Lower Rate of COVID-19 in Lupus Patients Receiving Immunosuppressive Drug Regimens

Introduction Recently, due to the COVID-19 pandemic much concern has been raised about chronic diseases, which could possibly make patients more susceptible, and vulnerable to COVID-19. One of them, is Systemic Lupus Erythematosus(SLE). Objective This study has tried to nd the prevalence of COVID-19 in SLE patients in Golestan province of Iran, and to characterize the clinical course of COVID-19 in these patients. This study has also sought to nd possible correlation between the incidence of COVID-19, its clinical manifestations and the medication taken by SLE patients. Methods We investigated patients who had been enrolled in our rheumatologic diseases registry system. Patients responded to a questionnaire which contained questions about their primary disease, comorbidities, medications, development of new symptoms, and medical services which they received, pertinent to COVID-19, during the period of COVID-19 outbreak. The data were analyzed using SPSS 16 software. Results This investigation found 25 (7%) COVID-19 positive patients out of the 355 responders. 8 (40%) of them were hospitalized, out of which 2 (8%) required intensive care and later expired. COVID-19 incidence was signicantly lower in the immunosuppressed group (2.2% vs 10% P-value 0.005). We didn’t nd a signicant correlation between hydroxychloroquine consumption, and the incidence of COVID-19 in SLE patients. Fever, fatigue, dyspnea, and dry cough were the most common clinical symptoms. Conclusion Our research has shown that COVID-19 prevalence was lower in immunosuppressed patients. However, broader studies should be conducted to clarify the role of immunosuppression in the development of COVID-19. More research is required.


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As COVID-19 became a pandemic, much concern was raised about patients with rheumatic diseases. One of which, is Systemic Lupus Erythematosus (SLE). Patients with SLE are more susceptible to developing infections, and may demonstrate more severe forms, compared to the normal population. Some of these patients are also on immunosuppressant drugs, which predispose them to developing infections. [1] One of the most common causes of death in these patients is infection. [2] In addition, there is research that claims hydroxychloroquine(HCQ) which is a common medication for SLE, shows e cacy in the treatment of COVID-19. [3] The immune system plays a major role in the development of COVID-19. The innate immune reaction to pulmonary tissue damage caused by the virus can lead to acute respiratory distress syndrome (ARDS), which could be the cause of death in these patients [4] So it may be that immune system weakness in immunosuppressed patients brings with it some advantage, with regards to COVID-19. This study has tried to investigate the clinical course of COVID-19 in patients with SLE, and to evaluate the effect of HCQ on the development of COVID-19 in these patients. Besides these objectives, we have tried to investigate possible correlation between immunosuppression status and COVID-19 among our patients, as well.

Methods
This study investigated the population of patients with a diagnosis of SLE, based on either ACR-1997, or EULAR-2019 criteria, whom had been registered in the database of Golestan Rheumatology Research Center, in Golestan province of Iran. A designed questionnaire consisting of patients' demographic variables, their disease status, medications and new clinical symptoms, was used to classify patients according to WHO COVID-19 case de nitions. [5] Patients were asked during phone calls about their experience of COVID-19 symptoms, laboratory tests and clinical imagings related to COVID-19, and any hospitalizations related to this infection.
We collected their information, and divided them into 3 groups, as de ned by WHO. Due to social distancing protocols, consideration of SLE patients' health status, and to prevent the spread of COVID-19, we were unable to visit the patients in person, and therefore, there was no opportunity to perform laboratory tests to measure SLE activity in these patients. So we considered disease status as active if they met one of the criteria below: 1. Presence of clinical symptoms, related to SLE, within 2 weeks, con rmed by the patient's rheumatologist.
2. Recent admission to hospital due to major organ involvement related to SLE.
3. Patients who take corticosteroids more than 15mg per day. 4. Patients who are on cyclophosphamide therapy. 5. Patients who take mycophenolate mofetil more than 1500mg per day.
We considered those on Azathioprine, mycophenolate mofetil or methotrexate (more than 12.5 mg/w) , as immunosuppressed patients.
All the participants have given their informed consent to participate in this study.
This study was approved by the Ethics committee of Golestan University of Medical Science.

Statistical analysis
Data were analyzed using SPSS 16 software. Chi square test was performed to assess the correlation between COVID-19, and other variables. P-value of less than 0.05 was considered signi cant.

Results
We contacted 500 SLE patients registered in Golestan Rheumatology Research Center. The mean age of all 500 patients was 40.8 (±11.9) years, 458 (91.6%) of whom were women. We successfully interacted with 355 patients (71%), and collected the relevant information. The mean age of the responders was 40.1 (±11.5) years, 326(91.8%) of whom were female. Table-1 shows demographics, disease status, comorbidities, medications, and organ involvements in our patients.
He also had pulmonary organ involvement related to lupus. The other expired case was a 63-year-old woman with a 3-year history of lupus. She was on prednisolone (10mg/d) and methotrexate (5mg/d). All 23 other patients recovered. Table-2 shows the characteristics of the patients within the COVID-19 positive, and the COVID-19 negative groups. The mean age of the COVID-19 positive group was higher than the COVID-19 negative group, but it wasn't statistically signi cant. COVID-19 was signi cantly more prevalent among patients with respiratory comorbidities than in patients who didn't have these comorbidities (29.4% VS 5.9% P-value<0.001). We also didn't nd any correlation between major organ involvement, and COVID-19 infection. There weren't any signi cant differences between disease activity and developing COVID-19. We also didn't nd any correlation between HCQ and COVID-19 incidence in this study. To control for the in uence of the dosage rate, we divided the patients' HCQ dosages into two groups of high dosage (400mg≤), and low dosage (<400mg). Although COVID-19 was less prevalent among patients on high doses of HCQ, the difference wasn't statistically signi cant ( 4.8% VS 6.7% Pvalue 0.55). The incidence of COVID-19 was signi cantly higher in non-immunosuppressed patients (10% VS 2.2% P-value 0.005).

Discussion
This study was a survey among SLE patients in Iran, evaluating COVID-19 incidence. The incidence of COVID-19 was 7% in our study, similar to the Cassion et al. study, and less than the Favalli et al. study (12.9%), both from Italy. [6][7] We didn't nd a comparable study for the comparison of the rate of hospitalization. Mathian et al. reported an 82 % (14) hospitalization rate among 17 patients, which was higher than our study, (32%), [8]which could be explained by the different admission protocols. The rate of ICU admission was similar to the Cassione et al. study (8% VS 8.3%). We also reported 2 (8%) deaths in our COVID-19 positive group. This number was 2 (11%) in the Mathian et al study. In this study, similar to others, we couldn't nd any evidence for the supposed protective effect of HCQ.
In our study, immunosuppressed patients were less susceptible to COVID-19, or more were asymptomatic than non-immunosuppressed patients. This result is compatible with the two previous major outbreaks of Corona virus, in which immunosuppression status was not considered to be a risk factor for more severe forms of SARS or MERS.
[9] It is noteworthy that due to their immunosuppressed states, most patients self-isolated, maintained social distancing, and personally followed strict rules regarding COVID-19. This point could act as a confounding factor for our results. More biochemical studies, such as measuring cytokine levels in these patients, and comparing it with other patient groups could help us explain the cause of these ndings. The Innate immune response to pulmonary damage caused by SARS-COV2, can lead to acute respiratory distress syndrome, and could be the cause of respiratory failure and death in these patients. Cytokine storm seems to play a major role in severe COVID-19 patients and hence, blocking IL-6, IL-1, and TNF might be bene cial in severe cases. [4] Therefore, the immunosuppressed state might be bene cial, and a point of advantage in SLE patients. This study illustrates the necessity for more research to investigate the role of immunosuppression in the development and progression of COVID-19.

Conclusion
In conclusion, similar to the Favalli study, we recommend rheumatologists to continue patients' ongoing treatment, because immunosuppression could be a protective factor for this outbreak by itself, in addition to the prevention of the are-ups of the primary disease.

Declarations
Funding info No speci c funding was received from any bodies in the public, commercial or not-for-pro t sectors to carry out the work described in this article.
Ethics approval This study was approved by the Ethics committee of Golestan University of Medical Sciences ID IR.GOUMS.REC.1399.034 to the effect that all human and animal studies have been approved as appropriate and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Consent to participate The participants in this study have given infomed oral consent to take part in this study. They have had the opportunity to ask, and they have received answers to, any questions they had regarding the study and the use and disclosure of information about themselves for the study. erythematosus under long-term treatment with hydroxychloroquine. Annals of the Rheumatic Diseases. 2020;79(6):837-9. 9. D'Antiga L. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic.
Liver Transpl. 2020.  a "+" stands for a positive condition and "-" stands for a negative condition.

Tables
b HCQ stands for hydroxychloroquine. Figure 1 Frequency distribution of clinical symptoms in COVID-19 positive group.