key: cord-0776446-8hvicq0b authors: Arachchillage, Deepa J; Rajakaruna, Indika; Pericleous, Charis; Nicolson, Philip L R; Makris, Mike; Laffan, Mike title: Autoimmune disease and COVID-19- a multicentre observational study in the United Kingdom date: 2022-04-04 journal: Rheumatology (Oxford) DOI: 10.1093/rheumatology/keac209 sha: 7cb6df2173626800513ef0094d30ccfaabf9b14d doc_id: 776446 cord_uid: 8hvicq0b OBJECTIVE: To establish the demographic characteristics, laboratory findings and clinical outcomes in patients with autoimmune disease (AD) in comparison to a propensity matched cohort of patients without AD admitted with COVID-19 to hospitals in the UK. METHODS: This is a multicentre observational study across 26 NHS Trusts. Data were collected both retrospectively and prospectively using a pre-designed standardised case record form. Adult patients (≥18 years) admitted between 1st of April 2020 and 31 July 2020 were included. RESULTS: Overall, 6288 patients were included to the study. Of these, 394 patients had AD prior to admission with COVID-19. Of 394 patients, 80 patients with systemic lupus erythematosus, rheumatoid arthritis or antiphospholipid syndrome were classified as severe rheumatologic AD. A higher proportion of those with AD had anaemia: 240(60.91%) vs 206(52.28%), p= 0.015, raised LDH 150(38.08%) vs 43(10.92%), p< 0.001 and raised creatinine 122(30.96%) vs 86(21.83%), p= 0.01 respectively. A significantly higher proportion of patients with severe rheumatologic AD had raised CRP : 77(96.25%) vs 70(87.5%), p= 0.044 and LDH 20(25%) vs 6(7.5%), p= 0.021. Patients with severe rheumatologic AD had significantly higher mortality [32/80(40%)] compared with propensity matched cohort of patients without AD [20/80(25%)], p= 0.043. However, there was no difference in 180-day mortality between propensity matched cohorts of patients with or without AD in general, p= 0.47. CONCLUSIONS: Patients with severe rheumatologic AD had significantly higher mortality. Anaemia, renal impairment and raised LDH were more frequent in patients with any AD whilst raised CRP and LDH were more frequent in patients with severe rheumatologic AD both of which have been shown to associate with increased mortality in patients with COVID-19. COVID-19 is associated with increased risk for thrombosis in addition to causing respiratory failure with or without multi organ failure and death. Some studies found that patients with autoimmune and inflammatory conditions are at increased risk for COVID-19-associated hospitalizations and worse disease outcomes 1 . However, autoimmune diseases are a broad category of diseases with differing severity, from requiring no treatment to multiple immunosuppressive treatments. It is likely that the clinical course and the outcomes of COVID-19 varies in patients with AD depending on the severity of the autoimmune disease and the immunosuppressive treatment. There are more than 80 autoimmune conditions affecting over four million people in the UK. AD such as Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are generally considered to be severe rheumatologic autoimmune diseases associated with higher risk of developing thrombosis in addition to their other complications. 2 In a propensity score matched analysis from a nationwide multi-centric research network study assessing the short-term outcome of COVID-19 patients with SLE, the mortality was comparable to the general population but SLE patients had higher risks of hospitalisation, admission to intensive care unit, mechanical ventilation, stroke, venous thromboembolism (VTE) and sepsis 3 . Additionally, many studies have demonstrated frequent occurrence of autoantibodies including antiphospholipid antibodies (aPL) in patients with COVID-19 4 . The prevalence of aPL was 5 even higher in patients with severe disease but there was no association between aPL positivity and disease outcomes including thrombosis, invasive ventilation, and mortality. As transiently positive aPL is a well-known phenomenon in patients with acute infection, the significance of these antibodies remains to be determined 5 although some studies demonstrated aPL from patients with COVID-19 caused thrombosis in a mouse model 6 . The aim of this study was to establish the demographic characteristics, laboratory findings and clinical outcomes in patients with autoimmune disease in comparison to a propensity matched cohort of patients with no autoimmune disease admitted with COVID-19 to hospitals in the UK. This study is reported according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) Study Design, population, and data collection Coagulopathy associated with COVID-19 (CA-COVID-19) is a multicentre observational across 26 NHS Trusts (listed in Supplementary Appendix page 1-2, available at Rheumatology online) within the UK (https://clinicaltrials.gov/ct2/show/NCT04405232). The study was approved by the human research authority (HRA) and health and care Research Wales (HCRW) and the local Caldicott Guardian at Scotland (reference number: 20/HRA/1785). We included adult patients (≥18 years) admitted to hospital during the first wave of the COVID19 pandemic in the UK between 1st of April 2020 and 31 July 2020. This paper includes only the patients with autoimmune disease diagnosed prior to admission to hospitals with COVID-19 and an equal size propensity matched cohort of patients with no autoimmune disease with COVID-19 admitted to hospital during the first wave of the COVID- 6 19 pandemic (1st of March to 31st May 2020). All patients had SARS-CoV-2 confirmed by real time polymerase chain reaction (RT-PCR) on nasopharyngeal swabs or lower respiratory tract aspirates. Data were collected both retrospectively and prospectively using a pre-designed standardised case record form (CRF) to a central electronic database (Coagulopathy associated with COVID-19 [CA-COVDI-19]) (REDcap v10.0.10; Vanderbitt University, US) hosted by Imperial College London. At the time of writing the paper, all outcomes have been completed and no patient remained in hospital. As the data were collected by clinicians directly involved in patient care with no breach of privacy or anonymity by allocating a unique study number with no direct patient identifiable data and therefore consent was waived by the HRA. Baseline patient demographics, comorbidities, haematological and biochemical blood results on the day of admission and clinical outcomes until the day of discharge/death were collected. At the time of writing this paper, all patients had completed follow-up until day 180 post hospital admission or death. The primary outcome was 180-day mortality. Secondary outcomes were thrombosis, major bleeding, the development of multiorgan failure (MOF) and ICU admission. All-cause mortality was collected and classified as directly related to COVID-19, directly related to thrombosis, directly related to bleeding, or related to other causes. 7 Thrombotic and bleeding complications were identified on clinically indicated computed tomography scan (CT) or ultrasound (US) imaging. Thrombotic events were defined as image confirmed pulmonary embolism (PE), deep vein thrombosis (DVT) or arterial thrombosis. Bleeding events were defined as major or clinically relevant minor haemorrhages according to ISTH classification 7 (Supplementary Table S1 , available at Rheumatology online). Defined as failure in two or more organ systems that required interventions to maintain homeostasis. This was defined as patients who required continuous positive airway pressure ventilation (CPAP) or mechanical ventilation with or without extracorporeal membrane oxygenation (ECMO) or required other organ support. Propensity score matching was performed using the nearest neighbours method, with a desired ratio of 1:1 between patients with and without autoimmune disease. Covariates (demographics and comorbidities) used for propensity score matching are summarised in Supplementary Figure S1, available at Rheumatology online. Laboratory results at presentation were not included in the propensity matching. Factors for propensity matching were chosen based on factors found to contribute to increased mortality in published studies of patients with COVID-19. Propensity matchings were performed for patients with any AD and for patients with severe rheumatologic AD separately. The characteristics of the treated and untreated patients were summarised and compared using descriptive statistics. The probability of survival between patients with and without AD were assessed using Kaplan- differences in the other laboratory parameters notably lactate dehydrogenase, C-reactive protein, or D-dimer levels between patients with or without AD at the time of admission to hospitals with COVID-19. Patient characteristics, comorbidities, and laboratory parameters at admission are summarised in Table 1 . As expected, there were no differences in the demographics and comorbidities of the patients with and without AD after propensity matching (Table 1 ). However even after propensity matching, a higher proportion of patients with any AD had low haemoglobin compared to patients without AD: 240(60.91%) vs 206(52.28%), p=0.015. Furthermore, a higher proportion of patients with AD had raised LDH and creatine levels; raised LDH in 150(38.08%) vs 43(10.92%), p<0.001 and raised creatinine in 122(30.96%) vs 86(21.83%), p=0.01. There were no differences in the other laboratory parameters between the two groups (Table 1) . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Comparison was made between the eighty patients classified as severe rheumatologic AD with 1:1 propensity matched cohort of patients without AD. As expected, no differences were seen in patient demographics and comorbidities between the two groups following the propensity matching. In patients with severe rheumatologic AD the female preponderance was higher than in the 'all AD' group: 55/80 (68.75%) female vs 25/80(31.25%) male (Table 2) . Furthermore, a significantly higher proportion of patients with severe rheumatologic AD had raised CRP levels and LDH levels compared to patients without AD: raised CRP in 77 (96.25%) vs 70 (87.5%), p=0.044 and raised LDH in 20 (25%) vs 6 (7.5%), p=0.021. There were no differences in the other laboratory parameters between the two groups ( Table 2) . Table 3) . Page 10 of 36 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Primary outcome: In contrast to patients with any AD, those with severe rheumatologic AD had significantly higher mortality [32/80(40%)] (all-cause mortality) compared to propensity matched cohort of patients with no AD [20/80(25%)], p=0.043 ( Figure 2B ). There was a trend towards higher mortality in patients with classified as severe rheumatologic AD (40%, 32/80) compared to patients with other AD (28.3%, 89/314), P=0. 056. Secondary outcomes: Similar to patients with any AD, no differences were observed in rate of thrombosis, major bleeding, the development of MOF or admission to ICU in patients with severe rheumatologic AD compared to those with no AD (Table 4 ) There were no differences in the clinical interventions during the hospital admission in the patients with or without AD as a whole group or with severe rheumatologic AD except significantly higher proportion of patients with any AD or severe rheumatologic AD received steroids compared to patients with no AD [82/394 (20.81%) vs 40/394 (10.15%), p <0.001 and 18/80 (22.5%) 5/80 (6.25%), p=0.003 respectively] ( Table 3 for any AD and Table 4 for severe rheumatologic AD). In this large multicentre observational study across UK assessing the clinical characteristics and outcomes of the patients with any AD and those with severe rheumatologic AD, we found that presence of any AD did not increase the risk of mortality or other outcomes (thrombosis, major bleeding, MOF, or admission to ICU) compared to propensity matched cohort of patients with no AD. However, patients classified as severe rheumatologic AD (SLE, RA or APS) had significantly higher mortality compared to patients with no AD. No differences were seen in the secondary outcomes between the two groups. Following propensity matching for demographics and comorbidities, a higher proportion of patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 with AD had low haemoglobin, raised LDH and creatine levels compared to patients with no AD. In those with severe rheumatologic AD, raised CRP and LDH were more common compared to patients without AD. Generally, AD are more common in women, occurring at a ratio of 2 to 1 8 whereas COVID-19 disease severity and admission rate is higher in men 9 . These differences were preserved in this study. Autoimmune diseases are heterogeneous group of conditions typified by dysregulation of the immune system. Most of the patients with AD received or were receiving immunosuppressive medications which make them more susceptible to infections and complications. Observational studies assessing the risk of acquiring COVID-19 and outcomes in patients with AD reported conflicting results. A cross-sectional study in northeast Italy reported that patients with AD had a similar rate of COVID-19 compared with the general population 10 . Another Italian study also found that presence of autoimmune disease did not increase the risk of COVID-19 11 . Furthermore, they suggested that outcome of patients with AD did not differ from patients with no AD 11 . However, this study did not perform propensity matching for the study groups which as shown in this study are significantly different in important respects. In contrast, the results of a multicentre retrospective study from China showed that patients with AD might be more susceptible to COVID-19 compared those without 12 . Additionally, a Spanish study which assessed the association between the outcome and the potential prognostic variables, adjusted by COVID-19 treatment in patients with AD to a matched (for sex and age, and blinded to outcome or other variables but not propensity matching for all comorbidities) cohort of patients with no AD reported that hospitalized patients with AD have a more severe course 13 . In the current propensity matched study, we did not observe a difference in the mortality or secondary outcomes between patients with any AD compared to patients with no AD (Table 3 ). This could be due a higher proportion of patients with any AD being given steroids which has been shown to improve the mortality in patients with COVID-19 14 . However, the mortality 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 rate was still significantly higher in patients with severe rheumatologic AD despite a higher proportion receiving steroids. Additionally, there was a trend towards higher mortality in patients classified as severe rheumatologic AD compared to patients with other AD (P=0.056). The higher mortality in patients with severe rheumatologic AD could indicate that these patients suffer more severe rheumatologic COVID-19 although no differences were seen in the secondary outcomes such as rate of thrombosis, major bleeding, development of MOF or admission to ITU. Therefore, cause for increased mortality in patients with severe rheumatologic AD was not clear. It is possible prior non-steroid immunosuppressive drugs contributed to the increase mortality in these patients (Supplementary Table S3, available at Rheumatology online). Anaemia is a frequent complication in patients with AD. It is generally classified as anaemia of chronic disease and usually multifactorial. Despite propensity matching for demographics and comorbidities, a higher proportion of patients with any autoimmune disease had anaemia on admission to hospital. However, a significantly higher proportion of patients with AD had raised LDH which could be due to ongoing tissue damage associated with AD and in some cases autoimmune haemolytic anaemia. Raised CRP, a marker of disease severity in many AD, was observed in a significantly higher proportion of patients with severe rheumatologic AD upon admission compared to patients without AD. Both raised CRP and LDH on admission are considered predictors of increased mortality in patients with COVID-19 15, 16 and indeed these patients had higher mortality rate compared to control group in this study. Finally, serum creatinine was elevated on admission in a higher proportion of patients with AD. Renal failure is a frequent complication in these individuals and may additionally contribute to anaemia. The main limitation of this study is that some of the data were collected retrospectively, but relevant information and clinical outcomes were recorded directly using a predefined well- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14 structured electronic CRF. However, this did not include disease activity scores such as Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or Disease Activity Score (DAS28). The classification of RA; SLE and APS as severe rheumatologic AD compared to other ADs in the study can therefore be regarded as arbitrary. It is possible that disease severity of any given AD at the time of admission with COVID1-9 has an impact on primary or secondary outcomes beyond the primary AD diagnosis and immunosuppressive medications. As the disease severity scores were not included in the data collection, we were not able to assess the impact of the individual disease severity in the clinical outcomes in this study. Although the number of patients included into study is relatively small, it comprises patients admitted to 26 NHS Trusts across UK providing a representative view of AD in the UK. In conclusion, we found no differences in the clinical outcomes in patients with any AD compared to patients with no AD admitted to hospitals with COVID-19 from the first wave of the pandemic. However, those with severe rheumatologic AD had significantly higher mortality. Anaemia, renal impairment and raised LDH were more frequent in patients with any AD whilst raised CRP and LDH were more frequent in patients with severe rheumatologic AD. Although vaccination has reduced the risk of mortality associated with COVID-19, patients with severe rheumatologic AD need additional attention if admitted to hospitals with COVID-19. DJA conceptualised the study and acquired the funding acquisition and lead for the methodology, project administration, validation, visualisation, writing the original draft reviewing and editing the study as well as being involved in data curation. IR was involved with formal analysis, software and valuation of the study as well as supporting the review & editing of the paper. CP contributed to data interpretation, review and editing of the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 15 manuscript. PN supported the project administration, data collection and review of the manuscript. MM supported Data curation, Project administration, resources, validation of the study and was involved in review and editing of the study. ML contributed to data interpretation, review and editing of the manuscript. All other authors reviewed and approved the final version of the study. Bayer plc supported the study by providing the investigator-initiated funding (P87339) to setup the multicentre database of the study. The funder had no access to data and played no part in analysis or writing. The corresponding author is responsible for the study design, had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors are grateful for the assistance of the Haematology Specialists in Training, Audit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 31 A: Probability of 180-day survival in patients with autoimmune disease vs no autoimmune disease admitted with COVID-19. B: Probability of 180-day survival in patients classified as severe autoimmune disease vs no autoimmune disease admitted with COVID-19 Page 31 of 36 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis COVID-19 and Systemic Lupus Erythematosus: Focus on Immune Response and Therapeutics Short term outcomes of COVID-19 in lupus: Propensity score matched analysis from a nationwide multi-centric research network Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review Viral infections and antiphospholipid antibodies Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19 Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients The Prevalence of Autoimmune Disorders in Women: A Narrative Review Clinical outcomes and the impact of prior oral anticoagulant use in patients with coronavirus disease 2019 admitted to hospitals in the UK -a multicentre observational study SARS-CoV-2 infection in patients with autoimmune rheumatic diseases in northeast Italy: A cross-sectional study on 916 patients Association between autoimmune diseases and COVID-19 as assessed in both a test-negative case-control and population case-control design COVID-19 in patients with rheumatic disease in Hubei province, China: a multicentre retrospective observational study Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study Dexamethasone in Hospitalized Patients with Covid-19 Association between biomarkers and COVID-19 severity and mortality: a nationwide Danish cohort study COVID-19 mortality risk assessment: An international multicenter study