Obstetric outcomes in women with rheumatic disease and COVID-19 in the context of vaccination status.

OBJECTIVE: To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy. METHODS: Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020-25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi-squared or Fisher's exact test. RESULTS: There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies, 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2% (n = 2). CONCLUSIONS: In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy.

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.

Mortality Among Minority Populations with Systemic Lupus Erythematosus, Including Asian and Hispanic/Latino Persons - California, 2007-2017.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with manifestations that vary widely in severity. Although minority populations are at higher risk for SLE and have more severe outcomes (1), population-based estimates of mortality by race and ethnicity are often lacking, particularly for Asian and Hispanic/Latino persons. Among 812 patients in the California Lupus Surveillance Project (CLSP) during 2007-2009 (2,3), who were matched to the 2007-2017 National Death Index (NDI), 16.6% had died by 2017. This proportion included persons of White (14.4%), Black (25%), Asian (15.3%), and Hispanic/Latino (15.5%) race/ethnicity. Standardized mortality ratios (SMRs) of observed-to-expected deaths among persons with SLE within each racial/ethnic group were 2.3, 2.0, 3.8, and 3.9, respectively. These findings provide the first population-based estimates of mortality among Asian and Hispanic/Latino persons with SLE. Coordination of robust care models between primary care providers and rheumatologists could ensure that persons with SLE receive a timely diagnosis and appropriate treatments that might help address SLE-associated mortality.

A narrative review on the validity of electronic health record-based research in epidemiology.

Electronic health records (EHRs) are widely used in epidemiological research, but the validity of the results is dependent upon the assumptions made about the healthcare system, the patient, and the provider. In this review, we identify four overarching challenges in using EHR-based data for epidemiological analysis, with a particular emphasis on threats to validity. These challenges include representativeness of the EHR to a target population, the availability and interpretability of clinical and non-clinical data, and missing data at both the variable and observation levels. Each challenge reveals layers of assumptions that the epidemiologist is required to make, from the point of patient entry into the healthcare system, to the provider documenting the results of the clinical exam and follow-up of the patient longitudinally; all with the potential to bias the results of analysis of these data. Understanding the extent of as well as remediating potential biases requires a variety of methodological approaches, from traditional sensitivity analyses and validation studies, to newer techniques such as natural language processing. Beyond methods to address these challenges, it will remain crucial for epidemiologists to engage with clinicians and informaticians at their institutions to ensure data quality and accessibility by forming multidisciplinary teams around specific research projects.

Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory diseases.

PURPOSE OF REVIEW: The novel coronavirus 2019 (COVID-19) pandemic is of special concern for patients with immune-mediated inflammatory disease (IMID) and those who care for them because of the potential for worse outcomes. This article analyzes peer-reviewed research on the epidemiology and outcomes of COVID-19 in those with IMID. RECENT FINDINGS: Published literature on approximately 1400 patients was included from rheumatology, gastroenterology, and dermatology. Data suggest that those who are older and have comorbidities have poorer outcomes. This is consistent with the reports from the general population of patients with COVID-19. Adjusted analyses from the largest published studies demonstrate independent effects of systemic glucocorticoids, as well as age and comorbidities with poorer COVID-19 outcomes (SECURE-IBD registry, n = 525; COVID-19 Global Rheumatology Alliance registry, n = 600); biologic or targeted synthetic disease-modifying antirheumatic drug therapy has not been associated with more severe outcomes. These early results will require validation in population-based studies as more data becomes available. SUMMARY: Current data suggest that similar to the general population, age, and comorbidities are risk factors for poorer COVID-19 outcomes in patients with IMID. Additional research is needed to quantify outcomes and risk across rheumatic disease types, comorbidities, and immunosuppressive drugs.

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease. METHODS: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed. RESULTS: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed. CONCLUSIONS: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.

Genetic risk factors for pediatric-onset multiple sclerosis.

BACKGROUND: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. OBJECTIVE: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. METHODS: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). RESULTS: HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10-16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10-16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02. CONCLUSION: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.

The impact of smoking on disease measures in rheumatoid arthritis: the need for appropriate adjustment of time-varying confounding.

In a recent publication, Quintana-Dunque et al. studied patients with early onset rheumatoid arthritis (RA) and showed that baseline smoking status was inversely associated with disease activity and disability at 36 months. The authors conclude that smoking may not be as deleterious as previously considered in RA disease course. However, the authors fail to highlight several limitations of study design and analysis, including time-varying confounding, which may have a direct impact on results and corresponding conclusions.

Correction to: Hydroxychloroquine dosing in immune-mediated diseases: implications for patient safety.

The given and family name of a co-author R. Adams Dudley was swapped in the published article. The correct given name is R. Adams and the family name is Dudley.

Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility.

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement.

Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

Hydroxychloroquine dosing in immune-mediated diseases: implications for patient safety.

Evidence suggests that hydroxychloroquine (HCQ) retinal toxicity is more common than previously thought. Adhering to careful weight-based dosing can significantly reduce the risk of this adverse event and is recommended in recent guidelines. We used electronic health record data from a large health system to examine HCQ dosing over a 5-year period and identify risk factors associated with higher dosage of HCQ. We constructed a longitudinal, retrospective cohort of patients with HCQ prescriptions (1681 patients with 3490 prescribing events) between 2012 and 2016. We measured HCQ dosing patterns relative to guidelines (<6.5 and <5.0 mg/kg) over time and used longitudinal multivariate mixed effects logistic regression to identify sociodemographic, clinical and health system factors associated with receiving higher than recommended doses of HCQ. The proportion of patients receiving doses above 6.5 mg/kg decreased from 12% in 2012 to 7% by 2016. Similarly, the proportion of patients with doses above 5.0 mg/kg fell from 38% in 2012 to 30% in 2016. Low body weight (<68 kg) was strongly associated with receiving doses of HCQ above 6.5 mg/kg across all time points, even after adjusting for other factors (odds ratios ranging from 13.2 to 21.0). Although the proportion of patients receiving higher than recommended HCQ doses has declined over a period of 5 years, a substantial number of individuals remain at increased risk for toxicity. Given the widespread use of HCQ in immune-mediated diseases, our study suggests that interventions aimed to ensure appropriate dosing are warranted to improve patient safety.