COVID-19 among Rheumatoid Arthritis Patients on Immunosuppressive Therapy During the First Wave of the COVID-19 Pandemic: a Prospective Comparative Study

be recruited into three groups: rheumatoid arthritis (RA) patients; rheumatoid arthritis with COVID-19 patients (RA-COVID); and a COVID-19 (COVID-19) group. Results: the mean age of the studied group was 50 years old. The three studied groups showed no statistically significant difference (p > 0.05) as regards age, sex, level of education, and marital status. But there was a statistically significant difference between groups regarding occupation and special habits in the form of hashish smoking. There was no marked difference in COVID-19 symptoms between group II and group III. The mean of the Modified Health Assessment Questionnaire (MHAQ) was 5.5 in RA group versus 8 in RA-COVID-19 group ,with statistically significant difference between group I and II as regard DAS28. The duration from being diagnosed with COVID-19 till recovery was significantly higher in RA-COVID-19 cases compared to COVID-19. RA-COVI-19 group did tend toward higher hospital admission rates (OR 0.81; 95% CI 0.35-0.88; p = 0.03). Conclusion: COVID-19 is accompanied by non-significant worsening of symptoms in RA patients on DMARDs, except the admission rates. More research into expanding cases is required .


INTRODUCTION
Coronavirus disease 2019 (COVID-19) has quickly become a pandemic virus that has resulted in severe morbidity and mortality around the world. Since the outbreak of COVID-19 in late 2019, global healthcare systems have faced numerous problems, ranging from many patients to a shortage of approved therapy alternatives. A lot of work has been done around the world to find effective ways to treat the virus [1].
According to the World Health Organization, there is insufficient evidence to recommend any specific COVID-19 treatment for patients who have been diagnosed with COVID-19 [2]. RA is a T-cell and B-cell-mediated autoimmune disease that primarily affects the joints but can also cause systemic symptoms [3]. The profile of RA includes increased levels of proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL6) [4], which is similar to the profile of COVID-19 [5], as disease severity of COVID- 19 was correlated with hypercytokinaemia, characterized by increased serum IL-2, IL-7, IL-10, granulocyte colonystimulating factor (G-CSF), monocyte chemoattractant protein 1, and granulocyte chemoattractant protein 1 [6].
People with rheumatic and musculoskeletal diseases have been impacted during this pandemic through their greater risk of infection due to immune dysregulation, comorbidities, and immune modulating treatments [7]. At the same time, many of these immune modulating treatments (e.g., hydroxychloroquine [HCQ], glucocorticoids [GCs], interleukin1 [IL1], IL6 inhibitors, JAK inhibitors) are being tested to prevent or treat COVID-19 [8], which have caused some confusion and concerns about the actual risks posed to individuals with rheumatic and musculoskeletal diseases [9]. Also, the available data on COVID19 infection rates and outcomes among patients receiving diseasemodifying antirheumatic drugs (DMARDs) for rheumatoid arthritis are quite reassuring [10]. To date, data on the epidemiology of COVID-19 in rheumatoid arthritis patients is still scarce. Therefore, this study was conducted to study COVID-19 severity and outcome among rheumatoid arthritis patients, including hospitalization, ICU admission, and mortality compared to others.

Study design and setting:
A prospective comparative study was undertaken on 146 patients at Zagazig University Hospitals from July to December 2020 .Protocols from the Egyptian Ministry of Health and Population were used to treat the people who took part in the study.

Participants:
They were divided into 3 groups: Group I: Included 52 patients suffering from RA,Group II included 44 patients suffering from RA with COVID-19, Group III included 50 COVID-19 patients.
The RA with COVID-19 cohort included all patients who were 18 years of age or older, had a pre-existing diagnosis of RA, and were diagnosed with COVID-19 anytime from January 20, 2020 to December 2020. The diagnosis of RA was based on the 2010 ACR/EULAR criteria for RA [11], and the diagnosis of COVID-19 was based on clinical findings and SARS-CoV-2 polymerase chain reaction (PCR) positivity. The comparison group was made up of any adult without a known history of RA who was diagnosed with COVID-19 between January 20, 2020 and December 20, 2020.

Instruments and tools for data collection:
-Demographic characteristics (age, sex, level of education, marital status, special habits, and Occupation).
-The practice of preventive measurement (Hygienic hands wash, safe space more than two meter, surfaces disinfectants, and wearing masks).
-Data on RA-related parameters: 3. The COVID 19 treatment protocol's; a uniform prescription form was produced and issued with the documented treatment protocol. The prescription called for hydroxychloroquine to be taken for five days, starting with 400 mg twice a day on day one and then 200 mg twice a day for the next four days. Patients with renal or hepatic impairment should not modify their dose. Zinc sulphate, 60 mg orally once daily for 5 days, paracetamol, and an antihistamine were also included in the prescription. The antibiotic azithromycin was not included in the prescription. Follow up within 3-7 days after starting therapy.

Data analysis:
The outcome variables included reported treatment protocol outcomes such as the percentages of patients who were hospitalized, admitted to the ICU, or died. IBM SPSS Statistics version 21 was used to analyze all the data. Considerations on morality Following a description of the study, the treating physician got informed permission from the participants. Those who refused to participate in the trial were removed from the study and were given standard supportive care instead. All information gathered will be kept private and used solely for the purpose of the study. Patients who were unstable at the time of presentation or who showed clinical progression/deterioration on days 3-7 were referred to the hospital, and the study team followed up on their progress.

RESULTS
This study included 146 randomly selected patients attending Zagazig university hospitals. The socio-demographic characteristics of the participants are shown in [table 1]. The three studied groups were matched and showed no statistically significant difference (p > 0.05) as regards age, sex, level of education, and marital status. But there was a statistically significant difference between the groups in terms of occupation and smoking hashish.
There was a statistically significant difference (p < 0.05) as regards the practice of preventive measurements (including safe spacing greater than 2 meters, applying surface disinfectants, and always wearing masks) among the studied groups except hygienic hands wash to be significantly higher among the RA group and Group II (RA and COVID19) in comparison to COVID -19 infected cases [

DISCUSSION
Both healthy people and those with chronic illnesses are susceptible to infection during the ongoing COVID-19 pandemic. 146 people were enrolled in this trial. 50 patients had COVID 19, age, sex, and comorbidity matched, and 44 of them had RA with COVID 19, were on DMARDs. They received the treatment plan prescribed by the Egyptian Ministry of Health and Population and went back to the clinics three to seven days after beginning the medication.
The practice of preventive measurements except hygienic measurements were significantly higher among RA patients either with or without COVID-19, compared to COVID-19 cases alone. In agreement with another study [15]. This may be attributed to the critical element is to guarantee honest, truthful communication with patients. Rheumatologists who are assisting patients with RMDs must make them feel supported because they are likely to be apprehensive. As recently acknowledged in the provisional recommendations of the European League Against Rheumatism (EULAR) [16].
Most infected people experience, minor symptoms including headaches, fever, tiredness, and sore throat. Because of a pathogenic host response that results in a state of intense inflammation and harm to multiple organs, some infected persons become sicker and sicker over time.

As regards the main outcomes:
The Respiratory distress (>30 breath/min) was recorded in 72% of cases of non-RA COVID and 75% cases of RA with COVID19, respectively. However, there was no statistically significant difference in the risk of most events (mortality, ICU admission, mechanical ventilation, and ischemic stroke), which is in line with other studies' findings [17,18]. This may be attributed to the effect of HCQ, is used to prevent endosome-lysosome system acidification and to reduce proinflammatory cytokines [19]. Although the therapeutic effectiveness of HCQ in COVID-19 is still debatable, some investigations demonstrated a benefit, other studies provided contradictory findings [20].
There is no evidence that people with RMDs, including those taking DMARDs, are more likely to get COVID-19 or that they will have a worse outcome if they do get it [21][22][23].
In that study, England et al. discovered that RA was linked to a higher risk of mortality using the US Veterans Affairs COVID-19 shared database. This Disparities in study populations could be the cause of this gap (England et al. study consisted primarily of older males, consistent with the demographic profile of the Veterans Affairs [24], whereas the current study consisted primarily of females, consistent with the general epidemiology of RA. The SARS-CoV-2 infection is accompanied by non-significant worsening of symptoms in RA patients on DMARDs, except the admission rates, this may be attributed to that 42(84.0%) of cases use moderate-to-high-dose corticosteroid, which was frequently used in RA patients that increases the risk of hospitalization [22].

As regards the management protocols:
The frequency of administration of HCQ was 44(100.0%) among Group II (RA+COVID19), while in only COVID- 19

Strength and limitations:
The conclusion of the causation of the outcome of COVID-19 among those patients would be implied by the cross-sectional design of this study and the potentially brief duration of evaluation. However, it might be claimed that this study is one of the few studies to focus on RA patients during the COVID-19 pandemic in Egypt. Large-scale longitudinal research in the future would be necessary. Lack of multicentricity, which would restrict the generalizability of results, was another issue.

CONCLUSION
The covid-19 is accompanied by non-significant worsening of symptoms in RA patients on DMARDs, except the admission rates. More research into expanding cases is required. The practice of preventive measurements except hygienic measurements were significantly higher among RA patients. Acknowledgment: I would like to express special thanks to all the recruited cases in this study.
Ethical considerations: A written informed consent for publication was obtained from all authors.

Conflicts of interest:
No conflict of interest.

1-Coronavirus disease 2019 (COVID-19) has
quickly become a pandemic virus that has resulted in severe morbidity and mortality around the world.
2-Rheumatoid arthritis (RA) is a chronic autoimmune and inflammatory disorder, and RA patients usually take immunosuppressive agents. Because of the impairment of the immune system and the iatrogenic effect of corticosteroids and immunosuppressive medicine, these patients may be at high risk for severe infections.
3-This study is one of the few to focus on RA patients during the COVID-19 pandemic in Egypt 4-This study found that COVID-19 infection is accompanied by significant worsening of symptoms in RA patients with higher admission rates. More research into expanding cases is required.