The effect of hydroxychloroquine against SARS-CoV-2 infection in rheumatoid arthritis patients
INTRODUCTION: The effectiveness of hydroxychloroquine in SARS-CoV-2 prophylaxis and treatment is still controversial. In this study, our aim is to investigate the potential effects of hydroxychloroquine therapy on patients with diagnosed with rheumatoid arthritis and a confirmed SARS-CoV-2 infection. METHOD: We included patients who were followed up with a diagnosis of rheumatoid arthritis and whose SARS-CoV-2 infection was confirmed. The patients were divided into two groups as those who previously used hydroxychloroquine and those who did not, and were compared in terms of clinical and laboratory data. RESULTS: Our study included 17 patients with adequate data (2 males, 15 females). The mean age of the patients was 57.2 ± 11.6 years. 7 (41.2%) patients were receiving hydroxychloroquine regularly for the last 6 months. When the effect of hydroxychloroquine on clinical and laboratory parameters of patients was examined, there was no significant difference between the groups of patients using and not using hydroxychloroquine. The patients using and not using hydroxychloroquine were compared for the presence of typical SARS-CoV-2 infection findings on computed tomography images, admission to the hospital and intensive care. No significant differences were observed between these two groups. CONCLUSIONS: Many studies on the effectiveness of hydroxychloroquine use in SARS-CoV-2 infection are still ongoing. Due to its importance in rheumatology practice, it is very important to clarify the position of hydroxychloroquine in SARS-CoV-2 therapy. Our findings suggest that having previously used hydroxychloroquine does not have any negative or positive effect on the infection.
Antimalarial drugs, which recently took an important place in the global agenda because of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, actually constitute one of the quite ordinary components of daily rheumatology practice. Hydroxychloroquine (HCQ) and chloroquine, which are 4-aminoquinoline derivatives, have been used as conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) for various rheumatic diseases, especially rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), for many years. Both drugs have a planar aromatic nucleus structure and a highly similar mechanism of action . However, chloroquine has been replaced by HCQ in most countries owing to its faster gastrointestinal absorption, favorable renal elimination rate, and better safety profile . HCQ was first approved for the prevention and treatment of malaria in the United States . However, the efficacy of the molecule is not limited to the control of malaria and inflammatory processes as its broad-spectrum activity against many bacterial, fungal, and viral infections have been demonstrated [4-7]. Chloroquine is a versatile bioactive agent with in vitro antiviral activity against RNA viruses including rabies virus, poliovirus, HIV, influenza viruses, chikungunya virus, dengue virus, zika virus, lassa virus, Crimean Congo hemorrhagic fever virus, and Ebola virus, as well as against various DNA viruses such as hepatitis B virus and herpes simplex virus. These in vitro antiviral properties have occasionally been confirmed during the treatment of patients; however, chloroquine therapy has not been successful at all times in clinical trials depending on the disease, the concentration of chloroquine used, the duration of treatment and the clinical team in charge of the trial . HCQ has several immunomodulatory effects such as the inhibition of chemotaxis, phagocytosis, toll-like receptor (TLR) signaling, calcium signals in B and T cells, macrophage-mediated cytokine production, and metalloproteinases . HCQ is a weak base and increases endosomal pH in host intracellular organelles, thereby preventing the virus from fusing with host cells and from replicating. Apart from that, it prevents antigen processing and MHC-2-mediated autoantigen presentation to T cells, thereby reducing the T cell activity and suppressing the expression of CD154 and other cytokines (IL-1, IL-6, and TNF-alpha). Moreover, it disrupts the interaction of cytosolic viral DNA / RNA with TLRs and the nucleic acid sensor. Thereby, it halts the transcription of proinflammatory genes and reduces the likelihood of a cytokine storm (type-I interferons, IL-1, and TNF-alpha) . Furthermore, it can inhibit the glycolysis of angiotensin-converting enzyme-2 receptor (ACE2R), which is the receptor used by SARS-CoV-2 to enter cells [10,11].
The study included patients who were previously followed up with the diagnosis of RA and who were admitted to Bezmialem Vakıf University Hospital for SARS-CoV-2 infection. The patients were divided into two groups as those who were already on HCQ for the treatment of RA (at least for the last 6 months) and those who were not on HCQ. The patients' demographic data, other anti-rheumatic drugs used, and comorbidities were recorded. The following data including fever, peripheral oxygen saturation (SpO2) levels, typical pneumonia findings of SARS-CoV-2 on computed tomography (CT) images, and laboratory findings including sedimentation, C-reactive protein (CRP), ferritin, d-dimer, hemoglobin (HGB), platelet (PLT), and absolute lymphocyte levels, which were obtained during the follow-up of the patients for the treatment of SARS-CoV-2, were evaluated from the database retrospectively. The rates of the requirement for hospitalization and / or intensive care admissions and the mean length of hospital stay were calculated. All data obtained were compared between the two groups to analyze whether HCQ had a prophylactic effect on SARS-CoV-2 and its effects on clinic. The study included patients who were diagnosed with RA according to the 2010 ACR & EULAR RA classification criteria, who were positive for the real-time reverse transcription polymerase chain reaction (rRT-PCR) test that was performed using nasopharyngeal swab samples and sputum samples, and who had available relevant data in the hospital database. Patients with a non-confirmed RA diagnosis, patients with irregular use of HCQ in the last 6 months, patients with negative rRT-PCR test result, and patients with inadequate data were excluded from the study.
Our study included 17 patients with adequate data (2 males, 15 females). The mean age of the patients was 57.2 ± 11.6 years. In order to better analyze the extent of clinical worsening in the patients, the poorest values of the vital signs and laboratory test results observed during the treatment of SARS-CoV-2 infection were noted. Because the levels of ferritin and d-dimer were not measured in 2 and 3 patients respectively, they could not be included in the analysis. The distribution of the patients' descriptive data is presented in detail in Table 1.
In the frequency analyses, 7 (41.2%) patients were receiving HCQ regularly for the last 6 months. The most common comorbidity was diabetes, observed in 7 patients (41.2%). While 11 patients (64.7%) were followed up inpatiently, 2 patients (11.8%) required intensive care. The number of patients with pneumonia findings consistent with SARS-CoV-2 infection on thoracic CT was 11 (64.7%). Table 2 presents the medications used, comorbidities, and other clinical parameters in detail.
There are adequate preclinical justification and evidence for the efficacy of 4-aminoquinolines in the treatment of SARS-CoV-2 infection and they are important to encourage new clinical studies on this subject. Except that, these drugs are inexpensive and have considerable quantities of adequate safety evidence as they have been in clinical use for other indications, especially for the treatment of rheumatic diseases, for a long time . The report from a multicenter collaboration group in China particularly supported the use of chloroquine phosphate . The Centre of Infectious Disease Control of the Netherlands also recommended chloroquine therapy for patients with severe infections requiring hospitalization, oxygen therapy, or intensive care. The guideline of the Italian Society of Infectious and Tropical Diseases, Lombardy recommended the use of 4-aminoquinolines at variable doses depending on the disease severity. The recommended target population ranged from patients with mild respiratory symptoms and comorbidities to patients with severe respiratory distress . Also, many clinical studies on this subject still continue in China. The Turkish Ministry of Health positioned the use of HCQ as the first-line treatment for SARS-CoV-2 infections in the recently updated guideline on June 19, 2020 .
Credited to Okan Küçükakkaş