INTRODUCTION
The COVID-19 pandemic, which predominantly affects the clinical features of acute respiratory syndrome, brought about a series of economic, social and political consequences from its very beginning, and due to this disease numerous health systems around the world have experienced and are still experiencing numerous problems in their operation. (1–4) The impact of COVID-19 on patients with inflammatory rheumatic diseases is the subject of numerous studies, in terms of detecting risk factors, evaluating the consequences of the disease, the impact of pharmacological therapy on COVID-19, as well as the dosage and timing of disease-modifying anti-rheumatic drugs. Although there is some general knowledge about these interrelationships, the results are contradictory. (5–7) Therefore, the aim of this research was to examine whether the use of biological disease-modifying antirheumatic drugs that change the course of the disease (bDMARDs) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) affects the course and outcome of the COVID-19 infection in patients with the most common inflammatory rheumatic diseases.
METHODS AND SUBJECTS
Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and radiographic and non-radiographic axial spondyloarthritis (axSpA), who had COVID-19 and who were treated with bDMARDs and tsDMARDs at the time of the disease, along with a possible background therapy with csDMARDs, were included in this retrospective study. Patient follow-up was performed at the Department of Rheumatology, Physical and Rehabilitation Medicine of the Sestre milosrdnice University Hospital Centre in Zagreb. The cohort consisted of a total of 28 subjects, 13 men and 15 women, who have had COVID-19 in the period from February 2020 until the end of July 2021. The follow-up of the outcome of COVID-19 included a period of at least 2 months from the onset of the infection. Medical history was used as a data source. Out of the total number of subjects, 10 suffered from RA, 10 from PsA, and 8 from axSpA (including ankylosing spondylitis). The following data were used in the research: age and gender of the subject, data regarding SARS-CoV-2 infection (place of infection, method of diagnosis, data on the existence of symptoms and type of symptoms, data regarding the implementation of hospital treatment, treatment and outcome of the infection, data regarding COVID-19 complications), data related to an existing inflammatory rheumatic disease (disease activity graded as remission, low, moderate and high), treatment with bDMARDs or tsDMARDs, systemic glucocorticoid therapy, administration of methotrexate (or other csDMARD) along with biological therapy, line of bDMARDs and tsDMARDs administration, presence of comorbidities, data regarding pregnancy. The activity of inflammatory rheumatic disease is graded according to the DAS 28 score (Disease Activity Score Calculator for Rheumatoid Arthritis) for RA, the BASDAI questionnaire (Bath Ankylosing Spondylitis Disease Activity Index) for axSpA and the DAPSA questionnaire Disease Activity Index for Psoriatic Arthritis) for PsA. The criteria for grading the severity of COVID-19 (asymptomatic, mild, moderate, severe and critical form of the disease) are determined according to the Guidelines for the treatment of patients with coronavirus disease 2019 (COVID-19) version no. 3 as of 21st October 2021 published by the Ministry of Health of the Republic of Croatia (in Croatian: Smjernice za liječenje oboljelih od koronavirusne bolesti 2019. (COVID-19) verzija 3 od 21. listopada 2021. Ministarstva zdravstva Republike Hrvatske).(8)
Descriptive statistics methods were used in the analysis of the available data, and the data were presented in the form of ranges, medians and mean values, and in the form of shares/percentages.
RESULTS
The age of the subjects ranged from 28 to 80, with a median value of 56.5 and a mean value of 54.5±14.5. There were 15 (53.57%) women and 13 (56.43%) men in the cohort, with an average age of 52.7±14.8 for men and 56±14.6 for women. For all patients, the source of infection was a close contact with a previously confirmed infection or suspected infection, with the exception of one patient for whom the source of infection was nosocomial, since this patient was a healthcare professional who was in close contact with another healthcare professional who was infected with the SARS-CoV-2 virus. In 26 patients (92.86%), the diagnosis of infection was established on the basis of a positive PCR test, and in 2 subjects (7.14%) it was a probable case of COVID-19 infection because the diagnosis was made solely on the basis of the clinical features and epidemiological history without microbiological diagnostics, which was in accordance with the recommendations of the Croatian Institute of Public Health (HZJZ) that were current at the time. Twenty-five patients had COVID-19 symptoms (89.29%), and 3 were asymptomatic (10.71%). Regarding treatment, not a single subject was treated with remdesivir, 25 patients (89.29%) received symptomatic therapy, and 2 of these patients (7.14%) were additionally treated with an antibiotic. Out of the total number of patients, only one patient (3.57%) received hospital treatment. Twenty-two patients (78.57%) fully recovered from COVID-19, 6 (21.43%) partially recovered and had prolonged symptoms of the disease (the symptoms lasted longer than 2 months from the onset of the disease), most often accompanied with the symptom of chronic fatigue, and with a median duration of 92.5 days. Regarding disease activity at the time of infection with the SARS-CoV-2 virus, 5 patients with RA had low or moderate disease activity (17.86% and 17.86%). In the case of PsA, 2 patients (7.14%) were in remission, 3 patients (10.71%) had low disease activity, 4 patients (14.29%) had moderate disease activity and 1 patient (3.57%) had high disease activity. Furthermore, in the case of axSpA, 3 patients (10.71%) had low disease activity, 4 patients (14.7%) had moderate disease activity, and 1 patient (3.57%) had high disease activity. Treatment with bDMARDs was represented in our cohort in the following way: 17 patients (60.71%) were treated with TNF-alpha inhibitors (tumour necrosis factor), 5 patients (17.86%) were treated with IL-17 inhibitors (interleukin 17), 2 patients (7.14%) were treated with IL-6 inhibitors (interleukin 6), 1 patient (3.57%) was treated with CD20 inhibitor, while 3 patients (10.71%) were treated with a tsDMARD, upadacitinib. Regarding the line of bDMARDs administration, 20 patients (71.43%) received them as the first-line treatment, 6 patients (21.43%) received them as the second-line treatment, and in two cases they were administered as the third-line treatment (7.14%). Three patients received systemic glucocorticoids (10.71%) in a low dose of up to 8 milligrams, while 6 patients (21.43%) received csDMARDs (methotrexate) as adjunctive therapy in addition to bDMARDs. None of the patients with PsA had clinically visible signs of psoriasis. In addition to that, there were no patients with inflammatory bowel disease in this cohort. In addition to inflammatory rheumatic disease, accompanying comorbidities were present in 17 patients (60.71%), the most common of which were: arterial hypertension, type II diabetes and hypercholesterolemia.
According to the severity of the clinical features of COVID-19, 3 patients in this cohort (10.71%) had symptoms of a mild form of COVID-19 (2 patients suffered from RA, 1 suffered from axSpA), 19 patients (67.86%) had a moderate form of COVID-19 (7 patients suffered from RA, 7 suffered from PsA, 5 suffered from axSpA), 5 patients (17.86%) had a severe form of COVID-19 (1 patient suffered from RA, 3 suffered from PsA, 1 suffered from axSpA) and 1 axSpA who suffered from axSpA (3.57%) had a critical form of COVID-19. It is important to note that, based on the guidelines for the treatment of patients with COVID-19, patients taking immunosuppressive drugs were classified in a higher category (severe disease).(8) Comparing the severity of the clinical features of COVID-19 and the activity of inflammatory rheumatic disease, in this cohort of 5 patients with a severe form of COVID-19, 1 patient (20.00%) was in remission, 1 patient (20.00%) had low disease activity, 2 patients (40.00%) had moderate disease activity, and 1 patient (20.00%) had a high inflammatory rheumatic disease activity. One patient (3.57%) with a critical form of COVID-19 also had a high inflammatory rheumatic disease activity and was the only one in this cohort who was hospitalized and oxygen therapy had to be administered to him. In relation to the patients with a severe and critical form of COVID-19, 4 patients had accompanying comorbidities, while 2 patients were without comorbidities. The aforementioned data are presented in Table 1. The median age of patients with a severe and critical form of COVID-19 was 59, with an average value of 56.67±18.32, which does not significantly deviate from the average age of all subjects in our cohort.
DISCUSSION AND CONCLUSION
This research indicated that the degree of inflammatory rheumatic disease activity, older age, gender and accompanying comorbidities impact the severity of the clinical features of COVID-19 in subjects in this cohort. Most of the subjects had accompanying comorbidities such as arterial hypertension or diabetes, which are well-known risk factors in the development of a more severe form of the disease and an adverse outcome of COVID. Since inflammatory rheumatic diseases are more common in women, the prevalence of COVID is higher in women with inflammatory rheumatic diseases. Taking comorbidities into account, the most common comorbidities in people with inflammatory rheumatic diseases infected with SARS-CoV-2 are cardiovascular diseases, endocrine diseases and respiratory diseases. According to the available literature, there is no significant difference in the prevalence of COVID in individuals with inflammatory rheumatic diseases compared to the general population. (9) The results of this research confirm data from the literature which point to the fact that in general there is no difference in the symptoms and rate of hospitalizations due to COVID-19 between individuals with inflammatory rheumatic diseases and the general population, although some literature data indicate that patients with inflammatory rheumatic diseases have a higher chance of ending up in intensive care and on mechanical ventilation, while on the other hand the mortality between the groups is at the same level. (10) There were no deaths in the cohort of our subjects, and only one person who was elderly, with accompanying comorbidities, receiving IL-17 inhibitor therapy and with a high degree of inflammatory rheumatic disease activity had to be hospitalized and oxygen therapy had to be administered to them. Our research indicated that the degree of activity of inflammatory rheumatic disease affects the severity of the clinical features and the course of COVID-19, which is in accordance with the research available in global medical literature. General risk factors for an adverse course and outcome of COVID-19 in people with inflammatory rheumatic diseases, as well as a higher rate of hospitalization and mortality, are the following: male gender, older age, cardiovascular and pulmonary diseases, chronic kidney disease, moderate to high level of inflammatory rheumatic disease activity and the diagnosis of inflammatory rheumatic disease. (11–14) Some studies have found that patients with PsA had a more favourable outcome of COVID-19 compared to patients with RA, but the real reason for this has not yet been determined. (12) It is an interesting fact that none of our subjects diagnosed with PsA had psoriatic manifestations on the skin and/or nails. This fact could be explained by the low to moderate inflammatory rheumatic disease activity of most of our subjects with PsA, but also by the likely beneficial effect of biological therapy or targeted synthetic drugs on cutaneous manifestations. By studying the pathophysiological mechanisms of SARS-CoV-2 infection, it was established that the body’s excessive inflammatory response to SARS-CoV-2 (the so-called cytokine storm) leads to the development of a more severe form of the disease and higher mortality rate. It is an excessive activation of the monocyte-macrophage system in a certain part of the patients, for a reason that still remains unknown, which consequently leads to diffuse damage to various tissues and organs. Since in patients with inflammatory rheumatic diseases inflammation is already present in the body, additional inflammation could lead to additional damage. It was also established that SARS-CoV-2 infection has similar pathophysiological inflammatory mechanisms as RA in terms of cytokine imbalance, and this opened up the possibility of using similar and the same drugs that are used in the treatment of inflammatory rheumatic diseases. (15,16) Treatment, as well as the choice of different therapy in the treatment of inflammatory rheumatic disease, can have an impact on the course and outcome of COVID-19. Given that the majority of patients in our cohort were treated with a TNF-alpha inhibitor and that there was no fatal outcome, it could be concluded that the use of TNF-alpha inhibitors is associated with a more favourable outcome of the infection. Since targeted synthetic molecules and biological drugs act as inhibitors of certain parts of the immune mechanisms, which favourably affects the course of the inflammatory disease, there has been concern about their further use in the course of COVID-19 when the activity of the immune system is crucial for the resolution of the infection. However, research from the available world literature supports the fact that the use of TNF-alpha inhibitors is associated with a better outcome of infection, while the use of JAK-inhibitors and rituximab compared to TNF-alpha inhibitors is associated with an adverse outcome of infection, i.e., there is a significantly higher likelihood of hospitalization or death. Moreover, the use of immunosuppressants (e.g. methotrexate, azathioprine) as monotherapy or in combination with other drugs and the use of high doses of glucocorticoids in the treatment of inflammatory rheumatic diseases have been detected as factors that result in an adverse outcome of COVID-19, and consequently in an increased mortality rate. (5,6,11,12) The absence of deaths caused by COVID-19 in our cohort can also be explained by the fact that only one severely ill patient was receiving glucocorticoid therapy at the time. It has been shown that exposure of patients to glucocorticoids in a dose greater than 10 milligrams per day is associated with a higher rate of hospitalization in patients with COVID-19, especially in patients with systemic connective tissue disease and vasculitis. (17) Although we do not have data on the vaccination status of all subjects in our cohort, vaccination is certainly the most effective method of prevention and protection against an adverse course and outcome of COVID-19. Since the invention of the vaccine against SARS-CoV-2, in a certain number of patients there has been a fear of adverse consequences of the vaccine on the activity of the underlying disease. However, data from literature show that an exacerbation of inflammatory rheumatic disease occurred in less than 5% of subjects. The majority of respondents were willing to temporarily stop taking DMARDs in order to improve the effectiveness of the vaccine. Also, the side effects of the vaccine were typical, as those in the general population. They included fatigue, malaise, fever, chills, headache, myalgias, and arthralgias. (18) In our cohort, only 6 subjects (5 women and 1 man) had a severe and critical form of COVID-19, and out of these subjects only one subject was hospitalized and oxygen therapy had to be administered to him. The advantage of this research is that it includes a sample of subjects from everyday clinical practice which reflects the real situation, while the main limitation is the small number of subjects, which prevents a more detailed analysis of the interrelationship of individual parameters of interest. We must note that most of the subjects recovered from COVID-19 at a time when the vaccine was not yet developed and widely available on the market, that is, before mass vaccination of the population began. Furthermore, those who recovered from the disease could be vaccinated at the earliest 3 to 6 months after recovery. Therefore. vaccination was not an analysed variable in this study. Smoking as an analysed variable was not included due to insufficient data in relation to it.
In conclusion, the results of our retrospective study suggest that higher inflammatory rheumatic disease activity and accompanying comorbidities are associated with a severe and critical form of SARS-CoV-2 virus infection, but without a fatal outcome. A more favourable outcome of the infection may be associated with the use of specific biological therapy. For a more detailed insight into this, research needs to be conducted on a larger sample of subjects, preferably with a prospective design. Therefore, during this pandemic, it is necessary to monitor patients and perform the follow-up of patients with inflammatory rheumatic diseases more intensively in order to control and manage disease activity and modify the therapy in a more efficient way.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / Literatura
18. Sattui SE, Liew JW, Kennedy K, Sirotich E, Putman M, Moni TT, et al. Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: Results from the COVID-19 Global Rheumatology Alliance Vaccine Survey. RMD Open. 2021;7(3):1–10.
Table 1 Demographic and clinical features of patients with severe and critical COVID-19 and inflammatory rheumatic disease
Tablica 1. Demografska i klinička obilježja ispitanika s teškim i kritičnim oblikom bolesti COVID-19 i upalnom reumatskom bolesti
Legend / Legenda: COVID: Coronavirus disease / koronavirusna bolest; bDMARD: biological disease modifying antirheumatic drug / biološka antireumatska terapija koja mijenja tijek bolesti; AxSpA: axial spondyloarthritis /aksijalni spondyloarthritis; PsA: psoriatic arhtritis / psorijatični artritis; RA: rheumatoid arthritis / reumatoidni artritis; F / Ž: female / ženski; M: male / muški; IL: interleukin; TNF: tumor necrosis factor / čimbenik nekroze tumora