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Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 5  

Review Article   

Comprehensive analysis and critical review of randomized clinical trials on 

safety profiling of Hydroxychloroquine and Belimumab  

Zahra Maryam1, Ausaf Ahmad2  

From, 1M S Scholar, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolou University, Turkey, 2MS Scholar, 

School of Life and Medical Sciences. University of Hertfordshire, UK.   

Correspondence to: Zahra Maryam, M S Scholar, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu 

University, Eskişehir 26470, Turkey. Email: zahra.maryam489@gmail.com  

ABSTRACT 

Systemic Lupus Erythematosus (SLE), an autoimmune disorder is characterized by multiorgan damage, flares, and heterogeneity in its 

clinical symptoms. The treatment strategy for this notorious disease focuses on long-term antiSLE treatment to improve the quality of 

life, prevent flares, and suppress the immune system. Thus, the chronic use of SLE medicines makes it inevitable to study the safety 

and tolerability of drugs in large populations. In this comprehensive analytical study, Hydroxychloroquine (HCQ), which is known for 

its safe use in SLE, and Belimumab, which is comparatively a novel monoclonal antibody were critically analyzed for their adverse 

events. We performed the absolute risk, relative risk ratio, and odds ratio analysis after critically scru tinizing the clinical trials for 

significant adverse effects. HCQ showed major effects on the eye and heart. However, based on the results, HCQ was found to be safer 

than Belimumab, as a few serious complications were found associated with Belimumab. Our results were found to be as per the 

previous metaanalysis. This comprehensive review is aimed at analyzing the safety profiles of two widely used drugs for SLE Ie HCQ 

and Belimumab. We have conducted this review, critical analysis was done to critically a nalyze the clinical trials, and to gather the 

information of interest from these trials. Both anti-SLE drugs; HCQ and Belimumab were found to be safe for use against SLE. But 

comparatively, HCQ showed a safer profile than Belimumab which can be attributed to HCQ’s longterm history of use since 1955.  The 

observation emphasized the researchers for further clinical trials with a more standardized approach, specifically for Belimumab to 

determine its safety and tolerability in the post-marketing stage. 

Key words: Systemic lupus erythematosus, belimumab, hydroxychloroquine, safety, risk analysis

ystemic Lupus Erythematosus is a systemic disease, 

involving a multiorgan system and is chronic. It results 

in severe damage to the organ system and its dysfunction. 

SLE is the result of a multistep cascade of immune system 

abnormalities starting with the inability of the cells to clear 

apoptotic bodies, which results in the activation of both arms of 

the immune system (adaptive and innate immunity), formation 

of immune complexes, and tissues’ inflammation that results in 

an autoimmune process [1].  Apoptosis has a crucial role in the 

development of lupus. Increased non-cleared apoptotic debris is 

linked to inflammation and the generation of autoantibodies [2].  

Autoantigens are released by apoptotic cells [3].   

These can produce noticeable levels of type 1 interferon by 

activating TLR7 and TLR9 in dendritic cells [4, 5]. The 

aetiology of SLE includes aberrant clearance of immunological 

complexes (ICs) and apoptotic cells and low thresholds of B and 

T lymphocyte activation that result in loss of self-tolerance and 

autoantibody synthesis. Interaction of genetic predisposition, 

immunological, and hormonal variables, and environmental 

triggers is necessary for the clinical commencement of SLE.  

SLE shows itself in a range of clinical manifestations. The 

symptoms can range from hair loss (that can be thought of as 

mineral deficiency) and light sensitivity to lethal conditions like 

inflammation of the myocardium, brain, and nephrons. Thus, 

symptoms of SLE are heterogeneous and may differ in different 

individuals or among the same individual for different periods 

[1]. The complex nature of SLE makes it more difficult to treat 

because of its unpredictable symptoms [6].    

SLE can affect both genders, but it affects women more than 

men. The ratio of SLE in males to females is 1 man against 13 

women making it a feminine disease [7].  The disease is 

common in African lineage and African Americans inhabiting 

European countries and the United States. Interestingly and 

controversially, the disease is rare in Africa itself [8]. 

According to the Centre for Disease Control and Prevention, 

there are around 322,000 probable or confirmed cases of SLE, 

with the prevalence being higher in African Americans, 

American Indians, and Alaska Natives [9, 10]. For SLE 

S 

mailto:zahra.maryam489@gmail.com


Maryam and Ahmad                                                          Safety Comparison of Hydroxychloroquine and Belimumab 

Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 6  

“Standard of care” therapy consists of immunomodulators, 

antimalarials, corticosteroids, immunosuppressive, and 

cytotoxic agents. The purpose of this treatment includes 1) 

minimizing the activity level of the immune activation by using 

immunosuppressants and by avoiding the triggers 2) protecting 

the organs from damage 3) minimizing the risk of comorbid 

conditions associated with lupus 4) reduction of pain and 

lethargy. The treatment is necessary for the early stages of SLE 

to avoid known triggers and to maximize the effects of 

immunomodulators. This critical review aims to analyse the 

safety profiles of the two drugs used for the treatment of SLE 

I-e HCQ and belimumab.   

SLE is a challenging disease with current therapy aimed to 

restore the imbalance of the dysregulated immune system. B 

cells are important in the development of SLE's 

pathophysiology. Therefore, attempts to interfere with disease 

activity by targeting B lymphocytes for selective depletion 

using monoclonal antibodies is a promising strategy to increase 

therapeutic effectiveness. Thus, recent therapies focus on the 

development of monoclonal antibodies. Belimumab is an 

immunoglobulin monoclonal antibody that was approved by 

Food and Drug Administration in 2011 for treating adults with 

SLE [11]. It is a fully human antibody that inhibits soluble B 

lymphocyte stimulator (BLyS), which in turn inhibits the 

production of a crucial cytokine that is essential for B cell 

survival, proliferation, and differentiation [12 – 14].   

Therapy with belimumab is a helpful treatment option for 

patients with active SLE despite conventional therapy due to 

the adaptability of the route of administration and the ease of 

the once-weekly regimen. The belimumab is metabolized by 

proteolytic enzymes and the proteolytic enzymes are not only 

restricted to hepatic tissue. Moreover, the level of hepatic 

enzymes e.g., Aspartate aminotransferase (AST) and alanine 

aminotransferase (ALT) had no discernible effect on the 

pharmacokinetics of belimumab in trials. Thus, no dose 

adjustment of Belimumab is necessary for patients with hepatic 

impairment. The previous studies reported Belimumab to cause 

bronchitis, diarrhoea, viral upper respiratory tract infections 

(URTI), multifocal leukoencephalopathy, fatal 

hypersensitivity, and infusion reactions [15, 16]. HCQ is an 

alkalinizing substance. It is a lysosomotropic medication 

having high cell permeability that is accumulated in lysosomes 

where it raises the pH [17].  

 
Figure 1 – Chemical structure of HCQ  

HCQ was originally used as an antimalarial drug, but also 

found beneficial for treating autoimmune conditions like 

rheumatoid arthritis and SLE. It has been demonstrated to slow 

the onset of disease, maintain remission, lessen the likelihood of 

complications, and decrease the frequency of disease flare-ups 

[18,19].  HCQ has a broad spectrum of activity and safety 

profiles; thus, it can be given to the majority of SLE patients and 

can be continued throughout pregnancy. HCQ-associated 

toxicity is uncommon, minor, and typically reversible and it can 

reduce lupus activity in pregnant women without endangering 

the unborn child [20].  The Adverse Drug Reactions (ADR) 

requiring clinical aid include ocular ADRs and effects on the 

heart [21].  

The present review is aimed at analyzing the safety profiles 

of HCQ and Belimumab by the critical review as HCQ was 

recently used in the global pandemic of covid-19 and recent data 

is available on HCQ safety profiling. The review will focus on 

statistically analyzing the adverse drug effects of the two drugs: 

HCQ and Belimumab and theoretically choosing the best drug 

choice for SLE. This can be done by signal detection from 

scientific databases; clinicaltrial.gov, PubMed, and other 

research articles.  

METHODOLOGY  

This critical review is aimed at analyzing the pharmacovigilance 

studies and comparing the adverse effects of the two drugs used 

for treating SLE.   

Database selection: We searched authentic electronic databases 

PubMed, Google Scholar, NCBI (National Center for 

Biotechnology Information), and ScienceDirect to collect data. 

These scientific databases help find citations for sources, which 

can broaden the scope of the articles retrieved. For unpublished 

data extraction and collection of data directly from clinical trials, 

the website clinicaltrials.gov was used. For the clinical trials 

search, the keywords HCQ, Belimumab, and SLE were 

employed. All clinical trials that focussed on the safety and 

efficacy of HCQ and Belimumab were considered acceptable for 

the study. Because the number of clinical trials was small, thus, 

the area of research was broadened to the published articles as 

well. The trials were then scrutinized for inclusion and exclusion 

criteria.      

Inclusion and exclusion criteria: A PICO (patient, 

intervention, comparison, and outcomes) approach was applied 

to include the studies in this comprehensive review. All the 

participants in the clinical trials were included in this study. 

Patients of both sexes (males and females) of age more than 18 

were enrolled. The outcomes considered for this critical analysis 

were serious adverse effects, all-cause mortality, serious adverse 

events, and non-serious adverse events. The adverse effects of 

the drugs after treating the patients with HCQ and Belimumab 

were compared with the adverse effects observed in the Placebo 



Maryam and Ahmad                                                          Safety Comparison of Hydroxychloroquine and Belimumab 

Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 7  

group. The data relating to adverse events were considered for 

extraction. The data was extracted in the form of the number of 

persons having adverse events.    

 
Figure 2 – Flow diagram of search strategy  

Statistical Analysis: All the statistical analyses were performed 

using Microsoft Excel software. We extracted the number of 

persons from trials and then the percentage of persons having 

Adverse Events was determined. 

 

The formula employed for the percentage determination is given 

in equation 1. The absolute risk, relative risk, risk difference, and 

odds ratio were calculated. The absolute risk was calculated by 

dividing the number of participants having Adverse Effects (AE) 

by the total number of participants for both drugs (HCQ and 

Belimumab) separately. The formula for absolute risk is given 

in equation 2. The risk difference was calculated by equation 3. 

The odds ratio shows the likelihood that an outcome will occur 

given a specific exposure in comparison to the chances of the 

event occurring without that exposure [22].  The odds ratio 

ranges from 0 to 1 and is always positive. If the OR is 1, it means 

that there is no difference in the outcome of interest between the 

treatment and the control. When the OR is greater than 1, the 

treatment is more likely than the control to cause the desired 

outcome [23].  The odd ratio was calculated using the following 

formula mentioned in equation 4. Relative risk compares the 

likelihood of a health event (in the present study, the adverse 

event) among two groups. Relative Risk was determined using 

equation 5.   

RESULTS  

We identified 90 records for Belimumab and 509 studies on 

HCQ. The clinical trials not focussing on safety and efficacy 

were excluded. The articles on safety and efficacy were then 

screened for inclusion in studies. Among the selected trials, the 

trials having no results posted were also excluded and finally, 

four articles were included in this critical analysis. To compare 

the data on adverse effects between Belimumab and HCQ, the 

risk difference and relative risk between the two were 

calculated. Table 1 shows the risk difference and relative risk 

between the two drugs.       

Table 1 – Risk difference and Relative Risk calculation  

  AR  

BEL   

AR 

HCQ   

RD   p1/p2 

(RR)   

Gastrointestinal 

disorders   

31.88   15.66   16.22   2.04   

General disorders   10.43   6.56   3.87   1.59   

Nervous system 

disorder   

20.80   3.27   17.53   6.36   

Psychiatric disorders   9.61   2.18   7.43   4.41   

Skin disorders   3.60   4.61   -1.01   0.78   

Cardiac Disorders   1.27   4.36   -3.09   0.29   

Eye Disorders   0.33   0.49   -0.16   0.67   

Immune Disorders   0.35   0.37   -0.02   0.95   

*AR – Absolute Risk, RD – Risk Difference, RR – Relative risk, 

HCQ – Hydroxychloroquine, BEL – Belimumab  

The results showed the major effects of Belimumab on the 

gastrointestinal tract, nervous system, and heart. In some of the 

participants, Belimumab was found associated with depression, 

suicidal thoughts, and changes in sleep patterns (insomnia). The 

positive value of risk difference in Table 1 indicates that 



Maryam and Ahmad                                                          Safety Comparison of Hydroxychloroquine and Belimumab 

Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 8  

Belimumab has an increased risk of causing gastrointestinal 

disorders, general disorders, nervous systems, and Psychiatric 

disorders compared to HCQ in patients. While the negative 

value of risk difference for Belimumab indicates the increased 

risk of skin disorder, eye disorders, immune disorders, and 

cardiac disorders by HCQ.   

The results show the relative ratio of Belimumab /HCQ of 2 

for GIT problems which indicates that the persons taking 

Belimumab are twice as likely to suffer from gastrointestinal 

issues as the people taking HCQ. Similarly, the relative risk ratio 

for the general disorder is 2 (2X risk to suffer from general 

problems if the person is taking Belimumab), for Nervous 

disorders, the RR ratio came out to be 6.4, and for Psychiatric 

disorders, it is 4.41. Skin disorders show a relative risk ratio of 

0.78 indicating that Belimumab is less likely to cause skin 

problems as compared to HCQ, in other words, HCQ is 1.3 times 

more likely to cause skin problems than Belimumab.   

Likewise, the RR ratio for the cardiac disorder is 0.29 

showing 3.5 times increased risk of having cardiac abnormality 

for people taking HCQ with dyspnoea and chest pain as major 

effects. for eye disorder RR ratio is 0.66 showing a 1.5X risk for 

patients taking HCQ, and the ratio for immune disorders is 

surprisingly 0.92 which somewhat shows the equal risk of 

getting an immune disorder with the use of HCQ and 

Belimumab. Moreover, 2 cases of mortality were observed in 

patients taking Belimumab, while no allcause mortality was 

observed when the patients were administered a placebo or 

HCQ. Then we compared the adverse effects of the drugs 

Belimumab and HCQ with respect to the placebo and calculated 

the odds ratio. Table 2 shows the odds-ratio calculation for 

Belimumab.  

Table 2 - Odd Ratio calculation for Belimumab  

  BEL   PL   OR   

Gastrointestinal disorders   31.88   33.00   0.95   

General disorders   10.43   10.45   1.00   

Nervous system disorder   20.80   23.84   0.84   

Psychiatric disorders   9.61   9.68   0.99   

Skin disorders   3.59   3.62   0.99   

Cardiac Disorders   1.27   1.91   0.66   

Eye Disorders   0.33   0.00   0.33   

Immune Disorders   0.34   0.17   2.00   

*BEL – Belimumab, PL – Placebo, OR – Odds Ratio  

The odds ratio for Belimumab showed the value of 1 for a 

gastrointestinal disorder, general disorder, Psychiatric disorders, 

and Skin problems. This predicts an equal probability of 

Belimumab and Placebo showing these disorders. In the case of 

Immune disorders, the odds ratio is 2, indicating two times 

increased risk of Belimumab to induce immune abnormality 

compared to placebo. 0.33 Odds-ratio for Eye disorder, and 0.66 

for Cardiac disorder show rather a protective role of Belimumab 

for these organs compared to Placebo. For HCQ, in one of the 

trials we selected, the adverse effects of HCQ have been 

compared with Ascorbic acid so, for this trial, the odds ratio was 

compared with Ascorbic acid. The results of this are illustrated 

in Table 3.   

In the present trial, Ascorbic acid acted as a placebo 

equivalent. While the second trial of HCQ as Chemoprevention 

for COVID-19 for High-Risk Healthcare Workers had no 

placebo as the trial was during an ongoing pandemic situation. 

The participants enrolled in the study were on-duty high-risk 

healthcare workers receiving HCQ and the placebo group might 

increase the chance of covid19. In the trial, HCQ did not show 

any risk to the Nervous system and Psychiatric related disorders. 

However, Oddsratio for eye disorder was found to be 98.96, 

indicating 99 times increased risk of having an eye disorder for 

a person taking HCQ as compared to Ascorbic acid. The odds 

ratios are 2.5, 277.5, and 3 for gastrointestinal disorders, skin 

disorders, and immune disorders respectively showing a 

multifold increase in the risk of these disorders if a patient is 

taking HCQ compared to Ascorbic acid.   

Table 3 – Odd Ratio calculation for HCQ  

  HCQ   AA   OR   

Gastrointestinal disorders   9.58   4.03   2.52   

General disorders   4.42   7.58   0.56   

Nervous system disorder   0.01   0.01   1.00   

Psychiatric disorders   0.01   0.01   1.00   

Skin disorders   2.7   0.01   277.46   

Cardiac Disorders   0.01   0.01   1.00   

Eye Disorders   0.98   0.00   98.96   

Immune Disorders   0.74   0.24   3.10   

*HCQ – Hydroxychloroquine, AA – Ascorbic acid, OR-Odds 

ratio  

DISCUSSION  

The recent advancements in the molecular mechanism of SLE 

and SLE’s association with the immune arm led to the 

development of novel monoclonal antibodies against SLE. SLE 

is an autoimmune disorder thus main clinical strategy behind 

antibody design is to target immune cells to inhibit the 

overactivation of the immune system and the overproduction of 

cytokines [24]. This critical analysis was focused on comparing 

the two SLE drugs Belimumab and HCQ. There is no doubt that 

B cells are crucial to the development of SLE and Belimumab 

has a recognized function in SLE treatment [25].    

Additionally, clinical trials have demonstrated the 

effectiveness of belimumab by demonstrating a beneficial 

improvement in disease activity. Based on its efficacy, Food and 

drug administration approved it in 2011 [26].  Whereas, HCQ 

has a long history of use in SLE since it was approved in 1955 

for SLE treatment [27].  Given its broad spectrum of activity, 



Maryam and Ahmad                                                          Safety Comparison of Hydroxychloroquine and Belimumab 

Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 9  

Recently, HCQ was frequently used as a protective treatment for 

Covid-19. The use of this drug globally provided a golden 

chance for clinicians and researchers to look widely at the 

adverse events associated with HCQ. Thus, we performed a 

critical review of the recent clinical trials conducted on diverse 

populations for HCQ during the Covid-19 pandemic.   

We compared the adverse events of HCQ with a relatively 

novel monoclonal antibody Belimumab by critically analyzing 

the clinical trials, and utilizing that data to calculate absolute 

risk, relative risk, and odds ratio for drugs. The trials of 

Belimumab reported a range of adverse events from 

gastrointestinal discomforts to serious Psychiatric disorders. 

However, the results of the trials observed under the scope of 

the study were not in harmonization. The results observed in one 

of the trials reported a 41.7% risk of gastrointestinal, and 

28.61% risk of Nervous system disorders. These results 

observed were almost double the AEs observed in the other trial 

of the same drug. Similarly, the risk for general disorders was 

almost 16 times greater than in another trial for Belimumab. 

However, the trials presented an equal percentage risk for 

Cardiac and eye disorders. The significant heterogeneity in 

results reported by the trials can be presented as the difference 

in the number of the study group and the ethnicity of the 

population selected for the trial as one trial employed Americans 

and the other trial was conducted on Americans, Europeans, and 

Asians.   

Trials for HCQ showed a safe profile in comparison to 

Belimumab. However, we also observed discrepancies in the 

results of the HCQ trials. The absolute risk for gastrointestinal, 

general, and skin disorders was found to be 21.74%, 8.7%, and 

6.52% for one trial against the minute values of 9.58%, 4.42%, 

and 2.7% for another. Interestingly, the trial also failed to 

provide any adverse effect on Cardiac disorders, the more 

pronounced effects for which HCQ is famous. Again, this can 

be attributed to uneven sample size, differences in entry 

requirements, and the environment in which the trials are being 

conducted. Belimumab caused 2 mortalities while HCQ showed 

no mortality. The odds ratio calculated for HCQ and Belimumab 

trials presented an abrupt trend with a range of values from 0.3 

to 277. The odds ratio for Belimumab/Placebo showed a value 

of 0.3 while 98.96 for HCQ/Placebo for eye disorders. 0.3 

indicates three times more effect of Placebo on eyes and rather 

a protective role of Belimumab for eyes. On the other hand, 

98.96 for HCQ/Placebo showed 99 times increased tendency of 

HCQ to cause eye ailments.   

The most common cardiac effects reported in our study by 

HCQ include chest pain, dyspnoea, QT prolongation, and QT 

syndrome. These results for HCQ are in concordance with 

previous studies as the previous studies conducted for HCQ 

showed the increased probability of the drug for 

cardiomyopathy, eye disorders, and skin hyperpigmentation 

[28]. In addition to corneal deposits, dysfunction in the ciliary 

body, posterior subcapsular lens opacity, uneven macular 

pigmentation, and hydroxychloroquine can result in side effects 

including a ring of macular pigment dropout. Additionally, the 

HCQ manufacturers claim that HCQ is contraindicated in 

already existing maculopathy conditions [29]. In some studies, 

for example, HCQ-induced retinopathy was found to be more 

common in those who used the drug for longer than five years, 

with a prevalence of 7.5%, and between 20 and 50% in people 

who used it for longer than twenty years [28].   

The results of our clinical trials’ analysis revealed that 

Belimumab has the highest drug-related adverse effects that 

range from gastrointestinal disorders, and general disorders, to 

more serious events in nervous systems, and Psychiatric 

disorders. Belimumab treatment presented one case of a 

successful suicidal attempt and 2 cases of mortality. The results 

of our study resonate with the Belimumab Assessment of safety 

study (BASE) trial and Medicines and Healthcare Products 

Regulatory Agency UK drug update who suggested the increase 

in Psychiatric disorders and mortality rate. After the critical 

analysis of the results, we concluded that except for the effects 

of HCQ on heart and retinopathy, HCQ was found to be safer 

than Belimumab. Previous studies also confirm the safety of 

HCQ [17].   

The safe safety profile of HCQ can be due to the tolerability 

of the drug attributed to the well-established and long-term use 

of HCQ in the general population while Belimumab in turn is a 

novel agent. However, a critical point here is that the trials 

conducted for Belimumab also showed adverse effects with 

Placebo. Thus, the odds-ratio calculated for Belimumab showed 

neglected adverse effects with Belimumab except for the 

immune system disorder that is again the known AE of 

Belimumab. However, contrary to HCQ, Belimumab was found 

associated with suicidal attempts and depression cases which 

makes HCQ a safer drug than Belimumab.       

CONCLUSION  

The critical analysis of the adverse effects of the drugs, 

Belimumab and HCQ showed the safe profile of both drugs. 

Like the previous studies, HCQ showed major adverse effects 

on the heart and eyes, while Belimumab was found associated 

with immune system disorders. Though both drugs were found 

to be safe for anti-SLE treatment because of their long-term use, 

HCQ was found to be safer, having less serious adverse effects 

than Belimumab. Thus, based on the results and observed 

heterogeneity in the results, it can be concluded that for result 

homogeneity and to further evaluate the safety and efficacy of 

Belimumab, high-quality randomized controlled clinical trials 

on larger population sizes are needed.  

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Maryam and Ahmad                                                          Safety Comparison of Hydroxychloroquine and Belimumab 

Vol 2 | Issue 1 | Jan – Mar 2023                                                                                     Indian J Pharm Drug Studies | 10  

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How to cite this article: Maryam Z, Ahmad A.  

Comprehensive analysis and critical review of randomized 

clinical trials on safety profiling of HCQ and Belimumab. 

Indian J Pharm Drug Studies. 2023; 2(1) 5-10.  

Funding: None                    Conflict of Interest: None Stated 

 

http://www.fda.gov/medwatch

