







































_____________________________________________________________________________________________________ 
 
++ Assistant Professor; 
*Corresponding author: E-mail: pranithaavunoori1310@gmail.com; 
 
Cite as: Gupta, N., Begum, S., Farooqui, V., Afreen, S., & Avunoori, P. (2024). A review on Iguratimod: Bridging Hope for 
Arthritis Patients through the Dual Power of Immunomodulation and Anti-inflammation. Asian Journal of Immunology, 7(1), 79–
89. Retrieved from https://journalaji.com/index.php/AJI/article/view/132 

 
 

Asian Journal of Immunology 
 
Volume 7, Issue 1, Page 79-89, 2024; Article no.AJI.115805 
 

 
 

 

 

A review on Iguratimod: Bridging Hope 
for Arthritis Patients through the Dual 

Power of Immunomodulation and  
Anti-inflammation 

 
Nikita Gupta a++, Sana Begum a++, Varda Farooqui a++,  

Summaiya Afreen a++ and Pranitha Avunoori a++* 

 
a Department of Pharmacy Practice, St. Pauls College of Pharmacy, Hyderabad, Telangana-510. 

India. 
 

Authors’ contributions  
 

This work was carried out in collaboration among all authors. All authors read and approved the final manuscript. 
 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2024/v7i1132  
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers,  

peer review comments, different versions of the manuscript, comments of the editors, etc are available here: 
https://www.sdiarticle5.com/review-history/115805 

 
 
 

Received: 13/02/2024 
Accepted: 16/04/2024 
Published: 18/05/2024 

 
 

ABSTRACT 
 

Iguratimod is a small novel compound considered as a disease-modifying anti-rheumatic drug 
(DMARD), which exhibits anti-inflammatory and immunomodulatory effects. Iguratimod acts directly 
on B cells by inhibiting the production of inflammatory cytokines (tumor necrosis factor-α, 
interleukin (IL)-1β, IL-6, IL-8, IL-17), thereby suppressing the production of immunoglobulin and 
inhibiting the activity of nuclear factor kappa-light chain enhancer of activated B cells. Preclinical 
studies demonstrate its positive impact on arthritis models in animals by reducing immunoglobulin 
production and various inflammatory cytokines. Iguratimod demonstrates its efficacy as well as 
tolerance when used as an additional therapy for rheumatoid arthritis patients who exhibit an 
insufficient response to both methotrexate and biological disease-modifying anti-rheumatic drugs. 

Review Article 

https://doi.org/10.9734/aji/2024/v7i1132
https://www.sdiarticle5.com/review-history/115805


 
 
 
 

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Additionally, iguratimod was found to possess an anabolic effect on bone metabolism, through both 
stimulations of osteoblastic differentiation and inhibition of osteoclastogenesis. 
Further, the mechanism also involves suppressing nuclear factor kappa B (NF-κB) activation 
without blocking NF-κB inhibitor α (IκBα) degradation. Although the true target molecules of 
iguratimod have been unclear, it would be necessary to suppose the multiple mechanisms 
including suppression of NF-κB. Clinical trials of rheumatoid arthritis patients have shown more 
effectiveness and tolerability when compared to salazosulfapyridine, making iguratimod a 
promising DMARD with unique novel properties and positive clinical outcomes. Further research 
will determine its suitability as an alternative for patients unable to use biologics. 

 

 
Keywords: Anti-inflammation; iguratimod; arthritis; immunomodulation. 

 
1. INTRODUCTION  
 

1.1 Rheumatoid Arthritis  
 

“Rheumatoid arthritis (RA) is a persistent 
autoimmune disorder with an unknown cause, 
marked by synovial inflammation in the joints, 
gradual bone damage, and a decline in joint 
functionality. In the absence of treatment, 
deteriorating joints can result in pain and 
stiffness, which limit physical function and lead to 
long-term disability” [1]. “The development of RA 
is associated with genetic, environmental, and 
immune factors. The objective of treating 
individuals with RA is to achieve clinical 
remission or maintain low disease activity, 
ultimately preventing damage to joint function, 
Current treatments for RA include non-steroidal 
anti-inflammatory drugs (NSAIDs), conventional 
synthetic disease-modifying anti-rheumatic drugs 
(csDMARDs), and biological disease-modifying 
anti-rheumatic drugs (bDMARDS). the use of 
biological DMARDs to treat RA is not suitable for 
all patients for various reasons, including 
complications, side effects, uncertain efficacy, 
and high costs that prevent their use” [2]. 
 

1.2 Iguratimod 
 
“Iguratimod, is a small novel compound 
considered as a disease-modifying anti-
rheumatic drug (DMARD), which exhibits anti-
inflammatory and immunomodulatory effects.IGU 
suppresses the production of inflammatory 
cytokines in cultured monocyte THP-1 cells and 
synovial cells derived from RA patients by 
inhibiting the activation of nuclear factor kappa-B 
(NF-κB)” [3]. “Additionally, it hinders 
immunoglobulin production through a direct 
impact on B cells without inducing cytostatic 
effects” [4]. “IGU exhibits anti-inflammatory 
effects and improves abnormal immunological 
conditions in various animal models of 

inflammation and autoimmune diseases, 
including RA” [5,6]. “Recently, it has been noted 
that IGU inhibits receptor activator of NF-κB 
ligand (RANKL)-induced osteoclast differentiation 
and migration in RAW264 cells by modulating the 
NF-κB and mitogen-activated protein kinase 
(MAPK) pathways. This finding is especially 
intriguing in relation to its stimulatory effect on 
osteoblastic differentiation” [7]. 
 

2. MECHANISM OF IGURATIMOD  
 

2.1 Anti-Inflammatory 
 
“Iguratimod possesses anti-inflammatory 
properties, as demonstrated by its ability to 
restrain the release of bradykinin in a mouse 
model of kaolin-induced arthritis. Initially created 
as an innovative nonsteroidal anti-inflammatory 
drug (NSAID)” [8]. Research has extensively 
documented the anti-inflammatory, analgesic, 
and antipyretic properties of Iguratimod in 
diverse animal models. Its mechanism involves 
suppressing the metabolism of arachidonic acid 
metabolite prostaglandin E2 [9], inhibiting the 
release of bradykinin, decreasing the production 
of interleukin (IL)-1 and interleukin (IL)-6 [10,11], 
and selectively inhibiting the activity of 
cyclooxygenase-2 [12]. “In different models of 
autoimmune disorders, Iguratimod demonstrated 
notable inhibitory effects. These effects were 
observed in experimental autoimmune 
encephalitis, chronic contractile injury linked with 
neuropathic pain, and dextran sodium sulfate-
induced colitis” [4,12-20]. “Significantly, 
iguratimod's ability to selectively inhibit COX-2 is 
crucial, leading to a reduction in prostaglandin 
levels and accomplishing its anti-inflammatory 
effects. Importantly, iguratimod is less prone to 
causing gastrointestinal ulcers because of its 
selective inhibition of COX-2, distinguishing it 
from nonsteroidal anti-inflammatory drugs 
(NSAIDs) that inhibit both COX-1 and COX-2” 



 
 
 
 

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[12]. “Iguratimod also hampers the secretion of 
inflammatory cytokines induced by TNF-α and 
curtails NF-κB activation in human synovial cells. 
This interference includes impeding the 
translocation of NF-κB P65 into the nucleus. 
Through the inhibition of NF-κB activity, it 
modulates transcriptional regulation to suppress 
the production of cytokines and chemokines, 
thereby exerting anti-inflammatory effects” 
[16,17]. “Iguratimod has been observed to disrupt 
the TNF-α-induced translocation of NF-κB from 
the cytoplasm to the nucleus. This interference 
leads to the inhibition of TNF-α-induced 
production of IL-6, IL-8, and monocyte 
chemoattractant protein 1. Hence, iguratiomud 
has the potential to modulate the expression of 
inflammatory factors by regulating the NF-κB 
signaling pathway” [18]. “In the regulation of 
neutrophils, it has been discovered that 
Iguratimod suppressed the expression of CPs by 
downregulating PAD in neutrophils from RA 
patients. Notably, this effect was comparable to 
the impact of MTX and DXM at suitable 
concentrations. These results offer valuable 
insights for refining the treatment of rheumatoid 
arthritis (RA). Iguratimod, at an optimal 
concentration comparable to MTX and 
dexamethasone, effectively hinders the 
expression of citrulline proteins in neutrophils 
from RA patients. This inhibitory effect is 

attributed to the downregulation of peptidyl 
arginine deiminase, shedding light on the 
mechanism of Iguratimod in RA treatment. The 
findings from this study can provide valuable 
guidance for the treatment of rheumatoid arthritis 
and facilitate the identification of additional 
therapeutic targets” [19]. 
 

2.2 Immune Response 
  
2.2.1 Regulating humoral immunity 
 

“In 2003, researchers initially observed that IGU 
had a direct inhibitory impact on B lymphocytes 
in both mouse and human subjects, leading to a 
decrease in the synthesis of immunoglobulins. 
Notably, this inhibition did not influence the 
proliferation or apoptosis of B cells [4]. In 
MRL/LPR mice, IGU demonstrated the ability to 
decrease circulating plasma cells through a 
mechanism that does not involve anti-
proliferative effects” [21]. “In a recent study, it 
was shown that IGU did not influence the 
activation and proliferation of B cells within the 
established in vitro human antibody-secreting cell 
differentiation system. However, its inhibitory 
effects were observed in the differentiation of 
human antibody-secreting cells, achieved by 
targeting the protein kinase C (PKC) and early 
growth response 1 (EGR1) axis” [22]. 

 

 
 

Fig. 1. Depicts the anti-inflammatory mechanism of IGU (Iguratimod) 
 IGU effectively suppresses inflammation through several pathways. Firstly, it inhibits the activity of MIF 

(macrophage migration inhibitory factor) and counteracts MIF-induced proinflammatory effects. Additionally, IGU 
disrupts IL-17-mediated signaling by interfering with the interaction between Act1 and TRAF5, as well as IKKi, 

thereby reducing the expression of various inflammatory factors induced by IL-17. Moreover, IGU interferes with 
the TNF-α-induced translocation of NF-κB from the cytoplasm to the nucleus, consequently suppressing the 

production of IL-6 and IL-8 induced by TNF-α 



 
 
 
 

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2.2.2 Suppression of immunoglobulin 
synthesis 

 

“In subsequent clinical trials, it was noted that 
iguratimod exhibited favorable therapeutic 
outcomes concerning both clinical symptoms and 
biological markers, including rheumatoid factor 
(RF) levels and immunoglobulin concentrations 
in plasma. Consequently, our investigations were 
directed toward assessing its impact on B-cell 
functions, particularly about immunoglobulin 
production and proliferation. In cultures of murine 
B-cells, iguratimod exhibited a notable reduction 
in IgM production and the isotype-switch to IgG1 
class induced by lipopolysaccharide (LPS) and/or 
IL-4. Additionally, it inhibits spontaneous IgG 
production without affecting cell proliferation in a 
human plasmacytoma cell line (ARH-77). 
Moreover, when human peripheral B cells were 
stimulated with autologous T cells and anti-CD3 
antibody, iguratimod demonstrated a 
concentration-dependent inhibition of both IgM 
and IgG production” [4]. 
 

In contrast, iguratimod did not exhibit any 
influence on the mitogen-induced proliferation 
response [23,24] and thymus and activation-
regulated chemokine (TARC) production in 
human B cells stimulated with anti-CD40 
antibody and IL-4 [25]. Hence, it seems that this 
compound hinders the production of 
immunoglobulins by B cells without causing a 
cytostatic effect.Subsequently, to elucidate the 
hyper-immunoglobulinemia observed in 
rheumatoid arthritis (RA) patients and the 
inhibitory effects of iguratimod, we examined the 
secretion of immunoglobulins from RA synovial 
tissues. The experimentation was conducted 
utilizing severe combined immune deficiency 
(SCID) mice that were implanted with human 
rheumatoid arthritis (RA) tissue.Consequently, 
the sera of the mice exhibited elevated 
concentrations of polyclonal human IgG. 
Furthermore, the iguratimod-treated group 
demonstrated a noteworthy reduction in IgG 
levels compared to the group treated with the 
vehicle. In chronic arthritis models such as 
adjuvant-induced arthritis (AIA) rats and MRL/lpr 
mice [11], the alleviation of arthritic lesions by 
iguratimod was concomitant with the 
improvement of hyperimmunoglobulinemia 
[3,26]. About the clinical effectiveness of B-cell-
targeted anti-CD20 antibody in rheumatoid 
arthritis (RA) patients, [27] these findings hold 
significant importance in understanding the 
mechanisms behind the anti-rheumatic effects 
exhibited by small molecule disease-modifying 
antirheumatic drugs (DMARDs). 

2.2.3 Suppression of cytokine synthesis 
 
“Another clear difference between iguratimod 
and classical NSAIDs is the inhibitory effect on 
cytokine production, as mentioned above. When 
tested on cultured monocytes/macrophages, 
iguratimod demonstrated the ability to inhibit the 
production of IL-1β, TNFα, IL-6, IL-8, and 
monocyte chemoattractant protein-1 (MCP-1) 
with IC50 values ranging from 1 to 20 µg/mL” 
[28-31]. “In synovial cells obtained from 
rheumatoid arthritis (RA) patients, iguratimod 
markedly decreased the synthesis of IL-6, IL-8, 
and colony-stimulating factors (CSFs) within 
concentration ranges of 0.3 to 30 µg/mL” 
[28,32,33]. “The suppression of mRNA 
expression coincided with iguratimod's inhibitory 
effect on the production of these 
cytokines”(29,31,33). Therefore, it is reasonable 
to suggest that iguratimod suppresses the 
expression of inflammatory cytokines at the gene 
level. Additionally, the research findings 
demonstrate [32] that iguratimod also impedes 
the increased expression of co-stimulatory 
molecules like CD54, CD58, and CD106 in 
synovial cells upon stimulation with IFN-γ. “This 
mechanism of action seems to involve the 
prevention of nuclear factor-kappa B (NF-κB) 
activation. The inhibitory effect on cytokine 
production was similarly observed in animal 
models. In a mouse air-pouch inflammation 
model, oral administration of iguratimod at doses 
of 30 and 100 mg/kg significantly decreased 
MCP-1 production induced by TNFα injection” 
[29]. “Moreover, at doses of 10 and 30 mg/kg, 
iguratimod reduced the rise in serum TNFα and 
IFN-γ levels in the concanavalin A-induced 
hepatitis model in mice, along with serum 
transaminase levels” [29]. “Iguratimod was also 
found to suppress the onset of active 
experimental autoimmune encephalomyelitis 
(EAE) in rats” [33]. “In this model, it was 
observed to inhibit TNFα and IFN-γ production 
by antigen-specific T cells and the infiltration of 
cells into the spinal cord of rats. Notably, 
iguratimod exhibited an anti-cachectic effect on 
adenocarcinoma colon-induced cachexia in mice 
by inhibiting IL-6 gene expression” [34]. 
“Furthermore, recent reports indicate that CIA 
rats treated with iguratimod showed reductions in 
mRNA expression of IL-17 in peripheral 
lymphocytes and circulating IL-17, suggesting 
that the compound exerts its immunoregulatory 
and bone-preserving effects by shifting 
responses away from IL-17-producing T cells 
(Th17 cells)” [35]. These findings suggest that 
iguratimod's inhibition of cytokine production may 



 
 
 
 

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contribute to its clinical efficacy in treating 
rheumatic conditions, making it a characteristic 
feature of this drug. 
 

2.3 Osteoprotective Mechanism 
 
“Osteoporosis frequently arises as a secondary 
consequence of rheumatoid arthritis (RA), 
potentially resulting in joint stiffness, 
malformation, and significant impairment in 
functionality. Employing early and efficient 
measures to safeguard bone health and enhance 
bone metabolism can be advantageous in 
thwarting joint deterioration.Several signaling 
pathways are crucial for osteoblast proliferation, 
differentiation, and the regeneration of damaged 
bone and cartilage. These include the bone 
morphogenetic protein (BMP)2–Smads pathway, 
the p38 mitogen-activated protein kinase (MAPK) 
pathway, and the TNF-α/NF-κB 
pathway.Research has demonstrated that IGU 
enhances the expression of osterix (Osx), a key 
factor in osteoblast differentiation. BMP2 has the 
ability to stimulate Osx expression by inducing 

the upstream transcription factor Dlx5. 
Additionally, the p38–MAPK pathway 
collaborates with the BMP2–Smads pathway to 
enhance Osx phosphorylation” [36]. 
 
“IGU has been found to boost osteoblast 
differentiation by upregulating the expression of 
Osx and Dlx5” [37]. “The p38 MAPK belongs to 
the MAPK superfamily and plays a role in the 
initial phases of osteoblast lineage proliferation 
by phosphorylating Dlx5, runt-related 
transcription factor (Runx)2, and Osx (36). IGU 
has the potential to enhance the activation of 
p38, thereby promoting osteoblastic 
differentiation. Additionally, the TNF-α/NF-κB 
signaling pathway is implicated in osteoblast 
proliferation, apoptosis, and differentiation” [38]. 
NF-κB facilitates the deterioration of osteocytes 
by diminishing the expression and 
phosphorylation of the BMP-Smad1 signaling 
pathway. IGU has the capacity to                        
sustain decreased NF-κB activation, thus 
mitigating the inhibitory effects of TNF-α on 
osteoblasts.  

 

 
 

Fig. 2. Illustrates the inhibitory effects of IGU on the immune response, particularly in the 
context of rheumatoid arthritis (RA) 

In RA, the initial interaction between Th1 cells and antigen-presenting cells (APCs), such as dendritic cells, 
involves T-cell receptors (TCRs) and major histocompatibility complex (MHC). Various environmental factors 

influence the production of autoantibodies like anti-citrullinated protein antibodies (ACPA) and rheumatoid factor 
(RF). These immune complexes activate synovial fibroblasts (SFs) and macrophages, leading to the production 

of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-6. Additionally, they affect 
Th17 cells, which produce IL-17, further contributing to joint destruction. IGU intervenes in this process by 
impacting the production of pro-inflammatory cytokines in both Th1 and Th17 cells, as well as affecting the 
production of immunoglobulins and antibodies in B cells. It also influences bone metabolism by inhibiting 

osteoclast activation and promoting osteoblast differentiation. NF-κB, a central player in the pathogenesis of RA, 
perpetuates the chronic cycle of inflammation underlying its pathology. Inflammatory mediators like TNF-α 
activate cells in the synovium, particularly macrophages and SFs, largely through NF-κB activation. SFs, in 

response to TNF-α or IL-1, synthesize many NF-κB-induced genes, including chemokines and matrix 
metalloproteinases (MMPs), which further promote inflammation and joint destruction 



 
 
 
 

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“Additionally, IGU fosters the formation of 
calcium nodules in vitro” [37]. “Osteoclast 
differentiation is primarily regulated by two 
essential cytokines: macrophage colony-
stimulating factor (M-CSF) and receptor activator 
of nuclear factor kappa-B ligand (RANKL)” [39]. 
“The RANKL/osteoprotegerin (OPG) system is 
crucial in bone erosion associated with 
rheumatoid arthritis (RA). An increase in the 
RANKL/OPG ratio contributes to bone erosion. 
IGU has the ability to reduce the production of 
RANKL, leading to a significant decrease in the 
RANKL/OPG ratio both in serum and in RA 
fibroblast-like synoviocytes (FLSs) induced by IL-
1β after treatment” [40]. “RANKL and its receptor 
RANK interact with osteoclast precursor cells, 
initiating downstream pathways such as 
peroxisome proliferator-activated receptor 
(PPAR)-γ, c-Fos, and nuclear factor of activated 
T cells (NFAT)c1” [41]. “IGU has the ability to 
inhibit osteoclast formation and bone                
resorption stimulated by RANKL through                      
the PPARγ/c-Fos signaling pathway. 
Furthermore, it decreases the expression of 
NFATc1 and subsequent osteoclast marker 
genes” [42]. 
 
Gan et al. found that “IGU effectively inhibited 
RANKL-induced osteoclast differentiation, 
migration, and bone resorption in RAW264.7 
cells, with the effect varying depending on the 
dosage administered”. “This effect was attributed 
to the activation of the MAPK and NF-κB 
pathways” [43]. “it indicates  that IGU directly 
suppresses the formation and activity of 

osteoclasts. Additionally, the TNF-α/NF-κB 
signaling pathway inhibit the production of matrix 
metalloproteinases (MMPs)” [38]. “MMPs are 
pivotal in the degradation of cartilage in 
rheumatoid arthritis (RA), predominantly 
synthesized by fibroblast-like synoviocytes 
(FLSs). Du et al. conducted in vitro experiments 
treating FLSs with varying concentrations of IGU, 
followed by stimulation with TNF-α, IL-1β, or IL-
17A. They observed a significant inhibition of 
MMP-3 at 5 μg/ml IGU, while MMP-1 inhibition 
occurred at 50 μg/ml. Clinical trials revealed a 
significantly reduction in MMP-1 and MMP-3 
levels following 24 weeks of IGU treatment (25 
mg, twice daily)” [44]. These findings indicate 
that IGU effectively prevents MMP-1 and MMP-3, 
thus preserving cartilage integrity. Moreover, 
OPG serves as a natural antagonist to RANKL, 
preventing its binding to the osteoclast receptor. 
The equilibrium between RANKL and OPG is 
critical for sustaining osteoclast homeostasis 
[45]. 
 
IGU can suppress the expression of MMP-3 and 
the RANKL/OPG ratio by inhibiting the 
phosphorylation of ERK1/2, consequently 
thwarting the degradation of bone in rheumatoid 
arthritis [46]. IGU not only enhances osteoblast 
differentiation but also suppresses osteoclast 
formation and the production of matrix proteins 
through its interaction with various signaling 
pathways. Consequently, IGU plays a crucial role 
in safeguarding bone health. Fig. 3 illustrates the 
intricate adjustments made by IGU within the 
signaling pathways. 

 

 
 

Fig. 3. Illustrates the osteoprotective mechanism of IGU, highlighting its impact on various 
signaling pathways crucial for osteoblast proliferation, differentiation, and bone/cartilage 

repair 
These pathways include the BMP2-Smads signaling pathway, the P38-MAPK pathway, and the NF-κB pathway. 
IGU, or Iguratimod, facilitates osteoblast differentiation by upregulating the expression of Osx and its upstream 

regulator Dlx5, while also enhancing P38 activation. Furthermore, IGU inhibits osteoclastogenesis and bone 
resorption induced by RANKL via the PPARγ/c-Fos signaling pathway. Additionally, IGU decreases the 

expression of nuclear factor in activated T cell c1 and downstream osteoclast marker genes 



 
 
 
 

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3. PROGRESS IN CLINICAL RESEARCH 
 
Numerous clinical trials have validated IGU as a 
promising novel treatment for rheumatoid arthritis 
(RA). Phase I, II, and III trials have demonstrated 
the effectiveness and safety of IGU monotherapy 
over a span of 24 weeks. Typically, IGU exhibits 
its therapeutic effects within 8 weeks, 
demonstrating a faster onset compared to 
methotrexate (MTX). IGU treatment exhibits early 
and sustained efficacy. Furthermore, the efficacy 
of a 50 mg dosage of IGU (25 mg twice daily) is 
comparable to that of a 15 mg dose of MTX (15 
mg per week). 
 
A multicenter, prospective observational study 
was conducted to assess the long-term safety 
and efficacy of IGU in rheumatoid arthritis (RA) 
patients. The study enrolled all eligible RA 
patients who had been treated with IGU since its 
introduction to the market in 2012. Efficacy was 
evaluated using Disease Activity Score 28 
(DAS28), while adverse drug reactions such as 
liver and renal dysfunction, interstitial lung 
disease, gastrointestinal and blood disorders, 
and infections were monitored up to week 52. 
The findings indicated that extended use of IGU 
demonstrated a manageable safety profile and 
led to enhanced control of rheumatoid arthritis 
(RA) activity. Additionally, another study 
assessing the 3-year efficacy of IGU in RA 
patients confirmed its effectiveness and safety. 
These outcomes suggest that IGU can be utilized 
for prolonged treatment durations. 
 
Methotrexate (MTX) serves as a cornerstone in 
the management of rheumatoid arthritis (RA), 
often forming the foundation of treatment. 
Typically, RA management entails a combination 
of several anti-rheumatic medications. 
Consequently, the combination of IGU with MTX 
has become a prevalent and novel therapeutic 
approach for RA. 
 
Ren et al. conducted a randomized study 
involving 82 patients, dividing them into two 
groups. The control group received MTX at a 
dose of 10 mg once weekly, which was escalated 
to 15 mg once weekly after 2 weeks. The 
observation group received IGU at a dose of 25 
mg twice daily in addition to the regimen followed 
by the control group, over a period of 6 months. 
The total effective rate in the observation group 
was 90.24%, markedly surpassing that of the 
control group, which stood at 78.05% [41]. The 
findings indicated that IGU enhances the 
therapeutic efficacy of MTX. 

When used in conjunction with leflunomide (LEF) 
for rheumatoid arthritis (RA) treatment, 
methotrexate (MTX) frequently leads to an 
increased incidence of adverse reactions. In the 
Tranmod Study, 66 patients with refractory 
rheumatoid arthritis (RA) were randomly 
assigned to two groups. The observation group 
received a combination of methotrexate (MTX) at 
a dose of 10 mg once weekly and iguratimod 
(IGU) at a dose of 25 mg twice daily, while the 
control group received MTX (10 mg once weekly) 
combined with leflunomide (LEF) at a dose of 10 
mg once daily for a duration of 16 weeks. Results 
showed that both groups experienced reductions 
in Disease Activity Score 28 (DAS28) scores 
compared to before treatment. At 8 weeks, there 
was a significant difference between the two 
groups in terms of achieving American College of 
Rheumatology (ACR)20 and ACR50 response 
criteria. However, by 16 weeks, there was no 
significant difference in ACR20, ACR50, and 
ACR70 response rates between the two groups. 
Compared to the combination of MTX and LEF, 
the combination of MTX and IGU demonstrated 
superior short-term clinical efficacy and fewer 
adverse reactions in RA patients. Furthermore, 
IGU is frequently employed in conjunction with 
biological agents like tocilizumab and etanercept. 
This underscores the versatility of IGU, as it can 
be combined with various anti-rheumatic 
medications for the treatment of rheumatoid 
arthritis (RA). 
 
In real-world clinical scenarios, certain 
rheumatoid arthritis (RA) patients exhibit 
insufficient response to multiple disease-
modifying antirheumatic drugs (DMARDs). A 
study verified that the effectiveness and 
tolerability of IGU in combination with MTX 
therapy persisted for a duration of up to 52 
weeks in active RA patients who had shown 
inadequate response to MTX alone. In another 
study, 131 patients previously treated with 
traditional disease-modifying antirheumatic drugs 
(DMARDs) were divided into three groups. Group 
1 consisted of 44 patients treated with a 
combination of IGU (25 mg, twice daily, orally) 
and MTX (10 mg weekly, orally). Group 2 
included 38 patients who received IGU alone (25 
mg twice daily, orally), while Group 3 comprised 
49 patients who received MTX alone (10 mg 
weekly, orally). Therapeutic effects with IGU 
were observed between 4 and 10 weeks after 
treatment initiation, effectively addressing 
patients with inadequate responses to prior 
DMARD treatments. The combination of IGU with 
MTX exhibited superior efficacy compared to IGU 



 
 
 
 

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or MTX monotherapy. IGU has demonstrated 
supplementary effectiveness in rheumatoid 
arthritis (RA) patients who exhibit inadequate 
responses to methotrexate (MTX). Consequently, 
combining IGU with MTX presents a promising 
emerging approach for treating active RA in 
individuals who have either inadequate 
responses to or intolerance to traditional disease-
modifying antirheumatic drugs (DMARDs). 
Moreover, IGU has shown additional 
effectiveness and safety in RA patients who 
demonstrate inadequate responses to biological 
DMARDs, such as tocilizumab. 
 

Wang et al. conducted a self-controlled study 
involving 20 rheumatoid arthritis (RA) patients 
with leukopenia to address the challenge of 
clinical drug selection due to the 
myelosuppressive adverse effects of many 
disease-modifying antirheumatic drugs 
(DMARDs). They administered IGU (25 mg twice 
daily) in combination with methylprednisolone 
(Medrol; 8 mg once daily) during the early stage 
of the disease. As white blood cell counts 
returned to normal with the help of hormones 
during the mid-stage, MTX was added to the 
regimen (7.5 mg once weekly), and 
methylprednisolone was gradually discontinued. 
Subsequently, IGU (25 mg twice daily) and MTX 
(7.5 mg once weekly) were employed as long-
term maintenance therapy for a duration of 12 
weeks. Results indicated improvements in 
erythrocyte sedimentation rate (ESR), C-reactive 
protein (CRP), Disease Activity Score 28 (DAS-
28), and white blood cell counts compared to 
pre-treatment levels. The ACR20 and ACR50 
response rates were 85% and 45%, respectively, 
and the overall rate of leukocyte elevation was 
95%. Only one case experienced mild liver 
damage during the treatment period, which 
resolved with liver protection treatment without 
discontinuing anti-rheumatic therapy. This 
underscores the favorable therapeutic                    
efficacy and high safety profile of                        
phased treatment with IGU, methylprednisolone, 
and MTX in RA patients with leukopenia. 
 

The aforementioned clinical trials have 
established that IGU is a valuable choice as an 
initial treatment for rheumatoid arthritis (RA), 
demonstrating notable effectiveness and safety 
whether used independently or in combination 
with other medications. 
 

4. CONCLUSION  
 

RA is a chronic autoimmune disorder 
characterized by synovial inflammation, joint 

damage, and decreased joint function. Treatment 
goals include achieving remission or low disease 
activity to prevent further joint damage. 
Iguratimod exerts its anti-inflammatory effects by 
inhibiting NF-κB activation, cytokine production, 
and COX-2 activity. It regulates humoral 
immunity by inhibiting immunoglobulin synthesis 
and B cell differentiation. Iguratimod's 
osteoprotective mechanism involves enhancing 
osteoblast differentiation and inhibiting osteoclast 
formation and activity.Clinical trials have 
demonstrated the efficacy and safety of 
iguratimod in RA treatment, both as monotherapy 
and in combination with other DMARDs. 
Combining iguratimod with methotrexate or other 
DMARDs has shown superior efficacy compared 
to monotherapy. Iguratimod has shown promise 
in patients with inadequate responses to 
traditional DMARDs or biological agents.Phased 
treatment with iguratimod, methylprednisolone, 
and methotrexate has been effective in RA 
patients with leukopenia. Iguratimod is a valuable 
treatment option for RA, offering early and 
sustained efficacy with a manageable safety 
profile. Its mechanism of action, including anti-
inflammatory, immunomodulatory, and 
osteoprotective effects, makes it a promising 
candidate for RA therapy. 
 

COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 

 
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