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      Response to: ‘Correspondence on ‘Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician reported registry’ by Arnaud and Devilliers

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          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.
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            Changing COVID-19 outcomes in patients with rheumatic disease—are we really getting better at this?

            The COVID-19 pandemic has continued to impact the world, and we are now on track to exceed two million deaths worldwide. Patients with rheumatic disease were an immediate concern, but research to date has not convincingly suggested that having a rheumatic disease per se increases the risk of poor outcomes. Instead, poor outcomes seem to be driven by comorbidities and certain medications, such as chronic glucocorticoids and rituximab.1, 2 An important question to ask is whether we are getting better at treating COVID-19. In The Lancet Rheumatology, April Jorge and colleagues 3 address this by exploring temporal trends in patients with rheumatic disease, comparing an early cohort (Jan 20 to April 19, 2020) with a late cohort (April 20 to July 19, 2020). They used a large network of hospitals and health systems across the USA from the TriNetX database with over 8500 patients with rheumatic disease, and completed both an unmatched and matched analysis to try to reduce confounding factors. They found that the risk of hospitalisation for COVID-19 decreased in the late cohort compared with the early cohort (874 [32·4%] of 2701 patients vs 1227 [45·4%] of 2701 patients; relative risk [RR] 0·71, 95% CI 0·67–0·76). Outcomes such as intensive care unit admission, mechanical ventilation, kidney injury, and death were also reduced in the late cohort compared with the early cohort. Among those patients that were hospitalised for COVID-19, the risks of intensive care unit admission, mechanical ventilation, and death were lower in the later part of the pandemic compared with the earlier part of the pandemic (334 [30·7%] of 1089 patients vs 450 [41·3%] of 1089 patients; RR 0·74, 95% CI 0·67–0·83). These improvements mirror recent findings within the general population, with reductions in COVID-19 mortality during the later months of the pandemic compared with the first few months. 4 The strengths of this study include its large sample size and detailed patient information, including comorbidities. 3 The authors also did appropriate sensitivity analyses, such as restricting analyses to hospitalised patients and accounting for a washout period. What are some of the potential explanations for these findings? First, artefacts should be considered, such as expanded testing capacity detecting milder cases in the later months of the pandemic. There is also the potential for factors that were not captured in the analysis, such as background glucocorticoid dose and rheumatic disease severity and activity being unbalanced between the early period and the later period, to bias the outcomes. Additionally, it has been shown that those infected in the later part of the pandemic had a different risk profile, leading to differing background risks of poor outcomes. 5 Insufficient information about outcomes across facilities and geographies, which were not included in propensity score matching, raises the issue of health-care facility differences driven by resource availability or hospital overload. For example, hospitals that were overwhelmed at the start of the pandemic in April might have lowered their threshold for hospitalisation in June as a result of increased bed capacity. By not adjusting for such features, the findings might be explained by these epidemiological and health-care system factors. 6 Therapeutics have also changed over the course of the COVID-19 pandemic, with treatments being used in the later cohort that were not routinely used in the earlier cohort. Agents such as remdesivir and glucocorticoids have become the standard of care in many health-care settings and, as Jorge and colleagues 3 have pointed out, non-pharmacological treatment has also changed, including avoidance of mechanical ventilation in favour of non-invasive ventilation, 7 altering ventilation strategies, 8 prone positioning, 9 and anti-coagulation treatment. 10 It is unlikely that our acquired knowledge of specific risks in patients with rheumatic disease affected results, as comorbidities and therapies such as glucocorticoids and rituximab are difficult to alter in the short term, and in the absence of active infection the recommendations have been to not alter therapy. Therefore, clinical improvements in the treatment of COVID-19 might explain the differences in outcomes over time. It is difficult to determine how much of the improvement seen in Jorge and colleagues’ study is due to clinical factors, such as therapies and practices, versus a selection bias of patients in earlier cohorts compared with later cohorts. A key finding of this study is that use of historical controls might overestimate the effect of treatments. As the pandemic evolves and we continue to measure patient outcomes, it will be important to appropriately account for changes over time and place in longitudinal studies. So, on one hand we must remain vigilant to consider the limitations of outcome studies published during the pandemic, but on the other hand, be hopeful that we are making progress. © 2021 Shutterstock 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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              Journal
              Annals of the Rheumatic Diseases
              Ann Rheum Dis
              BMJ
              0003-4967
              1468-2060
              February 18 2021
              : annrheumdis-2021-220058
              Article
              10.1136/annrheumdis-2021-220058
              47077c36-14b6-47a1-95e8-d5d2da99c20f
              © 2021

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              https://bmj.com/coronavirus/usage

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