INTRODUCTION

Inflammatory rheumatic diseases cause a predisposition to routine and opportunistic infections due to disease-related factors and immunosuppressive drugs used in the treatment (1). For this reason, both patients and doctors wondered whether inflammatory rheumatic diseases and immunosuppressive drugs used in the treatment increase the risk of getting or being severely affected by coronavirus disease-2019 (COVID-19). In the first period of the epidemic, patients tended to discontinue their immunosuppressive treatments due to the risk of contracting COVID-19 and the fear of severe illness, and they believed that stopping the treatment would reduce this risk (2-4). In addition, the risk of infection increases as the severity of rheumatic disease increases (5,6).

During the COVID-19 pandemic, conflicting results have been published regarding the risk of getting or being affected severely by COVID-19 for those with rheumatic diseases. There are studies reporting an increased risk of hospitalization and death due to COVID-19 in certain rheumatic disease groups or those using certain immunosuppressive drugs (7-9). On the other hand, some studies state that there is no increase in the risk of getting COVID-19 infection or severe course in rheumatic disease patients compared with the healthy population (10,11). The risk of hospitalization due to COVID-19 was associated with age, presence of comorbid diseases, and high prednisone dose (≥10 mg/day) in patients with rheumatic diseases (12). According to the results of studies evaluating the relationship between the use of disease-modifying antirheumatic drugs (DMARD) and poor outcomes of COVID-19, conventional synthetic DMARD (csDMARD), biological DMARD (bDMARD), and targeted synthetic DMARD (tsDMARD) groups are not associated with high risk; however, specific drugs such as sulfasalazine (SSZ), rituximab (RTX), and Janus kinase inhibitors may be associated with adverse outcomes (9,13,14). In this study, we evaluated the patients followed up in our rheumatic diseases outpatient clinic between July 2020 and January 2021, recorded their health status between March 2020 and January 2021, and questioned them again at each examination. This study aimed to investigate the health status of patients using DMARD for rheumatic diseases during the COVID-19 pandemic and to evaluate the relationship between demographic data, rheumatic disease, and DMARD use and COVID-19-related outcomes.

METHODS

We obtained the Clinical Research Ethics Committee approval from University of Health Sciences Türkiye, İstanbul Fatih Sultan Mehmet Training and Research Hospital (no: FSM EAH-KAEK 2020/95, date: 09.07.2020) for this study. Among the patients followed up in our rheumatic diseases outpatient clinic with the diagnosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA), those older than 18 years of age, using DMARD for treatment, and volunteering to participate were included. Those under the age of 18 years and individuals who refused to participate were not included Exclusion criteria were being under 18 years of age and not agreeing to participate in the study. Written informed consent was obtained from all participants.

We used a follow-up form to evaluate the health status of the patients. In this form; age, gender, height, weight, smoking status (active smoker/ex-smoker/never smoker), systemic diseases, rheumatic disease type and treatment, COVID-19-related conditions [reason for polymerase chain reaction (PCR) test if performed, computed tomography (CT) result if taken, COVID-19 treatment if received], COVID-19 risk perceptions (with Likert scale), routine follow-up and treatment compliance, changes in the complaints of those who made changes in rheumatic disease treatment, and rheumatic disease activity (last control before the pandemic and the first control during the pandemic period) were recorded. Conditions associated with COVID-19, including March-June 2020, were recorded at the initial evaluation and were re-questioned at each subsequent follow-up, and recorded if there was a change in the patient’s status. When comparing the data, we divided the patients into two groups in terms of getting or not getting COVID-19 and into three groups in terms of COVID severity as not infected, mild, or severe illness. The presence of pneumonia (confirmed by CT) or the hospitalization need, as accepted by the American College of Rheumatology, was determined as criteria for severe COVID-19 (15). According to this; cases with CT-confirmed pneumonia or requiring hospitalization for treating COVID-19 were classified as severe COVID-19. Cases with neither of these two conditions (i.e. confirmed by PCR only and treated at home) were classified as mild COVID-19. In the comparison of DMARD groups, we evaluated patients in three groups as csDMARD (monotherapy or combinations), b/tsDMARD, and combined DMARD (csDMARD + b/tsDMARD) users. In terms of rheumatic disease diagnoses, comparisons were made as RA, AS, and PsA groups separately and as RA and spondyloarthritis (SpA) (AS and PsA) groups.

Statistical Analysis

Categorical variables were summarized with frequencies and percentages. Numerical variables were summarized with mean and standard deviation or median and quartiles according to their distribution. The distribution of numerical variables was evaluated using the Kolmogorov-Smirnov test. Comparisons of numerical variables between dual COVID groups (getting/not getting) were made using t-test or Mann-Whitney U test according to their distribution. Comparisons of numerical variables between triple COVID groups (did not get/mild/severe) were made by ANOVA or Kruskal-Wallis test, according to their distribution. The relationship between categorical variables was examined using the chi-square test. The McNemar test was used to compare the disease activities before and during pandemics. P<0.05 was considered statistically significant. The R version 4.0.4 (2021-02-15) program was used for statistical analysis.

RESULTS

Patient Characteristics and Comorbid Diseases

A total of 156 patients (95 female, 61 male) were included in the study. The mean age of the patients was 43.4. Since vaccination did not start in our country at that time, none of the patients were vaccinated for COVID-19. The most common comorbid diseases in patients were hypertension (27.6%), diabetes mellitus (14.1%), cardiovascular diseases (15.4%), and chronic respiratory diseases (CRD) (15.4%), and others were hypothyroidism (n=17), chronic renal failure (n=2), focal nodular hyperplasia of the liver (n=2), familial Mediterranean fever (n=2), and benign prostatic hyperplasia (n=2). When we grouped the patients according to the number of comorbidities, we found that the rate of those with zero, one, and more than one comorbid disease was 57%, 26.9%, and 15.4%, respectively. Age, gender, body mass index (BMI), smoking status, comorbid diseases, and COVID-19 results are presented in Table 1.

No statistically significant relationship was found between age, gender, BMI, and occupational status of patients and COVID-19 or COVID-19 severity (p>0.05 for all). There was a significant association between smoking status and not getting COVID-19 (p=0.039). Those who had COVID-19 had a lower smoking rate than those who had never had COVID-19 (16.7% and 42.4%, respectively). No significant association was found between getting COVID-19 and any comorbid disease or the number of comorbid diseases (p>0.05 for all). A statistically significant correlation was found between having severe COVID-19 and having CRD (p<0.05). The relationship between the number of comorbid diseases and severe COVID-19 was also statistically significant (p<0.05).

Rheumatic Diseases and DMARD Treatments

The rheumatic disease diagnoses of the patients were RA in 71 (45.5%), AS in 71 (45.4%), and PsA in 14 (9%). Diagnoses of rheumatic diseases, DMARD used in treatment, and COVID-19 status are given in Table 2.

No significant relationship was found between the diagnosis and duration of rheumatic disease and the severity of COVID-19 or COVID-19 (p>0.05 for all). There were no statistically significant differences between the DMARD groups in terms of getting COVID-19 or COVID-19 severity (p>0.05 for all). Although not statistically significant (p=0.078), the relationship between leflunomide use and COVID-19 severity was closer than for other csDMARDs.

Characteristics of Patients with COVID-19

Of the 156 patients included, 24 (23 with a positive PCR result and 1 with typical findings seen on thorax CT although the PCR result was negative) were diagnosed with COVID-19. Of the 24 patients diagnosed with COVID-19, 16 were treated with mild symptoms, while 8 had severe COVID-19 findings [pneumonia/hospitalization and need for oxygenation/intensive care unit (ICU)]. One patient with severe disease symptoms required ICU admission and intubation, but was subsequently extubated, and discharged with recovery. None of the patients died. Demographic data, rheumatic disease diagnoses, DMARD treatments, PCR and CT findings, and treatments for COVID-19 in patients with COVID-19 are listed in Table 3.

COVID-19 Risk Perceptions and Adherence to Follow-up and Treatment

COVID-19 risk perceptions of patients, depending on their rheumatic diseases and the DMARD they use, are presented in Figure 1. Accordingly, 70.5% of the patients thought that they were in the risk group for COVID-19 because of their rheumatic disease and 53% because of the DMARD they used in the treatment.

Only 39 (25%) of the patients had come to their follow-up regularly during this period. Reasons for not attending were as follows; no complaints (13.7%), hesitation to come to the hospital (58.1%), and reaching the doctor by phone (43.6%). Forty-two (26.9%) of the patients made changes for treating their rheumatic disease on their own, 8 (5.1%) made a temporary change in the treatment, and then continued as before.

As expected, those who made changes in their rheumatic disease treatment were more likely to have increased rheumatic disease activity than those who did not change their treatment. An increase in rheumatic disease activity was observed in 52% of patients who changed their treatment, this rate was 27.4% in patients who continued their treatment with the same regimen, and this was statistically significant (p=0.003). Adherence to DMARD treatment was higher in the RA group than in the SpA group. The rates of continuing routine treatment were 83.1% in the RA group and 55.3% in the SpA group, which was statistically significant (p=0.001).

Rheumatic Disease Activities and COVID-19 Outcomes

When the rheumatic disease activities (Disease Activity score-28 for RA, Bath Ankylosing Spondylitis Disease Activity index for AS, Disease Activity in Psoriatic Arthritis for PsA) of the patients before and during the pandemic period (Table 4) were compared, an increase in disease activity was observed in 55 patients. Disease activity changes between the first evaluation during the pandemic period and the last evaluation before the pandemic were significant (p<0.001). It was observed that patients in remission progressed to low and moderate disease activity groups, and patients with low disease activity progressed to high disease activity groups.

When patients with rheumatic disease activity in remission or low were compared with patients with moderate or high activity (Table 5); a statistically significant relationship was found between having moderate or high rheumatic disease activity and getting COVID-19, but not in terms of COVID-19 severity.

DISCUSSION

In this study, we evaluated patients using DMARD for rheumatic diseases in terms of the relationship between demographic and clinical characteristics and COVID-19 or COVID-19 severity. We found that severe COVID-19 is more common in patients with CRD or with one or more comorbid diseases. We also found a higher rate of getting COVID-19 in those with moderate or high rheumatic disease activity. We showed that during the pandemic period, patients’ compliance with their follow-up and treatment was low, and that rheumatic disease activity increased more frequently in those who made changes in their rheumatic disease treatment.

Two studies have been published from the COVID-19 Global Rheumatology Alliance (GRA) registry data on the factors affecting the risk of hospitalization and death from COVID-19 in those with rheumatic diseases (12,16). Among these, in the study evaluating the risk of hospitalization, advanced age, presence of comorbidities, and prednisone use (≥10 mg/day) were associated with a higher rate of hospitalization. Monotherapy with b/tsDMARD is associated with lower odds of hospitalization, largely due to the effect of anti-TNF treatments (12). In the study about COVID-19-related death, advanced age, male gender, specific comorbidities, and moderate/high disease activity were associated with higher risk (16). Similarly, we found a significant association between having a CRD or having more than one comorbid disease and COVID-19 severity. We did not find any difference between the patient groups using csDMARD, b/tsDMARD, and combined DMARD (cDMARD + b/tsDMARD) in terms of COVID-19-related outcomes. In a review of patients with autoimmune diseases, baseline glucocorticoid use and some specific drugs such as RTX and SSZ are associated with adverse COVID-19 outcomes, but no increased risk is observed for DMARD classes (13). In line with the COVID-19 GRA results reporting a protective effect with bDMARD use (mainly attributed to TNFis), a lower risk of COVID-19 related hospitalization is reported in patients with inflammatory bowel disease using TNFi monotherapy (17) and in patients with psoriasis using bDMARD (compared to non-bDMARD) (18). In addition to the risk factors mentioned above, the delayed diagnosis of COVID-19 was found to be a risk factor for hospitalization (19). Although there was no difference in COVID-19-related outcomes between DMARD classes in our study, the relationship between leflunomide use and severe COVID-19 findings was remarkable, although not statistically significant. In a study evaluating the risk of COVID-19 in patients using DMARD, a positive association was found between the use of leflunomide and the risk of COVID-19 infection (20). On the other hand, another study highlights the potential antiviral effects of leflunomide, noting that it provides faster recovery and reduced viral clearance time in patients with COVID-19 (21).

Another remarkable finding is the opposite relationship between smoking and COVID-19 in our study. 16.7% of the patients who got COVID-19 and 42.4% of those who did not were active smokers. A study supporting this finding found lower probability of testing positive for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in active smokers than in non-smokers (22). In the study, this was explained by nicotine down-regulation of ACE-2 receptors, which SARS-CoV-2 uses to enter the cell, but the authors emphasized that this should not be interpreted as a protective effect of smoking against COVID-19 (22). In addition, another study reported that smoking is associated with negative progression and adverse outcomes of COVID-19 (23).

A significant portion of the patients in this study thought that they were in the risk group for COVID-19 because of their rheumatic diseases and the DMARD they used. A similar finding is seen in a study from Australia, where 41% and 55.7% of patients expressed concern about the increased risk of getting COVID-19 due to their rheumatological diseases and medications, respectively. In the same study, in terms of severe COVID-19 results, 52.3% of the patients had a perception of increased risk due to rheumatological diseases and 76.1% due to their medications (2). As a predictable consequence of this situation, patients’ compliance with follow-up and treatment decreased. In a study of individuals with RA in the United States, 30% of patients reported a change in treatment, and the proportion who canceled or postponed their appointments (varying in different DMARD groups) was between 28% and 35% (24). In this study, 25% of the patients attended their appointments regularly, and 67% continued their treatment as before. Similar results were observed in other studies in our country. In a study evaluating 330 patients with inflammatory rheumatic diseases in Ankara, it was observed that 27.2% of the patients continued their follow-up regularly and 11.9% changed their treatment without a doctor’s advice. In a web-based survey study from İstanbul, these rates for adherence were as follows; 14.4% for follow-up and 77% for treatment. In the latter, similar to our study, there was a significant difference between the RA (81.3%) and SpA (46.3%) patient groups who continued the treatment as before. Similarly, in the study of Kalyoncu et al. (25) evaluating the preferences of patients using bDMARD for the treatment of inflammatory arthritis, the proportion of patients who discontinued bDMARD therapy was significantly higher in the SpA group (20.5%) than in the RA group (13.8%). They also showed lower disease activity in SpA patients who continued bDMARD therapy, in line with the higher incidence of increased disease activity in patients who discontinued DMARD therapy in our study. In our study, the rates of continuing routine treatment were 83.1% in the RA group and 55.3% in the SpA group, which was statistically significant. In addition, the results of a survey study in Spain are similar to our results both in terms of treatment adherence, of which 79.7% of patients continued their treatment as before and in terms of the relationship between spacing-stopping treatment and worsening disease activity (26).

The most important limitation of our study is the absence of a control group consisting of patients with rheumatic disease who did not use DMARD. Therefore, COVID-19-related outcomes in patients with rheumatic diseases and using DMARD for treatment could not be compared with patients who did not use DMARD. Another limitation is the small number of patients compared with similar studies in the literature. Patients’ hesitance to come to the hospital may have caused this situation.

CONCLUSION

There is no difference in COVID-19-related outcomes between DMARD classes in patients with rheumatic diseases. Having a CRD or one or more comorbid diseases may increase the risk of severe COVID-19 manifestations. Patients with moderate or high rheumatic disease activity may get COVID-19 more frequently. Patients’ perception of risk for COVID-19 has reduced compliance with follow-up and treatment, making it difficult to maintain remission or low disease activity.

ETHICS

Ethics Committee Approval: We obtained the Clinical Research Ethics Committee approval from University of Health Sciences Türkiye, İstanbul Fatih Sultan Mehmet Training and Research Hospital (no: FSM EAH-KAEK 2020/95, date: 09.07.2020) for this study.

Informed Consent: Written informed consent was obtained from all participants.

Authorship Contributions

Surgical and Medical Practices: K.S., F.Ü.Ö., İ.A., Concept: K.S., F.Ü.Ö., İ.A., P.A., Design: K.S., F.Ü.Ö., İ.A., P.A., Data Collection or Processing: K.S., Analysis or Interpretation: K.S., F.Ü.Ö., İ.A., Literature Search: K.S., Writing: K.S., F.Ü.Ö., İ.A., P.A.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declare that this study received no financial support.