Interpreting hydroxychloroquine blood levels for medication non-adherence: a pharmacokinetic study.

OBJECTIVE: Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients. METHODS: We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses. RESULTS: For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements. CONCLUSIONS: We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy.

Implications of the accuracy of diagnostic algorithms for systemic lupus on our understanding of racial disparities in pregnancy outcomes.

OBJECTIVE: Disparities in pregnancy outcomes among women with SLE remain understudied, with few available racially diverse datasets. We sought to identify disparities between Black and White women in pregnancy outcomes within academic institutions in the United States. METHODS: Using the Common Data Model electronic medical record (EMR)-based datasets within the Carolinas Collaborative, we identified women with pregnancy delivery data (2014-2019) and ≥1 SLE International Classification of Diseases 9 or 10 code (ICD9/10) code. From this dataset, we identified four cohorts of SLE pregnancies, three based on EMR-based algorithms and one confirmed with chart review. We compared the pregnancy outcomes identified in each of these cohorts for Black and White women. RESULTS: Of 172 pregnancies in women with ≥1 SLE ICD9/10 code, 49% had confirmed SLE. Adverse pregnancy outcomes occurred in 40% of pregnancies in women with ≥1 ICD9/10 SLE code and 52% of pregnancies with confirmed SLE. SLE was frequently over-diagnosed in women who were White, resulting in 40-75% lower rates of adverse pregnancy outcomes in EMR-derived vs confirmed SLE cohorts. Over-diagnosis was less common for Black women with pregnancy outcomes 12-20% lower in EMR-derived vs confirmed SLE cohorts. Black women had higher rates of adverse pregnancy outcomes than White women in the EMR-derived, but not the confirmed cohorts. CONCLUSION: EMR-derived cohorts of pregnancies in women who are Black, but not White, provided accurate estimations of pregnancy outcomes. The data from the confirmed SLE pregnancies suggest that all women with SLE, regardless of race, referred to academic centres remain at very high risk for adverse pregnancy outcome.

Development and psychometric evaluation of a physician global assessment for type 2 systemic lupus erythematosus symptoms.

OBJECTIVE: Manifestations of SLE can be categorised as type 1 (classic signs and symptoms of SLE) or type 2 (fatigue, widespread pain and brain fog with an unclear relationship to inflammation). While measures of type 1 SLE activity exist, most current physician-reported measures do not encompass type 2 SLE manifestations. To better evaluate type 2 SLE symptoms, we developed and psychometrically evaluated a physician-reported measure of type 2 symptoms, the Type 2 Physician Global Assessment ('Type 2 PGA'). METHODS AND ANALYSIS: The Type 2 PGA was developed and evaluated by six rheumatologists practising in the same academic lupus clinic. The study began with a roundtable discussion to establish consensus guidelines for scoring the Type 2 PGA. Following the roundtable, the Type 2 PGA was psychometrically evaluated using data prospectively collected from 263 patients with SLE enrolled in the Duke Lupus Registry. RESULTS: There was strong intra-rater and inter-rater reliability (intraclass correlation coefficient=0.83), indicating the Type 2 PGA scores were consistent within a rheumatologist and across rheumatologists. The Type 2 PGA was correlated with patient-reported symptoms of polysymptomatic distress (r=0.76), fatigue (r=0.68), cognitive dysfunction (r=0.63), waking unrefreshed (r=0.62) and forgetfulness (r=0.60), and weakly correlated with the Type 1 PGA and the Systemic Lupus Erythematosus Disease Activity Index. CONCLUSION: The Type 2 PGA performed well as a physician-reported measure of type 2 SLE symptoms. The incorporation of the Type 2 PGA into a routine rheumatology visit may improve patient care by bringing the provider's attention to certain symptoms not well represented in conventional measures of disease activity.

Using pooled electronic health records data to conduct pharmacoepidemiology safety studies: Challenges and lessons learned.

PURPOSE: We assessed the suitability of pooled electronic health record (EHR) data from clinical research networks (CRNs) of the patient-centered outcomes research network to conduct studies of the association between tumor necrosis factor inhibitors (TNFi) and infections. METHODS: EHR data from patients with one of seven autoimmune diseases were obtained from three CRNs and pooled. Person-level linkage of CRN data and Centers for Medicare and Medicaid Services (CMS) fee-for-service claims data was performed where possible. Using filled prescriptions from CMS claims data as the gold standard, we assessed the misclassification of EHR-based new (incident) user definitions. Among new users of TNFi, we assessed subsequent rates of hospitalized infection in EHR and CMS data. RESULTS: The study included 45 483 new users of TNFi, of whom 1416 were successfully linked to their CMS claims. Overall, 44% of new EHR TNFi prescriptions were not associated with medication claims. Our most specific new user definition had a misclassification rate of 3.5%-16.4% for prevalent use, depending on the medication. Greater than 80% of CRN prescriptions had either zero refills or missing refill data. Compared to using EHR data alone, there was a 2- to 8-fold increase in hospitalized infection rates when CMS claims data were added to the analysis. CONCLUSIONS: EHR data substantially misclassified TNFi exposure and underestimated the incidence of hospitalized infections compared to claims data. EHR-based new user definitions were reasonably accurate. Overall, using CRN data for pharmacoepidemiology studies is challenging, especially for biologics, and would benefit from supplementation by other sources.

Association of Health Literacy and Numeracy With Lupus Knowledge and the Creation of the Lupus Knowledge Assessment Test.

OBJECTIVE: Limited health literacy and numeracy are associated with worse patient-reported outcomes and higher disease activity in systemic lupus erythematosus (SLE), but which factors may mediate this association is unknown. We sought to determine the association of health literacy and numeracy with SLE knowledge. METHODS: Patients with SLE were recruited from an academic center clinic. Participants completed validated assessments of health literacy (Newest Vital Sign [NVS]; n = 96) and numeracy (Numeracy Understanding in Medicine Instrument, Short Version [S-NUMI]; n = 85). They also completed the Lupus Knowledge Assessment Test (LKAT), which consists of 4 questions assessing SLE knowledge that were determined through consensus expert opinion for their wide applicability and importance related to self-management of the disease. Descriptive statistics and multivariable logistic regression modeling were used to analyze the results. RESULTS: In our SLE cohort (n = 125), 33% (32/96) had limited health literacy and 76% (65/85) had limited numeracy. The majority correctly identified that hydroxychloroquine prevented SLE flares (91%); however, only 23% of participants correctly answered a numeracy question assessing which urine protein to creatinine (UPC) ratio was > 1000 mg/g. The mean LKAT score was 2.7 out of 4.0. Limited health literacy, but not numeracy, was associated with lower knowledge about SLE as measured by the LKAT, even after adjusting for education. CONCLUSION: Patients with SLE with limited health literacy had lower knowledge about SLE. The LKAT could be further refined and/or used as a screening tool to identify patients with knowledge gaps. Further work is needed to improve patients' understanding of proteinuria and investigate whether literacy-sensitive education can improve care.

Breastfeeding in women with rheumatic diseases.

OBJECTIVE: Many rheumatologists and women with rheumatic disease worry that the disease or treatment will prevent breast feeding. International guidelines establish, however, that most antirheumatic medications are compatible with breast feeding. We sought to identify the frequency and predictors of desire to and actually breast feeding in women with rheumatic diseases. METHODS: Pregnant women with rheumatic disease were enrolled prospectively. Demographics and breastfeeding intention were collected at study entry, while actual breastfeeding decision was recorded postpartum. Maternal diagnosis, demographics and medication use was collected throughout the study. Predictors of breast feeding and intention were identified using stepwise logistic regression. RESULTS: A total of 265 pregnancies were included in the study, 88 with SLE, 33 with undifferentiated connective tissue disease, 100 with arthritis and 44 with other rare rheumatic diagnoses. Of these, 79% intended to breastfeed, 84% of women ever breast fed and 65% were still breast feeding at an average of 7.6 weeks postpartum. Medication concern was the most commonly cited reason not to breastfeed though only 5% of women were taking or planning to start a non-lactation compatible medication at their postpartum visit. In multivariate analysis, women with a college degree were more likely and women with SLE were less likely to intend to breastfeed. Actual breast feeding was most strongly predicted by the woman's intention to breastfeed, but also increased with maternal age, decreased if the baby was born preterm and decreased the further the postpartum appointment occurred from delivery. CONCLUSION: This study demonstrates that the majority of women with rheumatic disease want to and can breastfeed successfully. Additionally, very few women required a medication that was not compatible with breast feeding to control their rheumatic disease in the postpartum period. Despite this, an important minority of patients did not continue breast feeding due to their personal concerns about the risks of antirheumatic medications to their infant.

The importance of pregnancy planning in lupus pregnancies.

OBJECTIVE: In seeking new approaches to improve lupus pregnancy outcomes, we study the association between pregnancy planning, behaviors recommended by American College of Rheumatology's Reproductive Health Guideline 2020, and pregnancy and infant outcomes. METHODS: Lupus pregnancies in a prospective registry (1/1/2018 to 4/1/2020) were classified as planned or not-planned using the patient-reported London Measure of Unplanned Pregnancy. These groups were compared for demographics, pre-pregnancy disease activity, pregnancy planning behaviors, and delivery outcomes. RESULTS: Among 43 women with 43 singleton pregnancies the average age was 29.4 years and 42% were Black. Overall, 60% were planned pregnancies and 40% were not-planned (16 ambivalent, 1 unplanned). Women with not-planned pregnancies had lower age, income, and education, and more required Medicaid. Women with not-planned pregnancies were more likely to conceive when lupus activity was higher (p = 0.001), less likely to receive pre-pregnancy counseling with a rheumatologist (p = 0.02), and less likely to continue pregnancy-compatible medications (p = 0.03). Severe PROMISSE adverse pregnancy outcomes (APOs) and severe neonatal outcomes were higher among women with not-planned than planned pregnancies (43% vs 0% p = 0.003; 70% vs 30% p = 0.06). CONCLUSION: This study identifies pregnancy intention as a potentially modifiable risk factor for poor outcomes in women with lupus. It highlights a unique population of women with lupus at high risk for pregnancy and infant complications: those ambivalent about pregnancy. These women may not be effectively engaging in health behaviors that prevent pregnancy nor those that will prepare for a safe pregnancy. With effective pregnancy planning and contraception guidance, we may decrease their risk for maternal-fetal morbidity and mortality.

Impact of the COVID-19 pandemic on patterns of outpatient cardiovascular care.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic brought about abrupt changes in the way health care is delivered, and the impact of transitioning outpatient clinic visits to telehealth visits on processes of care and outcomes is unclear. METHODS: We evaluated ordering patterns during cardiovascular telehealth clinic visits in the Duke University Health System between March 15 and June 30, 2020 and 30-day outcomes compared with in-person visits in the same time frame in 2020 and in 2019. RESULTS: Within the Duke University Health System, there was a 33.1% decrease in the number of outpatient cardiovascular visits conducted in the first 15 weeks of the COVID-19 pandemic, compared with the same time period in 2019. As a proportion of total visits initially booked, 53% of visits were cancelled in 2020 compared to 35% in 2019. However, patients with cancelled visits had similar demographics and comorbidities in 2019 and 2020. Telehealth visits comprised 9.3% of total visits initially booked in 2020, with younger and healthier patients utilizing telehealth compared with those utilizing in-person visits. Compared with in-person visits in 2020, telehealth visits were associated with fewer new (31.6% for telehealth vs 44.6% for in person) or refill (12.9% vs 15.6%, respectively) medication prescriptions, electrocardiograms (4.3% vs 31.4%), laboratory orders (5.9% vs 21.8%), echocardiograms (7.3% vs 98%), and stress tests (4.4% vs 6.6%). When adjusted for age, race, and insurance status, those who had a telehealth visit or cancelled their visit were less likely to have an emergency department or hospital encounter within 30 days compared with those who had in-person visits (adjusted rate ratios (aRR) 0.76 [95% 0.65, 0.89] and aRR 0.71 [95% 0.65, 0.78], respectively). CONCLUSIONS: In response to the perceived risks of routine medical care affected by the COVID-19 pandemic, different phenotypes of patients chose different types of outpatient cardiology care. A better understanding of these differences could help define necessary and appropriate mode of care for cardiology patients.

Reproductive health needs of adolescent and young adult women with pediatric rheumatic diseases.

BACKGROUND: The purpose of this study was to identify reproductive health knowledge gaps and topics that concern adolescent and young adult (AYA) women with pediatric rheumatic diseases and their parents. METHODS: Data collection occurred in two cohorts. In the first cohort, young women (15-20 years old) with pediatric-onset rheumatic conditions and their parents were recruited from a single, academic pediatric rheumatology center. In the second cohort, young women (18-25 years old) with pediatric-onset rheumatic conditions were recruited from a national conference for families with pediatric rheumatic diseases. This resulted in 20 adolescents and young adults (18.3 ± 2.4 years old), and 7 parent focus group participants. Focus group leaders facilitated discussions centered on reproductive health topics that participants identified as important, their sources of knowledge, and preferences for patient education and ongoing follow-up. Data were summarized independently by 4 researchers to reduce potential bias and subsequently analyzed using rapid qualitative analysis. RESULTS: All participants, regardless of diagnosis, medication, current sexual activity, or current intention to have children, expressed concern about the effect of their rheumatic condition and medications on fertility, risks to mother and child during and after pregnancy, and obtaining safe and effective contraception. Additionally, some participants discussed the burden of disease and its potential impact on motherhood. Finally, participants raised concern around the effect of disease and medication on routine reproductive health care, such as menstrual cycles, feminine self-care, and preventive exams. Three themes emerged: 1) participants had been advised to avoid unplanned pregnancy, however reported receiving inadequate explanation to support this instruction, 2) participants conceptualized reproductive health as tied to rheumatic disease management and thus suggested ways to include family members in discussion, and 3) rheumatology practitioners were not considered a resource of reproductive health information. CONCLUSIONS: Young women and their parents reported dissatisfaction with the availability, quantity, and quality of reproductive health information they received, particularly when related to their pediatric-onset rheumatic disease. These findings provide an initial step in understanding the patient perspective of reproductive health in rheumatology, and how to address these concerns in the care of young women with rheumatic diseases.

Racial Disparities in Medication Adherence between African American and Caucasian Patients With Systemic Lupus Erythematosus and Their Associated Factors.

OBJECTIVE: Medication nonadherence is more common in African Americans compared with Caucasians. We examined the racial adherence gaps among patients with systemic lupus erythematosus (SLE) and explored factors associated with nonadherence. METHODS: Cross-sectional data were obtained from consecutive patients prescribed SLE medications seen at an academic lupus clinic between August 2018 and February 2019. Adherence was measured using both self-report and pharmacy refill data. High composite adherence was defined as having both high self-reported adherence and high refill rates. Covariates were patient-provider interaction, patient-reported health status, and clinical factors. We compared adherence rates by race and used race-stratified analyses to identify factors associated with low composite adherence. RESULTS: Among 121 patients (37% Caucasian, 63% African American), the median age was 44 years (range 22-72), 95% were female, 51% had a college education or more, 46% had private insurance, and 38% had high composite adherence. Those with low composite adherence had higher damage scores, patient-reported disease activity scores, and more acute care visits. High composite adherence rate was lower among African Americans compared with Caucasians (30% vs 51%, P = 0.02), and the gap was largest for those taking mycophenolate (26% vs 75%, P = 0.01). Among African Americans, low composite adherence was associated with perceiving fewer "Compassionate respectful" interactions with providers and worse anxiety and negative affect. In contrast, among Caucasians, low composite adherence was only associated with higher SLE medication regimen burden and fibromyalgia pain score. CONCLUSION: Significant racial disparities exist in SLE medication adherence, which likely contributes to racial disparities in SLE outcomes. Interventions may be more effective if tailored by race, such as improving patient-provider interaction and mental health among African Americans.

Development of ReproKnow, a reproductive knowledge assessment for women with rheumatic diseases.

BACKGROUND: The objective of this study was to develop an assessment tool, ReproKnow, to evaluate the reproductive health knowledge of women with a wide range of rheumatic diseases. METHODS: The 10-item multiple-choice questionnaire was developed with feedback from a panel of content experts and female patients with rheumatic diseases. Construct validity using known-groups analysis was evaluated through comparison of median total ReproKnow scores between rheumatology fellows and nurses. Female patients aged 18-50 years were recruited to take ReproKnow and demographic questionnaires in two outpatient clinics. Associations between patients' mean total knowledge scores and demographic characteristics were assessed using independent-sample t-tests. Questions were also categorized by topical area, and the percentages were calculated. RESULTS: The completion rate of questions in ReproKnow was 100% across all users. Median ReproKnow scores were significantly higher among rheumatology fellows than among nurses (p = 0.045). The 153 patients recruited to the study had at least one of 15 rheumatic diseases. Patients' mean knowledge score was 5.05 (SD 2.24) out of a possible high score of 10. Patients who were younger, White, and more educated had significantly higher scores than did other patients (p's < 0.05). Patients who bore children after their disease diagnosis had higher knowledge scores than did women whose children were born prior to their diagnosis; in contrast, women with histories of surgical sterilization or hysterectomy had lower knowledge scores than other women. Knowledge scores of women who used potentially fetotoxic medications did not vary from the remainder of the sample. Patients demonstrated gaps in knowledge about birth outcomes, contraceptive efficacy, and breastfeeding safety. CONCLUSIONS: Initial testing of ReproKnow suggests that it may be a promising tool to assess the reproductive health knowledge of women with diverse rheumatic diseases. Specific knowledge deficits elicited from ReproKnow may be important targets for future educational interventions.

Rheumatology Informatics System for Effectiveness: A National Informatics-Enabled Registry for Quality Improvement.

OBJECTIVE: The Rheumatology Informatics System for Effectiveness (RISE) is a national electronic health record (EHR)-enabled registry. RISE passively collects data from EHRs of participating practices, provides advanced quality measurement and data analytic capacities, and fulfills national quality reporting requirements. Here we report the registry's architecture and initial data, and we demonstrate how RISE is being used to improve the quality of care. METHODS: RISE is a certified Centers for Medicare and Medicaid Services Qualified Clinical Data Registry, allowing collection of data without individual patient informed consent. We analyzed data between October 1, 2014 and September 30, 2015 to characterize initial practices and patients captured in RISE. We also analyzed medication use among rheumatoid arthritis (RA) patients and performance on several quality measures. RESULTS: Across 55 sites, 312 clinicians contributed data to RISE; 72% were in group practice, 21% in solo practice, and 7% were part of a larger health system. Sites contributed data on 239,302 individuals. Among the subset with RA, 34.4% of patients were taking a biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) at their last encounter, and 66.7% were receiving a nonbiologic DMARD. Examples of quality measures include that 55.2% had a disease activity score recorded, 53.6% a functional status score, and 91.0% were taking a DMARD in the last year. CONCLUSION: RISE provides critical infrastructure for improving the quality of care in rheumatology and is a unique data source to generate new knowledge. Data validation and mapping are ongoing and RISE is available to the research and clinical communities to advance rheumatology.

Racial and Ethnic Disparities in the Pregnancies of Women With Systemic Lupus Erythematosus.

OBJECTIVE: Both systemic lupus erythematosus (SLE; lupus) and pregnancy individually have significant racial disparities, with black women experiencing higher rates of complications, yet no large studies have focused on the impact of race/ethnicity on pregnancy outcomes among women with lupus. METHODS: Using the Nationwide Inpatient Sample (NIS) for 2008-2010, pregnancy delivery discharges were identified and pregnancy outcomes were compared for women with lupus by maternal race/ethnicity. Adjusted odds ratios were used to compare pregnancy outcomes between black and white or Hispanic and white women with lupus. RESULTS: In this period, the NIS included 13,553 deliveries with lupus and 12,510,565 deliveries without lupus. Compared to white women with lupus, black and Hispanic women had higher rates of chronic hypertension, chronic renal failure, pneumonia, and acute renal failure. There was a high degree of pregnancy complication in all women with lupus, but especially in black and Hispanic women, with more than 40% cesarean-section delivery; preterm labor in 14.3% of white, 24.7% of black (odds ratio [OR] 1.97), and 20.6% of Hispanic (OR 1.56) deliveries; and preeclampsia and gestational hypertension in almost 20% of black and Hispanic pregnancies. After adjustment for predictors of pregnancy outcomes and racial differences in nonlupus pregnancy, black and Hispanic women with lupus had higher than expected rates of preeclampsia, preterm labor, and fetal growth restriction. CONCLUSION: Black and Hispanic women with lupus have disproportionately poor pregnancy outcomes. This study suggests that identifying the key causes of these differences and targeting interventions to the women of greatest need is an essential next step.