Immune-related adverse events in patients with pre-existing autoimmune rheumatologic disease on immune checkpoint inhibitor therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) enhance the immune system's ability to target and destroy cancer cells, but this non-specific immune overactivation can result in immune-related adverse events (irAEs). Patients with underlying autoimmune diseases were excluded from the original ICI clinical trials because of the theoretical risk of irAEs. This study aimed to evaluate the risk of irAEs in patients with pre-existing rheumatologic diseases on ICIs, impact of anti-rheumatic therapy on irAEs, and malignancy outcomes. METHODS: We performed a retrospective chart review of patients with a pre-existing rheumatologic diagnosis receiving ICIs at the University of North Carolina from 2014 to 2019. Risk differences (RD) and asymptotic 95% confidence intervals (95% CIs) using a continuity correction along with odds ratios (OR) and exact 95% CIs were produced between pre-specified risk factors and flares of the underlying rheumatologic disease and/or irAEs. Kaplan-Meier survival estimates for time to unfavorable cancer response between subsets of patients were compared using the log-rank test. RESULTS: We identified 45 patients receiving an ICI with an underlying rheumatologic diagnosis, including 22 with rheumatoid arthritis (RA). Overall, 13 patients (29%) had a flare of their autoimmune disease, 20 patients (44%) had a new-onset irAE, and 27 (60%) had either a flare or new-onset irAE. Patients with RA had higher risk of flares compared to those with other rheumatologic disorders (45% vs 13%, RD 32%, 95% CI 2.0-56.8); all RA flares were ≤ grade 2 and treated in the outpatient setting. Concurrent treatment of the rheumatologic disease at the start of ICI therapy was not associated with a reduced risk of flare (OR 0.86, 95% CI 0.19-3.76) or new onset irAE (OR 3.21, 95% CI 0.83-13.6) compared to those not on anti-rheumatic medications. Anti-rheumatic therapy did not impact time to unfavorable malignancy outcome (p = 0.52). CONCLUSION: The majority of our study cohort experienced a flare or new onset irAE with ICI treatment. Treatment with anti-rheumatic therapy did not prevent disease flares or new onset irAEs, but did not negatively impact malignancy outcomes. Research is needed to determine safe anti-rheumatic therapy options to prevent flares and irAEs that do not interfere with malignancy outcomes.

Perceived Impact of the COVID-19 Pandemic on Physical Activity Among Adult Patients With Rheumatologic Disease.

OBJECTIVE: The objective of this cross-sectional study was to investigate the impact of the COVID-19 pandemic on physical activity (PA) levels of patients with rheumatic and musculoskeletal diseases (RMDs) and to examine factors associated with decreased PA. METHODS: A sample of adult patients with RMDs (n = 7,776) was identified through electronic medical records from an academic health care system in North Carolina. Invitations to participate in an online survey were sent between July 2020 and September 2020 to assess self-reported changes in PA during the COVID-19 pandemic. Descriptive statistics, age-adjusted prevalence odds ratios (PORs), and 95% confidence intervals (CIs) were computed to examine patient characteristics associated with decreased PA. RESULTS: A total of 893 eligible participants completed the survey (mean age 57.8 ± 14.9 years, 75.8% female). The most common primary diagnoses reported among participants included rheumatoid arthritis (27.3%), osteoarthritis (16.0%), and systemic lupus erythematosus (SLE) (13.0%). More than half of participants (56.8%) reported engaging in less PA since the pandemic began. Factors associated with engaging in less PA included lower self-reported general health (POR, 2.21; CI, 1.64-2.97) and a diagnosis of SLE (POR, 1.57; CI, 1.03-2.38). Comorbidities associated with decreased PA included chronic pain (POR, 1.38; CI, 1.04-1.82), depression (POR, 1.48; CI, 1.09-2.01), and hypertension (POR, 1.44; CI, 1.10-1.90). CONCLUSION: The COVID-19 pandemic has exacerbated barriers to PA in patients with RMDs. There is a critical need to provide resources, support, and multifaceted programs to encourage PA in patients with RMDs during the COVID-19 pandemic.

Pilot study of an internet-based pain coping skills training program for patients with systemic Lupus Erythematosus.

BACKGROUND: Patients with Systemic Lupus Erythematosus (SLE) often experience pain and other symptoms that negatively impact quality of life. Interventions that enhance the use of behavioral and cognitive coping strategies may lead to improved outcomes among patients with SLE. Pain coping skills training (PCST) programs have been shown to improve outcomes among patients with other rheumatic conditions, but there have been no trials of PCST among patients with SLE. This study was a preliminary assessment of the feasibility and efficacy of painTRAINER, an automated, internet-based PCST program, among patients with SLE. METHODS: Participants (n = 60) with SLE from one health care system were randomly assigned with equal allocation to painTRAINER or a wait list control group. PainTRAINER involves 8 modules; participants were instructed to complete one module weekly, along with practice activities for each cognitive or behavioral coping skill. Outcome measures were assessed at baseline and 9-week follow-up, including the Pain Catastrophizing Scale, PROMIS Subscales (Pain Interference, Physical Function, Sleep Disturbance, Anxiety, Depression, Fatigue and Participation), and the LupusPRO questionnaire. Mean changes in outcomes from baseline to follow up and Cohen's d effect sizes were computed. RESULTS: Effect sizes for the painTRAINER group (relative to the wait list group) were small, with changes being greatest for the PROMIS Depression score (d = - 0.32). Among those randomized to the painTRAINER group, 50% accessed the program ("painTRAINER users"). Most of those who did not access the program stated that they did not receive instructions via email. Effect sizes for "painTRAINER users" (relative to wait list) were larger than for the whole painTRAINER group: Pain Catastrophizing d = - 0.60, PROMIS Pain Interference d = - 0.3., PROMIS Depression d = - 0.44, LupusPRO Health-Related Quality of Life d = 0.30. CONCLUSIONS: PainTRAINER users reported meaningful improvements in multiple physical and psychological outcomes, supporting the potential of PCST programs to benefit individuals with SLE. However, strategies are needed to improve engagement with the program and tailor content to comprehensively address key SLE symptoms and challenges. TRIAL REGISTRATION: NCT03933839 , May 1, 2019.

Immune Checkpoint Inhibitor-Related Pneumonitis in Lung Cancer: Real-World Incidence, Risk Factors, and Management Practices Across Six Health Care Centers in North Carolina.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer and have expanded use in small cell lung cancer. Although generally better tolerated than traditional chemotherapy, immune-related adverse events, such as immune checkpoint inhibitor-related pneumonitis (ICI-P), remain poorly understood toxicities that limit ICI treatment and can result in considerable morbidity. In this retrospective case-control study, we assessed a lung cancer cohort to identify ICI-P risk factors. RESEARCH QUESTION: What are the risk factors, clinical presentations, radiographic findings, and outcomes for ICI-P in a real-world lung cancer cohort? Do chronic pulmonary diseases confer increased risk for ICI-P? STUDY DESIGN AND METHODS: Medical records from lung cancer patients receiving nivolumab, pembrolizumab, or combination ipilimumab and nivolumab at six centers in North Carolina were reviewed (January 2004-July 2017). Patients with ICI-P and control participants were characterized, and logistic regression was used to assess for ICI-P risk factors. RESULTS: Three hundred fifteen lung cancer patients who predominantly received nivolumab (76.5%) or pembrolizumab (22%) were included. The incidence of ICI-P was 9.5%, with a median time to diagnosis of 52.5 days. Most patients with ICI-P had cases of high severity, and eight patients (27%) died with ongoing ICI-P treatment. Development of ICI-P was independently associated with the presence of baseline fibrosis on chest CT scan (adjusted OR [aOR], 6.61; 95% CI, 2.48-17.7), a composite measure of obstructive lung disease (aOR, 2.79; 95% CI, 1.07-7.29), and treatment with pembrolizumab (aOR, 2.57; 95% CI, 1.08-6.11). INTERPRETATION: In this cohort, ICI-P was more common and severe than previously reported and carried an unexpectedly high mortality rate. Risk for ICI-P was shown to be independently associated with several chronic pulmonary diseases, which may account for the higher incidence of ICI-P in patients with lung cancer.

Quantification of citrullinated histones: Development of an improved assay to reliably quantify nucleosomal H3Cit in human plasma.

BACKGROUND: Recent data propose a diagnostic and prognostic capacity for citrullinated histone H3 (H3Cit), a marker of neutrophil extracellular traps (NETs), in pathologic conditions such as cancer and thrombosis. However, current research is hampered by lack of standardized assays. OBJECTIVES: We aimed to develop an assay to reliably quantify nucleosomal H3Cit in human plasma. METHODS: We assessed the common practice of in vitro enzymatically modified histone H3 as calibration standards and the specificity of available intrapeptidyl citrulline antibodies. Based on our findings, we developed and validated a novel assay to quantify nucleosomal H3Cit in human plasma. RESULTS: We show that enzymatically citrullinated H3 proteins are compromised by high enzyme-dependent lot variability as well as instability in plasma. We furthermore demonstrate that the majority of commercially available antibodies against intrapeptidyl citrulline display poor specificity for their reported target when tested against a panel of semi-synthetic nucleosomes containing distinct histone H3 citrullinations. Finally, we present a novel assay utilizing highly specific monoclonal antibodies and semi-synthetic nucleosomes containing citrulline in place of arginine at histone H3, arginine residues 2, 8, and 17 (H3R2,8,17Cit) as calibration standards. Rigorous validation of this assay shows its capacity to accurately and reliably quantify nucleosomal H3Cit levels in human plasma with clear elevations in cancer patients compared to healthy individuals. CONCLUSIONS: Our novel approach using defined nucleosome controls enables reliable quantification of H3Cit in human plasma. This assay will be broadly applicable to study the role of histone citrullination in disease and its utility as a biomarker.

Clinician's Perceptions of a CME Activity to Increase Knowledge of Vaccination in Adults with Chronic Inflammatory Conditions.

OBJECTIVE: Annual influenza and pneumococcal vaccination rates remain suboptimal in patients with systemic lupus erythematosus despite their higher risk of infections and related complications. The CDC identified lack of knowledge about vaccine guidelines among adult patients and their providers as the most substantial barrier to vaccination coverage. As specialists working with particularly affected populations, rheumatologists, allergists, and immunologists can advise patients regarding gaps in recommended vaccinations.The aim of this study was to describe prescribers' perceptions of an educational activity that was developed to increase rates of appropriate pneumococcal and influenza vaccination in adults with chronic inflammatory conditions. We were interested in the impact of the educational activity on the knowledge and practice of providers. METHODS: We evaluated a multimodal educational activity aimed at increasing vaccination rates in high-risk adults. We assessed provider knowledge, perceptions of the activity, and impact on their practice. The activity was conducted at a single site "in house" education event in the live format and was disseminated nationally in print and online format. RESULTS: In the "in house" interactive education session, mean scores on the pre- and post-tests were 75% (SD 11.6%, 95% CI 70-80%) and 89% (SD 11.1%, 95% CI 85-95%; p=.0001 vs. pre-test score), respectively, demonstrating that knowledge was significantly increased after completing the activity. In the nationally available activity 93% (n=240) of respondents indicated that the activity significantly increased their awareness about the importance of vaccinations in these high-risk patients and recognition of when these vaccines were indicated or contraindicated, while 55% (n=142) planned to consequently change their practice. CONCLUSION: Provider education is a valuable strategy for practice-based improvements in vaccination coverage since provider failure to recommend vaccinations is a primary barrier in high-risk patients. Most patients received vaccinations based on physician recommendations and vaccination rates were markedly higher among patients receiving vaccine information from their providers. This educational activity increased clinicians' knowledge of and confidence in vaccinations for adults with chronic inflammatory conditions.