Effect of COVID-19 Pandemic on Anxiety in Rheumatology Patients Taking Immunosuppressive Drugs

Introduction: Coronavirus disease 2019 (COVID-19) pandemic is a public health emergency that is causing international concern. Patients with medical comorbidities are more likely to be infected and have a worse prognosis. The purpose of this study was to determine the prevalence of anxiety due to COVID-19 pandemic in patients with rheumatic and musculoskeletal diseases (RMDs) who used immunosuppressive drugs during the initial stage of the COVID-19 pandemic and to identify the risk and protective factors that cause anxiety. Methods: A total of 145 patients with RMDs aged ≥ 18 years who used regular immunosuppressive drugs and 95 healthy controls were included in the study. An anonymous survey comprising questions regarding the COVID-19 pandemic was used, and the Beck anxiety inventory (BAI) was used to measure the anxiety levels of participants. Additional information was collected such as demographic data, current RMDs, immunosuppressive drugs used, information and concerns about COVID-19, and the source of information about COVID-19. Results: About 42.1% patients reported that the epidemic caused concern due to the drug they were using, and 33.8% rated their concerns as moderate and severe. The BAI scores of patients and healthy controls were 4 (0-52) and 3 (0-18) respectively. According to the BAI scores, 16.5% patients had moderate to severe anxiety symptoms; and comparison of the groups showed that the anxiety level of the patient group was signicantly higher (38.6% vs. 18.9%, p=0.001). Female had more anxiety symptoms in both groups (p<0.005). In addition, anxiety was lower in patients with higher education levels (p=0.039). Conclusion: It should be ensured that patients in the high-risk group are not provided false information, the patients are individually informed, and they trust the treatment team. Providing online or smartphone-based psychoeducation and psychological interventions may be considered for these patients with high anxiety levels. and csDMARDs) included. The study comprised 145 patients including 26 (FMF), 33 rheumatoid 31 with


Introduction
Coronavirus disease 2019 (COVID-19) was rst described in Wuhan, China in December 2019 due to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) [1]. Since then, the number of cases has been increasing exponentially, and the virus is spreading all over the world. COVID-19 was declared as a global health threat by the World Health Organization (WHO) on January 30, 2020, and it was recognized as a pandemic on March 11, 2020 [2,3]. This pandemic is the largest outbreak of atypical pneumonia since the outbreak of SARS in 2003. After the rst outbreak, the total number of cases and deaths exceeded those of SARS [4]. There is human-to-human transmission via respiratory droplets containing the virus [5]. Patients with medical comorbidities are more likely to be infected and have worse prognosis [6]. Mortality rate is estimated to be 5.7%, and this rate ranges between 0.3% and 0.6% [7,8]. Since the beginning of the pandemic, strict measures have been undertaken for the prevention of infection all over the world. After the rst case was detected in Turkey on March 11, 2020, these measures have increased. Social isolation has been emphasized due to the exponential increase in the number of infected cases as well as the increase in mortality rates.
During infection outbreaks, a wide range of psychosocial effects are observed in people, and people experience the fear of falling ill or the fear of death as well as the feelings of desperation [9]. Anxiety is also a common negative feeling experienced by the entire population during pandemics [10]. During the COVID-19 pandemic, WHO made a number of recommendations regarding mental health and psychosocial issues [11]. Most studies on this pandemic have focused on determining the epidemiology and clinical characteristics of infected patients, genomic characterization of the virus, and challenges of global health management [5,6,12,13]. During SARS and COVID-19 pandemics, studies were conducted to evaluate psychological responses of the general society [14,15]. COVID-19 pandemic has become a stressful factor, especially because this new viral infection does not have any vaccine and can be treated only symptomatically. The effect of anxiety caused by COVID-19 in patients with rheumatic musculoskeletal diseases (RMDs) who use immunosuppressive drugs is unknown. The European League Against Rheumatism (EULAR) has reported that patients who use immunosuppressive [e.g. biological drugs, JAK inhibitors (targeted synthetic disease modi er drugs-tsDMARD), and steroid and conventional DMARDs (csDMARDs like methotrexate, hydroxychloroquine)] drugs during the current pandemic of COVID-19 may have various issues as well as anxiety [16]. However, there is no research on the psychological effect of COVID-19 in patients with RMDs who use immunosuppressive drugs. The purpose of this study is to determine the prevalence of anxiety due to COVID-19 pandemic in patients with RMDs who were using immunosuppressive drugs immediately after the rst case of COVID-19 was reported in Turkey and WHO declared the pandemic and to identify the risk and protective factors that contribute to the anxiety.

Participants
This study was started 16 days after the rst COVID-19 case in Turkey, and 145 patients aged ≥18 years with RMDs who were regularly using immunosuppressive drugs (biological drugs, tsDMARDs, and csDMARDs) were included. The study comprised 145 patients including 26 with familial Mediterranean fever (FMF), 33 with rheumatoid arthritis (RA), 31 with connective tissue disease (CTD), 25 with spondyloarthropathy (SpA), and 30 with vasculitis. Further, 95 healthy individuals without a known chronic disease or regular drug use were included in the control group. Patients who did not visit outpatient clinic regularly, who did not take their medication regularly, who had mental retardation, who had di culty understanding the questions, who did not volunteer to participate in the study, who used antidepressant drugs, and who were <18 years of age were not included in the study.

Study design
In this observational and cross-sectional clinical study, self-reported questionnaires were used. Previous studies on the psychological effects of SARS and in uenza outbreaks were reviewed [17][18][19]. Accordingly, an anonymous survey was developed that included additional questions about the COVID-19 pandemic. The structured survey comprised questions covering several areas as follows: (1) demographic data; (2) information and concerns about COVID-19; (3) where the information about COVID-19 was obtained; (4) knowledge of current number of COVID-19 cases; (5) anxiety due to the immunosuppressive drugs used by the participant; and (6) diagnosis of COVID-19 in the participant or someone they knew. Anxiety was measured using a valid clinical survey and scoring system. Patients were called by telephone and asked questions, and the data were collected. The survey was anonymously lled by 145 patients and 95 healthy controls.

Demographic data and social characteristics
The demographic data and social characteristics of the study participants included age, gender, education and marital status, and the number of children they had. The professional and business data included titles and information regarding the institutions they worked for. In addition, existing chronic diseases of patients and immunosuppressive drugs used were recorded.

Beck Anxiety Inventory (BAI)
The BAI was developed by Beck et al. to assess the degree of anxiety symptoms in an individual [20]. BAI is a self-reporting questionnaire comprising 21 items; each item is rated between 0 and 3 points and gives a total score of 0 to 63 points. The total score from the scale indicates the degree of anxiety of the individual. Those with BAI scores of 0-7, 8-15, 16-25, and 26-63 are classi ed to have "no anxiety symptoms," "mild symptoms," "medium symptoms", and "severe symptoms," respectively [20]. Ulusoy et al conducted the Turkish validity and reliability study [21] and grouped into no anxiety symptoms (0-7 points) and the presence of anxiety symptoms (8-63 points) based on the BAI scores.

Statistical analysis
The Statistical Package for Social Sciences version 22.0 software was used to evaluate the data. Descriptive statistical data are expressed as frequency (percentage), number and mean ± standard deviation, or median (min-max). The distribution properties of the numeric variables were evaluated by Kolmogorov-Smirnov test. Independent-samples t-test was used for intergroup comparisons of numeric variables with normal distribution, and Mann-Whitney's U test was used for variables without normal distribution. Categorical data were evaluated using chi-square test. A P-value of <0.05 was considered statistically signi cant.

Results
A total of 240 individuals, including 145 patients and 95 healthy controls, meeting the study criteria were included in the study by lling the survey. Mean age of the patient and control groups were 40.41 ± 13.51 and 42.34 ± 10.07 years, respectively. No difference was observed between the groups in terms of age and gender (p=0.183). No patient was diagnosed with COVID-19 in both groups. The demographic and clinical characteristics are shown in Table 1. that the pandemic caused concern due to the drug they used; and 33.8% rated their concerns as moderate and severe. The BAI scores of the patients and healthy controls were 4 (0-52) and 3 (0-18), respectively. According to the BAI scores, 16.5% patients had moderate to severe anxiety symptoms. The concern levels and BAI scores of both groups are shown in Table 2. Both groups were evaluated in terms of the factors affecting anxiety states within the groups. Upon examining the affecting factors such as gender, age, marital status, number of children, occupation, institution, biological medicine used, and DMARDs, female were found to have more anxiety symptoms in both the groups. In addition, anxiety symptoms was lower in patients with higher education levels (p=0.039). When comparing COVID-19 knowledge in terms of communication tools and occupational groups between the two groups, no signi cant difference was observed. Factors affecting anxiety in both groups are shown in Table 3. Although there was no signi cant difference in the anxiety levels and anxiety conditions of patients receiving biological drugs + tsDMARDs and csDMARDs as immunosuppressive drugs, patients taking biological drugs + tsDMARDs had more anxiety (p=0.056; Table 4).

Discussion
In this study, the prevalence of anxiety caused by COVID-19 pandemic and the risk and protective factors contributing to psychological stress in patients with RMDs who were using immunosuppressive drugs were investigated. Female sex was a risk factor for anxiety in the patients taking immunosuppressive drugs as well as in the control group. In addition, anxiety levels of patients who took immunosuppressive drugs were signi cantly higher than the control group, whereas anxiety was lower in those with higher education levels.
Based on the BAI scores, 16.5% patients showed moderate to severe anxiety symptoms.
COVID-2019 is a pandemic and pandemics have various psychological effects on humans, including anxiety [22]. During the in uenza epidemic (in uenza A H1N1v), approximately 10% and 30% of the population had high or severe anxiety [17]. In a study conducted on the general population on the COVID-19 pandemic in China, 53.8% participants rated the psychological effect of the pandemic as moderate or severe, and 28.8% reported moderate to severe anxiety symptoms [15].
Sensational popular media titles, lack of information, and incorrect information have shown to increase the health concerns and phobias [23]. Television (82.8%) and the Internet (13.1%) were the primary information channels during the initial stage of the COVID-19 pandemic. Most participants (76.6%) were aware about the number of cases, advice on prevention, and warnings for those with chronic diseases. However, it is believed that this information, the accuracy of which is controversial, can lead to an increase in patient anxiety levels.
A guideline has stated that it is important to medically and psychologically prepare the health systems and general public if widespread transmission occurs during a pandemic [24], and it is recommended to identify high-risk groups based on the sociodemographic information for early psychological intervention [15]. The sociodemographic data in this study have shown that women who take immunosuppressive drugs have a higher level of anxiety. This result supports the extensive epidemiological studies reporting that women are at a higher risk of anxiety [25][26][27].
In a study conducted on the general population in China, it was found that students experienced a higher level of anxiety and psychological impact due to the pandemic [15]. Schools of all levels have been inde nitely closed in Turkey as well as the rest of the world. In this study, there were no signi cant differences in terms of anxiety based on occupational groups including students. During pandemics, educational authorities should develop online portals and web-based applications for courses and other teaching activities [28]. Although schools are closed in Turkey, many teaching activities continue online. As the younger population is more familiar with smartphone applications [29], they are able to continue their education. It is believed that this may be the reason why high levels of anxiety have not been detected in the younger individuals.
A recent study in China found that the general population without formal education was more likely to be depressed during the pandemic [15]. In another study that evaluated population-based psychological morbidity after the SARS epidemic, there was a signi cant correlation between education level and psychiatric morbidity, and it was recommended to divide the population into sections based on the level of education to increase crisis communication [10]. In this study, anxiety was lower in those with higher education levels. Therefore, it may be recommended to provide audio-visual information with simple language, when required, to support patients based on their education levels during the pandemic.
In this study, anxiety was found in 38.6% patients. Behçet syndrome were reported to be 52%, 50%, 41%, and 38%, respectively [30]. The prevalence of anxiety in the SpA group was similar to the previous study [31], whereas the prevalence of anxiety in the FMF patient group was higher than the other groups. This suggests that FMF patient group may have been more affected by social isolation caused by the quarantine process due to younger age and being more active. Similarly, in studies that compared patients with in ammatory rheumatic diseases with healthy controls, anxiety was higher in the patient group [32][33][34][35][36][37][38][39].
In this study, the prevalence of anxiety was 18.9% in the control group, and there was a signi cant difference in anxiety levels between the patient and controls groups. In pre-pandemic studies, the prevalence of anxiety in healthy controls is signi cantly lower than that found in this study (6.6% -9.6%) [31,35,36]. Although the control group had increased anxiety levels, the difference was signi cant, suggesting that our patients had high anxiety. It may be recommended that health authorities consider providing online or smartphone-based psychoeducation and psychological interventions to reduce the risk of virus infection via face-to-face treatment.
In addition, they should be informed individually by the clinic where they are followed, and it should be ensured that they trust the treatment team.
This study has several limitations. Given the inability to meet face-to-face and time sensitivity of the COVID-19 pandemic, data were collected by contacting patients on the phone. The reported anxiety levels may not always correspond to the assessment by mental health professionals. Similarly, patients may have given socially desirable responses regarding their anxiety levels. Finally, a patient was diagnosed with COVID-19 and had no relatives around her/him. Therefore, surveys may have been conducted early. Despite the above limitations, this study, which was conducted on patients with in ammatory RMDs who were using immunosuppressive drugs 2 weeks after the appearance of COVID-19 in Turkey, was considered to be the rst that evaluated the effects of pandemic on anxiety. As the COVID-19 pandemic continues to spread, our results are expected to provide recommendations on the development of psychological support for patients in the risk group who are taking immunosuppressive drugs and in priority areas in Turkey and in other countries affected by the pandemic.

Conclusion
This observational cross-sectional study evaluated anxiety caused by immunosuppressive drugs used by patients diagnosed with RMDs during the COVID-19 pandemic in Turkey. Neither the participants nor their relatives encountered COVID-19 infection; however, a high level of anxiety was found in patients. Anxiety in female patients and patients who were using immunosuppressive drugs was higher. In this process, it should be ensured that these patients in the high-risk group are not provided false information, the patients are informed individually, and they trust the treatment team. Providing online or smartphone-based psychoeducation and psychological interventions may be considered for these patients with high anxiety.

Declarations
Ethical approval This study was conducted in accordance with the Helsinki Declaration. All participants were informed and their consent was obtained. The study was approved by the local ethics committee and the Ministry of Health (Approval number: 2020/132).

Declaration of con icting interests
The authors declared no con icts of interest with respect to the authorship and/or publication of this article.

Contributions
All authors have contributed equally to the development of the manuscript. All authors read and approved the nal manuscript.

Corresponding author
Correspondence to Tugba Izci Duran.