ABSTRACT
Rheumatoid arthritis is an autoimmune disorder that affects 0.5 % to 1 % of the general population. It is more frequent in women because of hormonal reasons. Although the etiopathology is not known exactly, the general symptoms caused by synovial inflammation are characterized by pain and swelling. Rheumatoid disease is considered to be an incurable disease but can stay in remission with a wide range of pharmacological spectrum from analgesics to biological agents. The outbreak caused by the new type of coronavirus infection in 2019 negatively affected the whole world. People with weakened immune systems, elderly and autoimmune diseases suffered from COVID-19 disease or resulted in their death. It has a high risk of transmission and a low mortality rate. COVID-19 disease may show itself in severe clinical pictures such as organ failure or cytokine storm. It is extremely challenging for a patient to survive such a clinical picture and requires serious treatment.
Keywords: Rheumatoid Arthritis; Synovitis; COVID-19; Outbreak
Abbreviations: RA: Rheumatoid Arthritis; ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein; Ig G: Immunoglobulin G; RA: Rheumatoid Arthritis; RF: Rheumatoid Factor; ACPA: Antibodies to Citrullinated Peptides/Proteins; CCP: Cyclic Citrullinated Peptides; ELISA: Enzyme-Linked Immunosorbent Assay; MTX: Methotrexate; N: Nucleocapsid Protein; S: Spike Glycoprotein; E: Envelope Glycoprotein; M: Membrane Protein; CTD: C-Terminal Peptidase; TMPRSS2: Type 2 Transmembrane Serine Protease; RBD: Receptor-Binding Domain; NAAT: Nucleic Acid Amplification Test; WBC: White Blood Cell; LDH: Lactate Dehydrogenase; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; CK: Creatine Kinase; CT: Computed Tomography; HRCT: High-Resolution CT
Introduction
Rheumatoid Arthritis (RA) is an autoimmune systemic multidisciplinary disease that affects 1 % of the general population [1]. The aetiology of this disease, which results in joint destruction, is characterized by chronic inflammation, progresses cumulatively, negatively affects many systems of the body, and is three times more common in women than in men [2]. Some factors such as genetic, environmental, age and gender are crucial in its progression [3]. The disease can be diagnosed by increasing inflammatory biomarkers in the inflamed synovium and distinguished from other types of arthritis [4]. Together with the earth-shaking COVID-19 outbreak that started in Wuhan, China in December 2019, some biomarkers in RA have become crucial [4,5]. The most popular markers (IL-6) that shed light on the progression and pathology of the disease are markers such as Interleukin-6, ACPA, and anti-CCP. In rheumatoid arthritis disease, inflammation shows a substantial increase [4].
Aetiology and Pathology of Rheumatoid Arthritis
Although the aetiology of RA is not known exactly, it occurs
in different clinical pictures that are considered to be involved in
infection, genetic, environmental, and endocrine dysregulation
[3]. Inflammation of the synovium is a pathological event that
destroys articular cartilage and bone. The most crucial condition that distinguishes it from other articular pathologies is joint
destruction [6]. Genetic factors explicitly play a role in the severity
and progression of rheumatoid arthritis. The prevalence of RA,
which is 1 % in the general population, is 12-15 % in monozygotic
(identical) twins, while this rate is approximately 2-5 % in dizygotic
twins or first-degree relatives [7]. Environmental factors in addition
to genetic factors (50 %) have a role in the pathogenesis of RA. One
of the most important environmental factors is infections. Many
pathogens have been argued in the pathogenesis of RA. Although
Mycobacterium tuberculosis, Proteus mirabilis, Escherichia coli,
Epstein-Barr virus, Parvovirus 19, and some retroviruses have been
blamed, no organism could not be held liable [8].
Rheumatoid Arthritis is a disease that is three times more
common in women than in men. Although the basis of the gender
difference cannot be set out in full, the higher incidence of RA in
women can be based on hormones [2]. To penetrate the joint
space, they must pass through the layer of synovial tissue, which
is very thin in healthy joints, but consists of a thick lining layer
of macrophages and fibroblastoid synovial cells in rheumatoid
joints. Deeper parts of synovial tissue accumulate lymphoid cells
histologically organized together with dendritic cells such as
lymphatic nodules. Deeper areas of the synovial tissue, in parallel
with dendritic cells such as nodules, stromal fibroblasts transform
from a long-stretched appearance to small round cells, increase
in number and are present with a proliferative response. These
pathologies refer to chronicity and severity. These pathologies are
not homogeneous within the same joint. B and T cells are not only
found much more in the stromal area, but they are also usually
found around blood vessels and are accompanied by dendritic cells
[9].
Clinical Characteristics of Rheumatoid Arthritis
Rheumatoid arthritis is a severe disease that may have many
extra-articular manifestations. Extra-articular involvement may
occur in 40 % of patients at the onset and course of the disease.
Extra-articular involvement is associated with increased mortality
in RA. The life expectancy of patients with RA without extraarticular
manifestations is like that of the general population
[10]. Pulmonary involvement is frequent in patients with
rheumatoid arthritis. Mortality rates are high as a result of
pulmonary involvement. Although asymptomatic, the prognosis of
Pleural disease is frequent in rheumatoid arthritis patients [11].
Rheumatoid nodules in the lung occur mostly in seropositive male
patients with synovitis. It rarely occurs to diagnose in the clinic. It
can be seen alone or in the form of a bunch of grapes in radiographic
imaging [10]. Interstitial lung disease is the most crucial pulmonary
involvement in rheumatoid arthritis [12]. The prevalence of the
involvement of the cardiovascular system is high in rheumatoid
arthritis. Cardiovascular disease, which usually occurs in patients
with early RA, shortens the patient’s life by 5 to 15 years and is
characterized by a mortality rate of 42 %.
Pericarditis is the most common heart condition. Many patients
with early RA may have pericarditis or develop pericarditis before
RA. Although less than 15 % of RA patients had clinical symptoms,
the ECG showed that 20 % to 50 % of patients had pericardial
involvement emerging as chest pain or shortness of breath. Heart
failure is the most important cause of death among RA patients.
Arrhythmia is another common cardiac complication in RA
patients that may occur secondary to conduction abnormalities
due to local ischemia, rheumatoid nodules, amyloidosis, or heart
failure. The main cause of cardiovascular disease contributing to
cardiac dysfunction remains unclear. Therefore, early diagnosis
and prevention of cardiac dysfunction are crucial [13]. Anaemia
is one of the most common extra-articular symptoms of RA. The
cause of Anaemia in RA is multifactorial. These are drug-induced
malnutrition, gastrointestinal bleeding, bone marrow suppression,
and ineffective erythropoiesis. Thrombocytosis is a common
finding in active RA and is associated with the number of actively
inflamed joints. Lymphadenopathy is sometimes observed in active
RA, usually seen as benign follicular hyperplasia on biopsy [10].
Laboratory Findings in Rheumatoid Arthritis
The first laboratory tests should include complete blood count,
biochemistry panel, erythrocyte sedimentation rate (ESR) and/or
C-reactive protein (CRP), complete urinalysis, rheumatoid factor
titer, and / or anti-CCP antibodies in patients examined with a
preliminary diagnosis of RA [4]. Anaemia, in which hematocrit
levels change, can be found in a minority of patients with RA. In
most cases, decreased erythrocyte (red cell) mass is the outcome of
Anaemia of chronic disease. The cause of Anaemia is usually not an
iron deficiency, but an inadequate response to erythropoietin due to
inflammation [14]. Although ESR and CRP levels are significant for
differentiating non-inflammatory diseases such as osteoarthritis or
fibromyalgia from RA, they do not show specificity for diagnosing
RA. It might be used to evaluate RA disease activity [15]. CRP levels
fluctuate faster than ESR during illness. Anaemia can change the
ESR value. It is very useful to check CRP in addition to ESR. CRP
synthesized by the liver has pro-inflammatory effects such as
activating the classical complement pathway and reducing the IL-6
receptor concentration.
CRP has a very short half-life, and its concentration rises within
a few hours with inflammation and peaks in 2 to 3 days. After the
inflammation subsides, its concentration quickly returns to normal.
In healthy people, the CRP level is below 0.2 mg / dL, but this level
may reach up to 1 mg / dL depending on microtraumas. It can also
be used to determine prognosis and monitor disease severity in
RA [16]. α1-acid glycoprotein analysis and secretion increase with the stimulation of cytokines such as IL-1 and TNF-α. CRP and α1-
acid glycoprotein were found to be most useful in assessing RA
disease activity. High levels of CRP are associated with mortality
and the need for intubation. CRP can increase due to many reasons
[16,17]. A factor in the serum of patients with rheumatoid arthritis
(RA) causing the agglutination of red blood cells sensitized
with immunoglobulin G (Ig G) antibodies, was first described in
1940. Later, this factor was named the rheumatoid factor (RF).
Rheumatoid factors (RFs) are antibodies directed to the Fc region
(crystallizable) of human IgG molecules. These are the hallmark
autoantibodies of rheumatoid arthritis (RA), an extravascular
immune complex disease [18].
The most commonly used test serum in the diagnostic criteria
of rheumatoid arthritis is the measure of rheumatoid factor (RF). Its
sensitivity is 60 % to 90 %, and its specificity is as high as 85 % [19].
The presence or absence of antibodies to citrullinated peptides/
proteins (ACPA) is an important parameter that helps a clinician
set a diagnosis of early rheumatoid arthritis and hence, initiate
treatment. Anti-cyclic citrullinated peptides (anti-CCP) are a type of
IgG autoantibodies recognizing citrullinated peptides and offering
improved specificity in the early diagnosis of RA compared to RF.
Traditionally Anti-CCP testing has been performed using ELISA
assays [20]. Administration of citrulline-containing peptide (CCP)
in the enzyme-linked immunosorbent assay (ELISA) revealed the
presence of anti-CCP autoantibodies in 76 % of rheumatoid arthritis
sera with 95 % to 100 % specificity. When this high specificity is
combined with the presence of the disease, even before the early
onset of the disease, it suggests a role for these autoantibodies in
the pathogenesis of rheumatoid arthritis [21].
Treatment of Rheumatoid Arthritis
Non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying drugs, and biological agents are used to treat rheumatoid arthritis. Methotrexate (MTX) is the first drug of choice in patients with aggressive RA, and it is an immunosuppressive drug that can make DNA synthesis irregular by inhibiting folic acid (vitamin B9) metabolism [22]. Based on in vivo and ex vivo tests, it increases adenosine and anti-inflammatory cytokine levels, while decreasing proinflammatory cytokines such as IL-6 and IL-1β. The exacerbation reason of the disease after the discontinuation of drug use is also related to these features [23]. Leflunomide, which was approved in 1998 and started to be used in active RA disease, is a prodrug. It turns into its active metabolite in the liver, stops the growth of lymphocytes, and inhibits T cell proliferation as pyrimidine synthesis inhibition [24].
Aetiology and Pathology of SARS-CoV-2
SARS-CoV-2 is surrounded by an envelope containing the viral
nucleocapsid. It is positive polarity, single-stranded RNA virus
with virion diameters ranging from 60 to 140 nm and distinctive
spikes of 9 to 12 nm. This virus is divided into four major structural
proteins, namely, nucleocapsid protein (N), spike glycoprotein (S),
envelope glycoprotein (E), and membrane protein (M) [25]. Spike
glycoprotein (S) mediates attachment of the virus to the host cell
surface receptors and subsequent fusion between the viral and host
cell membranes to facilitate viral entry into the host cell [26]. The
envelope glycoprotein (E) is the smallest of the major structural
proteins (between 8 kDa and 12 kDa) and has the lowest copy
number in the lipid envelope of mature virus particles [27]. The
nucleocapsid protein (N) is the most abundant protein in virusinfected
cells. The N protein, which ranges from 43 kDa to 50 kDa,
is the protein component of the helical nucleocapsid and is thought
to bind the genomic RNA in a beads‐on‐a‐string fashion. Membrane
protein (M) is the most abundant component of coronaviruses and
defines the shape of the viral envelope. The pre-glycosylated M
polypeptide ranges in size from 25 kDa to 30 kDa (221-262 amino
acids) [28].
SARS-CoV-2 infects the lower respiratory tract, causing
pneumonia. Causes of death are due to resulting in respiratory
dysfunction and hyper inflammation [29]. ACE-2 is the S proteinmediated
cell entry receptor for coronavirus and provides a
direct binding site for S proteins [30]. The ACE-2 protein contains
the N-terminal peptidase domain and the C-terminal peptidase
(CTD) domain. The S1 protein detected in SARS-CoV-2 provides
the attachment of cellular membranes. The S2 protein performs
membrane fusion [22]. The entry of the virus into the cell occurs
via endocytosis as a result of membrane fusion [31]. Type 2
transmembrane serine protease (TMPRSS2) cleaves the ACE-2
receptor, activates the S protein, and mediates its entry into the
cell [30]. To understand the infection potential of SARS-CoV-2 in
humans, it is necessary to analyze the receptor-binding domain
(RBD) of the S protein in contact with ACE-2. In a study, it was
shown that the affinity of SARS-CoV-2-CTD is higher than its affinity
for SARS-CoV-2-RBD [22].
Clinical Course of COVID-19
It was found that the COVID-19 outbreak, which started in
December 2019, can be transmitted up to distances of 7 to 8 meters
through small droplets emitted directly during sneezing [32]. The
symptoms of COVID-19 infection appear after an incubation period
of approximately 5.2 days [33]. The most common symptoms at
the onset of infection are fever, fatigue, dry cough, myalgia, and
shortness of breath; fewer common symptoms are headache,
dizziness, abdominal pain, diarrhoea, nausea, vomiting, anorexia,
and conjunctivitis [22,34]. If we look at the course of the COVID-19
disease on the respiratory system, lung functions deteriorate, and
dyspnoea emerges after 5-7 days. If there is a comorbid disease in
the patient’s history, this period might be shorter. This period may be
longer in young patients with good medical history. The subsequent
development of hypoxemia emerges with the disruption of gas exchange characterized by pulmonary inflammation. When oxygen
saturation (SpO2) is <93 at the time of the onset of hypoxemia
symptoms, the first treatment should be oxygen support [22,35].
Cytokine release syndrome is a life-threatening systemic
inflammatory syndrome involving elevated levels of circulating
cytokines and immune-cell hyperactivation that can be triggered
by various therapies, pathogens, cancers, autoimmune conditions,
and monogenic disorders. From a historical perspective, cytokine
storm was previously referred to as an influenza-like syndrome
that occurred after systemic infections such as sepsis and after
immunotherapies such as sepsis. The plague (Yersinia pestis
infection), known as Black Death, has led to major pandemics
and triggers alveolar macrophages to produce excessive amounts
of cytokines, resulting in cytokine storm [36]. Cytokine storm is
an umbrella term encompassing several disorders of immune
dysregulation characterized by constitutional symptoms, systemic
inflammation, and multiorgan dysfunction that can lead to
multiorgan failure if inadequately treated. Patients who develop
cytokine storm may have high fever, fatigue, anorexia, headache,
rash, diarrhoea, myalgia and neuropsychiatric findings. These
symptoms may be due directly to cytokine induced tissue damage
or acute-phase physiological changes or may result from immune
cell-mediated responses [37].
COVID-19 Laboratory, Radiological Findings and Tests
According to the COVID-19 diagnosis and treatment guidelines,
nucleic acid testing is recommended first in clinically suspected
cases to confirm the disease. There are two main methods of SARSCoV-
2 nucleic acid detection: gene sequencing and nucleic acid
amplification test (NAAT) [38]. Haematological biomarkers: White
blood cell (WBC) decreases in 80 % of patients and 72.3 % of patients
also develop lymphocytopenia. Compared with moderate cases,
severe COVID-19 patients have a significantly lower lymphocyte
count [39]. The biomarker lactate dehydrogenase (LDH) attracted
attention, especially in severe cases. In addition, it is followed
by aspartate aminotransferase (AST), alanine aminotransferase
(ALT), creatine kinase (CK), and creatinine [40]. LDH, troponin I,
and creatinine increase, and hypoalbuminemia may develop in
progressive cases causing mortality [41].
Radiological evaluation of suspected COVID-19 patients is
required for early detection of thoracic involvement, particularly
in emergency units, while waiting for definitive diagnosis of
SARS-CoV-2 by real-time reverse transcription-polymerase chain
reaction (RT-PCR) which has a gold standard sensitivity of 60 % to
70 % for diagnosis [42-44]. Chest and more specifically pulmonary
involvement is the most common site of organ involvement
in COVID-19. For Chinese radiologists, the use of computed
tomography (CT), especially high-resolution CT (HRCT), along
with the patient’s symptoms, are the most common approaches
to diagnose and stage the severity of pulmonary involvement
of COVID-19. The rate of missed COVID-19 diagnosis by CT is
3.9 % [45]. It is crucial to distinguish COVID-19 from bacterial
pneumonia, Mycoplasma pneumonia, and Chlamydia pneumonia in
imaging diagnosis. Bacterial pneumonia mainly occupies the lung
parenchyma, and here bronchial, or lobar pneumonia is the most
common form. The findings of CT imaging are characterized by
irregular consolidation of the pulmonary segment or subsegment,
whereas ground-glass opacity is uncommon for bacterial infection
[45].
Treatment of COVID-19
Glucocorticoids, antimalarial drugs, antiviral drugs, and biological agents are used in the treatment of COVID-19. Dexamethasone is a potent, long-acting, broad-spectrum glucocorticoid that acts as a synthetic version of the naturally occurring hormone cortisol [46,47]. Hydroxychloroquine and chloroquine, also known as antimalarial and anti-autoimmune agents, can also block virus infection by increasing the endosomal pH required for membrane fusion between virus and host cell [48]. Favipiravir, an RNA-dependent RNA polymerase inhibitor that was developed in 2002, was used in Japan in 2014 and has a strong and selective inhibitory effect against influenza viruses, which was investigated as a potential agent against RNA viruses in 2018, is also used in treatment [49,50]. Lopinavir-ritonavir is used as a combination of antiretroviral therapy to manage HIV-positive patients. Lopinavir inhibits HIV protease, an enzyme required for new viral assembly. Lopinavir is co-administered with ritonavir in order to prolong levels and increase exposure in the human body in consequence of its poor oral bioavailability and extensive biotransformation [48]. Remdesivir, developed against the Ebola virus in 2016, is a broad-spectrum antiviral agent that can stop viral genome replication by acting as an RNA-dependent RNA polymerase inhibitor in COVID-19 disease [48].
Discussion and Conclusion
It was an object of interest whether or not the COVID-19 outbreak, which affected the whole world, would exacerbate rheumatoid arthritis, an autoimmune disease [51]. The relationship between RA and infectious diseases is very complex. Compared with the general population, RA patients have an increased risk of infection [52]. At the beginning of the COVID-19 outbreak, concerns have arisen about the possible consequences of SARS-CoV-2 infection in patients with RA. Given the potential adverse effects of immunosuppressive drugs on viral clearance, there have been concerns that infection will be associated with increased severity of COVID-19 and excessive mortality in patients with rheumatic disease. However, the difficulty in determining the incidence of COVID-19 in RA patients is to review large numbers of patients and diagnose COVID-19 in terms of limitations of clinical testing [53]. We can conclude that individuals with a genetic susceptibility for rheumatoid arthritis are more likely to occur after COVID-19 infection and that the clinical course of COVID-19 may be more severe in existing RA patients than in healthy patients.
Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible for the content.
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