key: cord-0865868-p8mar41u
authors: Nuñez, Dalifer Freites; Leon, Leticia; Garcia, Alfredo Madrid; Arce, Jose Ignacio Colomer; Mucientes, Arkaitz; Gutierrez-Fernandez, Benjamin; Rodriguez, Luis; Cristóbal, Inés Pérez San; Álvarez, Paula; Prada, Cristina Martinez; Abasolo, Lydia
title: Mortality related to COVID-19 in patients with rheumatic and musculoskeletal diseases, first wave of the outbreak: a single-center study
date: 2022-04-29
journal: Ther Adv Musculoskelet Dis
DOI: 10.1177/1759720x221090296
sha: 089214689e3a6316a32294ebd4ccda8c52fa0e1e
doc_id: 865868
cord_uid: p8mar41u

OBJECTIVES: The aim of this study was to assess the cause-specific mortality rate related to COVID-19 (CMR) in patients with rheumatic and musculoskeletal diseases (RMDs) and COVID-19 and to analyze the role of the different RMDs in their mortality risk. METHODS: An observational longitudinal study was conducted during the first pandemic wave in our center. Patients with the diagnosis of RMDs and COVID-19 were included. Main outcome is the death related to COVID-19. Independent variable – type of RMDs: autoimmune rheumatic diseases (ARD), such as chronic inflammatory arthritis (CIA) and connective tissue diseases (CTD) and non-autoimmune Rheumatic Diseases (non-ARD). Survival techniques were used to estimate the CMR per 1000 patients-month with a 95% confidence interval (CI), and Cox multivariate regression analysis was run to examine the effect of ARD compared to non-ARD on mortality risk adjusted by confounders. Results were expressed by Hazard Ratio (HR) and CI. RESULTS: Overall, 405 patients were included (642.5 patients-month). During the study period, 44 (10.86%) deaths were recorded. CMR was 68.48 (50.96–92.01). After adjusting for confounders, HR of mortality in ARD compared to non-ARD did not achieve statistical significance [HR: 1.15 (0.64–2.07)], neither CTD versus CIA nor CTD versus non-ARD. Age and certain comorbidities which are being diagnosed in March compared to April or May [HR: 2.43 (1.1–5.55)] increased the mortality risk. Glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) dropped from the final model. CONCLUSION: In patients with RMDs and COVID-19, CMR was 6.8% patients-month. This study shows that mortality risk is higher in males, older patients, and similar between CTD, CIA, and non-ARD. COVID-19 management improved after the first month of pandemic. PLAIN LANGUAGE SUMMARIES: Mortality related to the outbreak of COVID-19 in patients with rheumatic and musculoskeletal diseases Why was this study done? - To report the COVID-19-specific mortality rate in patients with a variety of RMDs during the first pandemic peak in a tertiary hospital in Madrid and to analyze the role of specific types of ARD and other possible factors in the risk of death related to COVID-19. What did the researchers do? - We performed a retrospective observational study during the first wave of the COVID-19 pandemic in Madrid, Spain. What did the researchers find? - In this study, neither the different diagnoses of RMDs, including CIA, CTD, or non-ARD disease or its treatment were not implicated as a potential risk of death related to COVID-19 - In consonance with other studies, RMDs patients and COVID-19, older age, male sex, and certain comorbidities implied more mortality risk - Our data reflect COVID-19 severity in a particular context, time, and population. In times of the absence of COVID-19 vaccine, healthcare, social, and political measures taken to contain the coronavirus outbreak have worked properly. What do the findings mean? - The presence of comorbidities in RMDs patients represents a greater risk than the different types of RMDs themselves, in the development of COVID-19 fatal outcome. It is important to integrate the control of comorbidities in the daily management.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a global health crisis. 1, 2 Currently, the cumulative number of confirmed COVID-19 cases worldwide has exceeded 370 million. 3 The spectrum of symptomatic infection ranges from mild to critical; fortunately, most infections are not severe and have good prognosis. [4] [5] [6] [7] [8] [9] In general population, the proportion of severe or fatal disease occurs predominantly in patients with certain risk factors, such as advanced age, male sex, and with underlying comorbidities 4, 8, [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] Individuals with rheumatic and musculoskeletal diseases (RMDs), especially those with ARD, have a higher risk to be infected with SARS-CoV2 and develop COVID-19 than the general population. [21] [22] [23] [24] Concretely, the significance of ARD and their therapies, with respect to the course of COVID-19, is in a constant update of evidence, with preliminary findings suggesting that a poorly controlled systemic autoimmune condition and certain comorbidities increased the risk of hospital admission, 25 whereas most disease-modifying antirheumatic drugs (DMARDs) were not associated with hospital admission. 21, [26] [27] [28] [29] [30] [31] Regarding DMARDs, it has been recently published that the use of rituximab and Janus kinase (JAK) inhibitors seems to increase the disease severity. 32, 33 In addition, in patients with RMDs hospitalized with COVID-19, certain features might determine critical or fatal disease. 4, 9 Thus, individuals with RMDs and infected with COVID-19 require special consideration because the underlying immune conditions or other factors could affect the clinical prognostic. In this regard, several publications have raised with controversial results. In a meta-analysis of Wang et al., 5 they did not find that ARD had a higher risk of death due to COVID-19. Whereas in the meta-analysis of Xu et al., 34 the fatality rate was higher in rheumatic diseases, although age, gender and comorbidity were not matched. We have to note the heterogeneity found in different rheumatic diseases, reference population, geographic location or time period included in both meta-analyses.

-We performed a retrospective observational study during the first wave of the COVID-19 pandemic in Madrid, Spain.

What did the researchers find?

-In this study, neither the different diagnoses of RMDs, including CIA, CTD, or non-ARD disease or its treatment were not implicated as a potential risk of death related to COVID-19 -In consonance with other studies, RMDs patients and COVID-19, older age, male sex, and certain comorbidities implied more mortality risk -Our data reflect COVID-19 severity in a particular context, time, and population. In times of the absence of COVID-19 vaccine, healthcare, social, and political measures taken to contain the coronavirus outbreak have worked properly.

- Certainly, the epidemiological situation and disease severity after the introduction of COVID-19 vaccine have resulted in a better scenario; [35] [36] [37] [38] however, to understand how the pandemic is evolving, it is a matter of interest to know more about the severity of the disease and mortality rates of COVID-19 in patients with RMDs under non-vaccination conditions. The aim of our study is to report the COVID-19-specific mortality rate in patients with a big variety of RMDs, during the first pandemic peak in a tertiary hospital in Madrid. Moreover, we analyze the role of specific types of ARD and other possible factors, including the month of COVID-19 diagnosis in the risk of death related to COVID-19.

It was conducted in a public reference tertiary hospital, Hospital Clínico San Carlos (HCSC), in Madrid, Spain. The catchment area is almost 400,000 people.

We performed a retrospective observational study during the first wave of the COVID-19 pandemic from 1 March (when our health area had the first hospital admission related to COVID-19) to 20 May 2020. We preselected all the patients attended at our rheumatology outpatient clinic during the study period whose data were recorded in our departmental electronic health record (EHR Penelope). The inclusion criteria were patients older than 16 Services. In addition, deaths due to COVID-19 were obtained from HCSC Central Services, and last report received was on 20 May 2020.

The main outcome was mortality related to COVID-19 in patients with RMDs. The independent variable was the type of RMD: (a) ARD, including (a1) chronic inflammatory arthritis (CIA) and (a2) connective tissue diseases (CTD) and (b) non-ARD ( Table 1 ).

The co-variables recorded at the baseline were the following: (1) sociodemographic characteristics, including sex, age, and RMD duration. (2) Disability (using a seven-ordinal level scale from 1 = perfect health to 7 = unable to get out of the bed) from the Rosser Classification Index (RCI). 39 

During the study period, 405 patients with RMDs were diagnosed with COVID-19. The most common RMD was the non-ARD in 243 patients, followed by CIA in the ARD group (26%), including 65 Rheumatoid arthritis (RA) patients (Table 1) . Table 2 outlines the baseline demographic and clinical characteristics of ARD and non-ARD patients. From the total, 69.14% were women with a mean age of 59.37 years, without differences between diagnosis groups. The mean RMDs duration at the time of COVID-19 infection was different according to the condition with a mean of 11.48, 11.64, and 5.03 years for CIA, CTD, and non-ARD, respectively.

Regarding comorbidity, it was present in 34% of the patients at baseline, being highest in those with CTD. The most frequent were the traditional cardiovascular risk factors. The presence of any type of comorbidity related to COVID-19 severity (see footnote Table 2 ) was reported in 26% of the patients and results higher in CTD, followed by CIA and non-ARD with statistical significance between them. Specifically, by the types of comorbidities, there were no differences between RMD groups except for chronic liver disease that was lower in non-ARD.

Hospital admission due to COVID-19 was required in 146 patients. This percentage was primarily at the expense of CTD. Concerning RMDs chronic treatments, in CTD, the use of NSAIDs was less frequent, whereas exposure to glucocorticoids was more frequent compared to other RMDs groups. The median dose of glucocorticoids was 5 mg with a minimum of 2.5 mg and a maximum of 30 mg. Methotrexate was the most commonly used csDMARD followed by antimalarials. Among b/tsDMARDs, anti-TNF drugs were the most widely used.

Case fatality rate for COVID- 19 We found 44 deaths related to COVID-19 during the study period. The case fatality rate was 10.86%, being 12.7%, 12.15%, and 9.88% for CTD, CIA, and non-ARD, respectively, (p = 0.7). Death cases reported 54.55% were women with a mean age of 81.61 (7.29) years. ARD was present in 45.45%, including nine patients with RA. Almost two-thirds of the patients (70.45%) had at least one baseline comorbidity and the most prevalent was hypertension (45%). All cases had a positive SARS-CoV-2 PCR diagnostic test, and most of deaths (88%) occurred during hospital admission. Concerning treatments, 43.18% individuals were exposed previously to glucocorticoids with a mean (SD) prednisone equivalent dose of 5.78 (2.5) mg/day. Regarding DMARDs, five patients were receiving methotrexate, two patients anti-TNF, and one patient JAK inhibitors. None was previously received on regular treatment with NSAIDs or other biological agents.

In individuals with RMDs, the CMR was estimated in 68.48 cases per 1000 patients-month (95% CI: 50.96-92.01). Figure 1 represents cumulative incidence of deaths related to COVID-19, showing that deaths occurred early soon after the diagnosis. In the 44 death cases recorded, the median lag time from diagnosis to death was 6.5 (2-15) days, 75% occur within 12 days. In those patients who required hospital admission, the median lag time was 5 (2-11) days and 75% occur within 10 days. 

In the bivariate analysis ( Anti-TNF, tumor necrosis factor-alpha inhibitor; ARD: autoimmune rheumatic diseases; b/tsDMARDs, biologic/target synthetic disease-modifying antirheumatic drug; CI, confidence interval; CIA, chronic inflammatory arthritis; csDMARD, conventional synthetic disease-modifying anti rheumatic drug; CMR, cause-specific mortality rate; CTD, connective tissue diseases; JAKi, Janus Kinase inhibitors; MCTD, Mixed connective tissue disease; PCR, polymerase chain reaction; RMDs, rheumatic and musculoskeletal diseases.

Other biological agents including abatacept, rituximab, tocilizumab, and belimumab. csDMARDs, including methotrexate, leflunomide, antimalarials, azathioprine, sulfasalazine, cyclophosphamide, and azathioprine. a Polyarthritis: Undifferentiated inflammatory polyarthritis. b Comorbidity related to COVID-19: presence of at least one of the following: diabetes mellitus, heart disease (arrhythmias, valve disease, cardiomyopathy, and heart failure), ischemic vascular disease (stroke, cardiovascular, and peripheral vascular disease), chronic liver disease, and renal insufficiency, pulmonary embolism, lung disease (ILD and COPD). Anti-TNF, tumor necrosis factor-alpha inhibitor; ARD, autoimmune rheumatic diseases; b/tsDMARDs, biologic/target synthetic disease-modifying antirheumatic drug; CI, confidence interval; CIA, chronic inflammatory arthritis; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CTD, connective tissue diseases; HR, hazard ratio; RMDs, rheumatic and musculoskeletal diseases. a Comorbidity: presence of at least one of the following: diabetes mellitus, heart disease (arrhythmias, valve disease, cardiomyopathy, and heart failure), ischemic vascular disease (stroke, cardiovascular, and peripheral vascular disease), chronic liver disease and renal insufficiency, pulmonary embolism, lung disease (ILD and COPD).

those diagnosed on April or May. Mean chronic doses of prednisone (p = 0.680), exposure to csD-MARDs (p = 0.657), and bDMARDs (p = 0.257) dropped from the final model. Proportionality of these regression models was tested with a p-value ⩾ 0.45.

This is a real-world longitudinal study conducted during the whole first wave of the COVID-19 pandemic in Madrid, giving us a general picture of the situation in a great variety of RMDs patients infected by SARS-CoV-2, in terms of mortality related to COVID-19, severity among different rheumatic diseases, and other factors associated with this CMR related to COVID-19 over time.

In this sense, two findings, considered important for the management of these patients in clinical practice, should be highlighted: on the one hand, the risk of death seemed to be similar between 12 journals.sagepub.com/home/tab CTD, CIA, and non-ARD regardless of other factors. As a second relevant result, in the absence of vaccine scenario, mortality risk decreased after the first month of the pandemic, this might be explained by diverse possible reasons, involving the healthcare measures applied during severe coronavirus outbreak and some psychological factors, such as the delay in consulting emergency services. This fact may also have generated selection bias in those patients who did not require hospital admission. [41] [42] [43] This pandemic had a great impact, especially in Madrid, with more than 27,000 deaths related to COVID-19 until the last week of May 2020. 44 In this study with underlying RMDs, the case fatality rate for COVID-19 was 10.86%, (12.7% for CTD and 12.15% for CIA), being similar to the reported in Spain general population and to the published in RMDs patients in the same period of time. 44 This study shows that the overall CMR in RMD is estimated in 6.8% patients-month, being an early phenomenon from the moment of infection. In fact, and in accordance with other studies, most of the deaths relate to COVID-19 occurred during the first 15 days since the time of SARS-CoV-2 infection. 45, 46 In this study, the CMR for COVID-19 was somewhat higher in patients with ARD compared to non-ARD, and subtly more in CTD without statistical significance, in accordance with the results published by the French RMD COVID-19 cohort. 47 Moreover, regarding clinical outcomes, our findings are in consonance with those found in the recent meta-analysis conducted by Wang et al. 21 An added value for our study is that we have adjusted for several important aspects that influence mortality related to COVID-19.

Consistent with other studies, our data show that CMR for COVID-19 resulted higher in males, older patients, and in the presence of certain comorbid conditions 14, [47] [48] [49] Specifically, particular clinical conditions, such as diabetes mellitus, heart disease, ischemic vascular disease, chronic liver disease, renal insufficiency, pulmonary embolism, and lung disease implied more risk of mortality. Comorbidities previously identified as a risk for severe COVID-19 in RMDs by the Global Rheumatology Alliance registry and different representative cohorts. 33, 47, 48 Nevertheless, in our study, hypertension had no statistical association with death in the final model. This may suggest that the final effect of the cardiovascular continuum as implied by ischemic vascular disease, chronic kidney failure on fatal outcome was more relevant than the presence of hypertension. We found no deaths reported between obesity and smoking; however, these were only reported in few patients in our cohort, Interestingly in our data, less than 30% of patients with COVID-19 diagnosis and none of reported deaths were taking NSAIDs as regular treatment, being not able to stablish robust conclusions from these observational findings; however, our results may be cautiously in line with the findings, where in SARS-CoV-2 positive patients, exposure to NSAIDs was not associated with an excessive risk of hospital admission, death, or serious outcomes and similar to a recently published systematic review and meta-analysis, which concludes that the theoretical risks of NSAIDs in SARS-CoV-2 infection were not confirmed by observational data. 50, 51 The role of exposure to different RMD treatments in the severity of COVID-19 has received special focus during the pandemic. In consonance with previous reports, csDMARDs or anti-TNF drugs do not seem to be at higher risk of death related to COVID-19. 47, 48 Although, according to This study has some limitations, the main ones are those that affect any observational retrospective study in a single center. In this sense, data regarding rheumatic disease activity analytical data or treatment dosages were not available, variables that could potentially be related to the risk of death from COVID-19. 25 , 48 We collected ESR as a surrogate variable of disease activity, but we had almost 60% of missing data, not being possible to use this data. Besides, SARS-CoV-2 PCR diagnostic test should be required as a part of the inclusion criteria definition. However, at that time PCR was only available at the hospitals, in this sense if we had not included the milder cases, mortality rate would be overestimated. In addition, there was a percentage of admitted patients without tests due to a lack of available tests and extreme healthcare overload at that time, all of these reflected the critical situation in which we were immersed.

However, the main strength is that this is realworld setting study performed during the peak of pandemic in Spain. It includes a representative number of non-selected patients with a wide range of different RMD, with not standardized immunosuppressive therapy, followed-up during the whole first wave of pandemic. We were able to analyze differences between rheumatic diseases and see the effect of time in the analysis. Thus, we believe, this study contributes with gaps of knowledge until existing patient registries and administrative databases improve these data.

In conclusion, it seems that predisposition for COVID-19 fatal outcome, at expenses of age and certain comorbidities, occurs in general population, rather than types of RMDs or treatments exposed. This study shows how CMR decreased after the first month, regardless other factors. This potentially reflects that, in times of absence of COVID-19 vaccine, healthcare, social, and political measures assumed to contain the coronavirus outbreak have worked properly.

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The authors thank the patients for making this study possible. The authors also thank Ana M Perez for their help in the data collection. They also specially thank all rheumatologist and nurse colleagues who contributed in the care of patients in an innovative and so involved way.

journals.sagepub.com/home/tab and/or publication of this article: This work was supported by the Instituto de Salud Carlos III (ISCIII), Ministry of Health, Spain (CP16/00916; PI18/01188; and RD16/0012/0014), and cofunded by el Fondo Europeo de Desarrollo Regional (FEDER). The funders had no role in study design, data collection, analysis, article preparation, or decision to publish.

The study was approved by the Hospital Clínico San Carlos institutional ethics committee (Approval No. 20/268-E-BS). This study was conducted according to the principles of the Declaration of Helsinki. 

The datasets generated and analyzed for the present study are available from the corresponding author on reasonable request.

Supplemental material for this article is available online.