Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

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.

Temporal trends in COVID-19 outcomes among patients with systemic autoimmune rheumatic diseases: from the first wave through the initial Omicron wave.

OBJECTIVES: To investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the initial Omicron wave. METHODS: We conducted a retrospective cohort study investigating COVID-19 outcomes among patientswith SARD systematically identified to have confirmed COVID-19 from 1 March 2020 to 31 January 2022 at Mass General Brigham. We tabulated COVID-19 counts of total and severe cases (hospitalisations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared with the early COVID-19 period (reference group). RESULTS: We identified 1449 patients with SARD with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (28%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 46% of cases were severe in the early COVID-19 period (1 March 2020-30 June 2020) vs 15% in the initial Omicron wave (17 December 2021-31 January 2022; adjusted OR 0.29, 95% CI 0.19 to 0.43). A higher proportion of those unvaccinated were severe compared with not severe cases (78% vs 60%). CONCLUSIONS: The proportion of patients with SARD with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the initial Omicron wave. Advances in prevention, diagnosis and treatment of COVID-19 may have improved outcomes among patients with SARD.

Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance.

AIM: To determine characteristics associated with more severe outcomes in a global registry of people with systemic lupus erythematosus (SLE) and COVID-19. METHODS: People with SLE and COVID-19 reported in the COVID-19 Global Rheumatology Alliance registry from March 2020 to June 2021 were included. The ordinal outcome was defined as: (1) not hospitalised, (2) hospitalised with no oxygenation, (3) hospitalised with any ventilation or oxygenation and (4) death. A multivariable ordinal logistic regression model was constructed to assess the relationship between COVID-19 severity and demographic characteristics, comorbidities, medications and disease activity. RESULTS: A total of 1606 people with SLE were included. In the multivariable model, older age (OR 1.03, 95% CI 1.02 to 1.04), male sex (1.50, 1.01 to 2.23), prednisone dose (1-5 mg/day 1.86, 1.20 to 2.66, 6-9 mg/day 2.47, 1.24 to 4.86 and ≥10 mg/day 1.95, 1.27 to 2.99), no current treatment (1.80, 1.17 to 2.75), comorbidities (eg, kidney disease 3.51, 2.42 to 5.09, cardiovascular disease/hypertension 1.69, 1.25 to 2.29) and moderate or high SLE disease activity (vs remission; 1.61, 1.02 to 2.54 and 3.94, 2.11 to 7.34, respectively) were associated with more severe outcomes. In age-adjusted and sex-adjusted models, mycophenolate, rituximab and cyclophosphamide were associated with worse outcomes compared with hydroxychloroquine; outcomes were more favourable with methotrexate and belimumab. CONCLUSIONS: More severe COVID-19 outcomes in individuals with SLE are largely driven by demographic factors, comorbidities and untreated or active SLE. Patients using glucocorticoids also experienced more severe outcomes.

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.

The spliceosome is a therapeutic vulnerability in MYC-driven cancer.

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

Assessing the Severity of COVID-19 Lung Injury in Rheumatic Diseases Versus the General Population Using Deep Learning-Derived Chest Radiograph Scores.

OBJECTIVE: COVID-19 patients with rheumatic disease have a higher risk of mechanical ventilation than the general population. The present study was undertaken to assess lung involvement using a validated deep learning algorithm that extracts a quantitative measure of radiographic lung disease severity. METHODS: We performed a comparative cohort study of rheumatic disease patients with COVID-19 and ≥1 chest radiograph within ±2 weeks of COVID-19 diagnosis and matched comparators. We used unadjusted and adjusted (for age, Charlson comorbidity index, and interstitial lung disease) quantile regression to compare the maximum pulmonary x-ray severity (PXS) score at the 10th to 90th percentiles between groups. We evaluated the association of severe PXS score (>9) with mechanical ventilation and death using Cox regression. RESULTS: We identified 70 patients with rheumatic disease and 463 general population comparators. Maximum PXS scores were similar in the rheumatic disease patients and comparators at the 10th to 60th percentiles but significantly higher among rheumatic disease patients at the 70th to 90th percentiles (90th percentile score of 10.2 versus 9.2; adjusted P = 0.03). Rheumatic disease patients were more likely to have a PXS score of >9 (20% versus 11%; P = 0.02), indicating severe pulmonary disease. Rheumatic disease patients with PXS scores >9 versus ≤9 had higher risk of mechanical ventilation (hazard ratio [HR] 24.1 [95% confidence interval (95% CI) 6.7, 86.9]) and death (HR 8.2 [95% CI 0.7, 90.4]). CONCLUSION: Rheumatic disease patients with COVID-19 had more severe radiographic lung involvement than comparators. Higher PXS scores were associated with mechanical ventilation and will be important for future studies leveraging big data to assess COVID-19 outcomes in rheumatic disease patients.

Association Between Race/Ethnicity and COVID-19 Outcomes in Systemic Lupus Erythematosus Patients From the United States: Data From the COVID-19 Global Rheumatology Alliance.

OBJECTIVE: To determine the association between race/ethnicity and COVID-19 outcomes in individuals with systemic lupus erythematosus (SLE). METHODS: Individuals with SLE from the US with data entered into the COVID-19 Global Rheumatology Alliance registry between March 24, 2020 and August 27, 2021 were included. Variables included age, sex, race, and ethnicity (White, Black, Hispanic, other), comorbidities, disease activity, pandemic time period, glucocorticoid dose, antimalarials, and immunosuppressive drug use. The ordinal outcome categories were: not hospitalized, hospitalized with no oxygenation, hospitalized with any ventilation or oxygenation, and death. We constructed ordinal logistic regression models evaluating the relationship between race/ethnicity and COVID-19 severity, adjusting for possible confounders. RESULTS: We included 523 patients; 473 (90.4%) were female and the mean ± SD age was 46.6 ± 14.0 years. A total of 358 patients (74.6%) were not hospitalized; 40 patients (8.3%) were hospitalized without oxygen, 64 patients (13.3%) were hospitalized with any oxygenation, and 18 (3.8%) died. In a multivariable model, Black (odds ratio [OR] 2.73 [95% confidence interval (95% CI) 1.36-5.53]) and Hispanic (OR 2.76 [95% CI 1.34-5.69]) individuals had higher odds of more severe outcomes than White individuals. CONCLUSION: Black and Hispanic individuals with SLE experienced more severe COVID-19 outcomes, which is consistent with findings in the US general population. These results likely reflect socioeconomic and health disparities and suggest that more aggressive efforts are needed to prevent and treat infection in this population.

Coronavirus Disease 2019 Outcomes Among Recipients of Anti-CD20 Monoclonal Antibodies for Immune-Mediated Diseases: A Comparative Cohort Study.

OBJECTIVE: Patients with immune-mediated diseases treated with anti-CD20 monoclonal antibodies may have worse coronavirus disease 2019 (COVID-19) outcomes due to impaired humoral immunity, but differences compared with the general population are unknown. METHODS: We identified patients with immune-mediated diseases who received anti-CD20 monoclonal antibodies within 1 year prior to the index date of polymerase chain reaction-confirmed COVID-19 between January 31, 2020, and January 31, 2021. General population comparators with COVID-19 were matched up 5:1 by age, sex, and polymerase chain reaction date. Unadjusted and multivariable adjusted (for age, race, body mass index, and Charlson Comorbidity Index) hazard ratios (HRs) and 95% confidence intervals (CIs) for hospitalization, mechanical ventilation, and death in recipients of anti-CD20 monoclonal antibodies versus comparators were estimated by using Cox regression. RESULTS: We identified 114 cases patients COVID-19 who had received anti-CD20 monoclonal antibodies for immune-mediated diseases (mean age 55 years, 70% female) and 559 matched comparators with COVID-19 (mean age 54 years, 70% female). Patients treated with anti-CD20 monoclonal antibodies had higher mortality (adjusted HR 2.16; 95% CI: 1.03-4.54) than matched comparators. Risks of hospitalization (adjusted HR 0.88; 95% CI: 0.62-1.26) and mechanical ventilation use (adjusted HR 0.82; 95% CI: 0.36-1.87) were similar. Similar trends were seen in analyses according to type of indication (eg, rheumatic or neurologic disease) and duration of anti-CD20 monoclonal antibody use (<1 or ≥1 year) and after patients with interstitial lung disease, those with cancer, and those on glucocorticoids prior to COVID-19 diagnosis were excluded. CONCLUSION: Patients who received anti-CD20 monoclonal antibodies for immune-mediated diseases prior to COVID-19 had higher mortality following COVID-19 than matched comparators, highlighting the urgent need to mitigate excess risks in recipients of anti-CD20 monoclonal antibodies during the ongoing pandemic.

DMARD disruption, rheumatic disease flare, and prolonged COVID-19 symptom duration after acute COVID-19 among patients with rheumatic disease: A prospective study.

OBJECTIVE: To describe disease-modifying antirheumatic drug (DMARD) disruption, rheumatic disease flare/activity, and prolonged COVID-19 symptom duration among COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs). METHODS: We surveyed people with pre-existing SARDs who had confirmed COVID-19 at Mass General Brigham to investigate post-acute sequelae of COVID-19. We obtained data on demographics, clinical characteristics, COVID-19 symptoms/course, and patient-reported measures. We examined baseline predictors of prolonged COVID-19 symptom duration (defined as lasting ≥28 days) using logistic regression. RESULTS: We analyzed surveys from 174 COVID-19 survivors (mean age 52 years, 81% female, 80% White, 50% rheumatoid arthritis) between March 2021 and January 2022. Fifty-one percent of 127 respondents on any DMARD reported a disruption to their regimen after COVID-19 onset. For individual DMARDs, 56-77% had any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41%. Global patient-reported disease activity was worse at the time of survey than before COVID-19 (mean 6.6±2.9 vs. 7.6±2.3, p<0.001). Median time to COVID-19 symptom resolution was 25 days (IQR 11, 160). Prolonged symptom duration of ≥28 days occurred in 45%. Hospitalization for COVID-19 (OR 3.54, 95%CI 1.27-9.87) and initial COVID-19 symptom count (OR 1.38 per symptom, 95%CI 1.17-1.63) were associated with prolonged symptom duration. Respondents experiencing prolonged symptom duration had higher RAPID3 scores (p=0.007) and more pain (p<0.001) and fatigue (p=0.03) compared to those without prolonged symptoms. CONCLUSION: DMARD disruption, SARD flare, and prolonged COVID-19 symptom duration were common in this prospective study of COVID-19 survivors, suggesting substantial impact on SARDs after acute COVID-19.

Temporal trends in COVID-19 outcomes among patients with systemic autoimmune rheumatic diseases: From the first wave to Omicron.

Objectives: To investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the Omicron wave. Methods: We conducted a retrospective cohort study investigating COVID-19 outcomes among SARD patients systematically identified to have confirmed COVID-19 from March 1, 2020 to January 31, 2022 at a large healthcare system in Massachusetts. We tabulated COVID-19 counts of total and severe cases (hospitalizations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared to the early COVID-19 period (reference group). Results: We identified 1449 SARD patients with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (27.5%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 45.6% of cases were severe in the early COVID-19 period (March 1-June 30, 2020) vs. 14.7% in the Omicron wave (December 17, 2021-January 31, 2022; adjusted odds ratio 0.29, 95%CI 0.19-0.43). A higher proportion of those unvaccinated were severe compared to not severe cases (78.4% vs. 59.5%). Conclusions: The proportion of SARD patients with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the Omicron wave. Advances in prevention, diagnosis, and treatment of COVID-19 may have improved outcomes among SARD patients. KEY MESSAGES: What is already known about this subject?: Patients with systemic autoimmune rheumatic diseases (SARDs) may be at increased risk for severe COVID-19, defined as hospitalization or death.Previous studies of SARD patients suggested improving COVID-19 outcomes over calendar time, but most were performed prior to the wide availability of COVID-19 vaccines or the Omicron wave that was characterized by high infectivity.What does this study add?: The proportion of SARD patients with severe COVID-19 outcomes was lower over calendar timeThe adjusted odds ratio of severe COVID-19 in the Omicron wave was 0.29 (95%CI 0.19-0.43) compared to early COVID-19 period.The absolute number of severe COVID-19 cases during the peak of the Omicron variant wave was similar to the peaks of other waves.SARD patients with severe vs. not severe COVID-19 were more likely to be unvaccinated.How might this impact on clinical practice or future developments?: These findings suggest that advances in COVID-19 prevention, diagnosis, and treatment have contributed to improved outcomes among SARD patients over calendar time.Future studies should extend findings into future viral variants and consider the roles of waning immunity after vaccination or natural infection among SARD patients who may still be vulnerable to severe COVID-19.

DMARD disruption, disease flare, and prolonged symptom duration after acute COVID-19 among participants with rheumatic disease: A prospective study.

OBJECTIVE: To describe disease-modifying antirheumatic drug (DMARD) disruption, rheumatic disease flare/activity, and prolonged COVID-19 symptom duration among COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs). METHODS: We surveyed patients with SARDs after confirmed COVID-19 at Mass General Brigham to investigate post-acute sequelae of COVID-19. We obtained data on demographics, clinical characteristics, COVID-19 symptoms/course, and patient-reported measures. We examined baseline predictors of prolonged COVID-19 symptom duration (defined as lasting ≥28 days) using logistic regression. RESULTS: We analyzed surveys from 174 COVID-19 survivors (mean age 52 years, 81% female, 80% White, 50% rheumatoid arthritis) between March 2021 and January 2022. Fifty-one percent of 127 respondents on any DMARD reported a disruption to their regimen after COVID-19 onset. For individual DMARDs, 56-77% had any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41%. Global patient-reported disease activity was worse at the time of survey than before COVID-19 (mean 6.6±2.9 vs. 7.6±2.3, p<0.001). Median time to COVID-19 symptom resolution was 14 days (IQR 9,29). Prolonged symptom duration of ≥28 days occurred in 45%. Hospitalization for COVID-19 (OR 3.54, 95%CI 1.27-9.87) and initial COVID-19 symptom count (OR 1.38 per symptom, 95%CI 1.17-1.63) were associated with prolonged symptom duration. Respondents experiencing prolonged symptom duration had higher RAPID3 scores (p=0.007) and more pain (p<0.001) and fatigue (p=0.03) compared to those without prolonged symptoms. CONCLUSION: DMARD disruption, SARD flare, and prolonged symptom duration were common in this prospective study of COVID-19 survivors, suggesting substantial impact on SARDs after acute COVID-19.

Development of a Prediction Model for COVID-19 Acute Respiratory Distress Syndrome in Patients With Rheumatic Diseases: Results From the Global Rheumatology Alliance Registry.

OBJECTIVE: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. METHODS: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. RESULTS: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. CONCLUSION: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression.

Factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with idiopathic inflammatory myopathy (IIM). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with IIM were obtained from the COVID-19 Global Rheumatology Alliance physician-reported registry. A 3-point ordinal COVID-19 severity scale was defined: (1) no hospitalisation, (2) hospitalisation (and no death) and (3) death. ORs were estimated using multivariable ordinal logistic regression. Sensitivity analyses were performed using a 4-point ordinal scale: (1) no hospitalisation, (2) hospitalisation with no oxygen (and no death), (3) hospitalisation with oxygen/ventilation (and no death) and 4) death. RESULTS: Of 348 patients, 48% were not hospitalised, 39% were hospitalised (and did not die) and 13% died. Older age (OR=1.59/decade, 95% CI 1.31 to 1.91), high disease activity (OR=3.50, 95% CI 1.25 to 9.83; vs remission), ≥2 comorbidities (OR=2.63, 95% CI 1.39 to 4.98; vs none), prednisolone-equivalent dose >7.5 mg/day (OR=2.40, 95% CI 1.09 to 5.28; vs no intake) and exposure to rituximab (OR=2.71, 95% CI 1.28 to 5.72; vs conventional synthetic disease-modifying antirheumatic drugs only) were independently associated with severe COVID-19. In addition to these variables, in the sensitivity analyses, male sex (OR range: 1.65-1.83; vs female) was also significantly associated with severe outcomes, while COVID-19 diagnosis after 1 October 2020 (OR range: 0.51-0.59; vs on/before 15 June 2020) was significantly associated with less severe outcomes, but these associations were not significant in the main model (OR=1.57, 95% CI 0.95 to 2.59; and OR=0.61, 95% CI 0.37 to 1.00; respectively). CONCLUSIONS: This is the first large registry data on outcomes of COVID-19 in people with IIM. Older age, male sex, higher comorbidity burden, high disease activity, prednisolone-equivalent dose >7.5 mg/day and rituximab exposure were associated with severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with IIM.

Environmental and societal factors associated with COVID-19-related death in people with rheumatic disease: an observational study.

Background: Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally. Methods: In this observational study, we derived individual-level data on adults (aged 18-99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death. Findings: 14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 µg/m3 [95% CI 1·01-1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10-1·30]; p<0·0001), and population mobility (1·03 per 1% increase in number of visits to grocery and pharmacy stores [1·02-1·05]; p<0·0001 and 1·02 per 1% increase in number of visits to workplaces [1·00-1·03]; p=0·032) were independently associated with higher odds of mortality. Number of hospital beds (0·94 per 1-unit increase per 1000 people [0·88-1·00]; p=0·046), human development index (0·65 per 0·1-unit increase [0·44-0·96]; p=0·032), government response stringency (0·83 per 10-unit increase in containment index [0·74-0·93]; p=0·0018), as well as follow-up time (0·78 per month [0·69-0·88]; p<0·0001) were independently associated with lower odds of mortality. These factors sufficiently explained country-level variations in death attributable to COVID-19 (intraclass correlation coefficient 1·2% [0·1-9·5]; p=0·14). Interpretation: Our findings highlight the importance of environmental and societal factors as potential explanations of the observed regional disparities in COVID-19 outcomes among people with rheumatic disease and lay foundation for a new research agenda to address these disparities. Funding: American College of Rheumatology and European Alliance of Associations for Rheumatology.