Earlier vs. later time period of COVID-19 infection and emergent autoimmune signs, symptoms, and serologies.

OBJECTIVE: Autoantibodies and autoimmune diseases after SARS-CoV-2 infection are widely reported. Given evolving variants, milder infections, and increasing population vaccination, we hypothesized that SARS-CoV-2 infection earlier in the pandemic would be associated with more autoimmune connective tissue disease (CTD) symptoms and immunologic abnormalities. METHODS: Patients ≥18 years old with COVID-19 3/1/2020-8/15/2022 completed the CTD Screening Questionnaire and were tested for 27 autoimmune serologies, SARS-CoV-2 serologies, cell-bound complement activation products (CB-CAPs), and T and B lymphocyte immunophenotypes by flow cytometry. We assessed relationships between symptoms, serologies, and immunophenotypes in earlier (3/1/2020-1/31/2021) vs. later (2/1/2021-8/15/2022) periods, with different predominating SARS-CoV-2 viruses. RESULTS: 57 subjects had earlier and 23 had later pandemic COVID-19. 35 % of earlier vs. 17 % of later pandemic patients had CTD symptoms (p 0.18). More patients were antinuclear antibody (ANA) positive (44 % vs. 13 %, p 0.01) and had lupus anticoagulant (11 % vs. 4 %, p 0.67). After adjustment for age, race, and sex, earlier (vs. later) COVID-19 was associated with increased ANA positivity (OR 4.60, 95%CI 1.17, 18.15). No subjects had positive CB-CAPs. T and B cell immunophenotypes and SARS-CoV-2 serologies did not differ by group. In heatmap analyses, higher autoantibody variety was seen among those with infection in the early pandemic. CONCLUSION: In this sample, having COVID-19 infection in the earlier (pre-2/1/2021) vs. later pandemic was associated with more CTD symptoms, ANA positivity, and autoantibody reactivities. Earlier SARS-CoV-2 variants circulating in a less vaccinated population with less natural immunity may have been more immunogenic.

The link between post-traumatic stress disorder and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystem autoimmune disorder characterized by unpredictable disease flares. Although the pathogenesis of SLE is complex, an epidemiologic link between posttraumatic stress disorder (PTSD) and the development of SLE has been identified, suggesting that stress-related disorders alter the susceptibility to SLE. Despite the strong epidemiologic evidence connecting PTSD and SLE, gaps remain in our understanding of how the two may be connected. Perturbations in the autonomic nervous system, neuroendocrine system, and at the genomic level may cause and sustain immune dysregulation that could lower the threshold for the development and propagation of SLE. We first describe shared risk factors for SLE and PTSD. We then describe potential biological pathways which may facilitate excessive inflammation in the context of PTSD. Among those genetically predisposed to SLE, systemic inflammation that accompanies chronic stress may fan the flames of smoldering SLE by priming immune pathways. Further studies on the connection between trauma and inflammation will provide important data on pathogenesis, risk factors, and novel treatments for SLE.

Prevalence of ECG testing and characteristics among new hydroxychloroquine and chloroquine users within a multi-center tertiary care center.

COVID-19 raised concern regarding cardiotoxicity and QTc prolongation of hydroxychloroquine (HCQ) and chloroquine (CQ). We examined the frequency and patient factors associated with ECG testing and the detection of prolonged QTc among new HCQ/CQ users in a large academic medical system. 10,248 subjects with a first HCQ/CQ prescription (1/2015-3/2020) were included. We assessed baseline (1 year prior to and including day of initiation of HCQ/CQ through 2 months after initial HCQ/CQ prescription) and follow-up (10 months after the baseline period) patient characteristics and ECGs obtained from electronic health records. Among 8384 female HCQ/CQ new users, ECGs were obtained for 22.3%, 14.3%, and 7.6%, at baseline, follow, and both periods, respectively. Among 1864 male HCQ/CQ new users, ECGs were obtained more frequently at baseline (29.7%), follow-up (18.0%), and both periods (11.3%). Female HCQ/CQ users with a normal QTc at baseline but prolonged QTc (> 470 ms) at follow-up (13.1%) were older at HCQ/CQ initiation [mean 64.7 (SD 16.5) vs. 58.7 (SD 16.9) years, p = 0.004] and more likely to have history of myocardial infarction (41.0% vs. 21.6%, p = 0.0003) compared to those who had normal baseline and follow-up QTc. The frequency of prolonged QTc development was similar (12.4%) among male HCQ/CQ new users (> 450 ms). Prior to COVID-19, ECG testing before and after HCQ/CQ prescription was infrequent, particularly for females who are disproportionately affected by rheumatic diseases and were just as likely to develop prolonged QTc (> 1/10 new users). Prospective studies are needed to guide future management of HCQ/CQ therapy in rheumatic populations.

Satisfaction With a Virtual Learning Collaborative Aimed at Implementing Treat-to-Target in Rheumatoid Arthritis.

OBJECTIVE: Limited information is available concerning experiences of participants in a virtual learning collaborative (LC), and little qualitative data or participant feedback on how this format can be improved. One prior in-person LC in rheumatology successfully improved adherence with treat-to-target (TTT) for RA. We conducted a virtual LC on TTT and herein report on participant satisfaction. METHODS: We conducted a virtual LC with 18 rheumatology practices from across the United States during 2020 to 2021. The LC included a virtual kickoff meeting and monthly videoconferences, accompanied by data submission and feedback. At the conclusion of the LC, we surveyed the 45 LC participants concerning individual experience and satisfaction. RESULTS: All sites and 78% of participants responded to the surveys. The LC included small and large practices, 14 academic and 4 nonacademic, and respondents ranged in their roles: 24 physicians, 5 nurses or nurse practitioners, 3 administrators, and 3 other roles. Overall, 94% of respondents indicated they were either somewhat or very satisfied with the LC, and 94% said they would recommend a similar LC to a colleague. Aspects of the LC described as "very useful" included a kickoff meeting, intersite discussion, and monthly speakers; however, digital tools such as the Web site and meeting recordings were not found useful. CONCLUSIONS: Virtual LCs are feasible, and participants reported strong satisfaction. Virtual LCs were highly valued by rheumatologists, trainees, and their practice staffs. Potential topics were identified for future LCs that could improve the quality of care delivered to rheumatology patients.

Increased risk of adverse events among patients with vs. without systemic autoimmune rheumatic disease prescribed sodium-glucose cotransporter 2 inhibitors: a retrospective cohort study.

BACKGROUND: Systemic autoimmune rheumatic disease (SARD) patients have been excluded from sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials given putative risks, but this risk magnitude is unknown. We aimed to quantify SGLT2i adverse event risks among patients with vs. without SARD.   METHODS: In a retrospective cohort study, patients with SARD at Mass General Brigham, a multihospital system in Boston, Massachusetts, prescribed SGLT2i were age-, self-reported race-, and sex-matched to patients prescribed the same SGLT2i between 1/1/2016 and 12/10/2021. Cumulative incidence and Cox models, overall and sex-stratified, estimated patient-reported adverse event risks from prescription date, censoring for discontinuation, death, or study end (12/12/2022). RESULTS: Four hundred sixty-eight SARD and 420 matched non-SARD patients were compared: mean age 64 years (SD 11.3), 61% female, and 70% White. SARD patients had shorter SGLT2i use duration (8.4 vs. 12.7 months; p < 0.0001) and time to adverse event (0.59 vs. 0.85 years; p 0.04). Yeast infections (9.8% vs. 6.2%; p 0.047) and muscular symptoms (3.4% vs. 1.0%, p 0.01) were more prevalent among those with SARD. Adjusting for baseline demographics, adverse event risk was higher (MV HR 1.68; 95% CI 1.28, 2.21), in patients with vs. without SARD. Risk was higher in women than men overall and in women with SARD vs. without (adjusted HR 1.86; 95% CI 1.36, 2.54). CONCLUSION: Patients with vs. without SARD had 68% higher adverse event risk with SGLT2i use. Women with vs. without SARD had > 85% higher adverse event risks, although most were not serious. Trials of safety and efficacy of SGLT2i among SARD patients are warranted. Key Points •To our knowledge, this is the first study to compare adverse events associated with SGLT2i utilization in patients with vs. without SARD, despite RCT exclusion and documented SGLT2i use in the population. •In our comparison of 468 patients with SARD and 420 patients without, we identified a greater than 65% increase in risk of adverse event outcomes among patients with SARD. •Furthermore, we found that this risk disproportionately affected female patients, with a 4.4-fold increased risk among women with SARD compared to men without.

Posttraumatic stress disorder symptoms in systemic autoimmune rheumatic disease patients during the early COVID-19 pandemic.

AIM: Given reports of increased prevalence of PTSD symptoms at COVID-19 pandemic onset, we aimed to assess the prevalence of posttraumatic stress disorder (PTSD) symptoms at pandemic onset in individuals with and without systemic autoimmune rheumatic disease (SARD). METHODS: In May 2020, we invited 6678 patients to complete the Brief Trauma Questionnaire and the Posttraumatic Stress Disorder Checklist (PCL-5), validated PTSD symptom screenings. We compared responses from patients with and without SARD using multivariable logistic regression. RESULTS: We received 1473 responses (22% response rate) from 5/2020 to 9/2021 (63 with prior PTSD diagnoses, 138 with SARD history). The SARD population was more female (p .0001) and had a higher baseline prevalence of stress disorders (56% vs. 43%, p .004). SARD subjects reported more experiences with life-threatening illness, 60%, versus 53% among those without SARD (p .13), and more antidepressant or anxiolytic medication use pre-pandemic (78% vs. 59%, p .0001). Adjusting for pre-pandemic PTSD diagnosis, younger age and history of stress disorder were the most significant predictors of PCL-5 positivity. There were no significant differences in PCL-5 score or positivity among those with or without SARD. CONCLUSION: In this population, patients with SARD had a higher pre-COVID-19 prevalence of stress-related conditions, but it was not the case that they had an increased risk of PTSD symptoms in the early pandemic. Younger individuals, those with baseline depression, anxiety, or adjustment disorders, and those taking antidepressant or anxiolytic medications were more likely to have PTSD symptoms in the first waves of the COVID-19 pandemic.

Cost-Related Medication Behaviors for Patients With and Without Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: Medication nonadherence challenges the management of systemic autoimmune rheumatic diseases (SARDs). We investigated cost-related medication behaviors among patients with SARDs, and compared them to those of patients without SARDs, in a large diverse cohort across the United States. METHODS: As part of the All of Us (version 7), a nationwide diverse adult cohort with linked electronic health records begun in 2017, participants completed questionnaires concerning cost-related medication behaviors. Chi-square tests compared responses between patients with SARDs, by disease and medication type, and to those without SARDs. Logistic regression analyses were used to calculate odds ratios (95% confidence intervals [CIs]). RESULTS: We analyzed data from 3,997 patients with SARDs and 73,990 participants without SARDs. After adjustment, patients with versus without SARDs had 1.56 times increased odds of reporting unaffordability of prescription medicines (95% CI 1.43-1.70), 1.43 times increased odds of cost-related medication nonadherence (95% CI 1.31-1.56), and 1.23 times increased odds of using cost-reducing strategies (95% CI 1.14-1.32). Patients with SARDs who reported unaffordability were 16.5% less likely to receive a disease-modifying drug (95% CI 0.70-0.99) but 18.1% more likely to receive glucocorticoids (95% CI 0.99-1.42). In addition, unaffordability of prescription medicines was likely to have 1.27 times increased odds of one to two emergency room visits per year (95% CI 1.03-1.57) and 1.38-fold increased odds of three or more emergency room visits per year (95% CI 0.96-1.99). CONCLUSION: In this large diverse cohort, patients with versus without SARDs had more self-reported cost-related medication behaviors, and those who reported medication unaffordability received fewer disease-modifying drugs and had more emergency room visits.

Personalizing cardiovascular risk prediction for patients with systemic lupus erythematosus.

OBJECTIVE: Cardiovascular disease (CVD) risk is increased in SLE and underestimated by general population prediction algorithms. We aimed to develop a novel SLE-specific prediction tool, SLECRISK, to provide a more accurate estimate of CVD risk in SLE. METHODS: We studied patients in the Brigham and Women's Hospital SLE cohort. We collected one-year baseline data including the presence of traditional CVD factors and SLE-related features at cohort enrollment. Ten-year follow-up for the first major adverse cardiovascular event (MACE; myocardial infarction (MI), stroke, or cardiac death) began at day +1 following the baseline period (index date). ICD-9/10 codes identified MACE were adjudicated by board-certified cardiologists. Least absolute shrinkage and selection operator regression selected SLE-related variables to add to the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equations 10-year risk Cox regression model. Model fit statistics and performance (sensitivity, specificity, positive/negative predictive value, c-statistic) for predicting moderate/high 10-year risk (≥7.5 %) of MACE were assessed and compared to ACC/AHA, Framingham risk score (FRS), and modified FRS (mFRS). Optimism adjustment internal validation was performed using bootstrapping. RESULTS: We included 1,243 patients with 90 MACEs (46 MIs, 36 strokes, 19 cardiac deaths) over 8946.5 person-years of follow-up. SLE variables selected for the new prediction algorithm (SLECRISK) were SLE activity (remission/mild vs. moderate/severe), disease duration (years), creatinine (mg/dL), anti-dsDNA, anti-RNP, lupus anticoagulant, anti-Ro positivity, and low C4. The sensitivity for detecting moderate/high-risk (≥7.5 %) of MACE using SLECRISK was 0.74 (95 %CI: 0.65, 0.83), which was better than the sensitivity of the ACC/AHA model (0.38 (95 %CI: 0.28, 0.48)). It also identified 3.4-fold more moderate/high-risk patients than the ACC/AHA. Patients who were moderate/high-risk according to SLECRISK but not ACC/AHA, were more likely to be young women with severe SLE and few other traditional CVD risk factors. Model performance between SLECRISK, FRS, and mFRS were similar. CONCLUSION: The novel SLECRISK tool is more sensitive than the ACC/AHA for predicting moderate/high 10-year risk for MACE and may be particularly useful in predicting risk for young females with severe SLE. Future external validation studies utilizing cohorts with more severe SLE are needed.

A Mobile Health Application Integrated in the Electronic Health Record for Rheumatoid Arthritis Patient-Reported Outcomes: A Controlled Interrupted Time-Series Analysis of Impact on Visit Efficiency.

OBJECTIVE: Patient-reported outcome (PRO) collection between visits for rheumatoid arthritis (RA) could improve visit efficiency, reducing in-person visits for patients with stable symptoms while facilitating access for those with symptoms. We examined whether a mobile health PRO application integrated in the electronic health record (EHR) could reduce visit volume for those with RA. METHODS: We developed an application for RA that prompted patients every other day to complete brief PRO questionnaires. Results of the application were integrated into the EHR. We tested the application in a controlled interrupted time-series analysis between 2020 and 2023. Rheumatologists received EHR-based messages based on PRO results recommending the patient receive a visit earlier or later than scheduled. The primary outcome was monthly visit volume during the year before versus the year after initiation. RESULTS: A total of 150 patients with RA consented and used the application. The median age was 62 years, 83% were female, 7% had fewer than 2 years of disease, and 50% were seropositive; 150 controls were well matched. Among those in the application cohort, the estimated monthly median visit volume in the year before use of the application was 31.2 (95% confidence interval [95% CI] 28.0-34.3); in controls, this was 30.4 (95% CI 27.3-33.6). In the year using the application, the estimated monthly visit volume was 36.8 (95% CI 33.4-40.3) compared to 38.7 (95% CI 35.2-42.3) in controls. The difference in the differences between the cohorts was not statistically significant (-2.7 visits, 95% CI -9.3 to 4.0). No differences were noted in flare rates or visit delays. CONCLUSION: In this initial trial of a PRO application intervention to improve visit efficiency, we found no association with reduced visit volume.

Humoral and cellular immune responses in persons with rheumatoid arthritis after a third dose of mRNA COVID-19 vaccine.

OBJECTIVE: Disease-modifying anti-rheumatic drugs (DMARDs) that treat rheumatoid arthritis (RA) may reduce immune responses to COVID-19 vaccination. We compared humoral and cell-mediated immunity before and after a 3rd dose of mRNA COVID vaccine in RA subjects. METHODS: RA patients that received 2 doses of mRNA vaccine enrolled in an observational study in 2021 before receiving a 3rd dose. Subjects self-reported holding or continuing DMARDs. Blood samples were collected pre- and 4 weeks after the 3rd dose. 50 healthy controls provided blood samples. Humoral response was measured with in-house ELISA assays for anti-Spike IgG (anti-S) and anti-receptor binding domain IgG (anti-RBD). T cell activation was measured after stimulation with SARS-CoV-2 peptide. Spearman's correlations assessed the relationship between anti-S, anti-RBD, and frequencies of activated T cells. RESULTS: Among 60 subjects, mean age was 63 years and 88% were female. 57% of subjects held at least 1 DMARD around the 3rd dose. 43% (anti-S) and 62% (anti-RBD) had a normal humoral response at week 4, defined as ELISA within 1 standard deviation of the healthy control mean. No differences in antibody levels were observed based on holding DMARDs. Median frequency of activated CD4 T cells was significantly greater post- vs. pre-3rd dose. Changes in antibody levels did not correlate with change in frequency of activated CD4 T cells. CONCLUSION: Virus-specific IgG levels significantly increased in RA subjects using DMARDs after completing the primary vaccine series, though fewer than two-thirds achieved a humoral response like healthy controls. Humoral and cellular changes were not correlated.

Implementing a Treat-to-Target Approach for Rheumatoid Arthritis During the COVID-19 Pandemic: Results of a Virtual Learning Collaborative Program.

OBJECTIVE: A treat-to-target (TTT) approach improves outcomes in rheumatoid arthritis (RA). In prior work, we found that a learning collaborative (LC) program improved implementation of TTT. We conducted a shorter virtual LC to assess the feasibility and effectiveness of this model for quality improvement and to assess TTT during virtual visits. METHODS: We tested a 6-month virtual LC in ambulatory care. The LC was conducted during the 2020-2021 COVID-19 pandemic when many patient visits were conducted virtually. All LC meetings used videoconferencing and a website to share data. The LC comprised a 6-hour kickoff session and 6 monthly webinars. The LC discussed TTT in RA, its rationale, and rapid cycle improvement as a method for implementing TTT. Practices provided de-identified patient visit data. Monthly webinars reinforced topics and demonstrated data on TTT adherence. This was measured as the percentage of TTT processes completed. We compared TTT adherence between in-person visits versus virtual visits. RESULTS: Eighteen sites participated in the LC, representing 45 rheumatology clinicians. Sites inputted data on 1,826 patient visits, 78% of which were conducted in-person and 22% of which were held in a virtual setting. Adherence with TTT improved from a mean of 51% at baseline to 84% at month 6 (P for trend < 0.001). Each aspect of TTT also improved. Adherence with TTT during virtual visits was lower (65%) than during in-person visits (79%) (P < 0.0001). CONCLUSION: Implementation of TTT for RA can be improved through a relatively low-cost virtual LC. This improvement in TTT implementation was observed despite the COVID-19 pandemic, but we did observe differences in TTT adherence between in-person visits and virtual visits.

Acceptability of Vaccines Against Preventable Infections Including Coronavirus Disease 2019 Among Patients With Rheumatic Disease.

OBJECTIVE: Vaccination against preventable infections is widely recommended for patients with systemic rheumatic disease. The coronavirus disease 2019 (COVID-19) pandemic has highlighted variability in attitudes toward vaccination, particularly with the use of novel vaccine platforms. We studied attitudes toward vaccination against COVID-19 and other preventable infections among patients with systemic rheumatic disease and compared these against the general population. METHODS: We surveyed patients treated at Brigham and Women's Hospital for systemic rheumatic disease using a secure web-based survey or paper survey in English or Spanish, from December 2020 to April 2021. We included survey questions used in the nationwide Harris Poll (October 2020 and February 2021), allowing the comparison of responses with those from the general population. Response frequencies were estimated and compared using descriptive statistics. RESULTS: Of 243 participants (25% response rate), the mean age was 56 years, 82% were women, and 33% were nonwhite. Rheumatoid arthritis (50%) and systemic lupus erythematosus (28%) were the most common diagnoses. Thirty percent had been hospitalized previously for any infection. Seventy-six percent worried a lot or somewhat about contracting COVID-19. Attitudes toward vaccination were very favorable, with 92% having received a flu shot in the past year and 84% desiring a COVID-19 vaccine as soon as possible compared with 30% to 40% of Harris Poll respondents (P < 0.001). Physician recommendation to receive a vaccine and desire to avoid infection were the most common reasons for desiring vaccinations. CONCLUSION: Vaccine acceptability, including toward COVID-19 vaccines, was high among this population of patients with systemic rheumatic disease seen at an academic medical center cohort. Physician recommendation is a key factor for vaccine uptake.