Citations

Abstract Objective COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs); however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. Methods The first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups. Results We analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26; 95% CI: 0.24, 0.30, P < 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6; 95% CI: 2.9, 4.6, P < 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8; 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4; 95% CI: 1.9, 8.1, P < 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs – OR: 1.9; 95% CI: 1.2, 2.9, P = 0.001; IIMs vs HCs – OR: 5.4 95% CI: 3, 9.6, P < 0.001). Caucasians [OR 4.2 (1.7–10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8–0.97)]. Conclusion Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.

Study Design. Delphi method. Objective. To gain consensus on the following questions: (1) When should anticoagulation/antiplatelet (AC/AP) medication be stopped before elective spine surgery?; (2) When should AC/AP medication be restarted after elective spine surgery?; (3) When, how, and in whom should venous thromboembolism (VTE) chemoprophylaxis be started after elective spinal surgery? Summary of Background Data. VTE can lead to significant morbidity after adult spine surgery, yet postoperative VTE prophylaxis practices vary considerably. The management of preoperative AC/AP medication is similarly heterogeneous. Materials and Methods. Delphi method of consensus development consisting of three rounds (January 26, 2021, to June 21, 2021). Results. Twenty-one spine surgeons were invited, and 20 surgeons completed all rounds of questioning. Consensus (>70% agreement) was achieved in 26/27 items. Group consensus stated that preoperative Direct Oral Anticoagulants should be stopped two days before surgery, warfarin stopped five days before surgery, and all remaining AC/AP medication and aspirin should be stopped seven days before surgery. For restarting AC/AP medication postoperatively, consensus was achieved for low-risk/medium-risk/high-risk patients in 5/5 risk factors (VTE history/cardiac/ambulation status/anterior approach/operation). The low/medium/high thresholds were POD7/POD5/POD2, respectively. For VTE chemoprophylaxis, consensus was achieved for low-risk/medium-risk/high-risk patients in 12/13 risk factors (age/BMI/VTE history/cardiac/cancer/hormone therapy/operation/anterior approach/staged separate days/staged same days/operative time/transfusion). The one area that did not gain consensus was same-day staged surgery. The low-threshold/medium-threshold/high-threshold ranges were postoperative day 5 (POD5) or none/POD3-4/POD1-2, respectively. Additional VTE chemoprophylaxis considerations that gained consensus were POD1 defined as the morning after surgery regardless of operating finishing time, enoxaparin as the medication of choice, and standardized, rather than weight-based, dose given once per day. Conclusions. In the first known Delphi study to address anticoagulation/antiplatelet recommendations for elective spine surgery (preoperatively and postoperatively); our Delphi consensus recommendations from 20 spine surgeons achieved consensus on 26/27 items. These results will potentially help standardize the management of preoperative AC/AP medication and VTE chemoprophylaxis after adult elective spine surgery.

AbstractWaldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10‐year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960–1977, n = 12), Group 2 (1978–1995, n = 48), and Group 3 (1996–2013, n = 74). Among young patients, there was no disease‐specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5–23), 16 years (95% CI 14–22), and 15 years (95% CI 10‐NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years‐of‐life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age‐ and sex‐matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Abstract Regulatory T-cell (Treg) deficiency causes lethal, CD4+T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the development of Treg, Th1 and Th2 cells. It is currently unclear if Treg-deficiency autoimmune disorders can be treated by targeting the enteric microbiota. Our aims are to determine the autoimmunity, gut microbiota, and plasma metabolomics affected by probiotic Lactobacillus reuteri DSM 17938 (LR), and to further identify the mechanism of modulated metabolite(s) in suppressing autoimmunity in Treg-deficient scurfy (SF) mice. We demonstrated that Foxp3+Treg deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of SF mouse. Remodeling microbiota with LR prolonged survival and reduced multi-organ inflammation in SF mice. LR changed the metabolomics profile disrupted by Treg-deficiency with a major effect of restoring levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multi-organ inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors. Both A2A receptor specific antagonist or genetically knockout A2A to SF mice reversed the anti-inflammatory effects of both inosine and LR in vivo. In conclusions, A2A receptors mediate a substantial protective effect of inosine and LR. The LR-modulated-microbiota-inosine-A2A axis might represent a potential avenue for combatting autoimmune diseases mediated by Treg dysfunction.

Objectives Fontan-associated liver disease (FALD) is universal post-Fontan palliation; however, its impact on survival remains controversial and current diagnostic tools have limitations. We aimed to assess the prognostic role of liver fibrosis scores (aminotransferase to platelet ratio [APRI] and fibrosis-4 [FIB-4]) and their association with haemodynamics and other markers of liver disease. Methods 159 adults (age ≥18 years) post-Fontan undergoing catheterisation at Mayo Clinic, Minnesota, between 1999 and 2017 were included. Invasive haemodynamics and FALD-related laboratory, imaging and pathology data were documented. Results Mean age was 31.5±9.3 years, while median age at Fontan procedure was 7.5 years (4–14). Median APRI score (n=159) was 0.49 (0.33–0.61) and median FIB-4 score (n=94) was 1.12 (0.71–1.65). Correlations between APRI and FIB-4 scores and Fontan pressures (r=0.30, p=0.0002; r=0.34, p=0.0008, respectively) and pulmonary arterial wedge pressure (r=0.25, p=0.002; r=0.30, p=0.005, respectively) were weak. Median average hepatic stiffness by magnetic resonance elastography was 4.9 kPa (4.3–6.0; n=26) and 24 (77.4%) showed stage 3 or 4 liver fibrosis on biopsy; these variables were not associated with APRI/FIB-4 scores. On multivariable analyses, APRI and FIB-4 scores were independently associated with overall mortality (HR 1.31 [1.07–1.55] per unit increase, p=0.003; HR 2.15 [1.31–3.54] per unit increase, p=0.003, respectively). Conclusions APRI and FIB-4 scores were associated with long-term all-cause mortality in Fontan patients independent of other prognostic markers. Correlations between haemodynamic status and liver scores were weak; furthermore, most markers of liver fibrosis failed to correlate with non-invasive indices, underscoring the complexity of FALD.

Background: There are limited data about the stage D heart failure (advanced HF) in adults with congenital heart disease. Our study objectives were (1) to determine the incidence of new-onset advanced HF in patients and the relationship between advanced HF and all-cause mortality and (2) to determine the relationship between therapies for advanced HF and all-cause mortality. Methods: Retrospective cohort study of adults with congenital heart disease at Mayo Clinic (2003–2019). We defined advanced HF using the European Society of Cardiology diagnostic criteria for advanced HF. Therapies received by the patients with advanced HF were classified into 3 mutually exclusive groups (treatment pathways): (1) conventional cardiac intervention, (2) transplant listing, and (3) palliative care. Results: Of 5309 patients without advanced HF at baseline assessment, 432 (8%) developed advanced HF during follow-up (1.1%/y), and the incidence of advanced HF was higher in patients with severe or complex congenital heart disease. Onset of advanced HF was associated with 6-fold increase in the risk of mortality. Conventional cardiac intervention was associated with significantly higher risk of mortality as compared to transplant listing. The longer the interval from the initial onset of advanced HF to transplant evaluation, the lower the odds of being listed for transplant. Conclusions: Based on these data, we postulate that early identification of patients with advanced HF, and a timely referral for transplant evaluation (instead of conventional cardiac intervention) may offer the best chance of survival for these critically ill patients. Further studies are required to validate this postulation.

AbstractBackgroundβ‐amyloid plaques, a pathological hallmark of Alzheimer’s disease, are common in dementia with Lewy bodies (DLB). However, little is known about when β‐amyloid levels increase throughout the Lewy body disease (LBD) continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD), to a stage of mild cognitive impairment‐Lewy bodies (MCI‐LB), and finally DLB. Our objective was to investigate β‐amyloid deposition throughout the LBD continuum, as well as the influence of sex and APOE ε4 status, as potential factors contributing to Alzheimer’s disease pathological changes.MethodPatients with iRBD (n=24), MCI‐LB (n=62), and DLB (n=82) from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine were included. β‐amyloid levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex from the Mayo Clinic Study of Aging (MCSA). Clinical groups were compared using ANCOVA after adjusting by age.ResultMCI‐LB and DLB patients had significantly higher global cortical PiB SUVR than CU participants, while PiB SUVR in iRBD patients was comparable to that of CU participants (Figure 1). DLB patients also had significantly higher global cortical PiB SUVR compared to iRBD patients (p=0.004). In MCI‐LB and DLB, global cortical PiB SUVR was higher in APOE ε4 carriers compared to APOE ε4 non‐carriers (p<0.001), and women had higher global cortical PiB SUVR compared to men (p=0.024).ConclusionIn this cross‐sectional study, β‐amyloid pathology gradually increased throughout the clinically defined LBD continuum. Whereas β‐amyloid levels are comparable to cognitively unimpaired individuals in iRBD, a significant elevation in β‐amyloid levels coincides with cognitive impairment observed in MCI‐LB and DLB. Specifically, women and APOE ε4 carriers tend to have higher β‐amyloid levels than men and APOE ε4 non‐carriers. These findings have important implications for targeting patients within the LBD continuum, who may benefit from amyloid modifying therapies.

AbstractBackgroundReduced striatal uptake on ioflupane SPECT is considered an indicative biomarker for Dementia with Lewy Bodies (DLB), and has been proposed as an indicative biomarker for Mild Cognitive Impairment with Lewy Bodies (MCI‐LB). Little data exists on the profile of uptake on key striatal regions of interest (ROIs) in DLB or MCI‐LB.MethodParticipants with DLB or MCI‐LB at baseline based on the presence of ≥2 core clinical DLB features, and ≥2 ioflupane SPECT scans performed approximately annually, were identified from the Mayo ADRC database. Minimum brain laterality z‐score values for the putamen (whole, anterior and posterior), caudate and striatum were determined using DaTQUANT 2 software. Baseline clinical and scan data was used for all analyses, and the annualized minimum putamen z‐change was determined on serial scans. The scan was considered abnormal if the minimum putamen z‐score was <‐0.98 based on clinicopathologic data.Result27 participants were included (21 DLB and 6 MCI‐LB, 96% male). Compared to MCI‐LB, DLB had a lower mean MoCA score and a trend toward a higher UPDRS score compared to MCI‐LB; there were no statistically significant differences in age, sex, onset age or duration of cognitive decline, or presence of other core DLB features. The majority (89%) had an abnormal scan at baseline. All ROI z‐scores showed the expected general trend of DLB<MCI‐LB, and the annualized z‐change was more negative in DLB, but none of the findings reached statistical significance.ConclusionThese findings suggest in MCI‐LB and DLB that 1) an abnormal ioflupane SPECT scan is frequently present at diagnosis, 2) z‐scores become more negative over time, and 3) the annualized z‐change is similar. Similar findings in larger cohorts would support the use of ioflupane SPECT as a biomarker in both MCI‐LB and DLB clinical trials.