Su et al.

Molecular Biomedicine (2024) 5:54 Molecular Biomedicine

https://doi.org/10.1186/s43556-024-00217-8

REVIEW Open Access

Systemic lupus erythematosus:

pathogenesis and targeted therapy
Xu Su1†, Hui Yu2†, Qingqiang Lei3†, Xuerui Chen1, Yanli Tong4, Zhongyang Zhang5, Wenyong Yang1,6*,
Yuanbiao Guo1* and Liangbin Lin1,7,8*   

Abstract
Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune
responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease
severity. The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse
of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can
act as triggers. This review provides a comprehensive discussion of the pathogenesis and treatment strategies of SLE
and focuses on the progress and status of traditional and emerging treatment strategies for SLE. Traditional treat-
ment strategies for SLE have mainly employed non-specific approaches, including cytotoxic and immunosuppressive
drugs, antimalarials, glucocorticoids, and NSAIDs. These strategies are effective in mitigating the effects of the disease,
but they are not a complete cure and are often accompanied by adverse reactions. Emerging targeted therapeutic
drugs, on the other hand, aim to control and treat SLE by targeting B and T cells, inhibiting their activation and func-
tion, as well as the abnormal activation of the immune system. A deeper understanding of the pathogenesis of SLE
and the exploration of new targeted treatment strategies are essential to advance the treatment of this complex auto-
immune disease.
Keywords Systemic lupus erythematosus, Autoimmune diseases, Pathogenesis, Targeted therapeutic strategies

† 6
Xu Su, Hui Yu and Qingqiang Lei contributed equally to this work. Department of Neurosurgery, The Third People’s Hospital
of Chengdu, The Affiliated Hospital of Southwest Jiaotong University,
*Correspondence: Chengdu 610014, China
Wenyong Yang 7
Obesity and Metabolism Medicine‑Engineering Integration
[email protected] Laboratory, Department of General Surgery, The Third People’s Hospital
Yuanbiao Guo of Chengdu, The Affiliated Hospital of Southwest Jiaotong University,
[email protected] Chengdu 610031, China
Liangbin Lin 8
The Center of Gastrointestinal and Minimally Invasive Surgery,
[email protected] Department of General Surgery, The Third People’s Hospital
1
Medical Research Center, College of Medicine, The Third People’s of Chengdu, The Affiliated Hospital of Southwest Jiaotong University,
Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Chengdu 610031, China
Southwest Jiaotong University, Chengdu 610031, Sichuan, China
2
Department of Urology, The Third People’s Hospital of Chengdu, The
Affiliated Hospital of Southwest Jiaotong University, Chengdu 610014,
China
3
Center of Bone Metabolism and Repair, Department of Wound Repair
and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns
and Combined Injury, Trauma Center, Research Institute of Surgery,
Daping Hospital, Army Medical University, Chongqing 400000, China
4
Université Paris Cité, INSERM U1151, CNRS UMR8253, Institut Necker
Enfants Malades, Paris F‑75015, France
5
Department of Health Technology, The Danish National Research
Foundation and Villum Foundation’s Center IDUN, Technical University
of Denmark, Kgs. Lyngby, Denmark

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Su et al. Molecular Biomedicine (2024) 5:54 Page 2 of 30

Introduction triggers. These complex interactions ultimately result

Systemic lupus erythematosus (SLE) is a quintessential in the production of pathogenic autoantibodies. These
autoimmune disease, marked by recurring episodes and lupus-associated autoantibodies collaborate with adap-
periods of remission, with the potential to cause exten- tive and innate immune responses, facilitating the accu-
sive damage to multiple organ systems and tissues. This mulation of immune complexes in various tissues and
condition primarily affects the kidneys, central nervous organs. This process triggers acute and chronic inflam-
system, joints, and skin [1]. A defining characteristic of mation, ultimately leading to damage to the affected
SLE is the production of autoantibodies that target self- organs. Furthermore, we conduct an in-depth assessment
antigens, leading to the creation of immune complexes. of the therapeutic efficacy of conventional approaches
These complexes accumulate within blood vessels, trig- and newly emerging targeted therapies for SLE. We also
gering intense inflammatory reactions that can lead to offer insightful projections on the prospective evolution
the dysfunction of various organ systems. The multifac- of innovative treatment options in the field. SLE, as a
eted nature of SLE and its propensity for diverse organ systemic autoimmune disease with complex pathophysi-
involvement pose significant therapeutic challenges, ological characteristics, poses significant challenges to
necessitating a comprehensive understanding of the current therapeutic strategies. Accordingly, gaining an
underlying immunopathogenic mechanisms to develop in-depth comprehension of SLE’s pathogenic mecha-
targeted and effective treatment strategies [2, 3]. nisms and advancing precise, potent targeted treatments
Recent medical advances have shed light on the etiol- are of utmost importance in clinical practice.
ogy of SLE, with increasing recognition of dysregulated
immune mechanisms involving both the adaptive and
innate immune compartments. While the current man- Pathogenesis of SLE
agement of SLE predominantly relies on broad-spectrum SLE is characterized by its chronic nature and the multi-
immunomodulatory and immunosuppressive agents [4], faceted impact it has on various organs. The onset of SLE
the therapeutic landscape is evolving with the devel- is linked to the collapse of immunological tolerance cou-
opment of novel therapeutics tailored toward precise pled with the interplay of genetic factors that predispose
immunologic epitopes, some of which have garnered to SLE and a range of environmental triggers (Fig. 1).
endorsement from regulatory authorities [5, 6]. This complex interaction culminates in the generation of
In this review, we provide a comprehensive overview autoantibodies with pathogenic potential. These lupus-
of the pathogenic mechanisms and contemporary treat- associated autoantibodies collaborate with both innate
ment modalities for SLE, encompassing both tradi- and adaptive immune responses, promoting the accumu-
tional and emerging therapeutic strategies. The onset lation of immune complexes across diverse tissues and
of SLE is intricately linked to the interplay between organs. Such deposition initiates episodes of inflamma-
immune dysregulation, genetic predisposition, the col- tion, both acute and chronic, ultimately inflicting damage
lapse of immune tolerance, and a series of environmental upon the affected organs [1].

Fig. 1 The pathogenesis of SLE. The pathogenesis of SLE is complex and involves immune dysregulation, genetic predisposition, environmental
factors and immune complexes and tissue injury
Su et al. Molecular Biomedicine (2024) 5:54 Page 3 of 30

Immune dysregulation Aberrant immune cell activation

A pivotal factor in the pathogenesis of SLE is the In SLE, pathogenesis is driven by the abnormal activa-
immune response’s dysregulation, which encompasses tion of both adaptive and innate immune cells. Adaptive
both innate and adaptive immune systems. This dis- immune cells, including T lymphocytes, B lymphocytes,
ruption is instrumental in the development and pro- and plasma cells, play a central role in the disease’s devel-
gression of disease. Evidence suggests that the innate opment. T cells may suffer a loss of self-tolerance, result-
immune system’s dysfunction, which includes reduced ing in the stimulation of B cells by autoreactive cells. This
neutrophil phagocytic capacity and increased oxida- activation leads to an overproduction of autoantibodies
tive stress, is accompanied by a buildup of dendritic by B cells, which then form immune complexes. These
cells (DCs) at inflammatory locations [7], and defects complexes accumulate in tissues, initiating an inflam-
or mutations in the complement system [8], are linked matory response. Innate immune cells, such as neutro-
to SLE. Additionally, the compromised function of phils, monocyte-macrophages, natural killer cells and
adaptive immunity, such as augmented B cell activity, DCs, also contribute significantly to SLE pathogenesis
failure in the clearance of autoreactive B cells [9], and [12]. This interplay between adaptive and innate immune
the overactivation of T cells, can lead to an upsurge cells, along with the overproduction of pro-inflammatory
in autoantibody production [9, 10]. These discoveries cytokines and the disruption of regulatory mechanisms,
highlight the complex interaction between innate and culminates in chronic inflammation and multi-organ
adaptive immune responses in the development of SLE damage characteristic of SLE.
(Fig. 2). Studies have indicated that elevated levels of
type I interferons (IFNs) are detectable in SLE and are B cells B lymphocytes are distinguished by the pres-
associated with the severity of the disease [11]. We will ence of the B-cell receptor (BCR) on their cell membrane,
examine the mechanisms of aberrant immune cell acti- a receptor that is naturally designed for the detection
vation, the role of type I interferons and the breakdown of pathogens and the subsequent synthesis of specific
of immune tolerance. antibodies [13]. Throughout B-cell maturation, there

Fig. 2 Immunological interplay driving SLE pathogenesis. In SLE, the pathogenesis of lupus nephritis involves an intricate interplay among B
cells, T cells, DCs, and other immune components. Key aspects include: (1) Excessive production of autoantibodies by aberrant B cells leads
to the formation of immune complexes, which deposit in the kidneys, activating the complement system and inciting inflammatory responses. (2)
Autoreactive B cells present self-antigens to T cells, perpetuating immune dysregulation and fostering the release of pro-inflammatory mediators.
(3) Dendritic cells exhibit aberrant recognition and presentation of self-antigens, thereby initiating and propagating autoimmune responses
against renal tissue. (4) B cell differentiation into autoantibody-secreting plasma cells is dysregulated, resulting in the sustained production
of nephritogenic autoantibodies. Elucidating these pathogenic mechanisms is pivotal for the development of novel therapeutic strategies aimed
at halting or reversing the progression of lupus nephritis
Su et al. Molecular Biomedicine (2024) 5:54 Page 4 of 30

is potential for the emergence of autoreactive B cells. activation of the innate immune system, and enhances
Typically, the immune system employs tolerance mech- the functionality of B lymphocytes [30]. Studies have
anisms, such as clonal deletion and peripheral anergy indicated that IL-17 levels are correlated with the SLE
induction, to regulate the development of these poten- Disease Activity Index (SLEDAI) in patients with lupus
tially harmful cells. However, these regulatory processes nephritis [31, 32].
are not infallible and can at times be circumvented. This Regulatory T cells (Tregs) play a vital role in preserving
may result in the unintended expansion and stimulation peripheral tolerance towards self-antigens. In SLE, there
of autoreactive B cells, potentially instigating the onset is evidence of both quantitative and qualitative disparities
of autoimmune diseases [14–17]. The survival and prolif- in Tregs, yet research has yielded inconsistent findings,
eration of B cells after maturation, particularly those with leaving their precise role in SLE yet to be fully defined.
the capacity for autoreactivity, are significantly regulated Nonetheless, some investigations suggest that Tregs,
by various soluble factors. A key player among these owing to their suppressive effect on effector T lympho-
factors is B-cell activating factor (BAFF), also known as cytes, could be instrumental in foundational cellular
B lymphocyte stimulator (BLys) [18, 19]. The range of therapies for SLE [33–35]. T-follicular helper (Tfh) cells,
autoantibodies generated by B cells with autoreactive found in both germinal centers and extrafollicular areas,
properties is primarily targeted against antigens found are associated with the expansion of autoreactive B-cell
in the cell nucleus. Toll-like receptors (TLRs), particu- clones. This association has been observed in both mouse
larly TLR7 and TLR9, play a pivotal role in the genesis of models and in individuals with SLE [36]. These cells have
these autoantibodies. In SLE, the abnormal stimulation been observed to congregate with B cells in renal tissues,
of TLR9 and TLR7 has been shown to markedly increase mirroring their aggregation in germinal centers during
the generation of autoantibodies that target double- lupus nephritis [37]. Altogether, these findings highlight
stranded DNA (dsDNA) and RNA-related autoantigens, the crucial role of the interaction between CD4 + T cells
respectively [20–23]. Long-lived plasma cells (LLPCs), and B cells in the development of autoimmune condi-
resulting from the terminal differentiation of B cells, are a tions. This interaction significantly promotes the devel-
crucial source of autoantibody generation in SLE. Short- opment and maintenance of autoreactive B cells, as well
lived plasmablasts, upon interaction with CD4 + T cells as their differentiation into plasma cells that produce
within the germinal centers of lymph nodes, have been autoantibodies.
observed to evolve into high-affinity plasma cells. These
cells then migrate to specialized niches within the bone CD8 + T cells contribute to the immune-mediated
marrow where they are shielded from external influences, pathology observed in SLE. Researches have revealed
enabling them to persist over extended periods and con- that CD8 T lymphocytes in the peripheral blood of SLE
tinuously produce autoantibodies [24]. The autonomous patients exhibit functional deficits, such as an impaired
emergence of germinal centers, promoting the matura- ability to lyse target cells and a reduction in the synthe-
tion of LLPCs, is a characteristic evident in both mouse sis of granzymes and perforins [38]. A diminished circu-
models and human cases of SLE. This phenomenon sug- lating phenotype of CD8 T lymphocytes in SLE patients
gests a significant link to the etiology of autoantibody has been correlated with a reduced frequency of disease
generation [25]. Notably, in SLE, B lymphocytes have flares [39]. However, qualitative irregularities in CD8 + T
been demonstrated to act as antigen-presenting cells lymphocytes also predispose SLE patients to infections,
(APCs) to T lymphocytes with autoreactive potential, as a vulnerability that can be exacerbated by immunosup-
observed in mouse models [26, 27]. pressive therapy [40]. Lastly, γδ-T lymphocytes have been
observed at higher frequencies in SLE patients compared
T cells Autoreactive T cells are pivotal in the develop- to healthy controls, suggesting their involvement in auto-
ment of SLE. T-helper 1 (Th1) cells are particularly influ- immune responses [41, 42].
ential in SLE pathogenesis, as they foster oxidative stress
linked to the production of interferon-gamma (IFNγ)
[28]. Inversely, a reduction in Th2 cells, which produce Neutrophils In SLE, neutrophil dysfunction has been
IL-4, in the peripheral blood of SLE patients suggests observed at multiple levels. Initially, neutrophils exhibit
they may have a protective role, with disease activity a diminished capacity for phagocytosis and a failure to
possibly correlated to an increased ratio of IFNγ to IL-4 clear apoptotic cells, which are a source of self-antigens
[29]. Furthermore, T-helper 17 (Th17) cells play a role in typically sequestered from the immune system [43–45].
the pathogenesis of SLE, acting as the main producers Additionally, neutrophils have been shown to produce
of IL-17, a highly inflammatory cytokine. This cytokine type-I IFNs without the need for TLR stimulation, which
promotes the recruitment of neutrophils, triggers the can lead to abnormal B-cell development within the bone
Su et al. Molecular Biomedicine (2024) 5:54 Page 5 of 30

marrow of SLE patients [46, 47]. A particular subtype (cDCs). Once activated, cDCs facilitate the differentia-
of neutrophils, referred to as low-density granulocytes tion of effector T (Teff ) cells and intensify B cell activa-
(LDG), is commonly found in higher numbers in the tion and auto-antibody production within the germinal
peripheral circulation of SLE patients. There is a corre- center (GC). This sequence of events culminates in the
lation between these LDG cells and the presence of an disruption of immune tolerance and perpetuates tissue
interferon (IFN) signature, as well as the overall disease inflammation. In SLE, DCs exhibit heightened matura-
severity [48–50]. , and they can activate CD4 + T-cells, tion markers, including elevated levels of costimulatory
prompting them to generate IFNγ and TNFα [48]. molecules like CD86, and they secrete proinflammatory
In SLE, low-density granulocytes (LDGs) are distin- cytokines, which contribute to disease pathogenesis [61,
guished by their heightened capacity to produce neutro- 62]. Furthermore, follicular dendritic cells (FDCs) are
phil extracellular traps (NETs), particularly during the capable of capturing and retaining self-antigens through
process of NETosis, which occurs as they undergo apop- CD21, which triggers TLR7/interferon regulatory fac-
tosis [51]. NETs are composed of decondensed nucleic tor 5 (IRF5)-mediated IFN-I production. This process
acids and expelled chromatin, and their formation can enhances GC reactions and the generation of pathogenic
elicit autoreactive immune reactions against nucleic auto-antibodies in lupus pathogenesis [63]. Plasmacytoid
acid antigens [52]. Additionally, neutrophils are known dendritic cells (pDCs), which originate from the lym-
for generating reactive oxygen species (ROS), which, phoid lineage, are distinguished by their capacity to gen-
while typically crucial for pathogen elimination, can erate substantial amounts of type-I IFNs, thereby signifi-
inflict endothelial damage in SLE [52]. Various genetic cantly contributing to the development of SLE [64–66].
polymorphisms associated with neutrophil dysregula-
tion and increased NET formation have been identified Aberrant type I IFN activation
in SLE patients [53–55]. Furthermore, neutrophils from A significant discovery in the pathogenesis of SLE that
SLE patients with STAT3 function impairments have has paved the way for innovative drug development is the
been observed to form NETs more readily compared to identification of a heightened type-I interferon (IFN) sig-
those from healthy individuals [56]. Excessive NET for- nature among SLE patients [67]. In SLE, it is primarily the
mation coupled with impaired clearance may also result type-I IFN, particularly IFNα and IFNβ, that is implicated
in heightened inflammasome activation in macrophages, in disease pathogenesis. Type-I IFNs are initiated by the
thereby exacerbating the inflammatory response [57]. stimulation of PRRs, including TLRs, retinoic acid-induc-
In aggregate, these findings underscore the significant ible gene I (RIG-I), and melanoma differentiation-associ-
immunostimulatory role of neutrophils in SLE through ated protein 5 (MDA5). These receptors are activated by
NET formation, which substantially contributes to nucleic acids or bacterial substances such as lipopolysac-
immune dysregulation and subsequent tissue injury. charides and peptidoglycan [68]. While various cell types
can produce type-I IFN [69], pDCs are particularly nota-
DCs DCs, first identified by Ralph Steinman in 1973, ble for their high synthesis of this cytokine, as previously
serve as the principal antigen-presenting cells. They are mentioned [70–72]. Type-I IFNs engage with the inter-
crucial in the context of SLE, as they bridge the innate feron-alpha receptor (IFNAR), a heterodimeric complex
and adaptive immune responses [58]. DCs function as that initiates intracellular signaling cascades via Janus
key regulators in SLE-related autoimmunity, embodying kinase 1 (JAK1) and tyrosine kinase 2 (TYK2). Activation
both stimulatory and suppressive roles. They possess the of these kinases leads to the phosphorylation of signal
capacity to discern self and non-self-antigens through transducers and activators of transcription 1 and 2 (STAT
pattern recognition receptors (PRRs), initiating matu- 1 and STAT 2), which are key transcription factors. Once
ration and the secretion of inflammatory cytokines and phosphorylated, STAT proteins complex with IRF7 and
type I interferons (IFN-I). This process can lead to the IRF9 to form the ISGF3 complex. This complex migrates
activation of autoreactive T and B cells, which contribute into the nucleus, triggering the transcription of genes
to the inflammatory pathology of SLE. Conversely, DCs that harbor IFN-sensitive response elements (ISREs). The
with tolerogenic capabilities can foster immune toler- proteins encoded by these genes contribute to the ampli-
ance, either by promoting the function and development fication of inflammatory responses [73, 74].
of regulatory T or B cells or by inhibiting the activation Early experimental studies using animal models dem-
of these cells. This duality aids in curbing pathological onstrated that administration of type-I IFNs could induce
inflammation and autoimmunity [59, 60]. autoantibody production and lead to organ damage [75].
The first indications that type one interferon might play
Chronic exposure to autoantigens leads to the matu- a pivotal part in SLE development in humans came from
ration and activation of conventional dendritic cells observations that patients treated with IFNα for hepatitis
Su et al. Molecular Biomedicine (2024) 5:54 Page 6 of 30

C [76] or malignancies [77, 78] could develop antinuclear vessels and kidneys [85]. Other SLE-associated genes on
antibodies and, in some cases, lupus-like syndromes. chromosome 1 encompass PTPN22 [86], IL10 [87], and
These situations often resolved upon cessation of IFNα C1Q [88].
therapy [78, 79]. Further studies have discovered that The major histocompatibility complex (MHC) genes,
gene polymorphisms in the type-I IFN signaling pathway, as well as components of the complement system such
including the IRF gene family, are substantial genetic risk as C2 and C4, and tumor necrosis factor (TNF) genes
factors for SLE [80–82]. Additionally, polymorphisms TNFα and TNFβ, are located on chromosome 6. Poly-
have been found in TYK2, STAT3, and STAT4 genes [56, morphisms within these genes have been shown to con-
83], further underscoring the importance of this pathway fer susceptibility to SLE [89]. The programmed cell death
in the disease’s etiology. The IFN signature is increasingly 1 gene (PDCD1), which is raising in T cells to suppress T
recognized as a potential biomarker, guiding the tar- cell receptor (TCR) signaling and T and B cell survival,
geted use of emerging anti-IFN therapeutics for precision harbors a single nucleotide polymorphism (SNP) within
treatment. an intron that is associated with SLE risk in Europeans.
This SNP impacts the binding location of the runt-related
Loss of tolerance transcription factor 1 (RUNX1), implying its role in
The collapse of immune tolerance plays a pivotal role in SLE pathogenesis [90]. Additionally, CTLA4, a negative
the development of autoimmune conditions; however, costimulatory molecule that curbs T cell activation and
the precise mechanisms driving this breakdown remain potentially limits T cell reactivity during inflammatory
to be fully elucidated. Immunological tolerance is divided responses, exhibits genetic variability that has been cor-
into two main types: central and peripheral. Central tol- related with an increased risk of developing SLE [90, 91].
erance occurs in the thymus for T cells and in the bone
marrow for B cells, serving as the principal process Epigenetic modifications
through which the immune system learns to differentiate Epigenetic alterations encompass heritable changes that
self from non-self-antigens. Peripheral tolerance, on the occur without altering the underlying DNA sequence,
other hand, is established in tissues and lymph nodes fol- manifesting at the levels of DNA, RNA, or proteins [92].
lowing the maturation of lymphocytes. It serves to regu- Epigenetic mechanisms play a significant role in SLE and
late self-reactive immune cells and to prevent excessive are capable of modulating gene expression through sev-
immune reactions to environmental stimuli. When toler- eral pathways, including DNA methylation, histone post-
ance is compromised, it can lead to the development of translational modifications, and the action of microRNAs
autoimmune conditions, including SLE. [93]. In SLE, the global hypomethylation of T cell DNA
represents a characteristic epigenetic modification. This
Genetic predisposition alteration results in increased gene transcription, which
The origins and mechanisms behind autoimmune dis- is closely linked to the severity of the disease [94]. When
eases are exceedingly intricate. A combination of epi- epigenetic regulation becomes disrupted, it can lead to
genetic changes and genetic susceptibility contributes misexpression of genes and dysfunction in immune cells,
to the failure of immunological tolerance, leading to potentially triggering autoimmune reactions.
autoimmunity. In this review, we will delve into how In terms of adaptive immunity, these epigenetic dis-
epigenetic and genetic factors influence the collapse of ruptions are particularly pivotal in the activation of T
tolerance in autoimmune conditions. cells within the SLE context. The activation of Tfh cells
is known to foster the generation of autoantibodies.
Polygenic inheritance Furthermore, epigenetic dysregulation is implicated in
The genetic predisposition to lupus in humans is firmly the suppression of Treg differentiation, thereby ampli-
established, as evidenced by the markedly higher disease fying the pool of autoreactive lymphocytes [95].As for
concordance rates among monozygotic twins (ranging the innate immune response, epigenetic alterations are
from 25 to 57%) compared to dizygotic twins (2–9%) shown to enhance the production of IFNs, which in turn,
[84]. Among the genetic regions consistently implicated trigger the expression of genes regulated by type I IFNs in
in SLE are those located on chromosome 1. The 1q23 SLE. Consequently, these findings have shed light on the
linkage interval includes the genes for Fcγ receptors, intricate pathogenic mechanisms underlying SLE.
FCGR2A and FCGR3A. Variations in these receptors,
which have different affinities for IgG and its subclasses, Environmental factors
can result in inefficient clearance of immune complexes, Prominent environmental factors known to precipitate
potentially causing their accumulation in the blood SLE include viral infections, certain medications, tobacco
use, and exposure to ultraviolet (UV) radiation [96, 97].
Su et al. Molecular Biomedicine (2024) 5:54 Page 7 of 30

Infections the clearance of apoptotic cells is typically less efficient,

Infections, encompassing viruses, bacteria, parasites, and which extends the immune system’s exposure to these
fungi, are significant environmental contributors to the antigens [107–109]. This prolonged exposure can stimu-
genesis of autoimmune conditions. Notably, viral infec- late the generation of autoreactive CD8 + T-cells and the
tions have been particularly implicated in the etiology production of autoantibodies that target these seques-
of SLE [98]. Human endogenous retroviruses (HERVs) tered antigens [104]. Antibodies against Ro60 and Ro59,
are considered to predispose individuals to SLE due to known as anti-Ro antibodies, can intensify inflammation
genetic factors, while the Epstein-Barr virus (EBV) is by interfering with the regular functions of these pro-
recognized as an environmental trigger that may initi- teins [110]. The Ro60 protein is involved in the removal
ate SLE. It is hypothesized that B-cells infected with EBV of incorrectly folded non-coding RNAs, which can cause
might evade apoptosis, leading to their activation, pro- inflammation if they build up inside cells. In parallel, the
liferation, and the generation of autoantibodies. These Ro59 protein interacts with interferon regulatory fac-
autoreactive B-cells are implicated in the tissue damage tors (IRFs), thus affecting the cell’s reaction to interferon
characteristic of SLE. signaling.
EBV is also posited to play a part in the activation of
the innate immune system and B cell maturation, poten- Immune complexes
tially inciting the generation of autoantibodies that tar- Immune complexes (ICs) are a common characteris-
get amino acid sequences common to both self-proteins tic in immune-mediated responses that protect the host
and those encoded by EBV. The virus’s small RNAs are against diseases. However, under specific conditions,
known to provoke immune responses by inducing the they can become detrimental to health. SLE serves as a
production of IFNs. This occurs through binding to the recognized exemplar of immune complex involvement
dsRNA-dependent protein kinase, thereby triggering a in autoimmune disorders. It is plausible that the various
TLR-independent signaling pathway. Furthermore, anti- mechanisms of IC formation and their subsequent effects
bodies directed against the EBV-encoded Epstein-Barr contribute significantly to the development of lupus
nuclear antigen 1 (EBNA1) may exhibit cross-reactivity nephritis, cutaneous involvement, and other clinical fea-
with double-stranded DNA, indicating a possible link tures of SLE. The assessment of immune complexes plays
between EBV infection and the induction of autoimmune a practical role in disease monitoring and in the evalu-
responses [99]. While the exact molecular underpinnings ation of certain therapeutic interventions. SLE presents
of this cross-reactivity remain elusive, it is speculated as chronic or paroxysmal inflammation in multiple organ
that shared conformational epitopes between DNA and systems associated with the presence of circulating and
EBNA1 may be the basis for this phenomenon. tissue-deposited Immune complex, these Immune com-
plexes stimulate white blood cells through the FC gamma
Ultraviolet radiation receptor (FcγR) and subsequently inflammation.
UV radiation, encompassing both UVA and UVB wave- In SLE, the buildup of immune complexes and autoan-
lengths, plays a significant role in SLE pathogenesis. tibodies can trigger inflammation and damage in spe-
This radiation primarily induces apoptosis in keratino- cific organs [111]. Although SLE can impact any organ,
cytes through the producing of reactive oxygen species it frequently targets kidneys, joints, central nervous
(ROS) and the infliction of DNA damage. UVB radiation- system, hematologic system, and skin. Mucocutaneous
induced DNA damage triggers intracellular nucleic acid manifestations are particularly prevalent, with up to 75%
sensors and PRRs, including stimulator of interferon of patients experiencing them at some point and 25% at
gene (STING). This process leads to the production of diagnosis. The most typical cutaneous manifestation is a
type-1 IFNs [100]. Under conditions of elevated circulat- malar rash resembling a butterfly on the nose and cheeks,
ing type-1 IFN, Langerhans cells and keratinocytes that accompanied by photosensitivity, oral/nasal ulcers, scar-
have been exposed to UV radiation express high levels ring discoid lesions and non-scarring alopecia [98].
of pro-inflammatory cytokines including IL-6, IL-1β,
and TNF-α [101, 102].This cytokine-rich environment Targeted therapies of SLE
stimulates the T-cells recruitment, establishing a self- SLE is a chronic autoimmune disease, distinguished
sustaining inflammatory loop that activates the adaptive by its impact on multiple organs and the diverse clini-
immune system [103, 104]. cal presentations and disease severity it exhibits [112].
UV radiation-induced apoptosis can lead to the reloca- For many years, the treatment of SLE has primarily
tion of intracellular antigens such as Ro59, Ro60, and the involved non-specific approaches, including cytotoxic
interferon-inducible protein 16 (IFI16) to the cytoplas- and immunosuppressive drugs [4], antimalarial agents
mic membrane [105, 106]. In lupus-prone individuals, [113], non-steroidal anti-inflammatory drugs (NSAIDs),
Su et al. Molecular Biomedicine (2024) 5:54 Page 8 of 30

and glucocorticoids. However, in more recent times, the Methotrexate (MTX) functions by inhibiting the activ-
therapeutic landscape for SLE has evolved to incorporate ity of the enzyme aminoimidazole carboxamide ribonu-
more precise strategies, such as cellular therapies and cleotide transformylase, which results in an increase in
precision medicine [114]. adenosine levels. This elevation in adenosine contributes
to anti-inflammatory properties and can suppress the
Traditional therapies of SLE activity of neutrophils [116]. This mechanism is believed
SLE encompasses a spectrum of clinical presentations, to be, at least partially, responsible for its therapeutic effi-
reflecting its intricate autoimmune nature. Although cur- cacy in the treatment of autoimmune conditions [116].
rent treatment strategies can effectively reduce the sever- In SLE, methotrexate has shown effectiveness in patients
ity of the disease, they do not provide a cure and often exhibiting articular or dermatological symptoms, facili-
come with side effects. For milder cases of SLE, initial tating a reduction in steroid requirements and modestly
treatment typically includes nonsteroidal NSAIDs and attenuating disease activity [117, 118].
antimalarial medications. (Table 1). For more severe Azathioprine (AZA), a purine analog, suppresses
cases, particularly those with organ involvement, a nucleic acid synthesis and impacts both cellular and
range of glucocorticoids and immunosuppressive thera- humoral immune responses. It exhibits efficacy in SLE
pies, including azathioprine, mycophenolate mofetil, patients presenting with arthritis, serositis, and mucocu-
cyclophosphamide, cyclosporine, and methotrexate, are taneous involvement [119]. Frequently utilized as a
employed [115]. means to reduce steroid dependence, AZA has demon-
strated effectiveness in sustaining remission of the dis-
Cytotoxic and immunosuppressive therapies ease [119].
The use of cytotoxic and immunosuppressive medica- Cyclophosphamide (CYC), a nitrogen mustard-derived
tions is typically reserved for individuals with severe SLE alkylating and cytotoxic agent, functions by crosslinking
manifestations. This class of drugs encompasses metho- DNA and proteins associated with DNA, thereby imped-
trexate, azathioprine, cyclophosphamide, and mycophe- ing DNA replication and inducing cellular death. In com-
nolate mofetil (MMF). Less commonly, cyclosporine and bination with high-dose glucocorticoids, CYC has been a
leflunomide are also utilized. Most evidence supporting cornerstone therapy for severe SLE that poses a threat to
the use of these agents is derived from their application vital organs, encompassing lupus nephritis, neuropsychi-
in lupus nephritis. Except for azathioprine, these medica- atric manifestations of lupus, and severe systemic vascu-
tions are generally contraindicated during pregnancy. litis [119, 120].

Table 1 Traditional therapies in SLE

Type of agent Agent Mechanisms Risks

Cytotoxic and immu- Methotrexate Inhibiting the activity of the enzyme aminoimida- Gastrointestinal events, Development of pulmo-
nosuppressive zole, carboxamide, ribonucleotide, transformylase nary tuberculosis
therapies
Azathioprine Suppress indnucleic acid synthesis and impacting Gastrointestinal intolerance,
immune responses Bone marrow suppression
Cyclophos Crosslinking DNA and proteins associated Infection, Gonadal toxicity, Myelosuppression,
-phamide with DNA Carcinogenic effect, Bladder toxicity
Mycophenolate mofetil Inhibitor of inosine monophosphate dehydro- Fetal malformation and abortion
genase
Sirolimus Inhibitor of the mTOR signaling pathway Hematological abnormalities, mucocutaneous
abnormalities, dyslipidemia
Non-Steroidal Anti- Celecoxib Inhibitor of cyclooxygenase enzymes Gastrointestinal and cardiovascular complications
Inflammatory Drugs rofecoxib
(NSAIDs)
Antimalarials Hydroxy causing interference with cyclic GMP-AMP HCQ-related retinopathy, Gastrointestinal intoler-
-chloroquine (cGAMP) synthase ance, Skin pigmentation, Antimalarial-induced
myocardiopathy, Neuromyopathy, hypoglycemia,
tinnitus, vertigo, dizziness
Glucocorticoids (GCs) GCs Binding the cytosolic-GC receptor (cGR) Lacking evidence supporting the long-term
and being mediated by the GC-cGR complex, stability benefits, Increased risk of infections,
by membrane-bound GR (mGR) or by nonspecific Osteoporosis, fractures and weakness, Hypergly-
interactions with cellular membranes cemia/Diabetes, Cushing syndrome, Cardiovascu-
lar disease, Glaucoma, Cataracts
Su et al. Molecular Biomedicine (2024) 5:54 Page 9 of 30

MMF, a prodrug that converts to mycophenolic inhibitors, preferential Cox-1 inhibitors, and selective
acid (MPA), is a significant immunosuppressive agent Cox-2 blockers. Among NSAIDs, naproxen is consid-
employed in the treatment of SLE. MMF’s mechanism of ered to possess a relatively higher cardiovascular safety
action involves the inhibition of inosine monophosphate profile compared to other members of its class [132].
dehydrogenase, a key enzyme in the de novo pathway of Experts advocate for the use of NSAIDs with a high
guanosine nucleotide synthesis9. Furthermore, MPA is degree of selectivity for COX-2, such as celecoxib, to
known to modulate dendritic cell subsets, thereby dis- minimize adverse effects. In contrast, NSAIDs with lower
rupting the detrimental cycle of autoimmune reactions selectivity, like piroxicam and ketorolac, are generally
[121]. At present, MMF is extensively utilized for both not preferred. A retrospective study of 50 patients with
induction and maintenance therapy in LN [122, 123]. It mild SLE demonstrated celecoxib’s efficacy and safety,
has also been implicated in the management of patients with reduced gastrointestinal toxicity compared to other
with extrarenal manifestations of SLE [124, 125]. A NSAIDs. However, due to its sulfonamide structure,
24-month, multicenter, randomized clinical trial [126] celecoxib may not be suitable for patients with allergies
has demonstrated that MMF outperforms azathioprine to this chemical group [132, 133].
in the treatment of SLE, including the prevention of dis-
ease relapses. The results from a randomized clinical Antimalarials
trial indicate that MMF might decrease the frequency of Antimalarial medications are particularly effective in
severe disease exacerbations and reduce the likelihood of alleviating SLE constitutional symptoms, such as fatigue
developing LN in individuals with newly diagnosed SLE and fever, as well as musculoskeletal, dermatological, and
who have elevated levels of anti-dsDNA antibodies but mild pleuritic issues [113]. Research indicates that these
no significant involvement of major organs [127]. drugs are instrumental in maintaining remission in SLE,
Sirolimus, recognized alternatively as rapamycin, averting severe disease relapses, and shielding the kid-
represents an immunosuppressive agent that is being neys and central nervous system from considerable harm
explored for its therapeutic potential in SLE. Its mecha- [134, 135]. They also serve to decrease the necessary dos-
nism involves the inhibition of the mTOR signaling age of prednisone. Additional advantages of antimalarial
pathway, which in turn reduces immune cell activity and therapy include a diminished risk of thromboembolic
mitigates inflammatory and autoimmune reactions [128, events in individuals with antiphospholipid antibodies
129]. Clinical experiences have shown that sirolimus [9], improved glycemic management and insulin sensi-
can enhance the population of Tregs, ameliorate disease tivity in SLE patients, thereby reducing the likelihood
activity in patients with active SLE, and curb the produc- of diabetes development [136]. These medications also
tion of IL-17 and IL-4, all without raising safety issues enhance lipid profiles by curbing cholesterol synthesis
[130]. Moreover, sirolimus has demonstrated efficacy and upregulating LDL receptor activity [136, 137], bolster
comparable to tacrolimus and MMF in the treatment bone density [138], and lower the risk of cancer [139].
of SLE or LN patients. It has even shown superior sero- Hydroxychloroquine (HCQ) stands out as the predom-
logical improvements and a greater reduction in gluco- inant antimalarial agent for treating rheumatic condi-
corticoid use, as evidenced by real-world data from the tions in the United States, given its reduced risk of retinal
Research group (CSTAR) cohort studies and Chinese SLE toxicity compared to chloroquine. Moreover, hydroxy-
Treatment. Sirolimus has been well-tolerated among SLE chloroquine is considered relatively safe for use during
patients [131]. Nonetheless, its use must be approached pregnancy, making it a favorable choice in certain clinical
with caution due to immune suppression and potential scenarios [119]. Its use, either as a standalone treatment
side effects, requiring vigilant clinical monitoring. Fur- or in conjunction with steroids and immunosuppressive
ther research is essential to substantiate sirolimus’s thera- agents, has become integral to the management of SLE,
peutic efficacy in SLE. enhancing patient survival by mitigating lupus flares
and preventing the progression of organ damage. The
Non‑steroidal anti‑inflammatory drugs (NSAIDs) 2019 revisions to the EULAR guidelines for managing
NSAIDs are typically effective for alleviating mild SLE advocate for the administration of HCQ in all lupus
SLE symptoms, including arthralgia, musculoskel- patients, barring contraindications, with a high level of
etal issues, fever, headaches, and mild serositis [119]. evidence and recommendation grade (1b, grade A) [4].
These medications function as inhibitors of cyclooxy- A prospective cohort study has underscored HCQ’s effi-
genase enzymes, specifically cyclooxygenase-2 (Cox-2) cacy in alleviating classical manifestations of SLE, such
and cyclooxygenase-1 (Cox-1). The advent of selective as dermatological issues and arthralgia, through its anti-
Cox-2 inhibitors like celecoxib and rofecoxib has allowed inflammatory properties and the reduction of autoanti-
for a categorization of NSAIDs into non-selective Cox body levels [140].
Su et al. Molecular Biomedicine (2024) 5:54 Page 10 of 30

Glucocorticoids (GCs) through indirect regulation of B cell receptors, thereby

GCs are potent anti-inflammatory agents that swiftly governing B cell proliferation and differentiation [149].
mitigate inflammation and modulate both the innate
and adaptive arms of the immune system, leading to an Rituximab, a chimeric monoclonal antibody (mAb)
improvement in SLE symptoms [141]. The dosage of against CD20, its therapeutic impact on SLE is still a
glucocorticoids is tailored to the severity of the disease subject of debate [150–152]. However, Numerous obser-
and the extent of organ involvement [142–144]. For six vational studies and routine clinical applications have
decades, glucocorticoids have served as a cornerstone evidenced the effectiveness of rituximab in managing
in the management of SLE. An escalation in glucocorti- refractory lupus nephritis and severe non-renal SLE
coid dosing is frequently implemented to address small manifestations, encompassing hematological disorders,
spikes in disease activity [145]. However, it is important severe joint involvement, neuropsychiatric disease, and
to note that there is a lack of evidence supporting the dermatological conditions [153–156]. An investiga-
long-term stability benefits of augmented steroid therapy tion is designed to evaluate if the conjunctional use of
[146]. Oral glucocorticoids at a low dosage can be equally belimumab with a solitary course of rituximab can aug-
effective in managing systemic active extrarenal disease ment the efficacy of belimumab monotherapy, leading
as higher doses, such as 30 mg/day or more [147]. This to enhanced clinical outcomes alongside a beneficial
suggests that the standard dosage could be reduced in safety profile. This will be accomplished through a com-
routine practice. Consequently, during periods of disease parative analysis of subjects allocated to concurrent
exacerbation, it is recommended to utilize the minimum treatment with belimumab and rituximab versus those
effective dose of glucocorticoids, with a defined plan for receiving belimumab coupled with a rituximab-placebo
treatment duration and clear therapeutic objectives. (NCT03312907). Encouraged by the positive findings
from combined therapeutic strategies, a multicenter
Emerging targeted therapies phase III clinical trial is now in progress to further assess
Emerging targeted therapies for SLE are designed to the efficacy of this novel treatment method for patients
address specific components of the immune system that with severe SLE [157].
contribute to the disease’s pathogenesis. These thera-
pies aim to provide more precise treatment with fewer Ocrelizumab, a recombinant humanized mAb, is
side effects compared to traditional broad immunosup- designed to target and deplete CD20 + B cells from the
pressive approaches. Here’s an overview of some of the peripheral circulation. It has been the focus of two clini-
targeted therapies that are currently in development or cal trials addressing SLE [152, 158]. The phase III BEGIN
under investigation for SLE. study, which focused on non-renal SLE, was prematurely
halted due to the sponsor’s decision to discontinue this
Cellular therapies line of investigation [152]. Conversely, the BELONG
Cell therapy is a medical technique that uses cells as a study, a randomized, double-blind, phase III trial
therapeutic tool. It has shown great potential in the treat- (NCT00626197), assessed the efficacy of ocrelizumab in
ment of many diseases, including SLE. In the treatment conjunction with cyclophosphamide or mycophenolate
of SLE, cell therapy mainly targets B cells and T cells, mofetil in patients with lupus nephritis. Interim results at
because these cells play a key role in the pathogenesis the 32-week mark indicated renal response rates of 63%
of the disease. Here, we outline the targeting of B and T in the ocrelizumab group and 51% in the placebo group,
cells for the treatment of SLE. with a notable advantage observed in patients receiving
cyclophosphamide as their background treatment. None-
Targeting B cells as a therapeutic strategy for SLE The theless, an elevated occurrence of serious infections in
therapeutic strategies aimed at the B cell compartment participants treated with background mycophenolate
can be broadly outlined as targets B cell surface receptors mofetil led to the early cessation of the BELONG study
and targeting B cell related cytokines (Table 2; Fig. 3). [159].

CD20 is consistently expressed throughout the devel- Obinutuzumab, another fully humanized anti-CD20
opment of B cells, except for the fully differentiated mAb, exhibits superior efficacy in inducing B cell cyto-
plasma cells and earliest pre-B cells. Despite lacking toxicity in individuals with rheumatoid arthritis or SLE,
a known ligand, CD20 functions not only as a signifi- having concluded its phase II trial (NCT02550652) [160].
cant clinical marker for identifying B cells but also as a Conversely, obinutuzumab, a type II anti-CD20 antibody
target for therapeutic intervention [148]. CD20, poten- containing fucosylated Fc, demonstrates reduced com-
tially modulates calcium-dependent signaling pathways plement-dependent cellular cytotoxicity compared to
Su et al. Molecular Biomedicine (2024) 5:54 Page 11 of 30

Table 2 B-cell targeted therapies in SLE

Type of agent Agent Target Stage of development Reference

Targets B cell Surface Receptor Rituximab CD20 phase III trial NCT03312907
[148]
Ocrelizumab CD20 phase III trials [149]
NCT00626197[150]
Obinutuzumab CD20 phase II trial NCT02550652[151]
phase III trials NCT04702256
NCT04963296
Ofatumumab CD20 [152]
XmAb5871 CD19 phase II trial NCT02725515
MEDI551 CD19 Phas IIa trail NCT06570798
Epratuzumab CD22 phase IIb trail [153]
phase III trial [154]
Daratumumab CD38 phase II trials NCT04810754
NCT04868838
Mezagitamab CD38 phase Ib trial NCT03724916
Targeting B Cell Related Cytokines Belimumab BAFF phase III trials [155]
phase IV trail [156]
NCT04515719
Ianalumab BAFF phase III trials NCT05624749
phase II trial NCT06133972
NCT03656562
Tabalumab BAFF phase III trials [157]
[158]
Atacicept BAFF phase II/III trial NCT00624338[159]
phase IIb trail [160]
Telitacicept BAFF phase III trials NCT04082416
phase I trials NCT06456567
phase II trials NCT05339217
phase IV trials NCT05306574
NCT05247203
NCT05687526
NCT05929248
NCT05680480
NCT05899907
NCT05666336

rituximab, while exhibiting increased antibody-depend- the trial, achieved without resorting to corticosteroids
ent cellular cytotoxicity and heightened phagocytic exceeding a predetermined threshold (NCT04702256).
activity [161]. Clinical data and analyses have informed An ongoing phase III trial employing a randomized,
the development of obinituzumab, which is intended double-blind, placebo-controlled design, spanning mul-
to overcome limitations and resistance associated with tiple centers, aims to delineate the efficacy and safety
rituximab (RTX) treatment [162]. Presently, the phase of obinutuzumab relative to a placebo in participants
III REGENCY trial, designed to assess the efficacy and diagnosed with autoantibody-positive SLE exhibit-
safety of obinutuzumab in patients with ISN/RPS 2003 ing active disease despite receiving standard-of-care
class III or IV lupus nephritis, is ongoing. Concurrently, therapies(NCT04963296). The findings suggest a new
a phase III multi-central trial of a randomised, open label, therapeutic strategy for treating SLE patients who have
controlled, non-inferiority design is proceeding. The not seen responses to subsequent RTX treatments, by
principal purpose of this clinical investigation is to sub- administering obinutuzumab infusions.
stantiate the non-inferiority of a treatment regimen that
eschews supplemental oral corticosteroids yet integrates Ofatumumab, a fully human mAb that targets CD20,
obinutuzumab in conjunction with MMF, as compared has received approval for clinical utilization. Initially
to a traditional regimen that combines oral corticos- granted approval for the treatment of chronic lympho-
teroids with MMF. The primary endpoint is the attain- cytic leukemia (CLL) in 2009, it subsequently gained
ment of a complete renal response by the 52nd week of approval for use in relapsing forms of multiple sclerosis
Su et al. Molecular Biomedicine (2024) 5:54 Page 12 of 30

Fig. 3 Targeted therapies of SLE based on B and T cells. The therapeutic strategies aimed at B cells include targeting B-cell surface receptors (CD10,
CD20, CD22, CD38, CD40) and targeting B-cell related cytokines (BAFF). The therapeutic strategies aimed at T cells include co-stimulation blockade
(CD40–CD40L, CD80/86–CD28, ICOS–ICOSL) and cytokine blockade (IL-6, IL-12, IL-17, IL-23, IFN-γ)

(MS) in 2020. In a clinical study, ofatumumab was admin- is an engineered anti-CD19 mAb designed for high-affin-
istered to 16 patients with severe infusion reactions asso- ity binding to the inhibitory FcγRIIb receptor. It achieves
ciated with RTX. Fourteen patients experienced good this by simultaneously engaging CD19/BCR along with
tolerance to the infusion, resulting in B cell depletion FcγRIIb on B cells, thereby potently suppressing BCR-
and improved serological markers of disease activity induced B cell activation in vitro. This inhibition is medi-
[163]. Moreover, in patients with refractory LN who had ated through a pathway involving SH2-containing inosi-
adverse reactions to RTX infusions, administering ofa- tol polyphosphate 5-phosphatase (SHIP) [169, 170].
tumumab at a dose of 700 mg with a two-week interval
led to clinical improvements, notably a decrease in albu- Notably, obexelimab has demonstrated its capacity to
minuria levels [164]. Significantly, there have been docu- modulate in vivo antibody responses, as evidenced by its
mented cases of successful treatment with ofatumumab inhibitory effect on anti-tetanus antibody production in
in juvenile SLE patients, suggesting that ofatumumab immunodeficient SCID mice transplanted with human
may provide an alternative therapeutic choice to RTX for peripheral blood mononuclear cells [171].A double-blind,
SLE [165, 166]. randomized, placebo-controlled trial (NCT02725515) is
completed to assess the effectiveness of obexelimab in
CD19 is a transmembrane protein that is present on B sustaining remission in SLE following a brief regimen of
cells throughout their development, until they ultimately steroid therapy. The trial’s primary outcome, which was
differentiate into plasma cells. It physically links with the the percentage of patients maintaining disease improve-
BCR, enhancing the BCR’s signaling capabilities [167]. In ment without deterioration at the 225-day mark, did
addition to its role in B cell biology, CD19 also functions not achieve its goal. However, the secondary outcome,
as a significant clinical marker for B cells and is consid- measuring the duration until disease worsening, was sig-
ered as a possible target for therapeutic interventions nificantly prolonged in the obexelimab group, hinting at
[148]. potential benefits that merit further exploration. As of
now, phase III studies for obexelimab in the treatment of
Anti-CD19 mAbs like XmAb5871, now recognized SLE have not been initiated.
as obexelimab, can be therapeutically effective without
necessarily depleting B cells. Instead of causing physical It should be highlighted that the anti-CD19 mAb
removal, these mAbs inactivate B cells [168]. Obexelimab MEDI551, known as inebilizumab, is effective at
Su et al. Molecular Biomedicine (2024) 5:54 Page 13 of 30

depleting B cells while specifically preserving regulatory with elevated levels of autoantibody generation [177,
B cells [172]. This selective sparing enhances the appeal 178].
of this therapeutic agent. A Phase 2a, open-label, multi-
center platform trial (NCT06570798) is designed to eval- Epratuzumab, a mAb targeting CD22, modulates B
uate the safety, tolerability, and efficacy of inebilizumab cell activity by triggering the phosphorylation of CD22.
and blinatumomab in individuals with autoimmune dis- This initiates a cascade that results in the internaliza-
eases. The primary goal of this study is to determine the tion of CD79α and CD22, followed by the downregula-
safety and tolerability profiles of inebilizumab (Subproto- tion of CD21, CD19, and CD79β from the cell surface
col A) and subcutaneously administered blinatumomab through a process known as trogocytosis [179]. In the
(Subprotocol B) in adults with active, refractory SLE phase 2b EMBLEM trial, patients who received epratu-
exhibiting nephritis. zumab at various doses showed a higher rate of BICLA
responses compared to those on placebo [180]. However,
In a groundbreaking investigation, researchers gener- the phase 3 EMBODY 1 and 2 trials did not achieve their
ated anti-CD19 chimeric antigen receptor (CAR) T cells primary endpoints for epratuzumab [181]. Despite this,
to treat a SLE patient who was resistant to various exist- post hoc analyses of the EMBODY trials indicated ben-
ing therapies [173]. This approach resulted in the com- eficial effects in patients with SLE who also had Sjogren’s
plete elimination of circulating B cells and led to clinical syndrome.
and serological remission for the patients. An investiga-
tional trial is being conducted to evaluate the safety, tol- CD38, a type II glycoprotein, exhibits robust and con-
erability, initial therapeutic (preliminary efficacy), phar- sistent expression on plasma cells and plasmablasts that
macokinetic (PK) profile, and pharmacodynamic (PD) produce antibodies. In an ex vivo study assessing CD38
responses of CD19-directed chimeric antigen receptor expression on various immune cells within peripheral
(CAR)-T cell therapy in patients with refractory or mod- blood mononuclear cells (PBMCs) from SLE patients,
erately to severely active SLE. The recruitment pool con- plasma cells and plasmablasts were noted to have the
sists of these challenging patient populations who have highest levels of CD38 expression, succeeded by natural
not responded adequately to conventional treatments. killer (NK) cells, pDCs, a subset of regulatory T cells, and
Participants will undergo an administration of CD19- naive T cells [182]. These observations imply that CD38
specific CAR-T cells, followed by a comprehensive moni- represents an appropriate target for therapeutic explora-
toring period extending up to two years post-enrollment, tion in SLE [183].
thereby providing a thorough assessment of the therapy’s
long-term effects. This rigorous examination aims to Daratumumab, a humanized mAb targeting CD38, was
uncover potential benefits and risks associated with this first approved for the treatment of multiple myeloma and
innovative approach in managing SLE (NCT06106906). is currently being investigated for SLE and other condi-
tions. The mechanism of action involves binding to CD38
CD22, a member of the sialoadhesin subclass within on target cells, leading to cytotoxic effects through mul-
the Ig superfamily, functions as a lectin-like adhesion tiple pathways including antibody-dependent phagocy-
receptor and is integral to the B-cell activation complex tosis (ADP), complement-dependent cytotoxicity (CDC),
[174]. This receptor is present on cells of the B lineage, antibody-dependent cellular cytotoxicity (ADCC), induc-
spanning from immature B cells through to those in ger- tion of apoptosis, and modulation of immune responses.
minal centers, yet it is significantly lacking in plasma cells A case study involving the use of daratumumab, a mono-
and memory B cells. When the BCR is stimulated, CD22’s clonal antibody targeting CD38, in SLE has shown early
trio of tyrosine-based inhibitory motifs (ITIMs) undergo signs of therapeutic efficacy and validated its mechanism
phosphorylation. This process triggers the recruitment of action. In this instance, two individuals suffering from
of tyrosine phosphatase I (SHP-1) and other regulatory severe and life-threatening SLE exhibited notable clinical
factors, which in turn modulate and constrain the BCR improvements, which were correlated with substantial
signaling pathway [167, 174].Variations and polymor- reductions in autoantibody levels, decreases in plasmab-
phisms in the CD22 gene have been correlated with an last counts, and a dampening of type I IFN activity [184].
increased susceptibility to autoimmune conditions, such Additionally, the beneficial effects of daratumumab have
as SLE [175]. Research conducted on mice prone to auto- been documented in other conditions driven by autoan-
immunity has further established a connection between tibodies, including primary Sjögren’s disease, antineu-
the CD22 gene and the development of SLE [176, 177]. trophil cytoplasmic antibody (ANCA)-associated vascu-
Moreover, deficiencies in CD22 have been associated litis, and immune thrombocytopenia. This highlights the
Su et al. Molecular Biomedicine (2024) 5:54 Page 14 of 30

critical involvement of CD38 in the pathogenesis of auto- for the treatment of active SLE. Numerous clinical trials
immune conditions [185]. have consistently demonstrated its efficacy in reducing
disease activity, mitigating the risk of severe flares, and
Mezagitamab, known also as TAK-079, is an experi- decreasing reliance on corticosteroids [193–195]. Beli-
mental human immunoglobulin G1 (IgG1) mAb with mumab acts by binding and neutralizing soluble BAFF,
a high-affinity binding to CD38. Early non-clinical and thereby inhibiting its interaction with BCMA, TACI,
initial human data from studies involving patients with and BR3 and consequently blocking the BAFF activ-
multiple myeloma have shown mezagitamab to have a ity [196].The phase III trials, namely BLISS-North East
favorable safety profile and promising pharmacodynamic Asia (NEA), BLISS-52, and BLISS-76, established that
effects, particularly in the reduction of CD38-expressing the intravenous administration of 10 mg/kg belimumab
target cells [186, 187]. These findings have bolstered the in conjunction with standard care was more effective in
rationale for exploring mezagitamab as a potential treat- reducing disease activity than placebo [197, 198]. Post
ment for SLE, a condition noted for the frequent pres- hoc analyses from the BLISS trials indicated that beli-
ence of cells exhibiting aberrant CD38 expression. The mumab effectively achieved Lupus Low Disease Activ-
phase 1b clinical trial, identified as NCT03724916, evalu- ity State (LLDAS) [199, 200]. Furthermore, the NEA
ated the safety profile, pharmacokinetic behavior, and trial revealed that belimumab-treated patients had a
pharmacodynamic effects of mezagitamab in partici- significantly reduced risk of severe flares compared to
pants suffering from moderate to severe SLE. This phase the placebo group, with respective rates of 22% and
1b clinical study established the favorable safety profile 12% (p = 0.0004) [193]. A closer examination of the data
of mezagitamab, along with its anticipated pharmaco- showed that the efficacy of the 1 mg/kg belimumab dos-
dynamic effects and promising mechanistic outcomes in age was comparable to the 10 mg/kg dosage regarding
individuals with moderate to severe SLE. These results both LLDAS and SLE Responder Index-4 (SRI-4), par-
advocate for further exploration of mezagitamab as a ticularly in the BLISS-76 trial with extended follow-up
potential therapeutic agent in the context of autoimmune period [199]. Also, a retrospective analysis highlighted
diseases [188]. that belimumab can be beneficial early in the disease for
patients with active SLE and minimal baseline damage
BAFF, also recognized as B-lymphocyte stimulator [201]. At present, a phase IV multicenter, randomized,
(BLyS), a 285-amino acid type-II transmembrane pro- double-blind, placebo-controlled clinical trial is under-
tein belonging to the tumor necrosis factor (TNF) ligand way, with the objective of investigating the efficacy of
superfamily acts as a cytokine crucial for B cell prolif- low-dose belimumab in preventing disease flares in SLE
eration and development. Elevated levels of BAFF are patients exhibiting low disease activity. This study seeks
associated with an expansion of B cells, while the genetic to expand our understanding of the therapeutic potential
elimination or pharmacological neutralization of BAFF of belimumab, further delineating its role in the manage-
results in a decrease in B cell numbers [189]. Binding to ment of SLE in a subset of patients characterized by con-
receptors such as BAFF-R, B Cell Maturation Antigen trolled disease states (NCT04515719).
(BCMA), and Transmembrane Activator and Calcium-
modulator and cyclophilin ligand (CAML) Interactor Ianalumab, a monoclonal antibody, exhibits a dual
(TACI), BAFF exerts its effects [190]. BAFF-R is primarily mechanism of action by targeting BAFF-R and effectu-
expressed in immature B cells, whereas BCMA and TACI ating the deletion of peripheral BAFF-R + B cell [202].
are more commonly associated with mature B cells and Currently, there is an ongoing randomized, double-
plasma cells. Another protein, A Proliferation-Inducing blind, placebo-controlled multicenter phase III clini-
Ligand (APRIL), shares similarity with BAFF and func- cal study evaluating the efficacy, safety, and tolerability
tions parallelly in promoting B cell survival and develop- of lanalumab in patients with lupus erythematosus, in
ment, while also binding to the BCMA and TACI recep- addition to standard care treatment (NCT05624749).
tors [190, 191]. The therapeutic importance of targeting A phase 2 clinical trial (NCT03656562), encompassing
BAFF-R is highlighted by the use of anti-BAFF-R thera- a randomized, double-blinded, and placebo-controlled
pies in managing myeloma, leukemia, and lymphoma, design, is presently underway to assess the safety and
rendering BAFF-R an appealing therapeutic target in SLE efficacy of lanalumab in 107 individuals ranging from 18
as well [192]. to 75 years old with SLE. The primary objective of this
study is to evaluate the attainment of SRI-4 at week 53.
Belimumab, a human monoclonal antibody that targets Furthermore, an ongoing investigation in the form of a
BAFF, marked a milestone as the first biological agent double-blinded, randomized, placebo-controlled, and
approved by the Food and Drug Administration (FDA) multicenter three-arm study (NCT06133972) aims to
Su et al. Molecular Biomedicine (2024) 5:54 Page 15 of 30

evaluate the efficacy and safety of subcutaneous admin- were assigned to receive 75 mg or 150 mg of atacicept,
istration of lanalumab every 4 weeks or every 12 weeks, or a placebo [206]. Although the study’s main goal of
compared to placebo administered subcutaneously every achieving an SRI-4 response was not reached, there was a
4 weeks. This study specifically targets adults with active noticeable trend toward a higher response rate with atac-
LN. Upon completion, these trials are expected to yield icept, particularly among patients exhibiting high disease
substantial understanding of the role of anti-BAFF-R and serological activity. The drug exhibited a favorable
therapies in SLE patients. The SIRIUS-SLE 2 trial, a ran- safety profile in both the ADDRESS II trial and its sub-
domized, double-blind, placebo-controlled, multi-center, sequent extension. In contrast to the APRIL-SLE trial,
phase 3 study (NCT05624749), is devised to meticulously atacicept did not show an increased frequency of adverse
appraise the efficacy, safety, and tolerability of adjunctive events or serious infections when compared to the pla-
lanalumab therapy in conjunction with standard care in cebo [206]. Consideration is being given to phase III trials
individuals afflicted with SLE. This study endeavors to for SLE involving atacicept.
furnish comprehensive insights into the therapeutic value
and safety profile of Ianalumab as an enhancement to the Telitacicept, also known as RC18, is a BAFF antagonist
gold-standard SLE interventions. that is also a recombinant fusion protein comprising the
Fc domain of human IgG1 and the extracellular domain
Tabalumab, a human IgG4 mAb targeting BAFF, which of the TACI receptor. This molecule has demonstrated
does not only bind soluble BAFF but also membrane- efficacy in a phase 2b trial, achieving its primary end-
bound BAFF, has been evaluated in two substantial phase point with an SRI-4 response across all tested doses. Cur-
III clinical trials conducted with double-blind, rand- rently, a phase 3 trial of telitacicept has been concluded
omized controlled methodologies. In the initial trial, (NCT04082416).
neither the primary nor the secondary endpoints were
achieved, even though a notable decrease in anti-dsDNA Targeting T cells as a therapeutic strategy for SLE The
antibody levels was observed among participants who therapeutic strategies aimed at the T cell compartment
received the treatment [203]. The second trial involved include co-stimulation blockade, cytokine blockade and
patients who were administered one of two doses of kinase inhibition (Table 3; Fig. 3).
tabalumab or a placebo; it showed that the group with
more frequent dosing met its primary outcome [204]. Approximately a dozen experimental drugs are being
However, the efficacy in terms of response rate did not developed to target co-stimulatory molecules. Dapiroli-
surpass the results noted in trials featuring belimumab. zumab pegol [207], iscalimab, and ruplizumab are exam-
Additionally, critical secondary endpoints, such as the ples of agents that target the CD40L-CD40 signaling
time to severe flare, the potential for corticosteroid axis, while dazodalibep represents a next-generation
reduction, and the impact on fatigue, were not achieved. fusion protein intended to inhibit CD40 ligand (CD40L).
Given these trials’ outcomes, which did not demon- Additionally, the CD28 molecule, a T cell costimulatory
strate a compelling advantage for tabalumab, the sponsor factor crucial for the activation of pathogenic T cells in
decided to discontinue its further development for the autoimmune conditions, is being targeted by three inves-
treatment of SLE. tigational drugs: theralizumab, lulizumab pegol, and aca-
zicolcept, which also targets the ICOS pathway. Lastly,
Atacicept is a fusion protein that combines the TACI LY3361237 is a novel B- and T-lymphocyte attenuator
receptor, a BAFF receptor, with the Fc region of IgG. This (BTLA/CD272) agonist, representing a first-in-class
construction can bind and neutralize both BAFF and approach in this area.
APRIL, suggesting it might offer enhanced potency and
efficacy compared to treatments that target BAFF alone. Given that patients with SLE exhibit increased expres-
In the APRIL-SLE trial, participants were randomized to sion of CD40, the blockade of CD40 receptor presents a
receive atacicept at doses of 75 mg or 150 mg, or a pla- potential avenue for modulating the immunologic and
cebo, twice weekly for 48 weeks [205]. The 150 mg dosage clinical activity of SLE.
group was discontinued early due to two reported deaths,
and the 75 mg dose did not differ significantly from pla- BI655064 is classified as a humanized anti-CD40
cebo in the primary outcomes of flare rate or time to the mAb. In a phase 2 trial with a randomized, double-
first flare. However, a significant reduction in both flare blind, and placebo-controlled design, the safety and
rate and time to the first flare was noted among patients efficacy of BI655064 were assessed in patients with
who received the higher 150 mg dose of atacicept. In the active LN across three dose levels: 240 mg, 180 mg, and
phase IIb ADDRESS II study, individuals with active SLE 120 mg (NCT02770170). A total of 121 participants aged
Su et al. Molecular Biomedicine (2024) 5:54 Page 16 of 30

Table 3 T-cell targeted therapies in SLE

Type of agent Target Agent Stage of development Reference

Co-stimulation blockade CD40–CD40L BI655064 phase II trial NCT02770170

CD40–CD40L VAY736 phase II trial NCT03656562
CD40–CD40L Dapirolizumab pegol phase IIb trail [207]
phase III trial NCT04976322
CD40–CD40L CDP7657 phase I trials NCT01093911
NCT01764594
CD80/86–CD28 CTLA4-Ig Phase I/II trail NCT02429934
ICOS–ICOSL AMG 557 phase I trials NCT01683695
NCT00774943
NCT02391259
Cytokine blockade IL‑6R Tocilizumab phase I trial NCT00046774
IL‑6R ALX-0061 phase II trial NCT02437890
IL‑6 CNTO 136 phase I trial NCT01702740
phase II trial NCT01273389
IL‑12 and IL‑23 Ustekinumab phase III trials NCT03517722
NCT04060888
IL‑23 Guselkumab phase II trial NCT04376827
IL-17 Secukinumab phase II trial NCT03866317
IFN-γ AMG 811 phase I trials NCT00818948
NCT02291588
Kinase inhibition JAK Filgotinib phase II trial NCT03285711
JAK Upadacitinib phase II trial NCT04451772
JAK Deucravacitinib phase II trial NCT03920267
phase III trials NCT05617677
NCT05620407
JAK Tofacitinib phase Ib trail NCT02535689
JAK Baricitinib phase II trial NCT02708095
JAK lanraplenib phase II trials NCT03134222
NCT03285711
JAK Brepocitinib phase II trial NCT03845517
JAK solcitinib phase II trial NCT01777256
JAK baracetinib phase III trial NCT05432531
Calcineurin Voclosporin phase II trials NCT05306873
phase III trials NCT02949973
NCT02141672
NCT03597464
NCT06406205
NCT03021499
NCT05288855
NCT05962788
mTOR Sirolimus phase II trial NCT00779194
mTOR INK128 phase II trial NCT00775476

between 18 and 70 were allocated to receive either sub- patients who received BI 655,064, compared to 8 out of
cutaneous injections of placebo or BI655064. The pri- 20 patients in the placebo group. Currently, the future
mary outcome, complete renal response (CRR) at week development plans for this compound are not publicly
52, was achieved by 48.3% in the placebo group, 38.3% determined [208, 209].
in the 120 mg group, 45.0% in the 180 mg group, and
44.6% in the 240 mg group. Because of a notable pla- Iscalimab, a fully human anti-CD40 mAb, has been
cebo response observed in the study, a post-hoc analysis investigated in various medical conditions, includ-
was undertaken to verify the endpoint’s validity, which ing Sjogren’s syndrome, cancer, and kidney transplant
indicated a 15% effect size in the 180 mg dosage group. patients. At present, a meticulously designed study
There were serious adverse events (SAEs) in 22 of the 81 (NCT03656562) is underway to comprehensively
Su et al. Molecular Biomedicine (2024) 5:54 Page 17 of 30

evaluate the dynamic interplay between pharmacokinet- The traditional CD80/CD86-CD28 costimulatory path-
ics and pharmacodynamics, alongside the safety profile, way represents a key target for immunotherapeutic inter-
tolerability, and tentative therapeutic impact of VAY736 ventions in autoimmune diseases. Cytotoxic T-lympho-
(ianalumab) and CFZ533 (iscalimab) in participants diag- cyte-associated protein 4 (CTLA-4), a negative regulator
nosed with SLE. This investigation adopts a placebo-con- that is upregulated on activated T cells to prevent exces-
trolled, double-blind, randomized parallel-group meth- sive activation, binds more avidly to CD80/CD86 than
odology to ensure rigorous assessment while mitigating CD28. This characteristic has made it a therapeutic con-
bias. Throughout this inquiry, a primary objective is to tender for dampening T-cell responses by competitively
ascertain a nuanced understanding of the investigation inhibiting CD28. CTLA4-Ig, a fusion protein, has been
agents’ action mechanism, tolerability, and potential effi- extensively tested as an immunotherapy across various
cacy in alleviating the manifestations of SLE - all of which disease systems and models [213, 214]. In the context of
are integral to paving the pathway for innovative thera- SLE, CTLA4-Ig has emerged as a promising therapeutic
peutic avenues in the management of this complex auto- option, with promising preclinical findings from multiple
immune condition. models [215]. However, its clinical efficacy is still under
investigation, as results from a few phase II/III clinical
Dapirolizumab pegol (DZP) represents an emerging trials are pending.
therapeutic option for SLE, formulated as a PEGylated
anti-CD40 ligand Fab’ antibody fragment. This agent Co-stimulation of lymphocytes is a pivotal aspect of
functions by binding to CD40, a key molecule in the immunology, critical for regulating inflammation and
activation of immune cells, thereby dampening inflam- guiding immunotherapeutic strategies [216–219]. The
mation and alleviating SLE symptoms [210]. In a phase inducible T cell co-stimulator (ICOS) on T cells increases
IIb clinical trial, DZP demonstrated efficacy in reducing after interaction with peptide-major histocompatibility
disease activity indices, lowering anti-double-stranded complex (pMHC) in conjunction with CD28 co-stim-
DNA (anti-dsDNA) antibody levels, and restoring C3 ulation. This engagement leads to the binding of ICOS
and C4 complement levels versus placebo at the 24-week with its unique ligand, the inducible T-cell co-stimulatory
mark [207]. Nevertheless, the highest dosage of DZP, ligand (ICOSL), alternatively termed B7-related protein-1
specifically 45 mg/kg, was associated with a modestly or B7h. This binding initiates essential T cell functions,
increased rate of severe treatment-emergent adverse such as cytokine secretion and the specification of T cells
events (TEAEs) compared to other dosage groups [207]. into the Tfh lineage, which is crucial for B cell help and
Given the potential for thromboembolic risks associated antibody production, over other effector lineages [220,
with CD40L-targeting therapies [211], it is significant 221].
that DZP has shown a generally favorable safety profile,
exhibiting good tolerability and a comparatively lower AMG 557 is a humanized IgG2 mAb that specifically
risk of thromboembolic events compared to other mAbs targets the ICOSL. By binding to ICOSL, it inhibits the
targeting CD40L [212]. DZP is currently under investiga- functional engagement with its receptor ICOS on acti-
tion in phase III clinical trials for SLE (NCT04976322). vated T cells. Importantly, AMG 557 exhibits no cross-
reactivity with other members of the B7 family of co-
A phase I clinical trial (NCT01093911) is completed, stimulatory molecules.
evaluating CDP7657, which is a monovalent, PEGylated
Fab fragment of an anti-CD40L antibody, for its use in Tocilizumab is a humanized mAb that targets the
SLE. Given that individual IgG molecules are incapable α-chain of the IL-6 receptor, thereby blocking the inter-
of binding to or activating the platelet FcγRIIa recep- action of IL-6 with both membrane-bound and solu-
tor—this receptor is only triggered by clustered, multi- ble forms of the IL-6 receptor. Its safety and efficacy
meric IgG immune complexes [54]—this specific anti- have been assessed in clinical trials for conditions such
body format may offer a reduced risk of thromboembolic as rheumatoid arthritis, juvenile idiopathic arthritis,
events, thus potentially providing a safer therapeutic and Castleman’s disease [222]. In a Phase I, open-label,
option. A multicenter, randomized, double-blind, pla- dose-escalation study (NCT00046774), 16 individuals
cebo-controlled, parallel-group, and repeat-dose study with mild to moderate SLE disease activity received toci-
(NCT01764594) was also initiated to evaluate the impact lizumab bi-weekly for 12 weeks at one of three dosages
of CDP7657 in individuals with active SLE. This trial was (2 mg/kg for 4 participants, 4 mg/kg for 6 participants,
designed to assess the efficacy and safety of the interven- and 8 mg/kg for 6 participants). These patients were then
tion under rigorous scientific scrutiny. monitored for an additional 8 weeks. This preliminary
investigation offers initial evidence that tocilizumab can
Su et al. Molecular Biomedicine (2024) 5:54 Page 18 of 30

successfully inhibit IL-6 in SLE patients. The observed in patients with active LN. The trial is divided into three
enhancements in inflammatory biomarkers and the clini- phases: a screening period of approximately 8 weeks
cal and serological indicators of lupus activity are prom- leading up to randomization, a 24-week treatment phase,
ising. Further exploration in controlled trials is necessary and a follow-up phase extending to week 40. During
to substantiate these findings and to evaluate the poten- an 8-week run-in period, the stability of baseline renal
tial of tocilizumab in SLE treatment [223]. parameters will be confirmed before the administration
of the first study medication. The objective of this trial is
A Phase II multicenter clinical trial (NCT02437890) to assess the intravenous administration of Sirukumab in
is designed to evaluate the safety and efficacy of vobari- patients with active International Society of Nephrology/
lizumab (ALX-0061) when administered subcutane- Renal Pathology Society Class III and IV LN. This proof-
ously in individuals with moderate to severe active SLE. of-concept trial failed to establish the expected therapeu-
The primary objective of this randomized, double-blind, tic benefits of sirukumab and did not meet the required
placebo-controlled, dose-ranging study is to compare the safety standards for patients with active lupus nephritis
efficacy and safety of various subcutaneous dosages of who were concurrently undergoing immunosuppressive
ALX-0061 to placebo in subjects with moderate to severe therapy [227].
active, seropositive SLE. Secondary objectives include
assessing the pharmacokinetics (PK), pharmacodynam- Memory T cells are categorized into several subsets,
ics (PD), immunogenicity, flare rate, potential for steroid with Th1 cells being crucial for the initiation of cell-
reduction, and the impact on health-related quality of life mediated immunity, and Tfh cells being vital for the dif-
associated with different dosage regimens of ALX-0061. ferentiation and activation of B cells. The cytokine IL-12
This comprehensive evaluation aims to determine the is instrumental in the development of Th1 and Tfh cells
optimal dosing strategy for ALX-0061 in the treatment of in humans, and increased levels of serum IL-12 are
SLE. observed in individuals with active SLE [228]. Usteki-
numab, a monoclonal antibody targeting IL-12/IL-23
Sirukumab, previously known as CNTO136, is a (p40), has been approved for treating psoriasis and pso-
human monoclonal antibody that targets IL-6 with high riatic arthritis, with its efficacy and safety having been
affinity and specificity. It neutralizes IL-6 by inhibiting assessed. In a phase IIb global clinical trial that included
STAT-3 phosphorylation, thereby reducing IL-6’s bio- patients with highly active SLE, Ustekinumab (UST) was
logical effects. Initial human studies in healthy volunteers compared to a placebo. The trial’s primary endpoint was
indicated that a single intravenous dose of sirukumab, the SRI-4 response rate at 24 weeks, which was signifi-
ranging from 0.3 to 10 mg/kg, was generally well toler- cantly higher in the ustekinumab group compared to the
ated without any dose-related safety concerns [224]. A placebo group. This beneficial effect was sustained for up
two-part, Phase I clinical trial (NCT01702740), char- to one year, with no significant adverse events reported
acterized by randomization, double-blinding, and pla- [229].
cebo control, assessed the safety and pharmacokinetics
of multiple intravenous doses of sirukumab across three A Phase 3, multicenter, randomized, placebo-controlled
escalating dosage levels in 31 patients with cutaneous trial (NCT03517722) is to evaluate the efficacy and safety
lupus erythematosus (CLE) and at a single dosage level of ustekinumab in individuals with SLE. Eligible partici-
in 15 patients with SLE. Overall, the participants in this pants with active SLE, defined by a SLEDAI 2000 score of
study presented with mild, stable, yet active disease [225]. at least 6 during the screening phase and a SLEDAI-2 K
Sirukumab therapy was generally well tolerated among score of at least 4 at week 0, were enrolled despite ongo-
patients with both CLE and SLE. Patients who received ing treatment with oral glucocorticoids, antimalarial
sirukumab exhibited sustained, stable reductions in white agents, or immunomodulatory therapies. They were then
blood cell count, absolute neutrophil count, and platelet randomly assigned in a 3:2 ratio to receive either usteki-
count, which were not dose dependent. These reductions numab (intravenous infusion at approximately 6 mg/kg
are consistent with the known mechanism of action of at week 0, followed by subcutaneous injections of 90 mg
sirukumab and the role of IL-6 in hematopoiesis [226]. every 8 weeks starting at week 8) or a placebo, continu-
A similar effect has been observed with tocilizumab, ing through week 48. The primary outcome measure is
another anti-IL-6 receptor antibody [223]. the SLE Responder Index (SRI)-4 at week 52, with key
secondary outcomes including the time to flare and the
A multicenter, randomized, double-blind, placebo- achievement of SRI-4 at week 24. Regrettably, the trial
controlled, parallel-group study (NCT01273389) is com- results indicated that ustekinumab did not outperform
pleted to evaluate the efficacy and safety of Sirukumab placebo in the cohort of adults with active SLE. The
Su et al. Molecular Biomedicine (2024) 5:54 Page 19 of 30

adverse events observed were in line with the established significant efficacy in treating psoriasis and in conditions
safety profile of ustekinumab, leading to the premature unresponsive to steroid therapy, and the immunohisto-
termination of the study [230]. chemical data suggesting a role for IL-17 A in the inflam-
matory process of DLE, researchers are proposing a
Another phase 3, multicenter, randomized, dou- pilot study(NCT03866317) to investigate secukinumab’s
ble-blind, placebo-controlled, parallel-group study potential in managing discoid lupus erythematosus.
(NCT04060888) of Chinese patients with SLE is evalu-
ating the efficacy and safety of Ustekinumab. The objec- Interferon-gamma (IFN-γ) is a multifunctional type II
tive of this study was to assess the efficacy of ulinastumab interferon predominantly generated by effector CD4 + T
in Chinese patients with SLE, who do not respond well cells of the Th1 lineage, cytotoxic CD8 + T cells, and NK
to one or more standard therapies. The study design cells. It is also produced, albeit to a lesser extent, by other
included the randomization of participants to groups immune cells including DCs, macrophages, and B lym-
that received either ulinastumab (approximately 6 mg/ phocytes. Research has demonstrated that SLE patients
kg intravenously at week 0, followed by 90 mg subcutane- exhibit elevated serum levels of IFN-γ compared to
ously at week 8 and every 8 weeks thereafter) or placebo; healthy controls [233–236]. Moreover, an abnormal accu-
The study will continue until week 48. The primary end mulation of IFN-γ occurs within the body well in advance
point was the SLE response index (Sri-4) at week 52, and of an SLE diagnosis, preceding the emergence of autoan-
the primary secondary end points included the time to tibodies and interferon-alpha (IFN-α) [237].
exacerbate at week 52 and Sri-4 at week 24.
Clinical trials focused on targeting IFN-γ have begun
Guselkumab is a mAb that exhibits high-affinity bind- to show promise. AMG 811, a fully human mAb of the
ing to human IL-23, preventing the interaction of extra- IgG1 subtype against IFN-γ, has demonstrated good tol-
cellular IL-23 with its cell surface receptor. This blockade erability in patients with mild to moderate SLE. A single
impedes the intracellular signaling pathways specific to administration of AMG 811 has been shown to normal-
IL-23, thereby inhibiting the activation and cytokine pro- ize the expression of IFN-regulated genes, leading to
duction associated with IL-23. LN, a renal manifestation a dose-dependent reduction in serum CXCL-10 levels
of SLE, represents a significant area in need of novel and [238, 239]. While AMG 811 modulated IFN-γ-associated
effective treatment strategies that can offer superior long- biomarkers and demonstrated a favorable safety profile, it
term outcomes compared to existing options. A Phase 2 did not yield significant clinical improvements in patients
study (NCT04376827) aims to assess the safety and effi- with DLE [240]. Nonetheless, positive outcomes from
cacy of guselkumab when administered in conjunction phase Ib trials have highlighted the potential of blocking
with the standard-of-care, in comparison to placebo plus the IFN-γ pathway in treating extrarenal manifestations
standard-of-care. The study’s total duration spans up to of lupus [241]. These collective findings position IFN-γ
68 weeks, which includes a screening phase of up to 8 as a pivotal cytokine in LN, and further investigation into
weeks, a 48-week double-blind treatment phase, and a IFN-γ inhibition in LN is warranted, considering the tol-
12-week post-treatment safety follow-up phase. Partici- erable safety profile associated with its targeted blockade.
pants who reach the 52-week mark with a complete renal Two concluded studies, identified by the trial numbers
response (CRR) may be eligible to enroll in a long-term NCT00818948 and NCT02291588, have assessed the
extension (LTE) of the study, extending their involvement safety profile of AMG118 in the context of SLE treatment.
through to Week 152, followed by a final 12-week safety
follow-up visit. The JAK/STAT signaling pathway is a crucial cellu-
lar mechanism that responds to a broad spectrum of
IFN-α is recognized as a key cytokine in the pathogen- cytokines and growth factors [242]. Numerous inflam-
esis of SLE. A multitude of studies have demonstrated matory cytokines, which are involved in the pathogenesis
that IFN-α stimulates the production of interleukin-17 of SLE, such as type I and II IFNs, utilize the JAK-STAT
(IL-17), which has been identified as a significantly pro- pathway for signaling [243, 244]. Inhibitors of Janus
inflammatory cytokine in SLE [231, 232]. Discoid lupus kinase (JAK inhibitors, or jakinibs) have shown prom-
erythematosus (DLE) represents a dermatological pres- ise in various lupus models in mice [245]. Clinical trials
entation of lupus, which may occur as an aspect of SLE utilizing jakinibs have demonstrated efficacy in treating
or as a standalone chronic skin condition without sys- arthritis in individuals with mild-to-moderate SLE [246,
temic manifestations. Secukinumab, marketed as Cosen- 247].
tyx, is a monoclonal antibody directed against inter-
leukin-17 A (IL-17 A). Given its established safety, its
Su et al. Molecular Biomedicine (2024) 5:54 Page 20 of 30

In the context of treating SLE with JAK inhibitors, [250] of JAK1 and JAK2, is an orally administered drug
global phase II or III trials are presently being con- that has been approved for treating moderate-to-severe
ducted on filgotinib (NCT03285711), Upadacitinib active rheumatoid arthritis in adults across more than 75
(NCT04451772), and deucravacitinib (BMS-986165). countries, including the United States, Japan, and sev-
Notably, deucravacitinib, a TYK2 inhibitor, has drawn eral European Union nations. By inhibiting JAK1/JAK2,
significant interest. Unlike other JAK inhibitors that baricitinib potentially modulates the production of pro-
competitively bind to adenosine triphosphate (ATP) sites, inflammatory cytokines, including type I IFNs, IFN-γ,
deucravacitinib is an allosteric inhibitor, thus is antici- IL-6, IL-12, and IL-23 [247, 251]. In a Phase II clinical
pated to exhibit high specificity. In a phase II trial involv- trial (NCT02708095) investigating the effects of barici-
ing patients with active SLE (NCT03920267), the primary tinib in individuals with SLE, the administration of 4 mg
endpoint a SRI-4 response rate at week 32 was markedly of daily oral baricitinib in conjunction with standard care
higher in individuals administered deucravacitinib at demonstrated superior disease activity improvement at
3 mg twice daily (58%) compared to those given a placebo 24 weeks compared to placebo with standard care [247,
(34%). Additionally, numerous secondary endpoints were 252]. However, the study did not record any significant
achieved [248]. Currently, phase III trials are underway overall least squares (LS) which mean changes from
(NCT05617677, NCT05620407). Deucravacitinib has baseline in conventional serologic biomarker levels, such
also been shown to modulate type I IFN-associated gene as anti-dsDNA antibodies, complement component 3
expression. Considering that one possible reason for clin- (C3), or complement component 4 (C4), with baricitinib
ical trial failures is the inhibition of regulatory T cell dif- treatment. The conclusions derived from this study are
ferentiation and activation due to the suppression of IL-2 subject to certain limitations. The findings do indicate
signaling pathways by baricitinib, deucravacitinib, which a potential benefit of baricitinib for SLE treatment, but
preserves IL-2 signals, may offer promising efficacy. the study’s 24-week duration is insufficient to evaluate
its effectiveness over a more extended period. Further-
Tofacitinib, a medication under investigation, has dem- more, the limited number of participants in this Phase II
onstrated the ability to modulate irregular neutrophil trial may affect the robustness of the analysis. Additional
behavior and type I IFN reactions in a mouse model of data from three ongoing Phase III trials (NCT03616912,
lupus, as well as endothelial dysfunction and lipopro- NCT03843125, and NCT03616964) are expected to pro-
tein levels [245]. Furthermore, tofacitinib was evaluated vide a more detailed understanding of the drug’s long-
in a Phase Ib clinical trial (NCT02535689) that enrolled term benefits and safety profile.
patients with mild to moderate SLE, stratified based on
their STAT4 genetic risk profile. The trial’s primary focus Meanwhile, another two studies treated moderate to
was on assessing the tolerability and safety of tofacitinib, severe cutaneous lupus erythematosus (NCT03134222)
with secondary endpoints evaluating clinical responses as well as those afflicted with membranous lupus
and conducting mechanistic analyses. The study demon- nephropathy (NCT03285711) with filgotinib or lanra-
strates that tofacitinib is both well-tolerated and safe in plenib, to investigate the safety and efficacy of the Janus
mild-to-moderate SLE individuals. It reports no unex- kinase 1 inhibitor filgotinib (FIL) and the spleen tyros-
pected adverse events, no exacerbation of SLE disease ine kinase inhibitor lanraplenib (LANRA) in the treat-
activity, and no occurrences of severe adverse events, ment of cutaneous lupus erythematosus (CLE). They are
thromboembolic events, or opportunistic infections phase 2, randomized, double-blind, placebo-controlled,
associated with tofacitinib treatment. Furthermore, exploratory, proof-of-concept investigations, evaluating
treatment with tofacitinib has been shown to enhance the efficacy of LANRA (30 mg), FIL (200 mg), or placebo
high-density lipoprotein (HDL) cholesterol levels and (PBO) administered once daily over a 12-week period in
particle numbers, lecithin: cholesterol acyltransferase patients diagnosed with active CLE. Following the initial
levels, and cholesterol efflux capacity. It also ameliorates 12-week interval, participants originally assigned to the
endothelium-dependent vasorelaxation and arterial stiff- placebo group were re-randomized at a 1:1 ratio to com-
ness. Tofacitinib significantly reduced the presence of mence treatment with either LANRA or FIL for an addi-
circulating NETs, the levels of low-density granulocytes, tional period extending up to 36 weeks [253].
and the type I IFN gene signature. These improvements
were particularly pronounced in SLE patients carry- The mammalian target of rapamycin (mTOR) pathway
ing the STAT4 risk allele. Further long-term studies are is widely acknowledged for its role in regulating cellular
required to ascertain the efficacy of tofacitinib in pre- survival, metabolism, and proliferation [254]. The activa-
venting cardiovascular disease (CVD) in SLE patients tion of this pathway has been implicated in the develop-
[249]. Baricitinib, a selective and reversible inhibitor ment of SLE [255, 256], with both the activation of mTOR
Su et al. Molecular Biomedicine (2024) 5:54 Page 21 of 30

and the potential for therapeutic intervention being endpoint was the complete renal response at 52 weeks,
observed in T cells within the context of SLE [257–261]. marking a longer duration than prior trials of CNIs for
Rapamycin, known for its efficacy in suppressing antigen- lupus nephritis. The voclosporin group’s improved effi-
induced T-cell proliferation [262], has been formulated as cacy was realized with a steroid regimen that led to a sig-
sirolimus to prevent organ transplant rejection. Sirolimus nificantly lower cumulative steroid exposure than in any
binds with high affinity to its cellular receptor, FKBP12, prior study. The outcomes of this phase 3 trial corrobo-
a 12-kilodalton protein that is notably overexpressed in rate the efficacy demonstrated in the phase 2 trial and
T cells of individuals with lupus [263]. The sirolimus- indicate an enhanced safety for voclosporin.
FKBP12 complex inhibits the activation of the mamma-
lian target of mTOR [264]. In vivo studies have shown This study included patients who had a recent biopsy
that sirolimus can effectively eliminate autoimmunity indicating active lupus nephritis or a biopsy from 6
in mice prone to lupus [265, 266]and has been shown months to 2 years ago that demonstrated lupus nephritis
to suppress disease activity in a retrospective analysis of with current clinical signs of a renal flare, reflecting clini-
patients with SLE [267]. cal practice in real-world settings. The findings indicated
that voclosporin, when used in combination with MMF
A study (NCT00779194) aims to evaluate the tolerabil- and low-dose steroids, demonstrated greater efficacy
ity, safety, and the metabolic, immunological, and thera- than placebo, reinforcing the early treatment response
peutic impacts of sirolimus in patients with severe SLE and overall effectiveness observed with voclosporin in
who are either intolerant of or unresponsive to conven- the phase 2 trial [269]. Collectively, the outcomes from
tional treatment options. This mechanistic study offers both the phase 2 and phase 3 clinical studies of voclo-
initial indications that sirolimus is safe, well tolerated, sporin signify a significant step forward in the manage-
and demonstrates clinical efficacy in SLE patients under ment of patients with active lupus nephritis.
vigilant monitoring for reversible oral ulcers, headaches,
and cytopenia. The disease activity, as measured by the Precision medicine
reversal of pro-inflammatory T-cell lineage specification, Given the pronounced heterogeneity of SLE, it has
exhibited a positive trend at visit 6, corresponding to 12 proven challenging to achieve uniform therapeutic out-
months of sirolimus therapy [130]. comes across all patients through B cell-targeted thera-
pies aimed at B cell depletion. However, it is notable that
The mTOR inhibitor INK128 is an orally administered, significant variability in treatment response was iden-
potent, and selective ATP competitor that targets both tified based on the expression levels of IFN signature
mTORC1 and mTORC2 complexes. However, there are genes, as observed in the global Phase IIb trial of anif-
no clinical studies on INK128 for SLE. A phase II study rolumab [270]. This trial may represent an initial step
(NCT00775476) using N-acetylcysteine to treat SLE is towards precision medicine for SLE, which aims to strat-
being recruited. ify or subgroup patients to enhance diagnostic accuracy
and treatment efficacy [271]. Precision medicine in SLE
Voclosporin, a novel calcineurin inhibitor (CNI), has entails a tailored approach encompassing diagnosis, ther-
received approval for the treatment of adult lupus nephri- apy, and disease management. As depicted in the 2019
tis patients [268] and has demonstrated enhanced com- EULAR/ACR classification criteria, SLE presents a spec-
plete renal response rates in a phase 2 trial. This phase 2b trum of clinical features, serologic profiles, and immune
international study was a randomized, blinded, placebo- system mechanisms [272]. These standardized criteria
controlled trial that evaluated the effects of two different are instrumental in recognizing patient groups with com-
doses of voclosporin, in conjunction with mycophenolate mon traits, thus enabling more focused research endeav-
mofetil and steroids, against a placebo. The group receiv- ors and individualized therapeutic strategies.
ing 23.7 mg of voclosporin twice daily exhibited a nota- Since the completion of the Human Genome Project in
bly higher 6-month complete renal response rate com- 2003, genetic information has been instrumental in can-
pared to the placebo group. This dosage of voclosporin cer treatment for both therapy and prognosis monitoring.
was subsequently investigated in a phase 3 clinical trial. Although our comprehension of SLE’s genetic pathology
The phase 3 trial was a randomized, placebo-controlled has advanced, the disease’s heterogeneity remains incom-
study designed to assess the efficacy and safety of voclo- pletely understood. It is anticipated that future therapeu-
sporin in lupus nephritis patients. The study achieved tic approaches will be tailored to the disease’s subgroups
all primary and secondary endpoints with the use of at the cellular and molecular levels, informed by data
voclosporin combined with mycophenolate mofetil and gleaned from “omics” analyses, including immunophe-
a rapidly tapered low-dose steroid regimen. The primary notyping [273].Omics technologies, such as genomics,
Su et al. Molecular Biomedicine (2024) 5:54 Page 22 of 30

transcriptomics, and proteomics, play a pivotal role in precisely identifying genetic and molecular differences
distinguishing between SLE patients who are likely to and combining the latest cellular targeted therapeutic
respond to treatment and those who may not, by pin- methods, it plays a key role in distinguishing SLE patients
pointing genetic and molecular differences. By leverag- who may respond to treatment from those who may not.
ing these technologies, precision treatment in SLE can be By leveraging these technologies, precision medicine for
tailored to an individual’s specific diagnosis and genetic SLE can be tailored to an individual’s specific diagnosis
makeup, leading to enhanced treatment outcomes and and genetic makeup, thereby enhancing treatment effi-
an improved quality of life, all while aiming to reduce the cacy and improving quality of life, while aiming to reduce
incidence of adverse effects. the incidence of adverse reactions.
Acknowledgements
Future directions Not applicable.
Challenges in SLE research and treatment
The pathogenesis of SLE is complex and involves immune Author contributions
XS, HY and LL conceived the paper and wrote the manuscript. XS, HY and
system disorders, breakdown of immune tolerance, QL prepared the figures. QL, XC, YT, ZZ, WY, and YG provided a discussion
genetic predisposition to SLE and a range of environ- about the manuscript. All authors contributed to the article and approved the
mental triggers. These complex triggers have brought submitted version.
great challenges to the study of the pathogenesis of SLE. Funding
The immune system’s self-reactive actions culminate in This work was supported by the National Natural Science Foundation of China
a range of clinical manifestations characteristic of SLE, (82402108, 82303238); Science and Technology Support Program of Sichuan
Province (MZGC20240074, 2024NSFSC1761, 2024NSFSC1945, 20ZDYF0087
including, but not limited to, skin eruptions, oral ulcera- and 22ZDYF1357); Sichuan Province Special Funding Project for Postdoctoral
tions, inflammatory arthritis, serositis, neuropsychiatric Fellows (TB2024041); Science and Technology Support Program of Chengdu
manifestations, glomerulonephritis, and hematological (2024-YF05-01028-SN and 2024-YF05-02098-SN); Health Commission of
Chengdu Medical Research Program (2024014 and 2024063); The Third Peo-
disorders [120]. The multifaceted nature of SLE and its ple’s Hospital of Chengdu Scientific Research Project (2023PI18) and The Third
tendency to involve multiple organs pose significant chal- People’s Hospital of Chengdu Clinical Research Program (CSY-YN-01-2023-013,
lenges to treatment, requiring a comprehensive under- CSY-YN-01-2023-025 and SRF-02-2023-005).

standing of the underlying immune pathogenesis to Data availability

develop targeted and effective treatment strategies. Not applicable.
For many years, SLE has been treated mainly with
non-specific approaches, including cytotoxic and immu- Declarations
nosuppressive drugs, antimalarials, glucocorticoids and
Ethics approval and consent to participate
NSAIDs. While these treatment strategies are effec- Not applicable.
tive in mitigating the effects of the disease, they are not
a complete cure and are often accompanied by adverse Consent for publication
Not applicable.
reactions. In recent years, however, the field of SLE treat-
ment has evolved to include more precise strategies such Competing interests
as cellular therapy. These targeted therapeutic drugs aim The authors declare no potential conflict of interest.
to control and treat SLE by targeting B-cells and T-cells,
inhibiting the activation and function of these cells, as Received: 14 July 2024 Accepted: 16 October 2024
well as the abnormal activation of the immune system.
While some of these targeted drugs have achieved some
clinical effects, many others have failed after multi-
ple rounds of clinical trials. These phenomena raise the References
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