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.