key: cord-0970000-sw3rq0lr
authors: Xu, Chuanhui; Yi, Zixi; Cai, Ruyi; Chen, Ru; Thong, Bernard Yu-Hor; Mu, Rong
title: Clinical outcomes of COVID-19 in patients with rheumatic diseases: A systematic review and meta-analysis of global data
date: 2021-02-18
journal: Autoimmun Rev
DOI: 10.1016/j.autrev.2021.102778
sha: aaae84e552b529e1402c2393935dd9fc7d43e632
doc_id: 970000
cord_uid: sw3rq0lr

OBJECTIVES: The impact of rheumatic diseases on COVID-19 infection remains poorly investigated. Here we performed a systematic review and meta-analysis to evaluate the outcomes of COVID-19 in patients with rheumatic diseases. METHODS: We systematically searched PubMed, Embase, Cochrane Library, Scopus and preprint database up to 29th August 2020, for publications with confirmed COVID-19 infection in patients with rheumatic diseases. The primary outcomes were the rates of hospitalization, oxygen support, intensive care unit (ICU) admission and death. A meta-analysis of effect sizes using the random-effects models was performed, and meta-regression analyses were performed to explore heterogeneity. The data from the COVID-19 Global Rheumatology Alliance physician registry (the COVID-19 GRA) was used as a reference. RESULTS: A total of 31 articles involving 1138 patients were included in this systematic review and meta-analysis. The publications were from Europe, Asia and North America, but none from other continents. The overall rates of hospitalization, oxygen support, ICU admission and fatality among COVID-19 infected patients with rheumatic diseases were 0.58 (95% confidence interval (CI) 0.48–0.67), 0.33 (95% CI 0.21–0.47), 0.09 (95% CI 0.05–0.15) and 0.07 (95% CI 0.03–0.11), respectively. The rate of oxygen support in Europe (0.48, 95% CI 0.4–0.57) was higher than that in other continents. Among all hospitalized patients, the rates of oxygen support, ICU admission and fatality were 0.61 (95% CI 0.48–0.73), 0.13 (95% CI 0.07–0.21) and 0.13 (95% CI 0.09–0.18), respectively. The fatality rate was highest in Europe (0.19, 95% CI 0.15–0.24). The fatality rate was higher both in this meta-analysis and the COVID-19 GRA (7.0% and 6.7%, respectively) than that (3.4%) in WHO database, although the age, gender and comorbidity were not matched. CONCLUSION: Patients with rheumatic diseases remain vulnerable with substantial rates of severe outcomes and a geographic variation. More studies were urgently needed to elucidate the risk factors of severe outcomes in this population.

An outbreak of infection with the novel coronavirus (SARS-CoV2) since December 2019 has rapidly emerged as a pandemic [1] . Globally, more than 24 million confirmed cases of coronavirus disease 2019 (COVID -19) had been reported, with 833 951 confirmed death by 29th August 2020 [2] . COVID-19 does not only cause respiratory illness but also leads to uncontrolled inflammatory response and hypercoagulation through activating both the innate and adaptative immune system [3] . The presence of comorbidities, such as hypertension or diabetes mellitus, is a risk factor for disease severity and fatality [4] . It is imperative to evaluate the outcomes of COVID-19 in patients with rheumatic diseases. Firstly, patients with rheumatic diseases are vulnerable given the background of dysregulated immune response and the use of antirheumatic drugs with different degrees of immunosuppression. An exaggerated immune response may occur following an acute viral infection, for instance, the uncontrolled type I interferon activation in patients with systemic lupus erythematosus (SLE). Secondly, multiple cytokine has been involved in the pathogenesis of severe COVID-19 [5] [6] [7] . Anti-rheumatic drugs may dampen the hyperinflammatory state, becoming a potential treatment for COVID-19. Hydroxychloroquine (HCQ) and tocilizumab were promising candidates [8] , but subsequent studies did not demonstrate their efficacy to improve clinical outcomes in COVID-19 infected patients or for post-exposure prophylaxis of close contacts [9] [10] [11] . Glucocorticoids, which are widely used in rheumatic diseases, has remained controversial in the treatment of COVID-19 infected patients [12] . The RECOVERY trial, however, demonstrated the beneficial effect of dexamethasone resulting in lower mortality among those who were receiving either invasive J o u r n a l P r e -p r o o f Journal Pre-proof At present, the impact of COVID-19 on patients with rheumatic diseases is poorly understood. Whether a poorer outcome due to the immunocompromised status among patients with rheumatic disease, or better outcomes with anti-rheumatic therapies that mitigate the hyperinflammation is unknown [16] . No specific rheumatic diseases was identified as risk factors for poor outcomes with COVID-19 in version 2 of American College of Rheumatology guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic [17] . There is also a knowledge gap of the geographic differences in the severity and fatality rate among COVID-19 infected patients with rheumatic diseases. Recently, several studies reported the clinical and prognostic characteristics of COVID-19-infected patients with rheumatic diseases [18] [19] [20] [21] [22] [23] . However, there were concerns about the limitations of small sample sizes, heterogeneity of methodology, and a lack of generalizability to the overall population of COVID-19 patients with rheumatic diseases. The COVID-19

Global Rheumatology Alliance physician registry (The COVID-19 GRA) has been making a great effort to collect information pertinent to COVID19 infection in patients with rheumatic diseases, but it is voluntary and predominantly from western countries [24] . Therefore, we conducted this systematic review and meta-analysis of observational studies on COVID-19 patients with rheumatic disease, to summarize the published and preprint literature that described the clinical characteristics and outcomes of COVID-19 patients with rheumatic diseases, and to provide a higher level of evidence for better clinical decision making.

This systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Publications on preprint servers (medRxiv, bioRxiv and ChinaXiv) were also reviewed. Key/relevant MeSh terms and keywords included the following keywords:

"2019-ncov" , "novel coronavirus" , "COVID-19" , "SARS-CoV-2" , "new coronavirus" , "coronavirus disease 2019" , "wuhan pneumonia" ) AND ( "rheumatic disease" , "rheumatic condition" , "autoimmune disease" , "autoimmune condition" , "connective tissue disease" , "musculoskeletal disease" , "muscle and skeletal disease" , "Arthritis" , "Systemic Lupus Erythematosus" , "Spondylarthritis" , "spondyloarthropathy" , "vasculitis" , "Sjogren's Syndrome" , "Scleroderma" , "systemic sclerosis" , "Osteoarthritis" , "Antiphospholipid Syndrome" , "myositis" , The following information was extracted: country, continent, study design type, sample size, sex, age, rheumatological diagnosis, outcomes (hospitalization, oxygen support, ICU admission, death).

Our primary outcomes were rates of hospitalization, oxygen support, ICU admission and fatality in COVID-19 infected patients with rheumatic diseases. The stratification strategy we adopted for the subgroup analysis was by continent: patient populations in Europe, Asia, and North America were analyzed respectively.

The pooled proportions with their corresponding 95% confidence intervals (CI) were calculated to estimate the rates of hospitalization, oxygen support, ICU admission and fatality in COVID-19 infected patients with rheumatic diseases. The Freeman-Tukey double arcsine transformation was used for pooled estimates to stabilize the variances. The I 2 statistic and Q test were used to measure the between-study heterogeneity. If I 2 > 50% and P < 0.1, the heterogeneity was considered high, and the summary rates were combined under with a random effects model; otherwise a fixed-effects model were used. The Z test was used to assess the statistical significance of pooled rates, and two-tailed P < 0.05 were considered significant. To explore potential sources of heterogeneity, subgroup analyses were performed based on the continent. Visual inspection of funnel plots and Egger's regression asymmetry test were applied to assess potential publication bias. STATA 14.0 (Stata Corporation, College Station, Texas, USA) was used for statistical analyses.

The initial search of databases yielded 1822 articles, which were narrowed down to Overall study characteristics A total of 31 articles involving 1138 patients were assessed in this systematic review and meta-analysis. Characteristics of the included studies were shown in Table 1 and 2. Table 6 ). However, the outcomes were reported as aggregated outcomes for the respective cohort of patients without further classification by rheumatic disease type.

The outcomes would be different between the patients recruited from the community and those only from hospitalized patients. We first analyzed all the data excluding the studies which only recruited hospitalized patients (data from Figure   1A and Figure 1C ). The rate of oxygen support was higher in Europe (0.48, 95% CI 0.4 -0.57) than that in North American (0.20, 95% CI 0.10 -0.33) ( Figure 1B ). The fatality rate was higher in Asia(0.27, 95% CI 0.12 -0.46) ( Figure 1D ), but only one study was available from Asia (Iran, n = 30) [20] for subgroup analysis among different continents.

We then anlyzed the data among all hospitalized patients (data of hospitalized patients from Table 1 and all data from Table 2 America, respectively, without significant difference ( Figure 2B ). The fatality rate was higher in Europe (0.19, 95% CI 0.15 -0.24) than that in North America (0.12, 95%

CI 0.06 -0.19) and Asia (0.11, 95% CI 0.02 -0.23) ( Figure 2C ).

Comparison with data from the COVID-19 GRA and WHO There could be differences between this meta-analysis and the data from the COVID-19 GRA as the latter was voluntarily reported. As shown in Table 3 , there was a difference in specific diseases but largely comparable. There were fewer female patients (64%) in this meta-analysis compared with that (75.9%) in the COVID-19 GRA ( Table 3 ). The rate of hospitalization and death were higher in this meta-analysis than that in the COVID-19 GRA (58% vs 32.8% and 7.0% vs 6.7%, respectively) ( Table 3 ) [25] . It was not possible to compare the rates of oxygen support and ICU admission because there were 11.9% of patients who required ventilation, but the type of ventilation used was unknown in the COVID-19 GRA [25] .

The fatality rate was higher both in this meta-analysis and the COVID-19 GRA (7.0% and 6.7%, respectively) than that (3.4%) in WHO database [2] , but the age, gender and comorbidities were not matched.

Visual inspection of funnel plots and Egger's test were used to evaluate the Notably, 13 out of 15 studies were from Spain and Italy (except 1 from Germany and one from France. Table 1) where were most severely affected by COVID-19 in Europe [26] Thirdly, the genotypes of SARS-CoV2 due to mutation may vary in different regions, or may have evolved over time, both for imported and community transmitted cases, which may explain the different severities of the disease. A previous study showed that the virus genomes in Europe and America were different from those in Asia [27] . Fourthly, the ethnic disparities of outcomes in COVID-19

patients may contribute to the heterogeneity. For instance, the mortality is lower among South Asian compared to White British patients from the study in Bradford [28] . Similarly, the disparities in the risk and outcomes of COVID-19 were also reported by Public Health England [29] .

There were differences in terms of proportions of specific rheumatic diseases, gender and outcomes when this study was compared with the COVID-19 GRA data.

The COVID-19 GRA was a commendable effort from the global rheumatology J o u r n a l P r e -p r o o f community. The results were mutually corroborated between our meta-analysis and the COVID-19 GRA, although differences exist. Furthermore, our meta-analysis added the data from Asia, which were scant in the COVID-19 GRA with only <5 out of 600 from the Asian region [24] . Our meta-analysis included eight studies (n = 122) from Asia, mainly from China and Malaysia. There were studies that showed no case of rheumatic disease contracted COVID-19 in Hong Kong [30] , and the incidence of COVID-19 infection was low in the Asia Pacific Lupus Collaboration patient cohort [31] . Reporting on COVID-19 in patients with rheumatic diseases should be encouraged from other countries heavily burdened by COVID-19 infection, such as India, Indonesia and Philippine.

A meta-analysis on the prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases was published by Akiyama et al. [32] . However, the results should be interpreted with cautions. The fatality rate was higher (0.113, 95%

CI 0.098 to 0.13) than our study (0.07, 95% CI 0.03 -0.11) and the COVID-19 GRA data (0.067). There were total 16 publications included in our meta-analysis but not in the study by Akiyama et al. Three publications were missed [33] [34] [35] , eight were excluded because only hospitalized patients were recruited [18, [36] [37] [38] [39] [40] [41] [42] , four published after 31 st July 2020 when is the updated time of literature search by Akiyama et al. [19, 20, 43, 44] . Furthermore, we were not certain whether the cases were duplicated in published data and the COVID-19 GRA data. Therefore, it would not have been appropriate to include COVID-19 GRA data for the meta-analysis.

The strengths of our systematic review and meta-analysis were the rigorous application of systematic review methodology and a comprehensive search of the robust data has shown that anti-rheumatic drugs were effective for the treatment of COVID-19 [15] , including the most recently published randomized control trial of tocilizumab [45] . The use of anti-rheumatic drugs before the onset of COVID-19 infection may also have had an impact on COVID-19 rheumatology patients with bad prognostic factors and may be context-dependent [46] . For instance, accumulating data showed that methotrexate reduced the risk of cardiovascular events in patients with rheumatoid arthritis [47] , but not in the general population with a high risk of cardiovascular events [48] . Therefore, researchers and the COVID-19 GRA are strongly encouraged to report the outcomes in specific rheumatic disease and with a specific treatment, which may shed light on the safety and effectiveness of antirheumatic drugs in COVID-19 patients with rheumatic diseases. We appreciate that the heterogeneity of treatments even among a certain rheumatic disease, let alone the less common diseases may still make interpretation of aggregated data challenging.

This systematic review and meta-analysis inform a comprehensive picture of the clinical outcomes of COVID-19 patients with rheumatic diseases. These patients remain vulnerable, given the significant rates of ICU admission with a high risk of fatality. This study emphasized the urgent need for more data with a larger sample size, more detailed treatment and disease-specific outcomes, longer-term follow-up, and sociodemographic and clinicopathological variables.

This work is not funded by any organization. The authors declare that they have no competing interests. Overall: meta-analysis of the rates in Asia, Europe and North America.

Subtotal: subgroup meta-analysis of the rates in different continents. 

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