Anti-Rheumatic Drugs May Ameliorate the Clinical Course and Outcome of COVID-19 In Rheumatoid Arthritis Patients

Abstract

Current data demonstrated that in patients with coronavirus disease-19 (COVID-19), there is a dysregulation of the immune system during the severe form of the disease. This dysregulation is expressed with an uncontrolled release of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-17, tumour necrosis factor alpha (TNFa) and chemokines, associated with increased serum ferritin levels and other acute phase reactants. On the other side, these cytokines play a pivotal role in autoimmune rheumatic diseases (ARD), mostly in rheumatoid arthritis (RA) and the spondyloarthropathies. Patients affected with ARD represent a particular vulnerable group, considering that they may be in an immunocompromised status due to their ailment and its treatment on one side, but on the other side, they may be protected from their immunosuppressive therapy. To this end, we present five patients with RA treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and biologic (b) DMARDs who were affected from COVID-19 and we will try to give answers to the above hypothesis.

Full text

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E-ISSN: 2529-198X
MEDITERRANEAN JOURNAL OF RHEUMATOLOGY
Anti-Rheumatic Drugs May Ameliorate the Clinical Course
and Outcome of COVID-19 In Rheumatoid Arthritis Patients
Eleftherios Pelechas, Vassiliki Drossou,
Paraskevi V. Voulgari, Alexandros A. Drosos
Mediterr J Rheumatol 2022;33(1):68-74
March 2022 | Volume 33 | Issue 1

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This work is licensed
under a Creative Commons
Attribution 4.0
International License.
The pandemic of coronavirus disease 19 (COVID-19)
caused by the severe acute respiratory syndrome corona-
virus-2 (SARS-CoV-2) is a matter of concern worldwide.
Environmental factors
such as smoking,
obesity, cardio-respira-
tory diseases, diabetes
mellitus and age may
increase the severity of
COVID-19.1,2 Current
data demonstrated an
acute dysregulation of
the immune system
during the severe form
of the disease. The
above is demonstrated
by the clinical picture and laboratory ndings, suggesting
a severe inammatory response of the innate immunity, af-
fecting mainly the respiratory system with the recruitment
in the lung parenchyma of macrophages, monocytes,
and lymphocytes, followed by the thrombotic diathesis
and multiorgan failure. Beside the clinical manifestations,
the immune response is expressed with the activation
of macrophages and lymphocytes generating a plethora
of cytokines like interleukin (IL)-1, IL-6, IL-17, tumour
necrosis factor a (TNFa), and various chemokines. As a
consequence, high levels of acute phase reactants are
produced, such as C-reactive protein (CRP), hyperfer-
ritinaemia and hyper-brinogenaemia. Afterwards, a
dysregulation of the adaptive immunity with reduction
of lymphocytes mostly CD4+ and CD8+ T-cells takes
place.3,4
Keywords: COVID-19, rheumatoid arthritis, hydroxychloroquine, tocilizumab, csDMARDs, bDMARDs
©Pelechas E, Drossou V, Voulgari PVV, Drosos AA.
ABSTRACT
Current data demonstrated that in patients with coronavirus disease-19 (COVID-19), there is a
dysregulation of the immune system during the severe form of the disease. This dysregulation is
expressed with an uncontrolled release of pro-inammatory cytokines such as interleukin-1 (IL-
1), IL-6, IL-17, tumour necrosis factor alpha (TNFa) and chemokines, associated with increased
serum ferritin levels and other acute phase reactants. On the other side, these cytokines play a
pivotal role in autoimmune rheumatic diseases (ARD), mostly in rheumatoid arthritis (RA) and the
spondyloarthropathies. Patients aected with ARD represent a particular vulnerable group, considering
that they may be in an immunocompromised status due to their ailment and its treatment on one
side, but on the other side, they may be protected from their immunosuppressive therapy. To this
end, we present ve patients with RA treated with conventional synthetic (cs) disease-modifying anti-
rheumatic drugs (DMARDs) and biologic (b) DMARDs who were aected from COVID-19 and we will
try to give answers to the above hypothesis.
Mediterr J Rheumatol 2022;33(1):68-74
https://doi.org/10.31138/mjr.33.1.68
Article Submitted: 7 Mar 2021; Revised Form: 11 Oct 2021; Article Accepted: 20 Oct 2021; Available Online: 31 Mar 2022
Cite this article as: Pelechas E, Drossou V, Voulgari PVV, Drosos AA. Anti-Rheumatic Drugs May Ameliorate the Clinical Course and Outcome
of COVID-19 In Rheumatoid Arthritis Patients. Mediterr J Rheumatol 2022;33(1):68-74.
Corresponding Author:
Alexandros A. Drosos, MD, FACR
Professor of Medicine/Rheumatology
Rheumatology Clinic, Department of
Internal Medicine
Medical School, University of Ioannina
Ioannina 45110, Greece
Tel.: +30 2651 007 503
Fax: +30 2651 007 054
E-mail: adrosos@uoi.gr
Web: www.rheumatology.gr
Anti-Rheumatic Drugs May Ameliorate the Clinical Course and Outcome of
COVID-19 In Rheumatoid Arthritis Patients
Eleftherios Pelechas , Vassiliki Drossou , Paraskevi V. Voulgari , Alexandros A. Drosos
Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
CASE-BASED REVIEW

69
On the other hand, autoimmune rheumatic diseases
(ARD) are also characterised by a dysregulation of the
immune system in which several pro-inammatory cy-
tokines such as IL-1, IL-6, IL-17, and TNFa which are
involved in the pathogenesis of rheumatoid arthritis (RA),
the spondyloarthropathies (SpA), and inammatory bow-
el disease (IBM).5 In the last two decades the introduction
of biological (b) disease-modifying anti-rheumatic drugs
(DMARDs) targeting cytokines, T and B cells, and with
the use of conventional synthetic (cs) DMARDS, has
revolutionized the treatment of the above diseases.6,7
The questions which arise here are: what is the impact of
CΟVID-19 inection in patients with ARD “already treated
with cs and bDMARDs”? Does their immunocompro-
mised status due to the disease itself and its treatment put
their life in danger? Are they protected against COVID-19
infection due to long use of cs and bDMARDs?.8 For this
reason, we present ve patients with RA, treated with cs
and bDMARDs, who were infected with COVID-19, and
discuss the relevant literature trying to answer the above
questions. An informed consent has been obtained from
all patients.
CASE PRESENTATION 1
A 42-year-old woman was diagnosed 6 years earlier with
RA on the basis of clinical and laboratory ndings. More
specically, bilateral symmetrical polyarthritis of the small
joints of the hands, positive anti-citrullinated protein anti-
bodies (ACPA), positive IgM rheumatoid factor (IgM-RF),
as well as high CRP and erythrocyte sedimentation rate
(ESR). She was treated with hydroxychloroquine (HCQ)
and methotrexate (MTX), plus 10mg of prednisone. She
responded very well to the above treatment regimen
since last year that developed a disease are. Since then,
adalimumab (ADA), an anti-TNFa inhibitor, was added.
This treatment resulted in complete clinical and laborato-
ry remission until recently. Indeed, on September 2, 2020
she experienced low-grade fever (37.7 °C), myalgias,
arthralgias, and malaise. Clinical examination revealed
no frank arthritis and the laboratory tests showed only
a high CRP (14mg/dl - normal values <6) and high ESR
(48mm/h). Chest x-ray was normal. Serological tests for
viruses and bacteria, as well as blood and urine cultures
were negative. However, the test for SARS-CoV-2 was
positive. At that time, she was receiving HCQ (200mg/
day), MTX (15mg/week), prednisone (2mg/day) and
ADA (40mg/14 days subcutaneously) (sc). The last ADA
injection was administered a week before the appear-
ance of fever. She was not a smoker. Past medical and
family history were unremarkable. We advised her to
discontinue MTX and ADA, and to stay in isolation at
home according to the national, European and American
recommendations.9-11 Ten days later, her symptoms
gradually subsided, and the symptoms resolved com-
pletely after 3 weeks. The repeated test for SARS-CoV-2
was negative. One month later, she was symptom-free,
a new test for SARS-CoV-2 was also negative, and she
started receiving her immunosuppressive therapy.
CASE PRESENTATION 2
A 50-year-old man was diagnosed as having RA 4 years
ago, on the basis of symmetrical polyarthritis aecting the
wrists, elbows and the knees bilaterally, and with positive
IgM-RF and high ESR and CRP. He was treated with MTX
20mg/week, plus prednisone 10mg/day. He responded
well, but a year later he relapsed, thus tocilizumab (TCZ),
an IL-6 receptor antagonist was initiated (162mg/week
sc). He responded very well to this treatment regimen,
but on September 24, 2020, he complained of arthral-
gias, myalgias, sore throat, and fever up to 38°C. Clinical
examination revealed no frank arthritis, chest x-ray was
normal, and laboratory tests showed white blood count
of 3.9/109L with normal dierential, high acute phase
reactants and a SARS-CoV-2 test positive. The rest of
the laboratory tests were negative or within normal limits.
Past medical and family history were not signicant. He
was not a smoker. At this time, he was receiving MTX
15mg/week, prednisone 2,5 mg/day and TCZ 162mg/
week. The last TCZ injection was administered three
days before the initiation of his symptoms. MTX and TCZ
were discontinued, and he stayed in isolation at home.9-
11 A week later, he felt well, without sore throat and fever,
and after 2 weeks, he had complete resolution of the
SARS-CoV-2 symptoms. The repeated test for SARS-
CoV-2 was negative and ve weeks later a new test for
SARS-CoV-2 was also negative so he started receiving
the above-mentioned treatment (MTX and TCZ).
CASE PRESENTATION 3
A 62-year-old female with seronegative RA diagnosed 5
years earlier, was in clinical remission since 2018, receiving
HCQ 200mg/day plus Etanercept (ETN) 50mg/week sc.
She presented on 18th November 2020 with arthralgias,
muscle aches, weakness, sore throat, altered sense of
smell, and fever (38.5 °C). She visited our clinic, where af-
ter a detailed clinical and laboratory investigation, she was
diagnosed as having SARS-CoV-2 infection. She had high
ESR and CRP, as well as high ferritin levels (805mcg/L,
normal values <35). She remained isolated at home re-
ceiving HCQ 200mg/day and azithromycin (AZT) 500mg/
day, while ETN was discontinued. She was not receiving
other drugs and she was not a smoker. Seven days later,
she felt well without fever, sore throat and myalgias, but the
olfactory dysfunction was still present. After three weeks
she was free of symptoms. The patient started receiving
ETN after a new SARS-CoV-2 negative test.
CASE PRESENTATION 4
A 55-year-old female with seropositive RA since 2016
receiving MTX 20mg/week and golimumab (GLM) 50mg/
ANTI-RHEUMATIC DRUGS IN COVID PATIENTS

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month sc presented on 22nd November 2020 to us com-
plaining of arthralgias, myalgias, sore throat, and loss of
taste and smell. Clinical evaluation revealed no arthritis,
while the laboratory tests showed high ESR and CRP,
and positive SARS-CoV-2 test. She had no other co-
morbidities and was not a smoker. She stayed at home
receiving some analgesics, while MTX and GLM were
discontinued. Two weeks later she felt better, but the loss
of taste and smell had no improvement. After one month
she was free of symptoms with some improvement of
taste and smell. The SARS-CoV-2 test was negative,
and she started receiving MTX and GLM.
CASE PRESENTATION 5
A 38-year-old female with a 12-year history of seroneg-
ative RA presented on 15th December 2020 with severe
arthralgias and myalgias, as well as fever up to 38.5°C
lasting for 3 days. She was on treatment with HCQ
200mg/day and prednisone 2,5mg/day because she
delivered a healthy baby 6 months earlier. Past medical
and family history were unremarkable. Clinical examina-
tion revealed no frank arthritis and she tested positive for
SARS-CoV-2. The rest of the laboratory tests showed
only high CRP. She continued receiving her drugs plus
AZT 500mg/day and she stayed at home. After 10 days
she felt better without fever, myalgias and arthralgias.
One month later, the test for SARS-CoV-2 was negative.
DISCUSSION
In Table 1 we present the clinical and laboratory ndings
of those ve RA patients who were infected with SARS-
CoV-2. All infected patients presented systemic man-
ifestations and mild upper respiratory symptoms from
the nose and throat, while the laboratory investigation
revealed only high acute phase reactants, mostly CRP
and ESR, while one patient had also high ferritin levels. In
addition, one patient had low white blood cells. None of
these patients was hospitalized. Cs and bDMARDs were
discontinued with the exception of HCQ and prednisone.
The outcome of those patients was very good, lasting for
4-5 weeks until complete recovery.
Treatment decisions and therapeutic strategies in critically
ill patients of SARS-CoV-2 infection were initially limited.
Much of the therapy for severe Covid-19 are empirical
and depend mostly on clinical judgement.12 However,
up to date, dierent therapeutic protocols are applied
using anti-viral drugs, steroids (mostly dexamethasone),
supportive treatments, and several anti-rheumatic
drugs, such as HCQ, cytokine inhibitors, and others.13,14
Regarding the patients with ARD infected from SARS-
Table 1. Clinical and laboratory ndings of rheumatoid arthritis patients infected from SARS-CoV-2.
Patients Systemic
manifestations
Ear, nose,
and throat
symptoms
Respiratory
symptoms
Laboratory
tests Treatment Outcome
N:1
Arthralgias,
myalgias, malaise,
fever
None None High ESR
High CRP
HCQ
200mg/day,
prednisone
2.5mg
Good
N:2 Arthralgias,
myalgias, fever Sore throat None
High ESR
High CRP
Low WBC
Prednisone
2.5mg Good
N:3 Arthralgias, myalgia,
weakness, fever
Sore throat,
olfactory
dysfunction
None
High ESR
High CRP
High Ferritin
HCQ 200mg/
day AZT 500
mg/day
Good
N:4 Arthralgias, myalgias
Sore throat,
Loss of taste
and smell
None High ESR
High CRP None Good
N:5 Arthralgias,
Myalgias, fever None None High CRP
HCQ
200mg/day,
prednisone
2.5mg/d,
AZT 500mg/d
Good
SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; ESR: Erythrocyte sedimentation rate; CRP: C-reactive
protein; WBC: white blood cells; HCQ: hydroxychloroquine; AZT: Azithromycin.

71
TITLE
CoV-2, a study from Gianfrancesco et al. showed that
patients receiving prednisone >10 mg/day had a higher
probability to be hospitalised, while in those receiving
anti-TNFa therapy, the risk of hospitalisation was low.15
Haberman et al. showed that antimalarial therapy was
not associated with the likelihood of hospitalization in
patients infected from SARS-CoV-2. On the other hand,
bDMARDs and targeted synthetic (ts) DMARDs reduced
the odds of hospitalization.16 In a subsequent study,
the same investigators showed that among patients
with ARDs and SARS-CoV-2 infection, the outcome
was worse in those receiving corticosteroids, but none
in those receiving anti-cytokine therapies.17 HCQ has
been used in rheumatology for many years, especially for
the treatment of RA and systemic lupus erythematosus
(SLE). One questions that arises at this point is, how
could HCQ help patients suering from SARS-CoV-2
infection. The answer is simple: we do not know yet,
but what we do know is that HCQ inhibits or impairs
the presentation process of an antigen, or of a microor-
ganism to macrophages due to inhibition of toll-like re-
ceptors (TLRs). Another action of HCQ is that of helping
macrophages to destroy the ‘invader’ in the cytoplasm
through the action of lysosomes and blocks the major
histocompatibility complex (MHC), which is responsible
for the presentation of the ‘invader’ from macrophages
to T cells. Therefore, T cell activation is inhibited (Figure
1). Could the above mechanisms of HCQ block the virus
entry, and prevent its multiplication and spreading? We
do not know, yet.13,14 However, in vitro studies showed
that HCQ blocks viral replication by inhibiting the entry
of SARS-CoV-2 by interacting with glycosylation of
angiotensin converting enzyme-2 (ACE-2) receptor and
its binding with the spike protein.18 This remains to be
documented and there are some trials that are trying
to support it.19-21 Furthermore, high HCQ blood levels
are associated with reduced thrombotic events in SLE
patients,22 which is also a clinical manifestation of SARS-
ANTI-RHEUMATIC DRUGS IN COVID PATIENTS
Figure 1. Antigen-processing onto macrophage/APC and the action of hydroxychloroquine.
An antigen-presenting cell, takes up the pathogen (SARS-CoV-2) end engulfs it with phagocytosis (1). Lysosomes that
contain acids create an acidic environment and fuse with the phagocytosed “invader” creating the phagolysosome which
has an acidic environment too (2). Because of the acidic environment, the content of the phagolysosome breaks down
leaving various particles that will be processed as antigens (3). In the meantime, within the endoplasmic reticulum the ri-
bosomes are synthesizing MHC and allow the formation of an endosome which passes also through the Golgi apparatus
to form a new endosome. The viral breakdown particles will then fuse with the new endosome and the particles will bind
onto the groove of the MHC (4). Finally, the antigen presenting cell will express it on its self-surface (5). Hydroxychloro-
quine, accumulates in lysosomes, raising the pH establishing a non-acidic environment and inhibits the lysosomal activity
and, in this way, it prevents the MHC presentation to the surface of the antigen-presenting cell.

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CoV-2 patients. On the other hand, a study by Koning et
al. found no protection for SARS-CoV-2 infection or the
development of the severe form of the disease with the
use of HCQ in patients with SLE.23 Recent data regarding
the eect of HCQ in Covid-19 did not show a clear clini-
cal benet, while a systematic review and meta-analysis
demonstrated that HCQ use was not associated with
any benet or harm regarding Covid-19 morbidity.24
IL-6, IL-1, and TNFa are the pivotal cytokines responsible
for the clinical deterioration of patients suering from
SARS-CoV-2 infection. TCZ is an IL-6 receptor antago-
nist which is used in rheumatology for patients suering
from RA, juvenile idiopathic arthritis and temporal arteritis.
There are several reports, using TCZ for critically ill pa-
tients infected with SARS-CoV-2, showing encouraging
results.25-30 On March 3 2020, TCZ has been approved
in China for use in patients with the SARS-CoV-2 infec-
tion. Indeed, TCZ maintains a crucial role in critically ill
patients with acute progressive SARS-CoV-2. More
than 200 cases of SARS-CoV-2 treated with TCZ have
been published mostly from Chinese, Italian and Spanish
investigators.31,32 In almost all cases, TCZ was found to
be eective, with an acceptable safety prole. The clinical
improvement has been associated with normalization
of CRP and other acute phase reactants.26,28 In a few
studies pulmonary improvement has been also noted by
improvement of imaging ndings.30 On the other hand,
other studies, showed that high IL-6 was associated
with severe phenotype disease of SARS-CoV-2.25 This is
probably due to the fact that IL-6 levels may increase a
few days after TCZ administration.33
Anakinra, is an IL-1 receptor antagonist which is used
in RA, Still’s disease, cryopyrin-associated periodic syn-
drome (CAPS), and in patients with gout. Canakinumab,
is a monoclonal antibody against IL-1 and it is used in
CAPS and gout patients. Anakinra, showed reduction
of CRP and progressive improvement of respiratory
parameters in critically ill patients when administered in-
travenously and in high doses.34 Recently, Moutsopoulos
HM described a patient suering from CAPS who
received Canakinumab 10 days before of being tested
positive for SARS-CoV-2. He reported that the patient
had a mild disease course and a week later the test for
SARS-CoV-2 was negative.35 TNFa inhibitors are used
in the last two decades for the treatment of RA, SpAs,
and other inammatory arthritides. It has been shown
that the use of TNFa inhibitors in SARS-CoV-2 patients
may improve disease outcome and prevent organ dam-
age.36 The question that we addressed at the beginning,
regarding the impact of SARS-CoV-2 infection in ARD
patients, is still a matter of discussion due to limited data
so far. However, single reports, as above, case series
and observational studies published recently indicated
that in patients with ARD and SARS-CoV-2 infection the
disease is expressed with mild clinical symptoms without
severe consequences probably due to their concomitant
use of cs and bDMARDs.15-17,37-44
On the other hand, the Covid-19 Global Rheumatology
Alliance (GRA) has published a series of papers dealing
with the impact of COVID-19 in ARD patients.45 The
results suggest that as in the general population, age
and comorbidities are to blame as the risk factors for
poor outcome in ARD patients infected by SARS-CoV-2.
Furthermore, glucocorticoids are also associated with an
unfavourable outcome in these patients. Finally, Stangfeld
et al. who examined the casualties in a large amount of
patients with ARDs, found that moderate or high disease
activity, and specic drugs (sulfasalazine, azathioprine,
cyclosporine-A, mycophenolate mofetil, tacrolimus,
cyclophosphamide, and the use of rituximab) were as-
sociated with increased odds of COVID-19 deaths.46
However, all the above apply to a mixed population of
ARD patients (SLE, scleroderma, RA and others) who
may have many dierent systemic manifestations and
treatments. The Janus-kinase (JAK) inhibitors tofacitinib
(TOFA) and Baricitinib (BARI), have been proposed as
potential therapeutic agents for SARS-CoV-2 infection.
Especially BARI may block the viral entry into the cells
by inhibiting the members of the numb-associated
kinase (NAK) family, such as adaptor associated protein-
kinase-1 (AAKI) and cyclin-G associated kinase (GAK),
which are involved in the viral endocytosis.47 Currently,
both drugs are used to treat RA and other inammatory
arthritides in a dose of 5mg twice daily for TOFA and
2mg twice daily for BARI. It has been shown that BARI
is able to inhibit eectively AAKI and GAK with the above
approved dose for RA. Moreover, BARI as a selective
inhibitor of JAK 1 and 2 and TOFA as an inhibitor of JAK1
and 3 are also able to inhibit the inammatory response of
SARS-CoV-2, especially IL-1 and INF-γ. Several studies
indicated that JAK inhibitors may have some benecial
eect in the treatment of COVID-19.48,49 However, recent
studies evaluating the impact of the COVID-19 on mor-
bidity and mortality in patients with ARDs indicated that
the use of JAK inhibitors had a negative eect.50,51
In the present report we present ve patients with RA
in clinical remission without systemic manifestations and
comorbidities who were treated with cs and bDMARDs
that achieved a good outcome. Indeed, our RA pa-
tients during the SARS-CoV-2 infection were receiving
csDMARDs (HCQ and MTX), while three of them were
receiving also TNFa inhibitors, and one patient was on
treatment with an IL-6 receptor antagonist. All had mild
clinical manifestations and very good outcome with com-
plete resolution of their symptoms, without hospitalisa-
tion and no additional therapy. Another factor which may
have inuenced the clinical manifestations of our patients
is that none of them had other comorbidities, like diabe-
tes mellitus, coronary disease, hypertension, and other
diseases which may play crucial role in the deterioration

73
TITLE
of the clinical course and outcome of SARS-CoV-2. All
patients, except one, restarted their immunosuppressive
therapy for RA after a negative test for Covid-19, which
is in line with the international guidelines. Alternatively,
the immunosuppressive therapy should be restarted
after a two-week, symptom free period of the patient.52,53
Thus, we can hypothesise that anti-rheumatic drugs
may ameliorate the clinical picture and disease course of
COVID-19 in RA patients. However, further studies with
a large number of patients are needed in order to conrm
the above benecial eects of the anti-rheumatic drugs.
ACKNOWLEDGEMENT
The authors would like to especially thank Ms Areti Fili for
her excellent secretarial support.
CONFLICT OF INTEREST
The authors declare no conict of interest.
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