similarities and differences in clinical presentation, appearance and outcomes in RA-ILD and IPF.In addition, this review highlights previous research in molecular biomarkers in both conditions, exploring areas of overlap and distinction. This focus on biomarkers in IPF and RA-ILD aims to highlight potential areas of discovery and clues to a potential shared pathobiology through investigation of novel molecular markers or the repurposing of biomarkers from one condition to the other.The drive to better understand RA-ILD by leveraging our knowledge of IPF is underscored by our divergent treatment paradigms for these conditions and the concern for potential harm. As a result of advancing our understanding of the links between IPF and RA-ILD, current strategies for diagnosis, screening and treatment of ILD may fundamentally change in the coming years. Until then, clinicians face difficult clinical questions regarding the co-management of the articular disease and the ILD in RA.

IgA Antibodies Directed Against Citrullinated Protein Antigens Are Elevated in Patients With Idiopathic Pulmonary Fibrosis.

BACKGROUND: The etiology of idiopathic pulmonary fibrosis (IPF) is unknown. Because it shares genetic, histopathologic, and radiographic features with the fibrosing interstitial lung disease seen in rheumatoid arthritis (RA), the goal of this study was to investigate RA-related autoantibodies in IPF. METHODS: The study included patients with IPF from two separate cohorts at National Jewish Health and Brigham Women's Hospital (n = 181), general population control subjects (n = 160), and control subjects with disease (n = 86 [40 with RA-usual interstitial pneumonia and 46 with hypersensitivity pneumonitis]). Serum was tested for RA-associated antibodies (including IgG and IgA) to citrullinated protein antigens (ACPA). Lung tissue in 11 patients with IPF was examined for ectopic lymphoid aggregates. RESULTS: An increased prevalence of ACPA positivity was found in two separate IPF cohorts. In particular, positivity for IgA-ACPA was increased in these two IPF cohorts compared with general population control subjects (21.3% and 24.8% vs 5.6%; P < .01). Patients with IPF were more likely to be IgA-ACPA-positive than IgG-ACPA-positive (23.2% vs 8.3%; P < .01), whereas patients with RA were more likely to be IgG-ACPA-positive than IgA-ACPA-positive (72.5% vs 52.5%; P = .04). There was a strong correlation between IgA-ACPA level and the number of ectopic lymphoid aggregates on lung histologic examination in IPF (r = 0.72; P = .01). CONCLUSIONS: In this study, IgA-ACPA was elevated in patients with IPF and correlated with lymphoid aggregates in the lung, supporting the theory that IgA-ACPA may play a role in lung disease pathogenesis in a subset of individuals with IPF. Future studies are needed to determine whether this subset of ACPA-positive patients with IPF is distinct from patients with IPF but without antibodies.

Pseudoaneurysm of the facial artery as a late complication of bilateral sagittal split osteotomy and facial trauma.

Pseudoaneurysms, or arteriovenous fistulas, of the extracranial arterial system, particularly the facial artery, are rare. Its occurrence after reconstructive facial surgery has been reported rarely in the literature. In this article we describe a rare case of pseudoaneurysm developing over 4 weeks after an uneventful Le Fort I maxillary osteotomy, sagittal split osteotomy, and advancement genioplasty. A 22-year-old man presented with a severe class III skeletal deformity, mandibular hyperplasia, and maxillary hypoplasia. The patient's immediate postoperative course was uneventful for a 2-week period after surgery. Then the patient, while at home, experienced an accidental injury to his jaw and started to bleed from his left retromandibular side. He was taken to a local hospital where his bleeding was controlled by topical coagulant and pressure. During this short hospital visit he was given 3 units of blood and was subsequently discharged. He had no further bleeding and was monitored on a regular basis. One month after his double jaw surgery and 2 weeks after his bleeding episode, the left facial swelling diminished in size but was still visible. This mass was soft and pulsatile with a palpable thrill and auditory machinery murmur on auscultation. Although the patient was totally asymptomatic at this time, he was sent to the emergency room for a computerized tomography scan with 3-dimensional reconstruction. A Doppler ultrasound was also ordered. The ultrasound revealed the mass to be a pseudoaneurysm. Angiography revealed a pseudoaneurysm of the left facial artery. Coil embolization of the left facial artery was performed with a Cordis Trufill complex coil. The patient tolerated the procedure well and a repeat angiogram demonstrated no further evidence of aneurysm, arteriovenous malformation, vasospasm, or feeding branches to the fistula. The patient made an uneventful recovery and was discharged the day after the procedure. In this article, we review the anatomy of the extracranial arterial system of the head and neck, discuss the pathogenesis and clinical presentation of pseudoaneurysm, and present diagnostic imaging and treatment options for pseudoaneurysms of the face.

Maternal group B streptococcal (GBS) genital tract colonization at term in women who have asymptomatic GBS bacteriuria.

OBJECTIVE: To determine the rate of positive group B streptococcus (GBS) cultures at 35-37 weeks gestation in women who have first trimester asymptomatic GBS bacteriuria. METHODS: Pregnant women with asymptomatic first trimester GBS bacteriuria had genital cultures for GBS performed at 35-37 weeks gestational age. Serotyping was performed by the standard Lancefield capillary precipitin method. RESULTS: Fifty-three women with positive urine cultures had genital cultures performed at 35-37 weeks. Sixteen of the 53 (30.2%; 95% confidence interval: 18.4-44.3%) third trimester vaginal cultures were positive for GBS. Five of eight (63%) of the women with typable urine serotypes had the same typable serotype in the third trimester genital culture. CONCLUSION: Genital tract cultures at 35-37 weeks for GBS correlate poorly with first trimester asymptomatic GBS bacteriuria. Recommendations for GBS prophylaxis in labor in women who have first trimester asymptomatic GBS bacteriuria should be investigated further and reconsidered.