Effects of Hydroxychloroquine on markers of oxidative stress and antioxidant reserve in rheumatoid arthritis patients
Rawaa Jassim Ahmed1, Zeina Abdulmunim Althanoon2*
1IBN-SINA Teaching Hospital, Nineveh Province, Mosul, Iraq. 2Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq.
Correspondence: Zeina Abdulmunim Althanoon, Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq. [email protected]
ABSTRACT
Rheumatoid arthritis (RA) is a chronic condition which is a major contributor to disability in older adults. The cornerstone of rheumatoid arthritis care is now disease-modifying antirheumatic medication. The most widely used medication among these is hydroxychloroquine, which has been shown to have antioxidant properties and delay the course of the illness. Thus, the current study's objective is to compare the antioxidant and oxidant status of RA patients in Mosul City, Iraq, to that of healthy controls in order to assess the impact of hydroxychloroquine. For the study, a total of 80 people with rheumatoid arthritis and 80 people who appeared to be in good condition were enrolled. Patients with rheumatoid arthritis were further separated into groups I (those taking hydroxychloroquine) and II (those not taking hydroxychloroquine) (group II). All of the subjects had their lipid peroxidation index, malondialdehyde and total antioxidant activity, superoxide dismutase, and glutathione levels examined. Patients with arthritis treated with hydroxychloroquine had significantly higher levels of total antioxidant activity (p = 0.048) and lower levels of lipid peroxidation (p = 0.04) than patients who were not treated with hydroxychloroquine. Superoxide dismutase, an antioxidant enzyme, had a positive association with lipid peroxide levels, whereas MDA and total antioxidant activity had a significant negative correlation (p=0.01) in both patient groups. The results of this research recommend that hydroxychloroquine management for RA patients causes a reduction in oxidative stress which is a cardiovascular risk factor and increases some parameters of antioxidants (especially GSH-Px) in these patients.
Keywords: Rheumatoid arthritis, Hydroxychloroquine, Malondialdehyde, Glutathione
Introduction
The cause of the chronic systemic autoimmune disease rheumatoid arthritis (RA) is uncertain. The care of RA patients in the Middle East might be optimized, according to information first from the area [1]. In addition to publications from EULAR and the American College of Rheumatology (ACR), Iraqi rheumatologists also refer to unofficially disclosed governmental recommendations for the management of RA that have the Ministry of Health in Iraq's endorsement [2]. An all-encompassing word for joint inflammation is arthritis. Osteoarthritis (OA) and RA are two separate types of arthritis, though [3].
RA and OA both have an impact on the joints, but they are completely different manifestations of the same general condition [4]. A chronic inflammatory (nonsuppurative inflammation) illness involving many collateral joints primarily characterizes RA's clinical presentation. A vascular injury that is not limited to the joints may also accompany it and result in epidermal lumps, pericarditis, and myocarditis [5].
The osteoarthritic of the joint, that subsequently migrate to articular cartilage, bone tissue, joint ligaments, and tendons, is the primary pathogenic hallmark of RA. then an extensive inflammation of connective tissues is seen, such as serosa, heart, lung, and eyes [6]. Joint deformities, such as synovial inflammation, exudation, cell proliferation, granuloma development, cartilage, and bone tissue loss, and ultimately joint inflammation and malfunction, may be present immediately when the illness affects both cartilage and bone [7, 8].
Joint cartilage loss is linked to aberrant cytokine production, and the absence of balance that exists among the protective and damaging cytokines is regarded as the pathophysiology of RA. Additionally, immune-inflammatory cells and inflammatory chemokines work together to accelerate the pathogenic course of RA [9].
The present research proves that besides inflammation, oxidative stress products likewise have a crucial role in the progression of pathogenesis and pathological of RA [10]. Oxidative stress is The lack of balance between the production of free radical/reactive oxygen species (ROS) and antioxidant defenses, preferring prooxidants. Too many free radicals produced by oxidative stress will lead to the oxidation of several substances within the body [11, 12]. The level of malondialdehyde (MDA) rises in RA patients' bodies due to excessive reactive oxygen species, and the superoxide dismutase (SOD) system is disrupted, which weakens the antioxidant of the body defenses as well as exacerbates bone loss [13]. Additionally, oxidative stress and the energy metabolism of synovial tissue in RA individuals are tightly related [14]. Studies investigating the link between oxidative stress, SOD antioxidation, and monitoring in RA patients might consequently disclose the pathogenic process of RA and lead to the discovery of novel anti-rheumatoid arthritis medications [15-19]. Therefore, this study involves hydroxychloroquine management of RA against oxidative stress [20, 21].
Currently, numerous trials using treatments for oxidative stress have been made [22, 23]. It is impossible to [provide practicing Doctors as well as individuals with RA with literature and treatment options for the pathogenic mechanism of oxidative stress due to the diversity of these clinical trials interventions and results, as well as the inconsistent quality and degrees of the evidence, supplied [20-23].
Materials and Methods
Ninety (Male/Female; aged 30 to 65), made up the studied groups. These patients were chosen from the IBN-SINA Teaching Hospital's rheumatology clinic and other hospitals in Mosul. The individuals were all diagnosed with RA based on the most recent ACR guidelines. The sickness lasted an average of 4.7 years. As controls, people of the same sex and age were chosen. The aim of this research was enumerated to all participants, and consent was attained in writing. Patients taking NSAIDs for pain management were not allowed to participate in the trial, nor were those taking corticosteroids or experiencing an acute deterioration of their illness. The project received the project's approval from the institutional ethics committee.
The Study group of RA patients was grouped as follows:
Group I – consisted of 40 RA patients treated with Hydroxychloroquine.
Group II - consisted of 40 RA patients not treated with Hydroxychloroquine / DMARDs.
blood was collected from participants, Plasma MDA was measured [24] and total antioxidant activity (TAA) [25, 26]. Superoxide Dismutase (SOD) [27, 28] and whole blood glutathione (GSH) [29]. Data were statistically analyzed by Unpaired t-test and Pearson’s Correlation and expressed in terms of p value [30, 31].
A commercial kit was used to estimate the serum concentration of MDA for the total level of MDA (USCN Life Science Inc., Houston, USA). On a plate reader STAT FAX 2100, the results were read spectrophotometrically at 450 nm (Awareness Technology, Palm City, Florida, USA). The amount of MDA that was detected was measured in nanograms per milliliter (ng/mL).
The Windows version 12.6.1.0 of the MedCalc software was used to conduct statistical analysis. To check whether the data had a normal distribution, the Kolmogorov-Smirnov or Shapiro-Wilk tests were utilized. When comparing variables consisting of a normal distribution, the t-test for independent samples was utilized in showing the data as the mean standard deviation. The Mann-Whitney U-test was used to analyze the median and interquartile range for variables that did not have a normal distribution. For the statistical analysis of more than three groups, ANOVA and the Kruskal-Wallis test were utilized.
Results and Discussion
Table 1 Shows the results of the comparison of mean oxidative stress parameters (Malondialdehyde (MDA), total antioxidant status (TAOS)) of RA patients between group I, group II and group III. There are highly significant differences in MDA parameters among group I, group II and group III (control) (p= 0.001).
|
Table 1. Comparison in oxidative stress parameters among the three groups |
||||
|
Studied parameters |
Group I |
Group II |
Control |
P-value* |
|
MDA (ng\ml) |
105.7 ± 57.5B |
237.8 ± 108.9A |
22.1 ± 18.31C |
0.001 |
|
TAOS (U/ml) |
1.257 ± 1.20A |
1.150 ± 1.01A |
1.133 ± 0.872A |
0.882 |
* One-way ANOVA-test with Tukey's Pair wise comparisons was applied. Means that do not share a letter are significantly different.Data expressed as mean±SD
MDA (p = 0.0001) was elevated in RA individuals in comparison to controls. Whole blood GSH (p =0.005 ) & total antioxidant activity levels (p = 0.0001) were reduced in RA individuals in comparison to controls. Superoxide dismutase activity (p=0.005) was remarkably increased in RA individuals in comparison to controls.
Figure 1 Show highly significant differences in MDA among the three groups (group I, group II, group III), (p= 0.001).
|
|
|
Figure 1. The difference in MDA among the three groups. |
Table 2 Shows the results of the comparison mean serum lipid profile (cholesterol, TG, HDL, LDL, VLDL, Atherogenic index (AI)) of RA patients between group I, and group II and group III. There are highly significant differences in TG among group I, group II and group III (control) (p= 0.027).
|
Table 2. Comparison in lipid profile parameters among the three groups |
|||||
|
profile |
Group I |
Group II |
Control |
P-value* |
|
|
(mg\dl) |
195.70±38.24A |
184.47±30.89A |
175.07±36.02A |
0.081 |
|
|
TG (mg\dl) |
148.3±69.8A |
119.37±40.8AB |
114.53±37.71B |
0.027 |
|
|
HDL (mg\dl) |
48.87±8.26A |
49.13±7.18A |
52.93±6.95A |
0.068 |
|
|
LDL (mg\dl) |
114.39±38.88A |
110.0±35.83A |
99.23±40.63A |
0.296 |
|
|
VLDL (mg\dl) |
29.65±13.96A |
25.32±12.04A |
22.90±7.43A |
0.075 |
|
|
Atherogenic Index |
4.08±1.423A |
3.86±1.098A |
3.40±1.16A |
0.098 |
|
* One-way ANOVA-test with Tukey's Pair wise comparisons was applied. Means that do not share a letter are significantly different.
Figure 2 Show highly significant differences in TG among the three groups (group I, group II, group III), (p= 0.027).
|
|
|
Figure 2. The difference in TG among the three groups. |
Table 3 Show the results of Correlation matrix between different parameters (CRP, IL-1β, IL-6, TNF-α, MDA, TAOS, cholesterol, TG, HDL, LDL, VLDL, Atherogenic index) in group I. There are statistically significant positive correlation (r= 0.458)(p-value= 0.011) between IL-6β and TNF-α, statistically significant positive correlation (r=0.456) (p-value= 0.011) between MDA and TNF-α, statistically significant positive correlation (r=0.390)(p-value=0.033) between IL-1β and cholesterol, statistically significant positive correlation (r=0.474) (p-value=0.008) between IL-1β and TG, statistically significant positive correlation (r= 0.485) (p-value= 0.006) between IL-1β and VLDL and statistically significant negative correlation (r = -0.385) (p-value= 0.036) between TAOC and TG in the group I.
Figure 3 Show statistically significant negative correlation (r = -0.385) (p-value= 0.036) between TAOC and TG in the group I.
|
|
|
Figure 3. Correlation between TAOC and TG in the group I. |
The joints are affected by the chronic inflammatory illness known as rheumatoid arthritis (RA). A gradual symmetrical inflammation of the afflicted joints, which leads to cartilage loss, bone erosion, and incapacity, are its defining features [32]. Early on, only a few joints are afflicted; however, as the disease progresses, many more joints are damaged, and extra-articular symptoms are frequently reported [33]. Although there is no known cause of RA, both genetic and environmental variables have been demonstrated to have a role in its onset [34].
The present study was performed to evaluate the effect of hydroxychloroquine treatment on oxidants and antioxidant status {Malondialdehyde (MDA), total antioxidant status (TAOS)} and lipid profile {cholesterol, TG, HDL, LDL, VLDL, Atherogenic index (AI)}.
The current study involved sixty patients whose ages between (20-60) years of both sexes, known to have RA and referred by rheumatologists enrolled in this study.
The patients were separated into 2 groups: the first group (group I) included, thirty patients using conventional treatment (methotrexate, (MTX) and prednisolone) plus hydroxychloroquine (HCQ), Plaquenil tablet manufactured by Sanofi Aventis U.S., Bridgewater, UK, at dose 400 mg once daily.
The second group (group II) included thirty patients on conventional treatment (methotrexate, (MTX) and prednisolone) without using hydroxychloroquine. Both treatment groups had a duration of therapies of at least 6 months. The efficacy of both therapies on the clinical course of the disease was assessed by using Disease Activity Score-28 (DAS-28). As a control group III, 30 healthy, non-smokers, age and sex-matched to the patient, were considered).
|
Table 3. Correlation matrix between different parameters in Group I, [n = 30] |
||||||||||||||
|
Items |
Correl coef* |
ESR |
CRP |
IL-1 |
IL-6 |
TNF-α |
MDA |
T-AOS |
Chol |
TG |
HDL |
LDL |
VLDL |
|
|
r |
- 0.396 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
P |
0.031 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
IL-1 |
r |
0.030 |
- 0.060 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
P |
0.877 |
0.752 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
IL-6 |
r |
- 0.125 |
0.154 |
0.024 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
P |
0.512 |
0.417 |
0.898 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
TNF-α |
r |
- 0.033 |
0.255 |
0.178 |
0.458 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
P |
0.864 |
0.173 |
0.348 |
0.011 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
MDA |
r |
- 0.009 |
0.167 |
0.229 |
0.229 |
0.496 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
P |
0.963 |
0.378 |
0.223 |
0.223 |
0.005 |
--- |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
T-AOS |
r |
- 0.172 |
0.158 |
- 0.153 |
0.055 |
- 0.093 |
0.282 |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
P |
0.364 |
0.404 |
0.418 |
0.772 |
0.626 |
0.131 |
--- |
--- |
--- |
--- |
--- |
--- |
|
|
|
Chol |
r |
0.109 |
- 0.139 |
0.390 |
0.099 |
0.103 |
0.244 |
-0.171 |
--- |
--- |
--- |
--- |
--- |
|
|
P |
0.565 |
0.464 |
0.033 |
0.601 |
0.588 |
0.194 |
0.365 |
--- |
--- |
--- |
--- |
--- |
|
|
|
TG |
r |
0.074 |
- 0.060 |
0.474 |
0.049 |
0.099 |
-0.021 |
- 0.385 |
0.432 |
--- |
--- |
--- |
--- |
|
|
P |
0.698 |
0.755 |
0.008 |
0.798 |
0.605 |
0.912 |
0.036 |
0.017 |
--- |
--- |
--- |
--- |
|
|
|
HDL |
r |
- 0.166 |
0.269 |
- 0.149 |
0.159 |
0.135 |
0.079 |
0.284 |
- 0.694 |
- 0.599 |
--- |
--- |
--- |
|
|
P |
0.380 |
0.151 |
0.433 |
0.400 |
0.478 |
0.677 |
0.128 |
0.001 |
0.001 |
--- |
--- |
--- |
|
|
|
LDL |
r |
0.151 |
- 0.136 |
0.302 |
0.092 |
0.005 |
0.261 |
- 0.044 |
0.896 |
0.203 |
- 0.618 |
--- |
--- |
|
|
P |
0.426 |
0.475 |
0.104 |
0.629 |
0.979 |
0.163 |
0.819 |
0.001 |
0.281 |
0.001 |
--- |
--- |
|
|
|
VLDL |
r |
0.074 |
- 0.060 |
0.485 |
0.049 |
0.099 |
- 0.021 |
- 0.345 |
0.432 |
1.000 |
-0.599 |
0.203 |
--- |
|
|
P |
0.698 |
0.755 |
0.006 |
0.798 |
0.605 |
0.912 |
0.033 |
0.017 |
* |
0.001 |
0.281 |
--- |
|
|
|
AI |
r |
0.020 |
- 0.168 |
0.361 |
- 0.075 |
0.043 |
0.185 |
- 0.222 |
0.850 |
0.421 |
- 0.847 |
0.786 |
0.421 |
|
|
P |
0.916 |
0.374 |
0.040 |
0.695 |
0.820 |
0.329 |
0.238 |
0.001 |
0.021 |
0.001 |
0.001 |
0.021 |
|
|
* Pearson correlation method (r) was used.
The current results show that the results of comparison of mean oxidative stress parameters (Malondialdehyde (MDA) {(105.7 ± 57.5), (237.8 ± 108.9),(22.1 ± 18.31)}, total antioxidant status (TAOS) {(1.257 ± 1.20), (1.150 ± 1.01), (1.133 ± 0.872)}), are highly significant differences in MDA parameter among group I, group II and group III (control) respectively (p= 0.001) with non -significant differences in TAOS among group I, group II and group III (p= 0.882). Also, this study shows significant differences in MDA levels between RA patients in group I and group II. Salem & Zahran, 2021 agreed with the current study about the MDA parameter and showed highly significant differences in MDA levels between RA patients with or without taking HCQ while disagreeing about TAOS, which also showed highly significant differences in TAOS between groups. Le Zhang et al., 2020 disagreed with the current study and showed non-significant differences in MDA levels in RA patients with or without taking HCQ. While Nuttall et al., 2003: Spadaro et al., 2006: Firuzi et al., 2006 agreed with the current study, and showed non-significant differences in TAOS levels in RA patients with or without taking HCQ.
The current study shows that the results of the comparison mean serum lipid profile of RA patients between group I, group II and group III respectively, there are highly significant differences in TG among group I, group II and group III (p= 0.027) and highly significant differences in TG between group I and group II.
Salem and Zahran, 2021 showed highly significant differences in lipid profile( total cholesterol, TG, HDL, LDL, VLDL, AI) in RA patients with or without taking HCQ. This study agreed with the current study about TG while disagreeing with the current study regarding other parameters of lipid profile [35]. Nuttall et al., 2003 showed non-significant differences in lipid profile (total cholesterol, TG, HDL, LDL, VLDL, AI) in RA patients with or without taking HCQ. This study did not agree with the current study about TG while agreed with the current study regarding other parameters of lipid profile [36].
The results of the Correlation matrix between different parameters (CRP, IL-1β, IL-6, TNF-α, MDA, TAOS, cholesterol, TG, HDL, LDL, VLDL, Atherogenic index) in group I. There are statistically significant positive correlation (r= 0.458) (p-value= 0.011) between IL-6 and TNF-α. Jang et al., 2006 agreed with the current study and showed a significant positive correlation between IL-6 and TNF-α [37]. Samimi et al., 2020 disagreed with the current study and showed no correlation between IL-6 and TNF-α [38]. The current study shows statistically significant positive correlation (r= 0.456) (p-value= 0.011) between MDA and TNF-α. Abdollahzad et al., 2015 and Salem et al., 2021 agreed with the current study and showed a significant positive correlation between MDA and TNF-α [39, 40], while Gasmi et al., 2021 disagreed with the current study and showed no correlation between MDA and TNF-α [41].
The current study showed a positive correlation between IL-1β and cholesterol, TG, VLD versus IL-1β, and a negative correlation between TAOS and TG in group I. The effects of HCQ on MHC Class II expression and antigen demonstration, activities of pro-inflammatory cytokines [such as interleukin-1 (IL-1) tumor necrosis factor-(TNF)], control of toll-like receptor-9 stimulation, and leucocyte generation of reactive oxygen species (ROS), i.e. antioxidant capacity (TAOS) [42] were demonstrated by Rainsford et al. in 2015.
Ben-Zvi et al., 2012 [43] showed, In addition, it was demonstrated that hydroxychloroquine (HCQ) medication reduced triglyceride levels in RA patients regardless of concurrent steroid use, while Tam et al., 2000 shows HCQ had no significant effect on the serum lipid profile [44]. Finally, the current study shows that HCQ was a highly significant improvement in oxidative stress parameter (MDA), and TG concentrations in the serum patients with RA compared with RA patients on conventional therapy and control and was a highly significant improvement in MDA and TG levels in comparison with conventional therapy.
It is worthy to mention that hydroxychloroquine is used in COVID-19 with an obscure mechanism of action [45-49], either alone or with zinc as a cofactor for potential therapy [50]. While the proposed mechanism also involved reduced oxidative and pro-inflammatory damage, nonetheless, these data need further confirmation at a molecular level to confirm the therapeutic activities.
Conclusion
The addition of hydroxychloroquine to the regimen of patients with rheumatoid arthritis improved the outcome via reducing metabolic derangement and restoration of redox quasi-equilibrium.
Acknowledgments: We thank the regional research ethics committees at the University of Mosul, College of Pharmacy, and Health Administration Research Technical Support for their Ethics approval of the study. We are also very grateful and express our deep thanks to Dr.Gaidaa A.Ahmed(Consultant Rheumatologist) and to all of the medical staff of the in-patient and out-patient clinic in IBN-SINA Teaching Hospital in Mosul city for their valuable help and support in carrying out the requirement of the research study.
Conflict of interest: No potential conflicts exist. We had full access to all the information in the study and take full responsibility for the integrity of the information and the accuracy of the data analysis.
Financial support: The research was fully self-funded.
Ethics statement: The study was approved by the Research Ethical Committee and Scientific Committee in the College of Medicine/University of Mosul, Study approval letter CoM/UoM/4109
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