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COVID-19 is becoming the most serious problem of human society after World War II. The general recommendations of WHO, which include wearing mask, social distancing, washing hands and so on, are a widely accepted approach to preventing the spread of the virus. With lack of effective treatment, prophylactic strategies have attracted the attention of healthcare providers. Chemoprophylaxis is one of these strategies. Several in vitro studies showed that antimalarial agents interfere with the proliferation of various viruses, including the severe acute respiratory syndrome coronavirus, by inhibiting virus/cell fusion.1 However, the main challenge is translating the impact of in vitro models to clinics. Given the higher mortality of patients with COVID-19 with autoimmune diseases,2 we decided to investigate the efficacy of these medications by evaluating the incidence of COVID-19 in patients with rheumatoid arthritis (RA) already treated with hydroxychloroquine (HCQ) compared with HCQ-naive patients with RA.
In a multicentre cross-sectional study, patients with RA treated in the rheumatology clinics of the Tabriz University of Medical Sciences, Kashan University of Medical Sciences and Army Hospital of Tehran were recruited. For a period of 4 weeks from 19 August to 19 September 2020, data about symptoms suggestive of COVID-19 were obtained by telephone interview. Inclusion criteria were fulfilment of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA, disease onset at age ≥16 and disease onset before the COVID-19 outbreak. Exclusion criteria were change or addition of new disease-modifying antirheumatic drugs during the last 8 months, non-adherence to medication, refusal to answer the questions and non-response to three phone calls. Patients with symptoms suggestive of or a diagnosis of COVID-19 or with any change in RA disease activity were invited to visit a multidisciplinary clinic. Disease activity was assessed by a rheumatologist, and diagnosis of COVID-19 was evaluated by a pulmonologist. Remission was defined according to the ACR/EULAR definition. Diagnosis of COVID-19 was made in patients with clinical manifestations consistent with COVID-19 and meeting one of the following criteria: (1) positive PCR or (2) chest CT scan findings of COVID-19 pneumonia, with other causes of pneumonia ruled out.
The normal distribution of data was assessed using the Kolmogorov-Smirnov test. Continuous and categorical variables were presented as mean±SD and frequency (percentage), respectively. Comparisons between groups were done using the χ2 test, independent sample t-test and Mann-Whitney test, as appropriate. P<0.05 was considered statistically significant. Data analysis was performed using SPSS V.16.0 software.
After a telephone interview with 2341 patients with RA, 1858 patients were enrolled in this study. Forty-six patients had a diagnosis of COVID-19. Diagnosis was based on positive PCR in 35 (76.1%) and clinical criteria in 11 (23.9%) patients. Demographic and clinical characteristics and medications of patients with RA were compared between patients on HCQ and those not on HCQ (table 1). The dose of HCQ in all patients in the first group was 200–400 mg/day. No significant differences were observed in the demographic and clinical characteristics of the studied groups. Except for more patients treated with sulfasalazine in the HCQ-naive group, no significant differences were observed in the medications between the two groups. Since the start of the COVID-19 pandemic 8 months ago, 2.2% of patients with RA treated with HCQ and 2.8% of those HCQ-naive had developed COVID-19, which was not statistically significant (0.344) (table 1).
Our study showed that the prevalence of COVID-19 in patients with RA treated with HCQ is not lower than HCQ-naive patients with RA. Previous experiences have also shown that the effect of a drug on the virus in in vitro models does not necessarily lead to a clinical effect. Although antimalarial medications reduced the replication of viruses such as Zika, Ebola, chikungunya, dengue and influenza in cell culture media, they had no therapeutic effect in human or in animal models of these diseases.1 In accordance with the results of our study, several other studies did not report pre-exposure and postexposure prophylactic effects of HCQ. Boulware et al 3 in a randomised clinical trial (RCT) on 821 participants with moderate-risk to high-risk exposure to a confirmed COVID-19 case at home or at their workplace prescribed HCQ 3800 mg or placebo for a total course of 5 days. No significant difference was observed in the occurrence of COVID-19 in HCQ and placebo groups.3 Mitjà et al 4 in an RCT performed pre-exposure prophylaxis with HCQ in asymptomatic contacts of patients with PCR-proven COVID-19.4 The incidence of COVID-19 in the HCQ and the control group was 5.7% and 6.2%, respectively. The difference was not significant. In an observational cross-sectional study, Revollo et al 5 assessed the occurrence of COVID-19 among hospital healthcare workers (HCWs) working in COVID-19 wards. There was no significant difference in the incidence of COVID-19 in HCWs receiving HCQ as pre-exposure prophylaxis compared with HCWs who did not receive HCQ.5 In conclusion, the results of our cross-sectional study showed that HCQ may not be effective in the doses used to treat rheumatic diseases to prevent COVID-19 in patients with RA.
Patient consent for publication
The study was approved by the Institutional Review Board and Medical Ethics Committee of Tabriz University of Medical Sciences (ethics code: IR.TBZMED.REC.1399.101) and was conducted in accordance with theHelsinki Declaration for human research.
The authors thank all the patients and study site personnel for participating in this study.
Contributors Study design: MK, AJ, SS and AK. Data collection: LN, KE, MH, MS and AK. Data analysis: SS, AMM and AK. Interpretation of findings: MK, AJ, SS, AMM and AK. Preparation of the manuscript: MK, AJ, SS, AMM and AK. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.