Pregnancy Outcomes in Patients Treated with Upadacitinib: Analysis of Data from Clinical Trials and Postmarketing Reports.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVie's safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Safety of Upadacitinib in Immune-Mediated Inflammatory Diseases: Systematic Literature Review of Indirect and Direct Treatment Comparisons of Randomized Controlled Trials.

INTRODUCTION: Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondylarthritis (nr-axSpA), atopic dermatitis (AD), ulcerative colitis (UC), and Crohn's disease (CD) pose a substantial burden on patients and their quality of life. Upadacitinib is an orally administered, selective, and reversible Janus kinase inhibitor indicated for seven conditions, but data on its safety versus other active treatments are limited. A systematic literature review of indirect and direct treatment comparisons of randomized controlled trials (RCTs) was conducted to assess the safety profile of upadacitinib. METHODS: MEDLINE, Embase, and Cochrane Library databases were searched for indirect and direct treatment comparisons of RCTs that (1) included licensed upadacitinib dosages; (2) studied any of the seven conditions; (3) reported any adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, major adverse cardiovascular event, venous thromboembolism, malignancies, infections or serious infections, and death; and (4) were published between January 2018 and August 2022. RESULTS: A total of 25 studies were eligible for inclusion. SAEs, AEs leading to discontinuation, and any AEs were commonly studied. RA was the most studied condition, followed by AD and UC. Most studies (16/25, 64%) reported no statistically significant difference in the studied safety outcomes between upadacitinib and other active treatments (e.g., tumor necrosis factor blockers, interleukin receptor antagonists, integrin receptor antagonists, T cell co-stimulation modulator), or placebo (placebo ± methotrexate or topical corticosteroids). Other studies (9/25, 36%) reported mixed results of no statistically significant difference and either statistically higher (8/25, 32%) or lower rates (1/25, 4%) on upadacitinib. CONCLUSION: Most studies suggested that upadacitinib has no statistically significant difference in the studied safety outcomes compared to active treatments or placebo in patients with RA, PsA, AS, AD, UC, and CD. A few studies reported higher rates, but findings were inconsistent with limited interpretation.

Factors Associated with Severe COVID-19 Among Patients with Rheumatoid Arthritis: A Large, Nationwide Electronic Health Record Cohort Study in the United States.

INTRODUCTION: To evaluate factors associated with severe coronavirus disease 2019 (COVID-19) among patients with rheumatoid arthritis (RA) in the US. METHODS: Adults with RA who had a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, based on molecular or antigen test or clinical diagnosis, were identified from the Optum® COVID-19 Electronic Health Record dataset (March 1, 2020-April 28, 2021). The primary outcome was the occurrence of severe COVID-19 (hospitalization or death) within 30 days from SARS-CoV-2 infection. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models to assess the association between severe COVID-19 and patient characteristics, including demographics, baseline comorbidities, and recent RA treatments. RESULTS: During the study period, 6769 SARS-CoV-2 infections were identified in patients with RA, among whom 1460 (22%) developed severe COVID-19. Multivariable logistic regression analysis showed that being older, male, and non-White and having diabetes and cardiovascular conditions are associated with greater odds of severe COVID-19. In addition, compared with no use, the adjusted odds of severe COVID-19 were lower with recent use of tumor necrosis factor inhibitors (aOR 0.60, 95% CI 0.41-0.86) and higher with recent use of corticosteroids (aOR 1.38, 95% CI 1.13-1.69) or rituximab (aOR 2.87, 95% CI 1.60-5.14), respectively. CONCLUSION: Nearly one in five patients with RA developed severe COVID-19 disease within 30 days after SARS-CoV-2 infection. In patients with RA, recent use of corticosteroids and rituximab were two factors associated with a greater risk of severe COVID-19 in addition to the risk factors among demographics and comorbidities previously identified in the general population.

EpidemiologiCal POpulatioN STudy of SARS-CoV-2 in Lake CounTy, Illinois (CONTACT): Methodology and Baseline Characteristics of a Community-Based Surveillance Study.

INTRODUCTION: EpidemiologiCal POpulatioN STudy of SARS-CoV-2 in Lake CounTy, Illinois (CONTACT) is an observational, epidemiological study with a 9-month longitudinal follow-up of nonhospitalized persons aged 18 years or older currently living or employed in Lake County, IL. We describe the study design and report baseline characteristics of the study participants, including the proportion of participants with acute or previous SARS-CoV-2 infection at enrollment. METHODS: At enrollment and subsequent timepoints, participants recruited through digital and paper-based advertising campaigns reported their occupational and school-based exposure, risk factors, and behaviors, and provided nasal and serum specimens. Stratified enrichment was used to enhance enrollment into medium- and higher-risk groups within four occupational risk groups for SARS-CoV-2 infection. RT-PCR and serologic (IgG) testing were conducted to detect acute or previous SARS-CoV-2 infection in participants, respectively. RESULTS: Between November 2020 and January 2021, 1008 participants (female 70.7%, mean age ± SD 51 ± 13.8 years) completed the questionnaire and diagnostic testing. Among participants, 41.8% (n = 421) were considered low risk, 24.6% (n = 248) were medium-to-low risk, 22.3% (n = 225) were medium-to-high risk, and 11.3% (n = 114) were high risk. Of 56 (5.6%) participants with evidence of acute or previous SARS-CoV-2 infection at baseline, 11 (19.6%) were RT-PCR-positive, 36 (64.3%) were IgG-seropositive, and 9 (16.1%) were positive by both assays. Participants who were adherent vs nonadherent to social distancing measures (odds ratio [95% CI] 0.8 [0.4-1.8]) were less likely, while those in higher vs lower occupational risk groups (2.0 [1.0-4.4]) were more likely to have evidence for acute or previous SARS-CoV-2 infection. CONCLUSION: In fall/winter 2020/21, 5.6% of adults in a Lake County convenience sample had evidence for acute or previous SARS-CoV-2 infection at baseline. Nonadherence to social distancing measures and high-risk professions were associated with SARS-CoV-2 infection. The study is ongoing and future analyses will assess infection status over time. CLINICAL TRIAL REGISTRATION: NCT04611230.

Validation of claims-based algorithms to identify patients with psoriasis.

PURPOSE: Accurately identifying patients with psoriasis (PsO) is crucial for generating real-world evidence on PsO disease course and treatment utilization. METHODS: We developed nine claims-based algorithms for PsO using a combination of the International Classification of Diseases (ICD)-9 codes, specialist visit, and medication dispensing using Medicare linked to electronic health records data (2013-2014) in two healthcare provider networks in Boston, Massachusetts. We calculated positive predictive value (PPV) and 95% confidence interval (CI) for each algorithm using the treating physician's diagnosis of PsO via chart review as the gold standard. Among the confirmed PsO cases, we assessed their PsO disease activity. RESULTS: The nine claims-based algorithms identified 990 unique patient records. Of those, 918 (92.7%) with adequate information were reviewed. The PPV of the algorithms ranged from 65.1 to 82.9%. An algorithm defined as ≥1 ICD-9 diagnosis code for PsO and ≥1 prescription claim for topical vitamin D agents showed the highest PPV (82.9%). The PPV of the algorithm requiring ≥2 ICD-9 diagnosis codes and ≥1 prescription claim for PsO treatment excluding topical steroids was 81.1% but higher (82.5%) when ≥1 diagnosis was from a dermatologist. Among 411 PsO patients with adequate information on PsO disease activity in EHRs, 1.5-5.8% had no disease activity, 31.3-36.8% mild, and 26.9-35.1% moderate-to-severe across the algorithms. CONCLUSIONS: Claims-based algorithms based on a combination of PsO diagnosis codes and dispensing for PsO-specific treatments had a moderate-to-high PPV. These algorithms can serve as a useful tool to identify patients with PsO in future real-world data pharmacoepidemiologic studies.

Chronic opioid use and complication risks in women with endometriosis: A cohort study in US administrative claims.

BACKGROUND: Women with endometriosis are prescribed opioids for pain relief but may be vulnerable to chronic opioid use given their comorbidity profile. METHODS: A cohort study was conducted in the Clinformatics™ DataMart database between 2006 and 2017 comparing women aged 18-50 years with endometriosis (N = 36 373) to those without (N = 2 172 936) in terms of risk of chronic opioid use, opioid dependence diagnosis, and opioid overdose. Chronic opioid use was defined as ≥120 days' supply dispensed or ≥10 fills of an opioid during any 365-day interval. Among women with endometriosis, we evaluated factors associated with higher risk of chronic opioid use and quantified the risk of complications associated with the use of opioids. RESULTS: Women with endometriosis were at greater risk for chronic opioid use (OR: 3.76; 95%CI: 3.57-3.96), dependence (OR: 2.73, 95%CI: 2.38-3.13) and overdose (OR: 4.34, 95%CI: 3.06-6.15) compared to women without. Chronic users displayed dose escalation and increase in days supplied over time, as well as co-prescribing with benzodiazepines and sedatives. Approximately 34% of chronic users developed constipation, 20% experienced falls, and 8% reported dizziness. Among endometriosis patients, women in younger age groups, those with other comorbidities associated with pain symptoms, as well as those with depression or anxiety were at a higher risk of developing chronic opioid use. CONCLUSIONS: Women with endometriosis had a four times greater risk of chronic opioid use compared to women without. Multimorbidity among these patients was associated with the elevated risk of chronic opioid use and should be taken into account during treatment selection.

Estimating the Effect of Elagolix Treatment for Endometriosis on Postmenopausal Bone Outcomes: A Model Bridging Phase III Trials to an Older Real-World Population.

Elagolix, a gonadotrophin-releasing hormone antagonist, is used in premenopausal women with endometriosis. There is a risk of bone loss with elagolix, but the long-term effects of BMD loss later in life cannot be directly assessed and has not been quantified. To address this gap in knowledge, this study indirectly estimated the impact of elagolix on postmenopausal fracture risk. BMD change in premenopausal women with endometriosis treated with elagolix was modeled from the phase III program data (elagolix group) and used to simulate treatment effects on (fracture risk assessment tool estimated) 10-year risks of hip and major osteoporotic fracture in women ages 50 to 79 years from the 2005-2010 National Health and Nutrition Examination Survey (NHANES; N = 2303). Change in the proportion of women reaching risk-based antiosteoporotic treatment thresholds was also estimated. For elagolix versus NHANES, median 10-year risk of major osteoporotic fracture was 4.73% versus 4.70% in women ages 50 to 59 years, 7.03% versus 6.97% in women ages 60 to 69 years, and 10.83% versus 10.68% in women ages 70 to 79 years. Median 10-year risk of hip fracture in these same groups was 0.19% versus 0.18% for women ages 50 to 59 years, 0.51% versus 0.49% for women 60 to 69 years, and 2.22% versus 2.14% for women 70 to 79 years. The proportion of women reaching risk-based antiosteoporotic treatment thresholds caused by elagolix 150 mg daily for 12 months was 0.36% higher at age 50 to 59 years, 0.23% at age 60 to 69 years, and 1.79% at age 70 to 79 years. The number needed to harm was 643 for one additional hip fracture and 454 for one additional major osteoporotic fracture. Results were similar for elagolix 200 mg twice a day for 3 months. In the modeled scenarios, elagolix had minimal impact on long-term risk of fracture and reaching risk-based treatment thresholds. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Rotating Night-Shift Work and the Risk of Breast Cancer in the Nurses' Health Studies.

In 2007, the International Agency for Research on Cancer declared shift work that involved circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. Using data from 2 prospective cohort studies, the Nurses' Health Study (1988-2012; n = 78,516) and Nurses' Health Study II (1989-2013; n = 114,559), we examined associations between rotating night-shift work and breast cancer risk. In the 2 cohorts, there were a total of 9,541 incident invasive breast malignancies and 24 years of follow-up. In the Nurses' Health Study, women with 30 years or more of shift work did not have a higher risk of breast cancer (hazard ratio (HR) = 0.95, 95% confidence interval (95% CI): 0.77, 1.17; P for trend = 0.63) compared with those who never did shift work, although follow-up occurred primarily after retirement from shift work. Among participants in the Nurses' Health Study II, who were younger than participants in the other cohort, the risk of breast cancer was significantly higher in women with 20 years or more of shift work at baseline, reflecting young-adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; P for trend = 0.23), and was marginally significantly higher for women with 20 years or more of cumulative shift work when we used updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; P for trend = 0.74). In conclusion, long-term rotating night-shift work was associated with a higher risk of breast cancer, particularly among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk.

Association Between Rotating Night Shift Work and Risk of Coronary Heart Disease Among Women.

IMPORTANCE: Prospective studies linking shift work to coronary heart disease (CHD) have been inconsistent and limited by short follow-up. OBJECTIVE: To determine whether rotating night shift work is associated with CHD risk. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 189,158 initially healthy women followed up over 24 years in the Nurses' Health Studies (NHS [1988-2012]: N = 73,623 and NHS2 [1989-2013]: N = 115,535). EXPOSURES: Lifetime history of rotating night shift work (≥3 night shifts per month in addition to day and evening shifts) at baseline (updated every 2 to 4 years in the NHS2). MAIN OUTCOMES AND MEASURES: Incident CHD; ie, nonfatal myocardial infarction, CHD death, angiogram-confirmed angina pectoris, coronary artery bypass graft surgery, stents, and angioplasty. RESULTS: During follow-up, 7303 incident CHD cases occurred in the NHS (mean age at baseline, 54.5 years) and 3519 in the NHS2 (mean age, 34.8 years). In multivariable-adjusted Cox proportional hazards models, increasing years of baseline rotating night shift work was associated with significantly higher CHD risk in both cohorts. In the NHS, the association between duration of shift work and CHD was stronger in the first half of follow-up than in the second half (P=.02 for interaction), suggesting waning risk after cessation of shift work. Longer time since quitting shift work was associated with decreased CHD risk among ever shift workers in the NHS2 (P<.001 for trend). [table: see text] CONCLUSIONS AND RELEVANCE: Among women who worked as registered nurses, longer duration of rotating night shift work was associated with a statistically significant but small absolute increase in CHD risk. Further research is needed to explore whether the association is related to specific work hours and individual characteristics.

The association of body size in early to mid-life with adult urinary 6-sulfatoxymelatonin levels among night shift health care workers.

BACKGROUND: Adult body mass index (BMI) has been associated with urinary melatonin levels in humans; however, whether earlier-life body size is associated with melatonin, particularly among night shift workers, remains unknown. METHODS: We evaluated associations of birth weight, body shape (or somatotype) at ages 5 and 10, BMI at age 18 and adulthood, weight change since age 18, waist circumference, waist to hip ratio, and height with creatinine-adjusted morning urinary melatonin (6-sulfatoxymelatonin, aMT6s) levels among 1,343 healthy women (aged 32-53 at urine collection, 1996-1999) in the Nurses' Health Study (NHS) II cohort. Using multivariable linear regression, we computed least-square mean aMT6s levels across categories of body size, and evaluated whether these associations were modified by night shift work. RESULTS: Adult BMI was inversely associated with aMT6s levels (mean aMT6s levels = 34 vs. 50 ng/mg creatinine, comparing adult BMI ≥ 30 vs. <20 kg/m(2); P trend < 0.0001); however, other measures of body size were not related to aMT6s levels after accounting for adult BMI. Night shifts worked prior to urine collection, whether recent or cumulatively over time, did not modify the association between adult BMI and aMT6s levels (e.g., P interaction = 0.72 for night shifts worked within two weeks of urine collection). CONCLUSIONS: Our results suggest that adult BMI, but not earlier measures of body size, is associated with urinary aMT6s levels in adulthood. These observations did not vary by night shift work status, and suggest that adult BMI may be an important mechanism by which melatonin levels are altered and subsequently influence chronic disease risk.

Antihypertensive medication use and incident breast cancer in women.

The purpose of this study was to evaluate whether antihypertensive medication use, including long-term use, is associated with increased breast cancer incidence in women. We studied 210,641 U.S. registered nurses participating in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Information on antihypertensive medication use was collected on biennial questionnaires in both cohorts, and breast cancer cases were ascertained during this period. Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks of invasive breast cancer over follow-up (1988-2012 in NHS, 1989-2011 in NHS II) across categories of overall antihypertensive medication use and use of specific classes (diuretics, beta blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors). During follow-up, 10,012 cases of invasive breast cancer developed (6718 cases in NHS and 3294 in the NHS II). Overall, current use of any antihypertensive medication was not associated with breast cancer risk compared with past/never use in NHS (multivariable-adjusted relative risk = 1.00, 95 % CI = 0.95-1.06) or NHS II (multivariable-adjusted relative risk = 0.94, 95 % CI = 0.86-1.03). Furthermore, no specific class of antihypertensive medication was consistently associated with breast cancer risk. Results were similar when we considered hypertensive women only, and when we evaluated consistency and duration of medication use over time. Overall, antihypertensive medication use was largely unrelated to the risk of invasive breast cancer among women in the NHS cohorts.

Urinary melatonin concentration and the risk of breast cancer in Nurses' Health Study II.

Experimental and epidemiologic data support a protective role for melatonin in breast cancer etiology, yet studies in premenopausal women are scarce. In a case-control study nested within the Nurses' Health Study II cohort, we measured the concentration of melatonin's major urinary metabolite, 6-sulfatoxymelatonin (aMT6s), in urine samples collected between 1996 and 1999 among 600 breast cancer cases and 786 matched controls. Cases were predominantly premenopausal women who were diagnosed with incident breast cancer after urine collection and before June 1, 2007. Using multivariable conditional logistic regression, we computed odds ratios and 95% confidence intervals. Melatonin levels were not significantly associated with total breast cancer risk (for the fourth (top) quartile (Q4) of aMT6s vs. the first (bottom) quartile (Q1), odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.64, 1.28; Ptrend = 0.38) or risk of invasive or in situ breast cancer. Findings did not vary by body mass index, smoking status, menopausal status, or time between urine collection and diagnosis (all Pinteraction values ≥ 0.12). For example, the odds ratio for total breast cancer among women with ≤5 years between urine collection and diagnosis was 0.74 (Q4 vs. Q1; 95% CI: 0.45, 1.20; Ptrend = 0.09), and it was 1.20 (Q4 vs. Q1; 95% CI: 0.72, 1.98; Ptrend = 0.70) for women with >5 years. Our data do not support an overall association between urinary melatonin levels and breast cancer risk.

Night shift work at specific age ranges and chronic disease risk factors.

OBJECTIVES: We examined the association of night shift work history and age when night shift work was performed with cancer and cardiovascular disease risk factors among 54 724 women in the Nurses' Health Study (NHS) II. METHODS: We calculated age-adjusted and socioeconomic status-adjusted means and percentages for cancer and cardiovascular risk factors in 2009 across categories of night shift work history. We used multivariable-adjusted logistic regression to estimate odds ratios (ORs) and 95% CIs for key risk factors among 54 724 participants (72% ever shift workers). We further examined these associations by age (20-25, 26-35, 36-45 and 46+ years) at which shift work was performed. RESULTS: Ever night shift workers had increased odds of obesity (body mass index ≥30 kg/m(2); OR=1.37, 95% CI 1.31 to 1.43); higher caffeine intake (≥131 mg/day; OR=1.16, 95% CI 1.12 to 1.22) and total calorie intake (≥1715 kcal/day; OR=1.09, 95% CI 1.04 to 1.13); current smoking (OR=1.30, 95% CI 1.19 to 1.42); and shorter sleep durations (≤7 h of sleep/day; OR=1.19, 95% CI 1.15 to 1.24) compared to never night shift workers. These estimates varied depending on age at which night work was performed, with a suggestion that night shift work before age 25 was associated with fewer risk factors compared to night shift work at older ages. CONCLUSIONS: Our results indicate that night shift work may contribute to an adverse chronic disease risk profile, and that risk factors may vary depending on the age at which night shift work was performed.

Feasibility of using global positioning systems (GPS) with diverse urban adults: before and after data on perceived acceptability, barriers, and ease of use.

BACKGROUND: Global positioning systems (GPS) have emerged as a research tool to better understand environmental influences on physical activity. This study examined the feasibility of using GPS in terms of perceived acceptability, barriers, and ease of use in a racially/ethnically diverse sample of lower socioeconomic position (SEP). METHODS: Data were from 2 pilot studies involving a total of 170 African American, Hispanic, and White urban adults with a mean (standard deviation) age of 47.8 (±13.1) years. Participants wore a GPS for up to 7 days. They answered questions about GPS acceptability, barriers (wear-related concerns), and ease of use before and after wearing the GPS. RESULTS: We found high ratings of GPS acceptability and ease of use and low levels of wear-related concerns, which were maintained after data collection. While most were comfortable with their movements being tracked, older participants (P < .05) and African Americans (P < .05) reported lower comfort levels. Participants who were younger, with higher education, and low incomes were more likely to indicate that the GPS made the study more interesting (P < .05). Participants described technical and wear-related problems, but few concerns related to safety, loss, or appearance. CONCLUSIONS: Use of GPS was feasible in this racially/ethnically diverse, lower SEP sample.

Activity space environment and dietary and physical activity behaviors: a pilot study.

This study examined relationships among individual demographics, environmental features (e.g., fast food outlet density, park land use) of residential neighborhoods and activity spaces, and weight-related behaviors (diet, physical activity). Participants' movement was tracked for 7 days using global positioning systems (GPS). Two activity space measures (one standard deviation ellipse, daily path area) were derived from the GPS data. Activity spaces were generally larger than residential neighborhoods; environmental features of residential neighborhoods and activity spaces were weakly associated; and some activity space environmental features were related to dietary behaviors. Activity spaces may provide new insights into environmental influences on obesity-related behaviors.