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Prophylactic effects of hydroxychloroquine on the incidence of COVID-19 in patients with rheumatic arthritis: an observational cohort study

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Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with substantial morbidity and mortality. Anti-malarial drugs like hydroxychloroquine are indicated in several rheumatic diseases such as RA. Some reports have suggested hydroxychloroquine for prevention of COVID-19. Objectives: Whether hydroxychloroquine has prophylactic effects for COVID-19 in rheumatic patients. Patients and Methods: In this multicenter cohort-based observational study the preventive effect of hydroxychloroquine regarding the incidence and severity of COVID-19 was investigated in patients with RA who referred to rheumatology clinics of academic hospitals of Isfahan between April and July 2020 and already have been treated with hydroxychloroquine for more than three months. Around 215 patients with RA and current use of hydroxychloroquine were recruited and followed for three months. Patients’ information was gathered using the medical record or by phone call. Results: The incidence of COVID-19 in this selected sample was 4.2% (n=9). Only one in nine patients needed hospitalization, without need for intubation or ICU care. Symptoms including dry cough, headache, body pain, malaise, dyspnea, fever, sore throat, chills, and chest pain, were reported to be statistically higher in COVID-19+ group. Conclusion: In contrast to the mortality rate in the general population of Isfahan, Iran (4.8% - until June 2020), no mortality has been reported in these patients. Therefore, it seems that the use of hydroxychloroquine has been able to reduce the incidence and severity of the disease after reaching steady-state levels. This finding has clinical importance, especially for rheumatic patients using immunomodulatory drugs.
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Immunopathol Persa. 2021;7(2):e29 Original
Prophylactic effects of hydroxychloroquine on the
incidence of COVID-19 in patients with rheumatic
arthritis: an observational cohort study
Zohre Naderi1
ID
, Bahar Sadeghi2
ID
, Ziba Farajzadegan3
ID
, Ramin Sami1
ID
, Mansour Salesi1*
ID
, Vahid Mansouri4*
ID
,
Babak Amra5
ID
1Department of Internal Medicine, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2Student Research Committee, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3Department of Community Medicine, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
5Bamdad Respiratory and Sleep Research Center, Pulmonary and Sleep Ward, Internal Medicine Department, Isfahan University of
Medical Sciences, Isfahan, Iran
Immunopathologia Persa http www.immunopathol.com
*Correspondence to
Mansour Salesi,
Email: Salesi@med.mui.ac.ir;
Vahid Mansouri,
Email: Mansoury.vahid@gmail.
com
Received 2 Jan 2021
Accepted 28 Feb. 2020
Published online 6 Apr. 2021
Keywords: COVID-19,
Hydroxychloroquine,
Prophylaxis, Rheumatic
arthritis, Observational,
Prospective
Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with substantial morbidity and mortality.
Anti-malarial drugs like hydroxychloroquine are indicated in several rheumatic diseases such as RA. Some reports
have suggested hydroxychloroquine for prevention of COVID-19.
Objectives: Whether hydroxychloroquine has prophylactic effects for COVID-19 in rheumatic patients.
Patients and Methods: In this multicenter cohort-based observational study the preventive effect of
hydroxychloroquine regarding the incidence and severity of COVID-19 was investigated in patients with RA who
referred to rheumatology clinics of academic hospitals of Isfahan between April and July 2020 and already have
been treated with hydroxychloroquine for more than three months. Around 215 patients with RA and current use
of hydroxychloroquine were recruited and followed for three months. Patients’ information was gathered using
the medical record or by phone call.
Results: The incidence of COVID-19 in this selected sample was 4.2% (n=9). Only one in nine patients needed
hospitalization, without need for intubation or ICU care. Symptoms including dry cough, headache, body pain,
malaise, dyspnea, fever, sore throat, chills, and chest pain, were reported to be statistically higher in COVID-19+
group.
Conclusion: In contrast to the mortality rate in the general population of Isfahan, Iran (4.8% - until June 2020),
no mortality has been reported in these patients. Therefore, it seems that the use of hydroxychloroquine has been
able to reduce the incidence and severity of the disease after reaching steady-state levels. This finding has clinical
importance, especially for rheumatic patients using immunomodulatory drugs.
Abstract
Citation: Naderi Z,
Sadeghi B, Farajzadegan
Z, Sami R, Salesi M,
Mansouri V, Amra B.
Prophylactic effects of
hydroxychloroquine
on the incidence of
COVID-19 in patients
with rheumatic arthritis:
an observational cohort
study. Immunopathol
Persa. 2021;7(2):e29.
DOI:10.34172/
ipp.2021.29.
Introduction
COVID-19 caused by the 2019 novel
coronavirus (SARS-CoV-2) is characterized
by a presence of different symptoms including
fever, dry cough, dyspnea, fatigue, and some
extra-pulmonary symptoms accompanied
by lymphopenia (1). However, there is a
spectrum from asymptomatic to critically ill
condition in the COVID-19 pandemic that
has affected approximately millions of people
all around the world and caused many deaths,
influencing almost every aspect of life (2).
Rheumatoid arthritis (RA) is a systemic
autoimmune disease characterized by
chronic inflammation of the joints that
causes substantial cardiovascular, respiratory,
musculoskeletal and endocrine morbidity
and mortality (5-year survival of 80%)
(3). Conventional therapy for RA includes
Key point
The long-term usage of hydroxychloroquine has an
effective prophylactic impact on the incidence of
COVID-19. It seems that hydroxychloroquine has
been able to reduce the possibility of infection and
reduce the severity of the disease in patients who
continuously administered hydroxychloroquine for
several months and its blood level has reached a
steady state.
the administration of anti-inflammatory
drugs, followed by disease-modifying anti-
rheumatic drugs such as methotrexate,
hydroxychloroquine, and sulfasalazine.
Furthermore, in the case of acute disease
flare-up, glucocorticoids can be used to relieve
pain and swelling rapidly by controlling the
inflammation (4).
Previous studies showed that the complex
DOI:10.34172/ipp.2021.29
Naderi Z et al
Immunopathologia Persa Volume 7, Issue 2, 20212
relationship between infections and arthritis could be
interpreted in two ways. The first way, in the general
population, there is plenty of evidence on the role of
pathogens in development of acute and chronic arthritis.
The effects could be mediated by direct colonization or
individual improper autoimmune reaction. The second
way, is for the patients with autoimmune arthritis, in
which inflammatory arthritis – like other inflammatory
processes – could result in the disease flare-up (5-8).
Chloroquine and hydroxychloroquine are widely used as
anti-malarial drugs with well-known immunomodulatory
properties in which their indication of usage has been
extended to several rheumatic diseases such as RA (9).
Likewise, the ability of chloroquine as an anti-viral
agent has been known since the late 1960s (10). Indeed,
hydroxychloroquine in the body will concentrate on the
intracellular parts including endosome and lysosome, and
prevent viral replication as well as changing the binding of
protein-S in SARS-COV-2.
Some reports have stated that hydroxychloroquine can
be used to prevent COVID 19 in people exposed to the
diseases. In this regard, there are some ongoing clinical
trials to clarify the effect of hydroxychloroquine on post-
exposure cases (11).
Objectives
Considering the hard-to-control situation for
designing a study to assess the prophylaxis effect of
hydroxychloroquine, the cohort study on RA-patients
who use hydroxychloroquine is valuable to find the drug
prophylaxis effect. Therefore, we decided to investigate the
preventive effects of hydroxychloroquine regarding the
incidence of COVID-19 in patients with RA who already
have been treated with hydroxychloroquine for more than
three months.
Patients and Methods
Study design and participants
This multicenter cohort-based observational study was
performed on patients with RA referring to rheumatology
clinics of academic hospitals of Isfahan between April
and July 2020. All known cases of RA were evaluated
and ones with current use of hydroxychloroquine were
enrolled in the study. All RA patients with the history
of using hydroxychloroquine were included in the study
except for those who were taking angiotensin-converting
enzyme (ACE) inhibitors. Patients’ information including
demographic data and COVID-19 related information
was gathered using the medical record or by phone call.
Data collection and outcomes
The information was as follow; age, gender, RA disease-
duration, type of residential building, drug history
(hydroxychloroquine, azathioprine, methotrexate,
prednisolone, other biological drugs; infliximab,
adalimumab [CinnoRA], etanercept) along with the
dosage and history of their usage, and other comorbidities
(diabetes, hypertension, other cardiovascular diseases,
obesity, end-stage renal disease and respiratory
diseases). Additionally, COVID-19 symptoms including
constitutional, respiratory and extra-pulmonary
symptoms, history of exposure with the asymptomatic
individual, length of the disease course, COVID-19
diagnostic polymerase chain reaction (PCR) result were
gathered. In case of any suspicion for COVID-19 infection
on calls, the COVID-19 PCR test was used to confirm the
diagnose. Patients were divided into two groups according
to the interviews; patients with RA who at least once
diagnosed with COVID-19 based on the PCR test; and the
RA patients without positive results for COVID-19 PCR
test.
Ethical issues
The research followed the tenets of the Declaration of
Helsinki. The Ethics Committee of Isfahan University
of medical sciences approved this study (IR.MUI.MED.
REC.1399.067). Accordingly, written informed consent
was taken from all participants before any intervention.
This study was extracted from the M.D thesis of Bahar
Sadeghi at this university (Thesis#199038).
Statistical analysis
Descriptive statistics including frequency for qualitative
variables and mean± standard deviation for quantitative
variables were used. To compare the dichotomous
variables, chi-square or Fishers exact test was used.
Logistic regression was employed to assess the association
between different variables and infection with COVID-19.
Data were analyzed using SPSS software version 22 (IBM
SPSS Statistics for Windows, Version 22.0 Armonk, NY:
IBM Crop.). The significance level was considered 0.05 for
each test.
Results
Overall, 954 patients with rheumatic disease were evaluated.
Around 632 of total patients have other rheumatic diseases
rather than RA. About 322 patients had RA and in phone
contact, 64 patients were not reachable or did not tend to
enroll in the study. Among the 258 remaining patients,
43 patients did not use hydroxychloroquine as part of
their treatment or discontinue their usage. Finally, 215
patients with the diagnosis of RA by the rheumatologist
and current use of hydroxychloroquine were entered in
the study. The flow diagram of the population selection is
shown in Figure 1.
The characteristics of patients with RA have been shown
in Table 1. The mean age of the participants was 51.09 ±
12.01 years. Forty (18.6%) of them were male. They had
RA for an average of 3.41 ± 2.66 years. The treatment
regimen of 80 (37.2%) and 31 (14.4%) of them, in
addition to hydroxychloroquine, include prednisolone
and methotrexate, respectively. Their most common
Immunopathologia Persa Volume 7, Issue 2, 2021 3
COVID19 prophylaxis using hydroxychloroquine
underlying disease (except for RA) were hypertension,
diabetes, and cardiovascular disorders. The most common
associated symptoms of COVID-19 in this population
were sore throat, dry cough, fever, and chills, in the order
of frequency. On average, patients with these symptoms
experience them for 12.75 ± 2.76 days. The incidence
of COVID-19 in this selected sample was 4.2% (n=9)
(Table 1).
For evaluating the contributing factors for the incidence
of COVID-19, we divided the population into two groups
including COVID-19+ and COVID-19, as described
above. They were no significant difference between cases
and controls regarding age and gender. Additionally,
underlying diseases were not significantly different
between them, except for diabetes with a higher incidence
in the patients with COVID-19 (odds ratio [OR] = 7.048,
95% CI: 7.048-28.298, P = 0.002). Furthermore, two
groups were not significantly different regarding the
number of years of having RA. The usage of biological
drugs (mainly CinnoRA and etanercept) was significantly
higher in the COVID-19 group (OR= 3.571, P <0.001).
Due to few numbers of COVID-19 cases in this population
several of the associated symptoms including dry cough,
headache, body pain, malaise, dyspnea, fever, sore throat,
chills, and chest pain, were reported to be statistically
higher in COVID-19+ group. As expected, the number of
Figure 1. Flow diagram of the enrolled participants.
Table 1. Characteristics of enrolled patients with rheumatic arthritis
(n=215)
Variables Mean
Age, mean (median [IQR]) 51.09 (52 [43-60])
Gender, No (%)
Male 40 (18.6%)
Female 175 (81.4%)
Symptoms, No (%)
Dry cough 14 (6.5%)
Headache 2 (0.9%)
Body pain 6 (2.8%)
Nausea 1 (0.5%)
Vomiting 1 (0.5%)
Diarrhea 3 (1.4%)
Malaise 3 (1.4%)
Dyspnea 7 (3.3%)
Fever 13 (6%)
Sore throat 18 (8.4%)
Chills 10 (4.7%)
Anosmia 1 (0.5%)
Chest Pain 3 (1.4%)
Drugs used, No (%)
Hydroxychloroquine 215 (100%)
Prednisolone 80 (37.2%)
Biologics 3 (1.4%)
Azathioprine 2 (0.9%)
Methotrexate 31 (14.4%)
Underlying disorders, No (%)
Cardiovascular disorders 17 (7.9%)
Hypertension 38 (17.6%)
Respiratory disorders 13 (6%)
Diabetes 23 (10.6%)
Morbid Obesity (BMI>40) 5 (2.3%)
Dialysis 1 (0.5%)
Mean duration of RA (y), mean (median
[IQR]) 3.41 (3 [2-4])
Number of symptoms, No (%)
0 175 (81.4%)
1 19 (8.8%)
2 10 (4.7%)
3 7 (3.3%)
>4 4 (1.9%)
Confirmed COVID-19
Yes 9 (4.2%)
No 207 (96.3%)
The average number of days with
symptoms (n=9), mean (median [IQR])
12.75 (14 [11-
14.75])
COVID-19 associated symptoms in the COVID-19 group
was significantly higher, compared with the control group.
Figure 2 shows the distribution of common symptoms
of the COVID-19, including fever, dry cough, fever, and
other associated symptoms in the two groups. However,
the frequency of these symptoms was not significantly
954 Patien ts with rheumatological
diseases who have active medical
les in academic hosp itals of
Isfahan on 25 May, 2020 were
evaluated
954 Patien ts with rheumatological
diseases who have active medical
les in academic hosp itals of
Isfahan on 25 May, 2020 were
evaluated
322 patients with
diagnose of RA were
included
322 patients with
diagnose of RA were
included
632 Patien ts have other
rheumatological diseases
than Rheumatoid
Arthritis
632 Patien ts have other
rheumatological diseases
than Rheumatoid
Arthritis
64 Patients not reachable
by phone or did not
attend the evaluation
64 Patients not reachable
by phone or did not
attend the evaluation
RA Patients with
current use of
Hydroxychloroquine?
Yes
43 Patients with RA did
not use
hydroxychloroquine in
their treatment regimen
43 Patients with RA did
not use
hydroxychloroquine in
their treatment regimen
No
215 Patien ts with RA and
current use of
Hydroxychloroquine were
entered the study
215 Patien ts with RA and
current use of
Hydroxychloroquine were
entered the study
Naderi Z et al
Immunopathologia Persa Volume 7, Issue 2, 20214
different between the two groups (P=0.955). Figure 3 shows
the ORs of most common demographic characteristics and
drug/symptoms for the incidence of COVID-19 (Figure 2,
Table 2).
Table 3 shows the individual characteristics of the
confirmed cases of COVID-19 in this study. The mean
age was 53.56 ± 13.34 years since 8 out of 9 (88.8%) of
them were female. Their most common symptoms were
fever, dry cough, and sore throat and the most common
underlying diseases were diabetes and hypertension. Their
mean BMI was 23.82 ± 4.15 kg/m2 and two of them were
overweight and just one of them was obese. However, none
of them was morbidly obese. Mean RA-disease-duration
was 4 ± 1.87 years. Only one patient was smoker, however,
none of them reported previous respiratory disorders.
Only one of them hospitalized for her disease, but there
was no need for intubation of ICU care during her 6-hours
hospitalization.
Discussion
This study, on RA patients, showed that only 4.2% of
individuals undergoing hydroxychloroquine for at least
three months were affected by SARS-COV2. Contrary to
what is commonly seen in the general population, where
typically 80% of patients are asymptomatic or have mild
symptoms, in our patients with COVID-19, 77.7% had
three or more symptoms associated with the disease (12).
Statistics showed that 20% of patients in the community
need to be hospitalized due to severe form of COVID-19.
This proportion was even higher in rheumatic patients
(31.6%) (13), while this study showed that only one in
nine RA-patients required admission with no need to be
intubated or ICU care. Furthermore, the mortality rate
in the general population of Isfahan, Iran was 4.8% until
June 2020 (14), while in these patients, no mortality was
Figure 2. Number of patients with at least one of common symptoms of the
COVID-19 – including dyspnea or dry cough or fever- and other associated
symptoms in two groups.
Figure 3. Odds ratios of most common demographic characteristics and drug/
symptoms for the incidence of COVID-19.
17
9
14
0
5
10
15
20
25
30
35
Non COVID-19 Patients COVID-19 Patients
Number of patients with COVID-19 related symptoms
Common symptoms non-common symptoms
observed. Therefore, it seems that hydroxychloroquine has
been able to reduce the possibility of infection and reduce
the severity of the disease in patients who continuously
administered hydroxychloroquine for several months
and its blood level has reached a steady state. According
to previous studies, hydroxychloroquine takes an average
of three to six months to reach steady-state levels in the
blood (15).
Balevic et al examined the serum hydroxychloroquine
of rheumatoid patients such as lupus and concluded
that the blood level of the drug is less than the intended
therapeutic dose for COVID-19 patients. Their study also
showed that patients who receiving hydroxychloroquine
for longtime have tissue concentrations much higher
than the blood levels (16). Although the exact therapeutic
level of hydroxychloroquine is still unclear, it it has been
demonstrated that hydroxychloroquine with daily dosage
of 800 mg could significantly reduce the viral load and
increase the rate of PCR-negative patients (17). The above-
mentioned results showed rheumatic patients with at least
three months of hydroxychloroquine usage could benefit
from the prophylactic effect of high tissue concentration
of hydroxychloroquine. This study demonstrated the
prophylactic effect of hydroxychloroquine by comparing
the COVID-19 incidence rate in RA patients (4.2%) and
the general population (approximately 27.5%) (14).
However, the data is not completely consistent. A recent
large multicenter cohort study showed no beneficial
effect of hydroxychloroquine regarding hospitalization
and in-hospital mortality (18,19). Moreover, in another
prospective study in France, the clinical course of 17
patients with systemic lupus erythematosus (SLE) who got
COVID-19 was described. They did not find a significant
prophylactic effect of hydroxychloroquine for preventing
COVID-19, or at least its severe form in patients with SLE
and long-term use of hydroxychloroquine (20). Another
study on 120 patients with SLE demonstrated that the
Immunopathologia Persa Volume 7, Issue 2, 2021 5
COVID19 prophylaxis using hydroxychloroquine
frequency of COVID-19 related symptoms was not
significantly different between patients with and without
use of hydroxychloroquine (21). However, in contrast to
retrospective studies that recruited patients with rheumatic
disorders and COVID-19 reported mixed results, our study
was prospectively and followed a relatively high number of
patients with arthritis rheumatoid and monitor the rate of
COVID-19 incidence and its severity. Moreover, several
high-quality clinical trials for evaluating the prophylactic
effect of hydroxychloroquine are still underway (https://
www.clinicaltrials.gov) (22).
Finding out how the rheumatic patients could be
affected by COVID-19 is of special importance for
rheumatologists. First of all, these patients are more prone
to infections, due to treating with immunomodulatory
drugs (23). Moreover, some of their related drugs, such as
antimalarials, anti-IL-6 agents and JAK inhibitors might
have preventative effects for COVID-19 (24).
The major strength of this study was the considerable
number of rheumatic patients. In addition, to the best of
our knowledge, this study was the first study to evaluate the
prophylactic effect of hydroxychloroquine in RA patients.
Table 2. The association between demographic characteristics and symptoms with the incidence of COVID-19
Variables Non COVID-19 patients (n=206) COVID-19 patients (n=9) Exp(B) or Odds ratio P
Age, mean (SD) 51.09 (12.01) 53.56 (13.34) 1.017b0.548
Gender, No. (%)
Male 39 (18.9%) 1 (11.1%) 0.547a (M/F) 0.555
Female 167 (81.1%) 8 (88.9%)
Symptoms, No. (%)
Dry cough 8 (3.9%) 6 (66.7%) 49.5 a <0.001*
Headache 1 (0.5%) 1 (11.1%) 25.625 a 0.001*
Body pain 2 (1%) 4 (44.4%) 81.6 a <0.001*
Nausea 0 (0%) 1 (11.1%) - -
Vomiting 0 (0%) 1 (11.1%) - -
Diarrhea 0 (0%) 1 (11.1%) - -
Malaise 2 (1%) 1 (11.1%) 12.75 a 0.011*
Dyspnea 5 (2.4%) 2 (22.2%) 11.486 a 0.001*
Fever 6 (2.9%) 7 (77.8%) 116.66 a <0.001*
Sore throat 13 (6.3%) 5 (55.6%) 18.558 a <0.001*
Chills 7 (3.4%) 3 (33.3%) 14.214 a <0.001*
Anosmia 0 (0%) 1 (11.1%) - <0.001*
Chest pain 1 (0.5%) 2 (22.2%) 58.571 a <0.001*
Drugs used, No. (%)
Hydroxychloroquine 207 (100%) 8 (100%) - -
Prednisolone 77 (37.4%) 3 (33.3%) 0.837 a 0.806
Biologics 2 (1%) 2 (22.2%) 29.411 a<0.001*
Azathioprine 2 (1%) 0 (0%) - <0.001*
Methotrexate 29 (14.1%) 2 (22.2%) 1.745 a 0.385
Underlying disorders, No. (%)
Cardiovascular disorders 16 (7.8%) 1 (11.1%) 1.484 a 0.716
Hypertension 36 (17.5%) 2 (22.2%) 1.349 a 0.715
Respiratory disorders 13 (6.3%) 0 (0%) - 0.437
Diabetes 21 (10.2%) 4 (44.4%) 7.048 a 0.002*
Morbid Obesity (BMI>40) 5 (2.4%) 0 (0%) - 0.636
Dialysis 1 (0.5%) 0 (0%) - 0.834
Mean duration of RA (y), mean (SD) 3.39 (2.69) 4 (1.87) 1.065b0.507
Number of symptoms, No. (%)
0 175 (85.5%) 0 (0%) <0.001*
1 19 (9.2%) 0 (0%)
2 8 (3.9%) 2 (22.2%)
3 4 (1.9%) 3 (33.3%)
>4 0 (0%) 4 (44.4%)
a Data obtained by the chi-square test.
b Data obtained by logistic regression test.
Naderi Z et al
Immunopathologia Persa Volume 7, Issue 2, 20216
Conclusion
In contrast to the mortality rate in the general population
of Isfahan, Iran (4.8% - until June 2020), no mortality has
been reported in these patients. Therefore, it seems that
the use of hydroxychloroquine has been able to reduce the
incidence and severity of the disease after reaching steady-
state levels.
Limitations and strengths
The major limitation of this study was the unreliability
of patients’ self-reported suspected exposures with
COVID-19 patients. The results were not reliable enough
to be reported. Hence, it is unclear to what extent each
person has been exposed to SARS-COV-2 sources.
Therefore, similar studies on the other subgroups of the
rheumatic disease in other communities can unleash the
effect of some confounding factors and lead researchers to
a more accurate conclusion.
Acknowledgments
We are thankful to the receptionists of rheumatology clinics of AL-
Zahra, Noor and Ali-Asghar hospitals for their cooperation and
special thanks to all the families who kindly helped us in gathering
information.
Authors’ contribution
ZN and MS contributed to the study conception and design. Material
preparation, data collection and analysis were performed by ZN,
BS, ZF, MS and VM. The first draft of the manuscript was written
by VM and BS and ZN, MS, RS and BA left some comments on
previous versions of the manuscript. All authors read and approved
the final manuscript.
Conflicts of interest
None to be declared.
Ethical considerations
The authors observed the ethical issues including plagiarism, data
fabrication and publication duplication.
Funding/Support
This study was funded by Isfahan University of Medical Sciences
(Grant # 199038).
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Table 3. Individual characteristics of the confirmed cases of COVID-19
Gender Age Symptoms Drugs used (Except
Hydroxychloroquine) Risk Factors RA
duration
COVID-19
duration
Hours of Hospitalization
(need for supplemental
oxygen or ICU care)
BMI
(kg/m2)Smoking
Female 56 Dry cough and Sore
throat
Metformin and drug
for hypertension
Hypertension and
diabetes 3 13 Negative 22.4 Negative
Female 57
Dry cough, body pain,
fever, chills and chest
pain
Prednisolone
Cardiovascular
disorders,
hypertension and
diabetes
5 14
6 hours (No need for
Supplemental O2 or ICU
care)
24.21 Negative
Female 69 Fever and chills Drugs for diabetes and
hypertension
Hypertension and
diabetes 7 15 Negative 31.11 Negative
Female 39 Fever, chills, and
anosmia None None 3 14 Negative 18.77 Negative
Male 63 Dry cough, fever, and
sore throat None None 5 7 Negative 28.37 Positive
Female 38 Dry cough, body pain,
fever, and sore throat
Methotrexate and
prednisolone None 3 10 Negative 22.47 Negative
Female 62 Dry cough, dyspnea,
and sore throat
Prednisolone and
etanercept Diabetes 3 14 Negative 18.17 Negative
Female 65
Dry cough, headache,
body pain, malaise and
fever
Methotrexate and
prednisolone None 6 14 Negative 25.42 Negative
Female 33
Body pain, fever, sore
throat, chest pain,
nausea, vomiting,
diarrhea, dyspnea
Adalimumab None 1 21 Negative 23.43 Negative
Immunopathologia Persa Volume 7, Issue 2, 2021 7
COVID19 prophylaxis using hydroxychloroquine
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Preprint
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Background and Aim: The aim of this study was to description of the epidemiological features and hotspot of COVID-19 in Isfahan province of Iran. Method: In this descriptive, retrospective cohort, multicenter study, all patients admitted to one of the hospitals or health networks of Isfahan province from 3rd February to 13th June 2020 due to RT-PCR (Reverse transcription-polymerase chain reaction) test were enrolled to study. Trained staff followed up participants for two weeks by a Telephone number, and the outcome was recorded. Result: Up to 13 June, 41,498 patients recruited and their data were analyzed; the incidence of COVID-19 was 27.5% (95% CI: 27.1, 28.2). Among the participants with the positive test, 93.2% of them, treated by outpatient basis or discharged, 2.1% were hospitalized, and the case fatality rate (CFR) was 4.8%. Khansar and Aradestan was the hotspot of COVID-19 and had the highest incidence among cities of Isfahan province. Najafabad, Khomeinishahr, and Shahinshahr&Meymeh had the highest imported cases of COVID-19 to the capital of Isfahan province, Isfahan city. Also, Charmahal & Bakhtiari, Khuzestan, and Fars provinces had the highest number of imported cases from other provinces to Isfahan city. We found that 77.3% of intra-province imported cases and about 83% of inter-province cases were imported after reducing lockdown. conclusion: The incidence and fatality of COVID-19 in Isfahan province is alarming. Inter-city and inter-provincial unnecessary travels have a high impact on the transmission and spread of the COVID-19. Applying more restrictions will prevent this from happening. It is advised to restrict the inter cities travels again by policy makers for the benefit of public health.
Article
Full-text available
Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus Disease of 2019 (COVID‐19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID‐19 treatment. The data sources included were 1) longitudinal clinical, pharmacokinetic, and virologic data from patients with severe acute respiratory syndrome‐2 (SARS‐CoV‐2) infection who received HCQ with or without azithromycin (n=116), 2) in vitro viral replication data and SARS‐CoV‐2 viral load inhibition by HCQ, 3) a population pharmacokinetic model of HCQ and 4) a model relating chloroquine pharmacokinetics to QTc prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS‐CoV‐2 rate of viral decline and QTc prolongation. SARS‐CoV‐2 viral decline was associated with HCQ pharmacokinetics (p<0.001). The extrapolated patient EC50 was 4.7 µM, comparable to the reported in vitro EC50’s. HCQ doses > 400 mg BID for ≥5 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS‐CoV‐2 infection, and shorten treatment courses, compared to lower dose (≤400 mg daily) regimens. However, HCQ doses >600 mg BID were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID‐19’s variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.
Article
Objectives The impact of inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here, we compare the outcomes of a cohort of patients with rheumatic diseases with a matched control cohort to identify potential risk factors for severe illness. Methods In this comparative cohort study, we identified hospital PCR+COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or connective tissue diseases (CTDs). Non-rheumatic controls were randomly sampled 1:1 and matched by age, sex and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, intensive care unit admission or serious complications. We assessed the association between the outcome and the potential prognostic variables, adjusted by COVID-19 treatment, using logistic regression. Results The cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 (IQR 53–78) years and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and CTD (40%). Most patients (74%) had been hospitalised, and the risk of severe COVID-19 was 31.6% in the rheumatic and 28.1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe COVID-19 were increased age (OR 4.83; 95% CI 2.78 to 8.36), male sex (1.93; CI 1.21 to 3.07) and having a CTD (OR 1.82; CI 1.00 to 3.30). Conclusion In hospitalised patients with chronic inflammatory rheumatic diseases, having a CTD but not IA nor previous immunosuppressive therapies was associated with severe COVID-19.
Article
Since December 2019, the COVID-19 pandemic has become a major public health problem. To date, there is no evidence of a higher incidence of COVID in patients with autoimmune rheumatic diseases and we support the approach of maintaining chronic rheumatological treatments. However, once infected there is a small but significant increased risk of mortality. Among the different treatments, NSAIDs are associated with higher rates of complications, but data for other drugs are conflicting or incomplete. The use of certain drugs for autoimmune inflammatory rheumatisms appears to be a potentially interesting options for the treatment. The rationale for their use is based on the immune system runaway and the secretion of pro-inflammatory cytokines (Il1, IL6, TNFα) in severe forms of the disease. Notably, patients on chloroquine or hydroxychloroquine as a treatment for their autoimmune rheumatic disease are not protected from COVID-19.
Article
Objectives COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease. Methods Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed. Results A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed. Conclusions We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.
Article
Objective To characterize hydroxychloroquine exposure in patients with rheumatic disease receiving long-term hydroxychloroquine compared to target concentrations with reported antiviral activity against the 2019 coronavirus SARS-CoV-2. Methods We evaluated total hydroxychloroquine concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric lupus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted hydroxychloroquine concentrations to target concentrations with reported antiviral activity against SARS-CoV-2. Results The average total serum/plasma hydroxychloroquine concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/L in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/L), all studies had approximately one-tenth the necessary concentration for in-vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose. Conclusion We found that the average patient receiving treatment with hydroxychloroquine for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in-vitro. Nevertheless, patients receiving hydroxychloroquine long-term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for hydroxychloroquine in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for hydroxychloroquine.
Article
The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.