Clinical comparison ofefficacy between combinative therapies in management of SARS-CoV-2- induced arthritis: nsaids and steroids verses nsaids and chondroprotective agents

Shulyk Mykola Borisovych

associate professor, surgeon Kropyvnytskyi, Ukraine

Sobchenko Dmytro Anatoliyovych

assistant of the department of general and children's surgery Donetsk National Medical University, Kropyvnytskyi, Ukraine

Zavhorodnia Alina Viktorivna

Doctor

Donetsk National Medical University, Kropyvnytskyi, Ukraine

Onyia Chibundo Nwude

recipient of higher education at the international medical faculty Donetsk National Medical University, Kropyvnytskyi, Ukraine

Summary

Keywords: SARS-CoV-2, corticosteroid, nonsteroidal anti-inflammatory drugs, arthritis, pathogenesis, the latest research, complication, rheumatology, clinical research.

Introduction

arthritis sars-cov-2 corticosteroid chondroprotector

First discovered in Wuhan China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in a pandemic that had a significant impact on the world for approximately 2 years starting from December of 2019 [1]. SARS-CoV-2 is the virus responsible for coronavirus disease (covid-19). There have been over 7 million confirmed cases since, accompanied by over 6.8 million deaths as a result [2]. Coronaviruses have previously been found in humans, avian species, and other animals [3]. The Human variants of coronaviruses have been implicated in illnesses including the common cold as well as outbreaks such as SARS in 2003 and Middle East respiratory syndrome which occurred in 2012 [4].

Other members of the coronavirus family that have been known to infect humans are OC43, MERS-Cov, 229E, HKU1, SARS-CoV, and NL63 [4].SARS-CoV-2 appears to be of zoonotic origin possibly bats as has been insinuated in literature, which have been known to carry similar pathogens. SARS-CoV-2 is part of the coronavirus family, a family of positive-sense single-stranded RNA viruses. Coronaviruses are categorized under 4 genera including, Alphacoronavirus (alpha- Cov), Betacoronavirus (beta-Cov), Gammacorinavirus (gamma-CoV), and Deltacoronavirus (delta-Cov). Alpha-CoV and Beta-Cov have been associated with disease in mammals while gamma-CoV and delta-Cov generally affect birds. SARS- CoV-2 belongs to Sarbecovirus which is a subgroup of Betacoronavirus [5].

SARS-CoV-2 is comprised of a genome of approximately 30 kb, which is responsible for encoding 4 structural proteins including, envelope protein, nucleocapsid protein, spike protein, and membrane protein. Coronaviruses are particularly virulent because of the process of recombination [6]. Recombination of the spike protein seems to be important to the establishment of the COVID-19 pandemic. The spike protein generally interacts with the cells of the host and in the case of SARS- CoV-2, is responsible for binding the angiotensin-converting enzyme 2 (ACE2) located on the surface of human cells which leads to the entry of the SARS- CoV-2 into the body [6]. Endosomal cathepsin L and TMPRSS2 are proteins that cleave the spike protein which in turn facilitates the endocytosis and membrane fusion involved in SARS-CoV-2 cellular entry [7]. The RNA genome of SARS-CoV-2 is then released into the cytoplasm of the host cell, followed by translation. The polyproteins translated including pp1a and pp1ab are split to form Nsps, which in turn form the replicase-transcriptase complex [8]. The replicase-transcriptase complexes are located in double-membrane vesicles. The double membrane vesicles function in replicating RNA which is then translated to form structural proteins. The host cell's endoplasmic reticulum and Golgi complex are involved in the assembly of the resulting virus. Furin protease activates spike protein before the mature viruses are expelled out of the cell through exocytosis [8].

SARS-CoV-2 is primarily spread by respiratory droplets, aerosol, and by direct or indirect contact with respiratory droplets. Direct forms of transmission of covid- 19 include aerosol during dental or surgical procedures, contact with other bodily fluids (including saliva and tears), and mother-to-child (by talking, sneezing, and coughing) [9]. The indirect forms of transmission include fomites or surfaces within the vicinity of infected individual s and medical instruments used on an infected patient such as a stethoscope [9]. There is a higher rate of transmission in indoor venues (particularly in the case of poor ventilation) as opposed to outdoor ones. SARS-CoV-2 has been detected in air samples that were obtained from 2 -4.8 m away from an infected patient [10]. It has been demonstrated that SARS-CoV-2 proves more stable on materials such as steel and plastic than it is on cardboard and copper. SARS-CoV-2 was able to be isolated on these materials up to 72 hrs after application but the viral titers were significantly more diminished on cardboard and copper as opposed to stainless steel and plastic [11]. The incubation period for SARS-CoV-2 is 5-6 days with the Omicron and Delta variants having a shorter incubation period than alpha and beta variants. SARS-CoV-2 can be transmitted both by symptomatic and asymptomatic individuals. Transmission can occur 2-3 days before symptomatic presentation and last up to 10 days after symptom onset [12].

Clinical presentation of patients with SARS-CoV-2 is variable, depending on the strain causing the infection. Commonly encountered symptoms of covid-19 include cough, fever, dyspnoea, myalgia, headache, sore throat, fatigue, anosmia, congestion, diarrhea, nausea, and vomiting. There are also a variety of long- term complications that have been observed in patients infected with SARS-CoV-2. The long-term pulmonary complications include dyspnoea (which can be seen in 22.953% of patients after initial treatment), oxygen dependence (6.6%), fibrotic changes of lung tissues, dependence on a respiratory ventilator and changes in pulmonary functions tests (25%) [13]. Pulmonary fibrosis is a result of the ACE2 receptors undergoing endocytosis as a consequence of the spike protein of SARS- CoV-2 being cleaved during viral entry. ACE2 receptors usually cleave angiotensin II which is known to have proinflammatory and profibrotic purposes. As a consequence of increased angiotensin II, IL-6 and TNFa are activated and there is an elevation in the recruitment of macrophages and neutrophils. Angiotensin II also increases the activation of the collagen I gene. A combination of these factors contributes to fibrotic changes in lung tissue [14]. Cardiovascular complications as a result of Covid- 19 include myocarditis (particularly in individuals with high viral loads) with troponin I elevation. Other cardiovascular complications comprise of acute myocardial infarction, dysrhythmias, acute heart failure, cardiomyopathy, and venous thromboembolic events [15]. Studies have shown an incidence of liver injury (14.853%) in patients with Covid-19 with elevated bilirubin and aberrant alanine transaminase (ALT) and aspartate transaminase (AST) levels [16]. Neurologic manifestations/complications of Covid-19 include Anosmia, dysgeusia, encephalopathy, cerebrovascular events, Guillain-Barr e syndrome, focal and multifocal neuropathies, seizures, meningoencephalitis, acute transverse myelitis, multisystem inflammatory syndrome in children, generalized myoclonus, and cognitive impairment [17].

There have been previous studies and reports of reactive/inflammatory arthritis in patients with Covid-19 [18]. Reactive arthritis can be described as swelling or pain of joints (arthralgia) due to the influence of an infection affecting a different part of the body. These are generally seen in infections that affect the intestines and urinary tract. The joints generally impacted include the knees, ankles, spine, and joints of the feet. The causative bacteria involved in reactive arthritis usually include campylobacter, chlamydia trachomatis, Escherichia coli, shigella, clostridium difficile, salmonella, and yersinia. Additional risk factors that contribute to the susceptibility of patients to reactive arthritis include age (20-50 years), sex, and heredity (HLA-B27).

The mechanism by which SARS-CoV-2 leads to arthritis is uncertain. There is a hypothesis that SARS-CoV-2 leads to viral arthritis rather than reactive arthritis.

Viruses known to cause viral arteritis include parvovirus B19, HIV, alphaviruses (belonging to the Togaviridae family), and hepatitis B and C [19]. A study found up to 37% prevalence of arthritis in recovering or already convalesced Covid-19 patients [20]. The treatment used for Covid-19 associated arthritis/ arthralgia includes nonsteroidal anti-inflammatory drugs (NSAIDs), steroid cream(such as hydrocortisone), steroid injection (such as triamcinolone), oral steroids such as hydrocortisone, and disease-modifying antirheumatic drugs [21].

Objective. This study focused on the difference in efficacy between patients treated with a combination of nonsteroidal anti-inflammatory therapy (ketorolac trometamol and diclofenac) and steroids (hydrocortisone, dexamethasone) and patients treated with a combination of nonsteroidal anti-inflammatory therapy (ketorolac trometamol and diclofenac) and chondroprotective drugs (glucosamine sulfate, chondroitin sulfate, sodium sulfate).

A total of 37 patients who previously had confirmed cases of SARS-CoV-2 later presenting with arthritis, were observed during a study that was conducted in a three-month period between 2022 and 2023. The participants were of varying ages. 65% of the participants (24 patients) were between the ages of 20 and 52, and 35% of the participants (13 patients) were between the ages of 5 3 and 74 (Table 1). 46% of the participants (17 patients) had comorbid conditions. 5 patients had cardiology pathologies, 10 patients had respiratory pathologies and 2 patients had pathologies of the Gastrointestinal system (Table 2). 19 patients were treated with the combination of nonsteroidal anti-inflammatory therapy (ketorolac trometamol and diclofenac) and steroids (hydrocortisone, dexamethasone). 18 patients were treated with a combination of nonsteroidal anti-inflammatory therapy (ketorolac trometamol and diclofenac) and chondroprotective drugs (glucosamine sulfate, chondroitin sulfate, sodium sulfate). The difference in effect between the two treatment regimes was recorded based on the patients' subjective determination of improvement of their symptoms. During the period of the study, the use of medications that could influence the results of the study were excluded. There was no control over the individual diets of the patients.

Table 1Illustrates the age range of participants in the study