Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.

Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups (median (interquartile range), D + Q -4.1% (-13.2, 2.6), control -7.7% (-20.1, 14.3); P = 0.611). The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks (+16%, P = 0.020) and 4 weeks (+16%, P = 0.024), but was not different from control at 20 weeks (-9%, P = 0.149). No serious adverse events were observed. In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 (also known as CDKN2A) mRNA levels) in which D + Q concomitantly increased P1NP (+34%, P = 0.035) and reduced CTx (-11%, P = 0.049) at 2 weeks, and increased radius bone mineral density (+2.7%, P = 0.004) at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics. ClinicalTrials.gov identifier: NCT04313634 .

Validation of Different Dementia Code-based Definitions in a Population-based Study of Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) has been associated with an elevated dementia risk. The study aimed to examine how different diagnostic dementia definitions perform in those with RA compared to individuals without RA. METHODS: This study population included 2050 individuals (1025 with RA) from a retrospective population-based cohort in southern Minnesota and compared the performance of three code-based dementia diagnostic algorithms with medical record review diagnosis of dementia. For the overall comparison, no time frames were used, and each patient's complete medical history was used. Sensitivity analyses were performed using 1, 2, and 5-year windows around the date that dementia was identified in the medical record (reference standard). RESULTS: Algorithms performed very similarly in persons with and without RA. The algorithms generally had high specificity, negative predictive values, and accuracy, regardless of the time window studied (>88%). Sensitivity and positive predictive values varied depending on the algorithm and the time window studied. Sensitivity values ranged from 56.5% to 95.9%, and positive predictive values ranged from 55.2% to 83.1%. Performance measures declined with more restrictive time windows. CONCLUSION: Routinely collected electronic health record (EHR) data was used to define code-based dementia diagnosis algorithms with good performance (vs. diagnosis by medical record review). These results can inform future studies that use retrospective databases (especially in the same or similar EHR infrastructure) to identify dementia in individuals with RA.

Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation in Patients With Chronic Lymphocytic Leukemia.

Background: The use of an artificial intelligence electrocardiography (AI-ECG) algorithm has demonstrated its reliability in predicting the risk of atrial fibrillation (AF) within the general population. Objectives: This study aimed to determine the effectiveness of the AI-ECG score in identifying patients with chronic lymphocytic leukemia (CLL) who are at high risk of developing AF. Methods: We estimated the probability of AF based on AI-ECG among patients with CLL extracted from the Mayo Clinic CLL database. Additionally, we computed the Mayo Clinic CLL AF risk score and determined its ability to predict AF. Results: Among 754 newly diagnosed patients with CLL, 71.4% were male (median age = 69 years). The median baseline AI-ECG score was 0.02 (range = 0-0.93), with a value ≥0.1 indicating high risk. Over a median follow-up of 5.8 years, the estimated 10-year cumulative risk of AF was 26.1%. Patients with an AI-ECG score of ≥0.1 had a significantly higher risk of AF (HR: 3.9; 95% CI: 2.6-5.7; P < 0.001). This heightened risk remained significant (HR: 2.5; 95% CI: 1.6-3.9; P < 0.001) even after adjusting for the Mayo CLL AF risk score, heart failure, chronic kidney disease, and CLL therapy. In a second cohort of CLL patients treated with a Bruton tyrosine kinase inhibitor (n = 220), a pretreatment AI-ECG score ≥0.1 showed a nonsignificant increase in the risk of AF (HR: 1.7; 95% CI: 0.8-3.6; P = 0.19). Conclusions: An AI-ECG algorithm, in conjunction with the Mayo CLL AF risk score, can predict the risk of AF in patients with newly diagnosed CLL. Additional studies are needed to determine the role of AI-ECG in predicting AF risk in CLL patients treated with a Bruton tyrosine kinase inhibitor.

Kidney function in patients with adrenal adenomas: A single-center retrospective cohort study.

OBJECTIVE: Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD), however factors associated with CKD are unknown. We aimed to identify the factors associated with CKD and assess the impact of adrenalectomy on kidney function in patients with NFA or MACS. DESIGN: Single-center cohort study of patients with NFA and MACS, 1999-2020. METHODS: MACS was diagnosed based on post-dexamethasone cortisol (DST) ≥ 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and post-adrenalectomy delta eGFR. RESULTS: Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 ml/min/1.73m2, p < 0.001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, post adrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow up. Factors associated with increased eGFR were younger age, lower pre-adrenalectomy eGFR and longer follow-up period. CONCLUSION: DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Both patients with MACS and NFA demonstrate an increase in eGFR post-adrenalectomy, especially younger patients with lower eGFR pre-adrenalectomy.

Risk of dementia and psychiatric or sleep disorders after diagnosis of adrenal adenomas: a population-based cohort study.

OBJECTIVE: Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders. DESIGN: Population-based cohort study, Olmsted County, MN, 1995-2017. METHODS: Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes. RESULTS: Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia. CONCLUSIONS: Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion.

The Incidence and Outcomes of Breast Implants Among 1696 Women over more than 50 Years.

OBJECTIVE: To investigate the incidence of women with breast implants in 1964-2017 MATERIALS AND METHODS: All women with breast implants in Olmsted County, MN between January 1, 1992 and December 31, 2017 were identified, and a comprehensive review of individual medical records was performed, adding to a previously identified cohort of women with breast implants in 1964-1991. Incidence rates were calculated and were age- and sex-adjusted to the US white female 2010 population. RESULTS: In 1992-2017, 948 women with breast implants were identified, totaling 1696 Olmsted County, MN women with breast implants in 1964-2017. Overall incidence was 63.3 (95% CI 60.2-66.4) per 100,000 women, but incidence varied significantly over time. Women in 1964-1991 were more likely to have implants for cosmetic reasons and more likely to have silicone implants compared to the 1992-2017 cohort. The overall standardized mortality ratio was 1.17 (95% CI 0.99-1.38) in 1964-1991 and 0.94 (95% CI 0.66-1.29) in 1992-2017. In 1992-2017, breast reconstruction patients had a significantly elevated risk of implant rupture and implant removal versus breast augmentation patients. CONCLUSION: The incidence of breast implants among women in Olmsted County, MN has varied drastically over the past five decades, with significant changes in the trends for implant type and reason. The findings of this study may provide further insight regarding how risks associated with implants may vary over time. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

High prevalence of frailty in patients with adrenal adenomas and adrenocortical hormone excess: a cross-sectional multi-centre study with prospective enrolment.

OBJECTIVE: Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. DESIGN: Multi-centre, cross-sectional study (March 2019-August 2022). METHODS: Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. RESULTS: Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio-OR 19.2, 95% confidence interval-CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). CONCLUSIONS: Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Validating the Fracture Risk Assessment Tool Score in a US Population-Based Study of Patients With Rheumatoid Arthritis.

OBJECTIVE: The World Health Organization fracture risk assessment tool (FRAX) algorithm for risk prediction of major osteoporotic and hip fractures accounts for several risk factors, including rheumatoid arthritis (RA), since individuals with RA have an excess burden of fractures. FRAX has not been validated in population-based RA cohorts in the US. We aimed to determine the accuracy of FRAX predictions for individuals with RA in the US. METHODS: This retrospective population-based cohort study included residents of Olmsted County, Minnesota, who were followed until death, migration, or last medical record review. Each patient with RA (1987 American College of Rheumatology criteria met in 1980-2007, age 40-89 years) was matched 1:1 on age and sex to an individual without RA from the same underlying population. Ten-year predictions for major osteoporotic and hip fractures were estimated using the FRAX tool. Fractures were ascertained through follow-up, truncated at 10 years. Standardized incidence ratios (SIRs) and 95% CI were calculated to compare observed and predicted fractures. RESULTS: The study included 662 patients with RA and 658 non-RA comparators (66.8% vs 66.9% female and a mean age of 60.6 vs 60.5 years, respectively). Among patients with RA, 76 major osteoporotic fractures and 21 hip fractures were observed during follow-up (median follow-up: 9.0 years) compared to 67.0 predicted major osteoporotic fractures (SIR 1.13, 95% CI 0.91-1.42) and 23.3 predicted hip fractures (SIR 0.90, 95% CI 0.59-1.38). The observed and predicted major osteoporotic and hip fracture risks were similar for patients with RA and non-RA comparators. CONCLUSION: The FRAX tool is an accurate method for estimating major osteoporotic and hip fracture risk in patients with RA.

Glucocorticoid withdrawal syndrome following surgical remission of endogenous hypercortisolism: a longitudinal observational study.

OBJECTIVE: Glucocorticoid withdrawal syndrome (GWS) is a scarcely studied phenomenon that complicates the recovery following surgical remission of hypercortisolism. We aimed to characterize the presence and trajectory of glucocorticoid withdrawal symptoms in the postoperative period and to determine presurgical predictors of GWS severity. DESIGN: Longitudinal observational study. METHODS: Glucocorticoid withdrawal symptoms were prospectively evaluated weekly for the first 12 weeks following surgical remission of hypercortisolism. Quality of life (CushingQoL and Short-Form-36) and muscle function (hand grip strength and sit-to-stand test) were assessed at the baseline and at 12 weeks after surgery. RESULTS: Prevalent symptoms were myalgias and arthralgias (50%), fatigue (45%), weakness (34%), sleep disturbance (29%), and mood changes (19%). Most symptoms persisted, while myalgias, arthralgias, and weakness worsened during weeks 5-12 postoperatively. At 12 weeks after surgery, normative hand grip strength was weaker than at baseline (mean Z-score delta -0.37, P = .009), while normative sit-to-stand test performance improved (mean Z-score delta 0.50, P = .013). Short-Form-36 Physical Component Summary score worsened (mean delta -2.6, P = .015), but CushingQoL score improved (mean delta 7.8, P < .001) at 12 weeks compared to baseline. Cushing syndrome (CS) clinical severity was predictive of postoperative GWS symptomology. CONCLUSION: Glucocorticoid withdrawal symptoms are prevalent and persistent following surgical remission of hypercortisolism with baseline CS clinical severity predictive of postoperative GWS symptom burden. Differential changes observed in muscle function and quality of life in the early postoperative period may reflect the competing influences of GWS and recovery from hypercortisolism.

Determinants of muscle function and health-related quality of life in patients with endogenous hypercortisolism: a cross-sectional study.

OBJECTIVE: Prospective data on determinants of muscle strength impairment and quality of life in patients with various subtypes and severity of endogenous hypercortisolism are lacking. DESIGN: Single-center cross-sectional study, 2019 to 2022. METHODS: Patients with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) were assessed with clinical and biochemical severity scores, muscle function (nondominant hand grip strength and sit-to-stand test), and quality of life (Short Form-36 [SF36] and CushingQoL). Referent subjects were recruited from the local population undergoing abdominal imaging for reasons other than suspected adrenal disorder. RESULTS: Of 164 patients, 81 (49%) had MACS, 14 (9%) had adrenal CS, 60 (37%) had pituitary CS, and 9 (5%) had ectopic CS. Median age was 53 years (interquartile range: 42-63 years), and 126 (77%) were women. The SF36 mental component score was similarly low in patients with MACS vs CS, but physical component score was lower in CS when compared to MACS (mean of 34.0 vs 40.5, P = .001). Compared to MACS, patients with CS had lower scores on the standardized CushingQoL (mean of 47.1 vs 34.2, P < .001). Compared to referent subjects, patients with MACS demonstrated reduced muscle strength, similar to patients with CS (mean sit to stand Z-score of -0.47 vs -0.54, P = .822). Clinical severity (r = -0.22, P = .004) but not biochemical severity was associated with sit-to-stand test performance. CONCLUSIONS: Both patients with overt CS and MACS demonstrate reduced muscle strength and low quality of life. The clinical severity score utilized is associated with both physical and psychosocial components of CushingQoL and with the physical component of SF36.

Trends in Incidence of Chronic Heart Failure in Patients With Rheumatoid Arthritis: A Population-Based Study Validating Different Heart Failure Definitions.

OBJECTIVE: To assess trends in the incidence of heart failure (HF) in patients with incident rheumatoid arthritis (RA) from 1980 to 2009 and to compare different HF definitions in RA. METHODS: The study population comprised Olmsted County, Minnesota residents with incident RA (age ≥ 18 yrs, 1987 American College of Rheumatology criteria met in 1980-2009). All subjects were followed until death, migration, or April 30, 2019. Incident HF events were defined as follows: (1) meeting the Framingham criteria for HF, (2) diagnosis of HF (outpatient or inpatient) by a physician, or (3) International Classification of Diseases, 9th revision (ICD-9), or ICD, 10th revision (ICD-10), codes for HF. Patients with HF prior to the RA incidence/index date were excluded. Cox proportional hazards models were used to compare incident HF events by decade, adjusting for age, sex, and cardiovascular risk factors. HF definitions 2 and 3 were compared to the Framingham criteria. RESULTS: The study included 905 patients with RA (mean age 55.9 years; 68.6% female; median follow-up 13.4 years). The 10-year cumulative incidence of HF events by any chart-reviewed method in the RA cohort in the 1980s was 11.66% (95% CI 7.86-17.29), in the 1990s it was 12.64% (95% CI 9.31-17.17), and in the 2000s it was 7.67% (95% CI 5.36-10.97). The incidence of HF did not change across the decades of RA incidence using any of the HF definitions. Physician diagnosis of HF and ICD-9/10 code-based definitions of HF performed well compared to the Framingham criteria, showing moderate to high sensitivity and specificity. CONCLUSION: The incidence of HF in patients with incident RA in the 2000s vs the 1980s was not statistically significantly different. Physician diagnosis of HF and ICD-9/10 codes for HF performed well against the Framingham criteria.

Lower Frequency of Comorbidities Prior to Onset of Giant Cell Arteritis: A Population-Based Study.

OBJECTIVE: To assess the frequency of comorbidities and metabolic risk factors at and prior to giant cell arteritis (GCA) diagnosis. METHODS: This is a retrospective case control study of patients with incident GCA between January 1, 2000, and December 31, 2019, in Olmsted County, Minnesota. Two age- and sex-matched controls were identified, and each assigned an index date corresponding to an incidence date of GCA. Medical records were manually abstracted for comorbidities and laboratory data at incidence date, 5 years, and 10 years prior to incidence date. Twenty-five chronic conditions using International Classification of Diseases, 9th revision, diagnosis codes were also studied at incidence date and 5 years prior to incidence date. RESULTS: One hundred and twenty-nine patients with GCA (74% female) and 253 controls were identified. At incidence date, the prevalence of diabetes mellitus (DM) was lower among patients with GCA (5% vs 17%; P = 0.001). At 5 years prior to incidence date, patients were less likely to have DM (2% vs 13%; P < 0.001) and hypertension (27% vs 45%; P = 0.002) and had a lower mean number (SD) of comorbidities (0.7 [1.0] vs 1.3 [1.4]; P < 0.001) compared to controls. Moreover, patients had significantly lower median fasting blood glucose (FBG; 96 mg/dL vs 104 mg/dL; P < 0.001) and BMI (25.8 vs 27.7; P = 0.02) compared to controls. Multivariable logistic regression analysis revealed negative associations for FBG with GCA at 5 and 10 years prior to diagnosis/index date. CONCLUSION: DM prevalence and median FBG and BMI were lower in patients with GCA up to 5 years prior to diagnosis, suggesting that metabolic factors influence the risk of GCA.

Long-Term Opioid Therapy Among Patients With Systemic Lupus Erythematosus in the Community: A Lupus Midwest Network (LUMEN) Study.

OBJECTIVE: There is little information about the epidemiology and factors associated with opioid therapy in systemic lupus erythematosus (SLE). We aimed to assess the prevalence of opioid therapy and explore factors associated with long-term opioid therapy (LTOT) in patients with SLE. METHODS: Patients with SLE were matched with controls without SLE in a population-based cohort on January 1, 2015. We captured demographics, manifestations of SLE, comorbidities (ie, fibromyalgia, mood disorders, osteoarthritis, chronic low back pain [CLBP], chronic kidney disease (CKD), avascular necrosis, osteoporosis, fragility fractures, and cancer), and the Area Deprivation Index (ADI). Opioid prescription data were used to assess the prevalence of LTOT, defined as contiguous prescriptions (gaps of < 30 days between prescriptions) and receiving opioid therapy for ≥ 90 days or ≥ 10 prescriptions before the index date. RESULTS: A total of 465 patients with SLE and 465 controls without SLE were included. In total, 13% of patients with SLE and 3% of controls without SLE were receiving opioid therapy (P < 0.001), and 11% of patients with SLE were on LTOT vs 1% of controls without SLE. Among patients with SLE, acute pericarditis (odds ratio [OR] 3.92, 95% CI 1.78-8.66), fibromyalgia (OR 7.78, 95% CI 3.89-15.55), fragility fractures (OR 3.72, 95% CI 1.25-11.07), CLBP (OR 4.00, 95% CI 2.13-7.51), and mood disorders (OR 2.76, 95% CI 1.47-5.16) were associated with LTOT. We did not find an association between opioid therapy and ADI. CONCLUSION: Patients with SLE are more likely to receive LTOT than controls. Among patients with SLE, LTOT was associated with pericarditis and several comorbidities. However, LTOT was not associated with CKD despite the limited pain control options among these patients.

Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study.

Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score [Formula: see text] 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.

Progression and survival of MBL: a screening study of 10 139 individuals.

Monoclonal B-cell lymphocytosis (MBL) is a common hematological premalignant condition that is understudied in screening cohorts. MBL can be classified into low-count (LC) and high-count (HC) types based on the size of the B-cell clone. Using the Mayo Clinic Biobank, we screened for MBL and evaluated its association with future hematologic malignancy and overall survival (OS). We had a two-stage study design including discovery and validation cohorts. We screened for MBL using an eight-color flow-cytometry assay. Medical records were abstracted for hematological cancers and death. We used Cox regression to evaluate associations and estimate hazard ratios and 95% confidence intervals (CIs), adjusting for age and sex. We identified 1712 (17%) individuals with MBL (95% LC-MBL), and the median follow-up time for OS was 34.4 months with 621 individuals who died. We did not observe an association with OS among individuals with LC-MBL (P = .78) but did among HC-MBL (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). Among the discovery cohort with a median of 10.0 years follow-up, 31 individuals developed hematological cancers with two-thirds being lymphoid malignancies. MBL was associated with 3.6-fold risk of hematological cancer compared to controls (95% CI, 1.7-7.7; P < .001) and 7.7-fold increased risk for lymphoid malignancies (95% CI:3.1-19.2; P < .001). LC-MBL was associated with 4.3-fold risk of lymphoid malignancies (95% CI, 1.4-12.7; P = .009); HC-MBL had a 74-fold increased risk (95% CI, 22-246; P < .001). In this large screening cohort, we observed similar survival among individuals with and without LC-MBL, yet individuals with LC-MBL have a fourfold increased risk of lymphoid malignancies. Accumulating evidence indicates that there are clinical consequences to LC-MBL, a condition that affects 8 to 10 million adults in the United States.

Incidence, Risk Factors, and Mortality of Clinical and Subclinical Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Population-Based Cohort.

OBJECTIVE: To identify the incidence, risk factors, and outcomes of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to assess time trends in the incidence and mortality in RA-ILD. METHODS: We included adult residents of Olmsted County, Minnesota with incident RA between 1999 and 2014. Subjects were followed until death, emigration, or April 30, 2019. ILD was defined as the presence of a radiologist-defined pattern consistent with ILD on chest computed tomography (CT). When chest CT was absent, the combination of chest radiograph abnormalities compatible with ILD and restrictive pattern on pulmonary function testing was considered consistent with ILD. Potential risk factors included age, sex, smoking, obesity, seropositivity, extraarticular manifestations (EAMs), and medications. For survival analysis, we matched RA-ILD patients to RA-non-ILD comparators. The frequency and mortality from clinician-diagnosed RA-ILD from 1999 to 2014 was compared against a cohort from 1955 to 1994. RESULTS: During the 1999-2014 time period, 645 individuals (70% women) had incident RA, were a median age of 55.3 years, and 53% never smoked. Twenty-two patients had ILD before RA, and 51 (67% women) developed ILD during follow-up. The 20-year cumulative incidence of RA-ILD was 15.3%. Ever-smoking (hazard ratio [HR] 1.92), age at RA onset (HR 1.89 per 10-year increase), and severe EAMs (HR 2.29) were associated with incident RA-ILD. The RA-ILD cases had higher mortality than their matched RA comparators (HR 2.42). Incidence of RA-ILD was non-significantly lower from 1999 to 2014 than from 1955 to1994, but mortality was improved. CONCLUSIONS: RA-ILD occurs in nearly 1 in 6 patients with RA within 20 years and is associated with shorter survival. Lack of significant change in RA-ILD incidence over 6 decades deserves further investigation.

Time to transition from psoriasis to psoriatic arthritis: A population-based study.

OBJECTIVE: To identify demographic and clinical characteristics associated with time between psoriasis and psoriatic arthritis (PsA). METHODS: A retrospective, population-based cohort of incident PsA patients ≥18 years (2000-17) from Olmsted County, MN was identified. PsA patients were divided into two groups: patients with concurrent psoriasis and PsA (within 1 year), and patients with psoriasis before PsA (>1 year). Patients with PsA prior to psoriasis were excluded. Age- and sex-adjusted logistic regression models were used to examine factors associated with the time between psoriasis and PsA diagnosis. RESULTS: Among 164 patients with incident PsA, 158 had a current or personal history of psoriasis. The mean (SD) age at PsA diagnosis was 46.3 (12.0) years, and 46% were females. The median (interquartile range) time from psoriasis to PsA was 35.5 (0.8-153.4) months. 64 patients (41%) patients had concurrent psoriasis and PsA while 94 (59%) had onset of psoriasis before PsA. The estimated age at onset of psoriasis symptom (OR per 10-year decrease = 1.63, 95% CI: 1.26-2.11) and psoriasis severity (OR = 3.65, 95% CI: 1.18-11.32 for severe vs. mild) were associated with having a psoriasis diagnosis more than one year prior to incident PsA. CONCLUSION: In this population-based study, approximately 60% of the patients had psoriasis before PsA, and the rest had concurrent psoriasis and PsA. Patients with lower age at psoriasis onset or severe psoriasis were more likely to have a longer time to transition from psoriasis to PsA.

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10-29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10-63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10-5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.