key: cord-0829952-1e4u7nqb authors: Ammitzbøll, Christian; Andersen, Jakob Bøgh; Vils, Signe Risbøl; Mistegaard, Clara Elbæk; Mikkelsen, Susan; Erikstrup, Christian; Thomsen, Marianne Kragh; Hauge, Ellen‐Margrethe; Troldborg, Anne title: Isolation, behavioral changes and low seroprevalence of SARS‐CoV‐2 antibodies in patients with Systemic Lupus Erythematosus or Rheumatoid arthritis date: 2021-05-31 journal: Arthritis Care Res (Hoboken) DOI: 10.1002/acr.24716 sha: 21506dae74418e752dc1bc4a183d3803d2cdca0d doc_id: 829952 cord_uid: 1e4u7nqb OBJECTIVES: Patients with chronic rheumatic diseases (CRD), such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA), require special attention during the COVID‐19 pandemic, as they are considered at risk of severe infections. We assessed the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) antibodies in patients with SLE and RA and patient behavior, disease‐related symptoms, and mental health. METHODS: More than 900 participants were included: 405 patients with RA or SLE (CRD‐patients) and 513 blood donors. All participants had blood SARS‐CoV‐2 total antibodies measured (sensitivity 96.7%, specificity 99.5%) and answered a questionnaire concerning behavior, anxiety, and symptoms of depression (PHQ‐9). The CRD patients were further asked about physical activity, adherence to medication, and disease‐related symptoms. RESULTS: CRD‐patients had a significant lower seroprevalence of SARS‐CoV‐2 antibodies (n=1/365, 0.3%) compared to blood donors (n=10/513, 1.9%) (p=0.03). Almost 60% of patients were unable to exercise as usual, increased pain was experienced by 34% of patients and increased disease activity by 24%. Almost 10% of patients reduced or discontinued their immunosuppressive treatments at their own initiative. Symptoms of moderate depression were present in 19% of patients compared to 6,8% blood donors (p<0.001). CONCLUSIONS: Low seroprevalence in patients with CRDs indicates successful mitigation of exposure to SARS‐CoV‐2. However, this appears to occur at the expense of physical activity, experience of increased pain, disease activity, and symptoms of depression. There is a need for care providers to be aware of these negative side‐effects and for further studies to investigate the possible long‐term consequences. The coronavirus disease 2019 (COVID-19) pandemic has complicated the management of Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) (throughout the paper referred to as chronic rheumatic diseases (CRDs)). Patients with CRDs are immunocompromised and generally vulnerable to infection (1) . The fear of COVID-19 and the shielding strategy undertaken by many CRD-patients introduced new challenges in the management of the patients. Although recommendations have been developed to manage patients with CRDs by, i.e., European League Against Rheumatism (EULAR) (2) , strong evidence is still lacking to guide treatment decisions. The hypothesis of being at a higher risk of getting severe COVID-19 when treated with immunosuppressants is not definitive (3) . Some reports indicate that risk of a severe outcome of COVID-19 is similar in most patients with CRDs to people without CRDs (3), other reports have indicated the opposite (4). Denmark has been a low incident country with a seroprevalence in June 2020 of 1.9% (5) . One explanation for the low seroprevalence was a nationally mandated lock-down during March to June 2020. The immediate need for information and lack thereof, particularly about patients risk of COVID-19, triggered anxiety and isolation for many patients. Thus, the question remains whether the consequences of the lock-down, e.g., isolation, depression, anxiety, lack of exercise, and reduced accessibility of rheumatology consult, overshadowed the benefits considering the low prevalence of COVID-19 in Denmark. This study aimed to assess the seroprevalence of blood SARS-CoV-2 total antibodies in patients with CRDs and blood donors (BDs) during the first wave of the pandemic. We further evaluated patient behavior regarding medication, exercise, pain, and experienced disease activity during the pandemic. Finally, we investigated the differences in anxiety and depression in patients with CRDs compared with BDs . This article is protected by copyright. All rights reserved SLE and RA outpatients at the Department of Rheumatology, Aarhus University Hospital, were included in the study. Patients were identified through hospital records. Inclusion criteria for RA patients were treatment with either a biologic or small molecule disease-modifying anti-rheumatic drug (DMARD), and fulfillment of either the 1987 ACR or 2010 ACR/EULAR Classification Criteria. Inclusion criteria for SLE patients were fulfillment of the 1982 updated ACR criteria for SLE. Comorbidity was assessed using the Charlson Comorbidity Index. Disease-specific morbidity for SLE patients was evaluated by the SLICC score. The two patient groups were selected, as they represent some of our potential "high risk" patients concerning COVID-19. Danish BDs, included in The Danish Blood Donor Study, who answered a specific COVID-19-related questionnaire, were included in the present study as controls. All subjects were from the same geographical area. After informed consent, CRD-patients completed an electronic questionnaire concerning their mental and physical health, exercise, and behavior (the questionnaire was answered between May 25th and June 7 th , supplementary file 3). Two patient research partners and two patient advisors from The Danish Rheumatism Association assisted in creation of the questions. Symptoms of depression were assessed using the Patient Health Questionnaire-9 (PHQ-9) (6), and symptoms of anxiety were evaluated using a national anxiety-symptom-questionnaire. Disease characteristics and Charlson Comorbidity Index were obtained from the electronic health record. The BDs' questionnaire corresponded to that completed by the patients with CRDs, except for specific questions regarding rheumatic diseases. CRD-patients positive for SARS-CoV-2 antibodies or previously tested positive with a PCR test were interviewed concerning their symptoms of COVID-19, disease duration, and severity. This article is protected by copyright. All rights reserved Blood samples from both CRD-patients and BD were collected between June 8 th and June 19 th and analyzed at the Department of Clinical Microbiology at Aarhus University Hospital. Serum was tested for antibodies against SARS-CoV-2 using a SARS-CoV-2 total antibody enzymelinked immunosorbent assay (Wantai Biological Pharmacy Enterprise Co., Ltd., Beijing, China) according to the manufacturer's instructions. The assay detects total antibodies in serum binding SARS-CoV-2 spike protein receptor-binding domain. Results were based on a single test result. The sample absorbance (A) value was divided by a cut-off (CO) value for the ELISA plate based on an average absorbance value for 3 negative kit controls. A/CO values: < 0.9 (negative), 0.9-1.1 (inconclusive), and ≥ 1.1 (positive). Performance characteristics of the assay have been determined in a Danish validation study (sensitivity 96.7%, specificity 99.5%) (7) . No cross-reactivity was observed. All values reported are medians with interquartile range (IQR) unless otherwise stated. The statistical significance of differences was assessed using the Mann-Whitney nonparametric test for continuous variables and Pearson's chi-square test for categorical variables. Multivariate logistic regression with depression and behavioral changes as dependent variables and CRD, age and sex as independent variables were performed (supplementary table 2) . The This article is protected by copyright. All rights reserved Through the hospital registries, we identified 455 RA patients who fulfilled the ACR 1987 classification criteria and were undergoing active treatment with either a biologic or small molecule DMARD. RA-patients were contacted consecutively from a random list with the goal of including Table 1 ). RA-patients had a significantly higher Charlson Comorbidity Index of 3 compared to 2 for the SLE-patients (p>0.001). The CRD-cohort had a combined median age of 57 years and the BD 47 years (p>0.001). The CRDpatients had a BMI of 25.0 which was no different than the BD of 25.5 (p=0.06). All the BDs (n=513) and 365 (90.1%) of the CRD-patients had SARS-CoV-2 antibodies measured ( Figure 1 ). Significantly more BDs (n=10, 1.9%) than patients (n=1, 0.3%) tested positive for SARS-CoV-2 antibodies (p=0.03). A subsequent interview revealed the antibody-positive CRD-patient had a This article is protected by copyright. All rights reserved subclinical, asymptomatic infection. Fifty-one CRD-patients (13.2%) reported a total of 60 PCR-test performed for SARS-CoV-2 RNA prior to inclusion, all tests were negative. More CRD-patients reported a change in behavior compared to BDs (Table 2 ). Whereas both CRDpatients and BDs adjusted their behavior regarding handwashing (p=0.90) and sneezing in the elbow (p=0.70), CRD-patients were more likely to avoid public transportation, avoid large gatherings, and stay home compared to BDs (all p≤0.001) ( Table 2 ). Logistic regression adjusting for age and gender did not change this conclusion (Suppl. Table 2 ). More than half (n=227/N=387, 58.7%) of the CRD-patients were unable to exercise as usual and 45% (n=173) reported being less physically active. CRD-patients experienced increased pain (n=131, 34 %) and increase in disease activity (n=91, 23.5 %). The pandemic also affected how CRD-patients took their medication; 8.0% (n=31) started taking other medications or supplements to reduce the risk of COVID-19, and 9.3% (n=36) reduced or discontinued their prescribed treatment at their own initiative. A significantly larger proportion of CRD-patients (n=73, 18.9%) had symptoms of moderate depression evaluated by a PHQ-9 score ≥ 10, compared to BDs (n=34, (p<0.001) ( This article is protected by copyright. All rights reserved The study aimed to assess how the first wave of the global COVID-19 pandemic affected patients with CRDs compared to BDs in a well-defined geographical region and with comparable exposure time. Assessed by SARS-CoV-2 total antibodies in blood, we found that CRD patients had a significantly lower prevalence compared to BDs. However, this appears to occur at the expense of decreased physical activity, experience of increased pain, self-perceived disease activity, and symptoms of depression. Even though Denmark has so far been a low incidence country (5), we were surprised by the low seroprevalence of SARS-CoV-2 antibodies in the CRD-patients. A person becomes SARS-CoV-2 antibody positive 1-2 weeks after the onset of COVID-19. The assay used in the present study has a high diagnostic sensitivity and specificity, and no cross-reactivity was observed in a large validation study which included samples from patients with autoimmune diseases (7). Antibodies against SARS-CoV-2 were measured as we also aimed to identify CRD-patients and controls who had sub-clinical infection (8) . Up to 18% of SARS-CoV-2 infections are subclinical (9) . The antibody response is potentially weaker in patients with CRDs, which could be due to the use of DMARDs or their underlying immune-mediated condition. This may lead to false-negative results. However, in a severely immune-compromised patient population (chronic lymphatic leukemia), anti-SARS-CoV-2antibodies were still present in 67% of patients three months after clinical COVID-19 (10). An alternative explanation for our observations is provided by the results of the questionnaire, as CRDpatients were significantly more isolated compared to BDs and thus less exposed to SARS-CoV-2. Substantiating this interpretation, none of the patients (13.2%) that were tested for SARS-CoV-2 (PCR-test) prior to inclusion, tested positive. The effects of physical isolation, inactivity, pain, disease activity and mental health on the patient with CRD intertwine and are hard to untangle. Nearly 10 percent of the study population reduced or discontinued their immunosuppressive medication, which could possibly lead to disease flare and increased pain in some of the patients. EULAR has stated that patients with CRDs should stay on their This article is protected by copyright. All rights reserved medication (2) , however, uncertainty about immunosuppressants and risk of COVID-19 has led to some patients ignoring expert recommendations. The present study underlines that the COVID-19 pandemic facilitates an environment that endorses physical inactivity. Nearly 60 percent of CRD-patients were not able to exercise as usual, resulting in almost 50 percent being less physically active and a third experienced increased pain. Structured physical activity is an integral part of the treatment for patients with CRDs and is advocated by EULAR as an essential part of the standard of care (11) . Inactivity in patients with chronic diseases is associated with poor physical and mental health and an increased risk in both all-cause mortality and disease-specific mortality (12) . A larger proportion of patients with CRD experienced symptoms of depression compared to BDs, but it is well known that depression is significantly more prevalent amongst patients with CRDs than in the general population. Thus, we cannot conclude that symptoms of depression in the current study per se were related to physical inactivity and/or physical isolation during the pandemic. Furthermore, age could be a potential confounder of our results, as the CRD-patients were significantly older than the controls. However, SLE-patients, with the highest rate of depression, had an age comparable to our controls and thus age is unlikely to be a confounding factor. It is apparent that the global pandemic will be prevalent for a protracted period, and we should acknowledge the potential long-term consequences of the current recommendations for patients with CRDs. Patients on immunosuppressants in regions of high incidence of SARS-COV-2 infection in Italy did not seem to have a higher risk of serious complications compared to the general population (13) , and studies indicate that most patients with CRDs do not have a higher frequency of mortality and poor outcome compared with the general population (3, 14) , although further studies are needed to clarify this aspect. Looking at the consequences of the self-imposed isolation strategy that some patients with CRDs have chosen, it is possible that a superior approach would be to obey the recommendation targeted the general population and avoid strict physical isolation. This article is protected by copyright. All rights reserved The strengths of this study are, this is the first study to evaluate the number of SARS-CoV-2 infected individuals in a cohort of patients with CRDs by measuring the sero-prevalence of antibodies against SARS-CoV-2. The study included approximately 80% of all SLE-patients and over 40% of all RApatients treated with either a biologic or small molecule DMARD in our clinic, representing a group of significantly immunosuppressed CRD-patients. Further, the study included BDs from the same region included and sampled during the same two-week inclusion period as the CRD-patients. Thus, the exposure time for patients and BDs in this study is unbiased. There are also limitations to the study. We wished to answer the question of whether having a CRD or being on DMARD treatment would put CRD-patients at a high or low risk of COVID-19. However, due to shielding and thus non-exposure, incidence of infected individuals in the CRD group were too low for these questions to be addressed. Low seroprevalence of SARS-CoV2-Ig in the CRD-patients could be due to immunosuppressive treatment. We do not think this is the case, as symptomatic CRD patients were tested with pharyngeal swap and PCR-test, and none of the CRDpatients in the study had tested positive prior to inclusion. The potential patients with asymptomatic disease and unmeasurable antibodies cannot be ruled out. A social desirability bias cannot be excluded. It is likely that patients would answer questions in a manner that would be viewed favorably by their treating rheumatologist, i.e., to questions about stopping medication. However, for the seroprevalence, we do not think social desirability has influenced the result. BDs are not representative of the general population, and hence could represent a selection bias. However, the seroprevalence of SARS-CoV-2 in the BDs included in the study, reflected the seroprevalence in the general population of June 2020 in Denmark (5) and would therefore not bias our results. We had a high participation and response rate in the study, but we are aware, that non-participants and non-responders could influence our result. Still, the most common reason for CRD-patients not to participate was fear of leaving home to have blood drawn. We would as follows expect the nonparticipation to cut the bias towards negative seroprevalence for the non-responders. This article is protected by copyright. All rights reserved CONCLUSION Although our results suggest that isolation is associated with apparent protection against COVID-19, it also raises a concern regarding the possible consequences of isolation for patients with CRDs. The potential consequence of physical isolation is a risk of severe mental health issues, physical inactivity, self-medication, increased pain, and increased disease activity. The long-term consequences of our recommendations for patients with CRDs should be taken into account when tackling the continuing pandemic. Have you been tested for COVID-19 (%) 13.2 -Did you test positive (%) 0 Have you been able to exercise as usually, yes (%) 41.4 Have you been less physically active due to COVID-19, yes (%) 44.7 Has the degree of physical activity increased the pain from your rheumatological disease? yes(%) 33.9 Have you experienced increased disease activity during COVID- This article is protected by copyright. All rights reserved Accepted Article The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2 Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry Risk of severe coronavirus infection (COVID-19) in patients with inflammatory rheumatic diseases Estimation of SARS-CoV-2 infection fatality rate by real-time antibody screening of blood donors The PHQ-9: validity of a brief depression severity measure Comparison of sixteen serological SARS-CoV-2 immunoassays in sixteen clinical laboratories Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19) Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship Anti-SARS-CoV-2 antibody response in patients with chronic lymphocytic leukemia EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic Coronavirus disease 2019 outcomes among patients with rheumatic diseases 6 months into the pandemic This study was funded by the Danish Rheumatism Association. 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