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Emerging biologic frontiers for
Sjogren’s syndrome: Unveiling
novel approaches with emphasis
on extra glandular pathology
Xiao Xiao Li
1
, Maierhaba Maitiyaer
1
, Qing Tan
1
, Wen Hui Huang
1
,
Yu Liu
2
, Zhi Ping Liu
3
, Yue Qiang Wen
4
, Yu Zheng
5
, Xing Chen
6
,
Rui Lin Chen
1
, Yi Tao
1
and Shui Lian Yu
1
*
1
Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University,
Guangzhou Medical University, Guangzhou, China,
2
Department of Clinical Medicine, The First Clinical
Medical School of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China,
3
Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou,
China,
4
Department of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University,
Guangzhou Medical University, Guangzhou, China,
5
Department of Urology, The Second Affiliated
Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China,
6
Department of Geriatrics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou
Medical University, Guangzhou, China
Primary Sjögren’s Syndrome (pSS) is a complex autoimmune disorder
characterized by exocrine gland dysfunction, leading to dry eyes and mouth.
Despite growing interest in biologic therapies for pSS, FDA approval has proven
challenging due to trial complications. This review addresses the absence of a
molecular-target-based approach to biologic therapy development and
highlights novel research on drug targets and clinical trials. A literature search
identified potential pSS treatment targets and recent advances in molecular
understanding. Overlooking extraglandular symptoms like fatigue and
depression is a notable gap in trials. Emerging biologic agents targeting
cytokines, signal pathways, and immune responses have proven efficacy.
These novel therapies could complement existing methods for symptom
alleviation. Improved grading systems accounting for extraglandular symptoms
are needed. The future of pSS treatment may involve gene, stem-cell, and tissue-
engineering therapies. This narrative review offers insights into advancing pSS
management through innovative biologic interventions.
KEYWORDS
Sjögren’s syndrome, extraglandular symptom, biologic therapies, primary Sjögren’s
syndrome, cytokines and chemokines
1 Introduction
Sjögren’s Syndrome (SS) is a complex chronic autoimmune disorder, occurring in both
primary and secondary forms. The manifestations of SS can be broadly classified into non-
specific, peri-epithelial (encompassing both glandular and extraglandular areas), extra-
epithelial (inherently extraglandular), and lymphoma-related types. Typically, SS is
characterized by diminished function of the salivary and lacrimal glands (Pertovaara
et al., 1999), leading to symptoms such as dry eyes and dry mouth (Mariette and
Criswell, 2018). Despite the prominent glandular symptoms, SS also involves a broader
range of extranglandular features, characterized by diverse symptoms affecting both visceral
OPEN ACCESS
EDITED BY
Efstathia K Kapsogeorgou,
National and Kapodistrian University of Athens,
Greece
REVIEWED BY
Stergios Katsiougiannis,
Biomedical Research Foundation of the
Academy of Athens (BRFAA), Greece
Loukas Chatzis,
Laiko General Hospital of Athens, Greece
*CORRESPONDENCE
Shui Lian Yu,
shuilian2008@gmail.com
RECEIVED 26 January 2024
ACCEPTED 29 April 2024
PUBLISHED 17 May 2024
CITATION
Li XX, Maitiyaer M, Tan Q, Huang WH, Liu Y,
Liu ZP, Wen YQ, Zheng Y, Chen X, Chen RL,
Tao Y and Yu SL (2024), Emerging biologic
frontiers for Sjogren’s syndrome: Unveiling
novel approaches with emphasis on extra
glandular pathology.
Front. Pharmacol. 15:1377055.
doi: 10.3389/fphar.2024.1377055
COPYRIGHT
© 2024 Li, Maitiyaer, Tan, Huang, Liu, Liu, Wen,
Zheng, Chen, Chen, Tao and Yu. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction in
other forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in this
journal is cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 17 May 2024
DOI 10.3389/fphar.2024.1377055
and non-visceral systems. Visceral manifestations involve the
pulmonary, cardiac, renal, gastrointestinal, endocrine, central
nervous, and peripheral nervous systems. Concurrently, non-
visceral manifestations predominantly present in the
musculoskeletal and cutaneous systems (Fox, 2005). A growing
body of research indicates that, in evaluating patients with SS,
individuals presenting with extraglandular symptoms such as
fatigue, depression, and anxiety tend to experience a lower
overall quality of life compared to their counterparts (Kotsis
et al., 2014;Miglianico et al., 2022). A study of 639 SS patients
found that 49.5% showed symptoms of depression and anxiety,
significantly higher than the general population’s 15.7% prevalaence.
Concurrently, an evaluation of the health-related quality of life for
these patients highlighted pain and depression as the two
predominant factors significantly impacting the life quality
assessment in individuals with SS (Lendrem et al., 2014).
Additionally, these patients often face poorer long-term
outcomes, including an increased likelihood of complications.
Recognized increasingly for diverse systemic complications
affecting various organs, cognitive impairments, and persistent
FIGURE 1
Overview of the Pathogenesis and Biologic Treatments for Sjögren’s Syndrome. (A) After environmental stimulation, pDCs secrete IFN-α, while
conventional DCs release IL-12. This triggers IFN-γand GM-CSF production via innate and adaptive immunity. IFN-αand IFN-γjointly induce BAFF,
promoting B cell activation and IL-6 secretion. APRIL, regulated by IFN-αand IFN-γ, contributes to B cell proliferation. (B) CD4+ Th cells, combined with
CD80/86, activated by APCs, infiltrate organs, producing cytokines inducing B cell activation. Th1 secretes IFN-γ, Th2 targets B cells and neutrophils,
secreting IL-4, IL-21, and IL-25, while Th17, stimulated by IL-23, secretes IL-17 and IL-22. In glands and lymphoid tissues, T and B cells activate with CD40/
CD40L. IFN-α, IFN-γ, IL-6, IL-22, and IL-23 use the JAK-STAT pathway for effects. Activation results in gland destruction and extraglandular symptoms,
revealing the complex immune interplay causing autoimmune manifestations. Several biologics have been developed to target key factors in this process.
Notable examples include rituximab (anti-CD20 monoclonal antibody), epratuzumab (anti-CD22 monoclon al antibody), daratumumab (anti-
CD38 monoclonal antibody), belimumab (BAFF inhibitor) and ianalumab (BAFFR inhibitor), telitacicept (BAFF and APRIL inhibitor), iscalimab (anti-
CD40 monoclonal antibody), abatacept (anti-CD80/86 monoclonal antibody), infliximab and etanercept (anti-TNF-αmonoclonal antibodies),
tocilizumab (IL-6R receptor inhibitor), bortezomib (IL-17 receptor inhibitor), ustekinumab (IL-12/23 receptor inhibitor), and baricitinib and filgotinib (JAK
inhibitors). These targeted biologics offer specific interventions for autoimmune conditions. Abbreviations: pDCs, plasmacytoid dendritic cells; IFN,
interferon; DCs, dendritic cells; GM-CSF, Granulocyte-macrophage colony-stimulating factor; BAFF, B cell-activating factor; IL, interleukin; APRIL, a
proliferation-inducing ligand; Th cells, T helper cells; APC, antigen-presenting cell; JAK, Janus kinases; STAT, signal transducer and activator of
transcription. In this diagram, white color blocks denote medications not utilized in SS, categorized as unverified. Yellow denotes pharmacological
interventions with established efficacy, whereas gray designates medications administered but determined to be ineffective.
Frontiers in Pharmacology frontiersin.org02
Li et al. 10.3389/fphar.2024.1377055
fatigue, SS’s pathogenesis supports a molecular-target-based
approach to biologic therapy, as illustrated in Figure 1. This
approach emphasizes the unique cellular invasion by
mononuclear cells, notably CD4
+
T lymphocytes, into lacrimal
and salivary glands, correlating with diverse extraglandular
manifestations and underlying autoimmune foundations
characterized by elevated cytokine production, aberrant B cell
activation, and heightened risk of B cell-derived malignancies
(Theander et al., 2011;Nocturne and Mariette, 2018).
In recent years, the treatment landscape for SS has experienced a
significant paradigm shift, highlighted by the emergence of
innovative biologic drugs. Rigorous clinical exploration, especially
targeting molecules critical to SS’s pathogenesis, has proven effective
in alleviating both glandular and systemic symptoms. However, the
path of these therapeutic approaches through clinical trials and
regulatory approval has been complex. Many large randomized
controlled trials (RCTs) exclude patients with various
extraglandular manifestations, ranging from neurological to
pulmonary symptoms, due to the complexity of managing and
measuring treatment effects on these diverse and systemic issues
(Rihl et al., 2009). This exclusion significantly limits the applicability
and relevance of trial results to a broader spectrum of SS patients,
often relegating the diverse array of extraglandular symptoms to the
margins of research and clinical focus (Ramos-Casals et al., 2020).
Nevertheless, This comprehensive review aims to navigate the
evolving landscape of biologic interventions for SS, focusing keenly
on the unexplored territories of extraglandular pathology. By
shedding light on novel molecular targets and recent
breakthroughs in clinical trials, the review seeks to unveil the
latent potential of biologic therapies in reshaping the holistic
management of both glandular and extraglandular
manifestations. Inherent to this discussion is the oft-neglected
facet of SS management-the intricate treatment of extraglandular
symptoms encompassing fatigue, depression, and anxiety.
Scrutinizing the potential of pioneering biologic agents, the
review endeavors to illuminate new strategies for effectively
addressing these multifaceted challenges.
2 Heterogeneity of SS: In-depth
analysis from multiple perspectives
Given the complexity and variability of autoimmune diseases,
deeper research and classification were needed to improve treatment
outcomes and prognosis evaluation. Several large-scale studies have
explored the heterogeneity of patients with SS from diverse
perspectives, to enhance the precision and personalization of
treatment and management for these individuals.
2.1 Based on immune dysregulation patterns
PRECISESADS is a project aimed at reclassifying systemic
autoimmune diseases based on molecular features determined
using various omics platforms (Barturen et al., 2018). In the
previous PRECISESADS IMI JU project, it was noted that
systemic autoimmune diseases can be categorized into four
disease clusters: ‘inflammatory’,‘lymphoid’,‘interferon’, and
‘healthy-like’patterns. Each cluster includes all diagnoses and is
defined by genetic, clinical, serological, and cellular features
(Barturen et al., 2021). These clusters contribute to the
heterogeneity in the initiation, propagation, and flares of
the diseases.
Recently, the research team led by Professor Jacque Olivier Pers
employed data collected from the PRECISESADS project to
investigate immune dysregulation patterns in patients with pSS.
This research aims to provide a comprehensive molecular
understanding that could inform personalized treatment
approaches (Soret et al., 2021). The research involved
300 patients with pSS and matched healthy volunteers.
Comprehensive multi-omics analyses were performed on whole
blood samples, which included transcriptomics, genomics,
epigenetics, cytokine expression, and flow cytometry,
incorporating detailed clinical parameters. This study has
established a framework to enhance our comprehension of the
pathogenic mechanisms in pSS, emphasizing the substantial
heterogeneity of the disease.
In their analysis of molecular heterogeneity among pSS patients,
researchers identified four distinct patterns of immune
dysregulation—C1, C2, C3, and C4—each corresponding to
varying disease manifestations and potential treatment
approaches. Patients from C2 displayed a healthy-like profile,
which has a lower EULAR Sjögren’s Syndrome Disease Activity
Index (ESSDAI) compared to the 3 other clusters, but they still
experienced the objective symptoms of dryness, pain, and fatigue.
Type I interferon (IFN) has traditionally been regarded as the
principal factor in the pathogenesis of SS, however, Type II IFN
also contributes significantly to the pathogenesis of the disease
(Nezos et al., 2015). Notably, C1 and C3 patterns exhibited a
significant upregulation of IFN signaling. C1 patients
demonstrated the highest scores for both Type I and Type II
IFN, while C3 also showed overexpression in the lymphoid
pathway, the quantity of peripheral blood B cells was higher
compared to other groups. Additionally, C1 and C3 were
associated with elevated blood protein levels of C-X-C motif
chemokine ligand 10 (CXCL10)/IP-10 (James et al., 2020).
Conversely, the C4 pattern prominently expressed signals
associated with inflammation and myeloid transcription, it was
further characterized by significant lymphopenia and elevated
neutrophil levels, with the neutrophil-to-lymphocyte ratio (NLR)
previously demonstrated to correlate with disease activity in
systemic autoimmunity (Toro-Domínguez et al., 2019;Han et al.,
2020). Further analysis uncovered significant differences in
serological features and disease activity among these patterns.
C1 and C3 showed high levels of hypergammaglobulinemia and
anti-ENA antibodies. C4 had intense inflammation and myeloid
transcription signals, with the most severe clinical symptoms and
disease activity, which have the highest levels of ESSDAI and Patient
Global Assessmetn (PGA). These findings provide a theoretical basis
for employing Type I IFN inhibitors as therapeutic agents in groups
C1, C3, and C4. Specifically for group C3, targeting B cells in
treatment strategies appears to yield enhanced therapeutic
efficacy. All these findings shed light on the intricate
immunological diversity inherent in the SS patients cohort.
Crucially, distinct therapeutic strategies emerged for different
patterns. The study offers insights into personalized treatment
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Li et al. 10.3389/fphar.2024.1377055
directions, including the inhibition of the IFN signaling pathway,
targeted interventions in the lymphoid pathway, and specific
interventions in inflammation and myeloid transcription. This
theoretical foundation provides a solid basis for the future
development of precision medicine and immunotherapy,
underscoring the importance of heterogeneity in pSS management.
Currently, the biological diagnosis of SS primarily relies on anti-
Ro60/SSA antibodies (Shiboski et al., 2017). The PRECISESADS
database was employed for the association between anti-Ro52/
TRIM21 antibodies and SS. Participants were classified into four
distinct groups based on antibody presence: double-positive (Ro52
+
/
Ro60
+
), double-negative (Ro52
−
/Ro60
−
), and two single-positive groups
(Ro52
+
)/(Ro60
+
). Patients who were double-positive exhibited more
pronounced parotid gland enlargement and elevated β2-microglobulin
levels. These patients also had more severe disease activity and higher
ESSDAI scores (Bettacchioli et al., 2023). Transcriptomic analyses
suggest that the presence of a greater number of identified
antibodies correlates with stronger IFN signaling in patients.
Therefore, the presence of anti-Ro52/TRIM21 antibodies can be
linked to the activation of the interferon pathway. Consequently,
these antibodies can serve as valuable markers for assessing the
severity and prognosis of SS in affected patients.
2.2 Based on clinical phenotypes
In the study conducted by Jessica R. Tarn et al. (Tarn et al.,
2019), 608 patients with SS was systematically classified into four
subgroups based on the severity of five prevalent symptoms of pSS:
pain, fatigue, dryness, anxiety, and depression. These subgroups
were designated as low symptom burden (LSB), high symptom
burden (HSB), dryness-dominant with fatigue (DDF), and pain-
dominant with fatigue (PDF). The DDF subgroup had significant
symptoms of dryness and fatigue, as well as decreased anxiety and
depression, displaying the most significant glandular dysfunction,
with elevated levels of CXCL13, β2-microglobulin, and κ-free light
chains (κ-FLC) compared to other subgroups. The PDF subgroup
experienced significant symptoms of pain and fatigue, with reduced
anxiety and depression levels. Transcriptomic data analysis across
the subgroups indicated that both the LSB and DDF subgroups
showed increased expression of IFN module activity. And the DDF
subgroup also exhibited enhanced activity in the mature B-cell
modules, a correlation that likely contributes to the severe
glandular dysfunction observed in this subgroup. Furthermore,
the DDF subgroup exhibited the highest incidence of lymphoma,
highlighting its distinct clinical and pathological profile. These
findings were subsequently validated in patient cohorts from
France and Norway, confirming the universality and efficacy of
the symptom-based patient stratification model.
To ascertain whether the heterogeneity based on clinical
symptoms can be effectively applied in the treatment and
management of SS, different medications were trialed across
various subgroups, reflecting their distinct characteristics. The
results demonstrated that hydroxychloroquine was effective in
the HSB subgroup, while rituximab showed therapeutic efficacy
in the DDF subgroup. The findings demonstrate that classification
based on clinical symptom heterogeneity is highly significant for the
selection of clinical pharmacotherapy.
2.3 Based on histological phenotypes
It is well understood that the profile of infiltrating cells in the
salivary glands (SG) of patients with SS evolves as the disease
progresses. In the early stages of pSS, when infiltration is mild,
the lymphocytic infiltration of the salivary and lacrimal glands is
predominantly composed of CD4
+
T cells (Voulgarelis and Tzioufas,
2010). These cells contribute to disease progression by producing
pro-inflammatory cytokines such as IFN-γ, IL-17, and IL-21, and by
inducing B cell activation. As the disease advances to later stages,
with more severe infiltration, B cells begin to dominate the
pathological landscape (Verstappen et al., 2021a). This shift,
associated with more severe tissue infiltration and exacerbated by
the activation and proliferation of B cells, underscores a critical
transformation in the immunological landscape of pSS.
Furthermore, the degree of lymphocytic infiltration in the
salivary glands correlates with the severity of the disease. This
transformation highlights the potential for interventions targeting
these specific cellular transitions, suggesting that treatments for pSS
should consider the dominant immune cells at different disease
phases, adopting a stage-dependent approach.
To effectively manage the progression of diseases such as SS,
treatment strategies should adapt to the predominant immune cells
at each stage. In the early stages of the disease, the therapeutic focus
might be on suppressing T-cell activity. Agents that inhibit T cell
signaling pathways, such as calcineurin inhibitors such as
Cyclosporine or more targeted biologics like anti-CD4 antibodies,
can be considered. Since Th1 and Th17 cells are active in this phase,
medications that inhibit pro-inflammatory cytokines produced by
these cells, such as IFN-γand IL-17, could also be effective. In the
later stages of the disease, when B cells become dominant, the
treatment strategy should shift towards interventions targeting
B cells. Biologics that target B cells, such as Rituximab, or drugs
that inhibit BAFF, such as Belimumab, may be employed. This
approach acknowledges the dynamic nature of immune cell
involvement in disease progression and tailors treatment to the
specific characteristics and demands of each disease stage.
3 Current therapies for extra glandular
symptoms in SS
The ESSDAI serves as a vital metric in evaluating disease activity
across 12 domains (including Lymphadenopathy and lymphoma,
articular, cutaneous, pulmonary, renal, muscular, central and
peripheral neurological, and hematological domains) (Ramos-
Casals et al., 2020). In a study of 921 patients with SS in Spain,
only 8% of had no disease activity according to ESSDAI scoring. The
highest cumulative scores were in the articular, pulmonary,
haematological, and peripheral nervous system domains (Ramos-
Casals et al., 2014).
This indicates that extraglandular symptoms are prevalent
among SS patients, and a significant majority concurrently
endure both glandular and extraglandular manifestations.
However, the mechanisms behind the glandular and
extraglandular effects of SS are not yet clear. Therefore,
treatments for SS often focus on easing the symptoms rather
than directly addressing the root cause of the disease.
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Salivary gland epithelial cells (SGECs) have recently been
recognized for their critical role in SS. Notably, SS is
characterized by a significant reduction in salivary gland
function, a decline partly attributable to specificdeficits in the
glandular epithelium (Verstappen et al., 2021b). Additionally,
SGECs may also play a significant role in extraglandular symptoms.
A study revealed that SGECs from patients with primary SS
(pSS) possess a unique capacity to enhance the survival and
activation of B-lymphocytes (Rivière et al., 2020). Epithelial cells
secrete pro-inflammatory cytokines and autoantigens, leading to the
infiltration and activation of T and B cells, which significantly
contribute to inflammation and tissue damage (Verstappen et al.,
2021b). Recent research has shown that cytokines secreted by
dysfunctional glandular epithelial cells, such as TNF-αand IFN-
γ, can disrupt the junctional structure of the epithelium. This
disruption facilitates the circulation of these cytokines and
triggers inflammatory responses in peripheral tissues, thus
providing a potential explanation for the connection between
glandular dysfunction and systemic symptoms, including joint
pain and fatigue (Negrini et al., 2022). Additionally, according to
Katsiougiannis et al., epithelial cells in SS exhibit abnormal
expression of autoantigens and adhesion molecules, potentially
provoking an autoimmune response not just locally but
systemically (Katsiougiannis et al., 2019).
3.1 Musculoskeletal involvement
SS is associated with both joint and muscle manifestations,
including arthralgia and arthritis, as well as myopathy, which is
often asymptomatic. As for joints, approximately 50 percent of
patients with primary SS report arthralgia, with or without evidence
of arthritis (Pease et al., 1993). Current research indicates that
patients positive for rheumatoid factor (RF) or anti-citrullinated
peptide antibodies (ACPA) generally suffer from a more severe form
of inflammatory arthritis, which is often erosive and poses an
increased risk of evolving into rheumatoid arthritis (RA) (Kamali
et al., 2005;Mohammed et al., 2009;Ryu et al., 2013;Molano-
González et al., 2019). Additionally, in a comprehensive study,
around 40 percent of SS patients tested positive for RF, and
ACPA are found in 5–10 percent of patients with pSS (Payet
et al., 2015).
Concerning muscle involvement, SS can lead to mild
inflammatory myopathy, presenting either as subclinical
symptoms or gradual proximal muscle weakness. More than
70 percent of SS patients experience myalgias. However, a
detailed study of 395 SS patients in France revealed that of
38 initially suspected of having myositis, only four cases were
confirmed (Felten et al., 2021a). Additionally, antibodies to
cytosolic 5′-nucleotidase 1A, a marker for inclusion body
myositis, are detectable in nearly half of the SS patients without
manifest muscle disease (Rietveld et al., 2018).
The management of musculoskeletal symptoms in SS primarily
aims at providing symptomatic relief. For mild joint symptoms or
when patients exhibit only arthralgia and myalgia without
inflammatory synovitis, non-steroidal anti-inflammatory drugs
are typically prescribed. In cases of moderate to severe arthritis,
methotrexate (MTX) and hydroxychloroquine (HCQ) are the
treatments of choice (Price et al., 2017). Biologic agents such as
rituximab (RTX) or tumor necrosis factor-α(TNF-α) inhibitors are
reserved for a small subset of refractory cases, particularly in patients
with overlapping features of RA (Carsons et al., 2017).
3.2 Lung involvement
In 9%–20% of cases, SS is associated with various respiratory
symptoms. The pulmonary lesions in these instances are typically
determined by symptoms, pulmonary function tests, or
abnormalities observed in chest radiographs. The most common
manifestations are chronic interstitial lung disease (ILD) and
tracheobronchial disease (Flament et al., 2016). Among them,
non-specific interstitial pneumonitis (NSIP) emerges as the
predominant histopathologic anomaly. However, similar lesions
may also appear in other immune disorders, necessitating an
investigation into the possibility of coexisting rheumatic diseases.
Notably, patients with ILP often exhibit either polyclonal or
monoclonal gammopathy (American Thoracic Society, 2000).
The management of ILD in challenging due to the lack of
histological correlation with known factors. To date, therapeutic
options for SS patients are mostly empirical, and there is a significant
need for evidence-based recommendations for treating pulmonary
manifestations. Currently, oral prednisone is the treatment of choice
for ILD. If patients exhibit intolerance or non-responsiveness to
glucocorticoids, alternatives like azathioprine and mycophenolate
mofetil (MMF) may be beneficial. Additionally, biologics such as
nintedanib, proven effective in managing ILDs associated with
connective tissue disorders, including SS. Some studies also
indicate potential improvement in pulmonary symptoms with
RTX. However, its efficacy in SS-related pulmonary conditions
remains limited (Luppi et al., 2020). Moreover, shared
transcriptional activities in fibroblasts between SS and interstitial
pneumonia suggest fibroblasts as potential therapeutic targets (Jin
et al., 2019;Korsunsky et al., 2022).
3.3 Skin involvement
Cutaneous involvement is a relatively common manifestation of
SS, presenting with various symptoms such as xeroderma, eyelid
dermatitis, annular erythema, and cutaneous vasculitis (Generali
et al., 2017). Xeroderma, or skin dryness, is the most common skin
manifestation of SS, afflicting 67% of patients (Roguedas et al.,
2004). The pathogenesis of xerosis may involve alterations in the
stratum corneum, the outermost layer of the skin, coupled with
decreased secretion from sebaceous and sweat glands (Bernacchi
et al., 2004;Bernacchi et al., 2005). Unlike atopic dermatitis, SS-
related dry skin exhibits unique pathophysiological features,
including changes in keratins and total skin proteins (Bernacchi
et al., 2005;Katayama, 2016).
Recent studies have supported the role of T helper 17(Th17) cells
in SS-related skin conditions, evidenced by elevated levels of
Interleukin-17 (IL-17), IL-6, and IL-12 (Grisius et al., 1997;
Manoussakis et al., 2007;Nguyen et al., 2008;Yoshimoto et al.,
2011;Ciccia et al., 2012;Ciccia et al., 2015;Fogel et al., 2018). The
majority of these factors are related to T-cells. Therefore, for patients
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with relevant skin lesions, it is worth considering whether T-cell
targeted therapies and inhibitors of related factors should be the
preferred treatment options. Currently, the most effective approach
for mitigating pruritus in SS including skin moisturization, reducing
the frequency of bathing, application of body lotion, and avoiding
medications with anticholinergic effects. When these measures are
insufficient, antihistamines such as cetirizine, fexofenadine, and
famotidine should be considered. In instances resistant to
conventional treatments, oral corticosteroids may be used. If
these interventions fail to alleviate pruritus, screening for primary
biliary cholangitis (PBC) is crucial, which is a frequent extrahepatic
manifestation of SS (Chalifoux et al., 2017).
3.4 Liver involvement
SS can be associated with liver abnormalities, which typically
include mild biochemical indicator deviations and histological
changes indicative of PBC or autoimmune hepatitis. Patients
diagnosed with PBC exhibit a prevalence of pSS of approximately
38%. However, clinical evidence of PBC is observed in fewer than 2%
of patients with SS, according to large cohort studies (Trevisani et al.,
2022). In instances where SS is accompanied by liver dysfunction,
treatment usually involves the isolated use of hepatoprotective drugs
such as ursodeoxycholic acid, aimed at symptomatically improving
liver function. This approach does not emphasize the routine use of
conventional medications for treating SS.
3.5 Psychological involvement
A gap exists in the literature concerning a comprehensive
theoretical model that explains the emergence of psychological
symptoms such as fatigue, depression, and anxiety in patients
with SS. Nonetheless, existing research has highlighted
correlations with certain factors. Fatigue in SS correlates with
factors like IL-1, IL-36α, and humoral autoimmunity-related
components (Zeng et al., 2022), while inversely correlating with
pro-inflammatory cytokines, including IFN-γ, TNF-α, lymphotoxin
α, and CXCL10 (Davies et al., 2019). Research also suggests
involvement of the hypothalamic-pituitary-adrenal (HPA) axis in
fatigue development, potentially due to autoimmune-mediated
adrenal gland destruction by autoantibodies (Mæland et al.,
2021). An RCT conducted in Brazil provided support for this
association, demonstrating that enhancement of cortical
excitability via transcranial direct-current stimulation could
reduce fatigue in SS patients (Pinto et al., 2021).
Currently medications such as HCQ, dehydroepiandrosterone,
and RTX have proven ineffectiveness in alleviating fatigue in
controlled studies (Hartkamp et al., 2008;Devauchelle-Pensec
et al., 2014;Mariette et al., 2015a). Ongoing clinical trials explore
novel fatigue treatment targets in primary SS, including
experimental drugs like Lanraplenib (spleen tyrosine kinase
inhibitor), Filgoinib (Janus kinase-1 inhibitor), Tirabrutinib
(Bruton’s tyrosine kinase inhibitor), CDZ173 (PI3K inhibitor),
and Dazodalibep (CD40L antagonist and Tn3 fusion protein)
(Mæland et al., 2021). However, Lanraplenib, Filgotinib, and
Tirabrutinib have not shown significant benefits over placebo
(Price et al., 2022), whereas Dazodalibep showed promising
effects in reducing fatigue (St et al., 2023). RSLV132, an RNaseFc
fusion protein, is also showing promise in fatigue management in a
phase II investigation (Posada et al., 2021).
Depression in SS is potentially linked to disruptions in
neurotransmitter functionality and brain-derived neurotrophic
factor, with additional considerations given to the intestinal
microbiota, amino acid metabolism, and neuropeptide-targeting
autoantibodies (Caspani et al., 2019;Tian et al., 2020). Anxiety
correlates with autoantibodies against α-melanocyte-stimulating
hormone (Karaiskos et al., 2010), and may be exacerbated by
B-cell activating factor (BAFF), which contributes to brain
inflammation, neuronal impairment, and hippocampal
remodeling (Crupi et al., 2010). N-3 polyunsaturated fatty acids
have shown potential in inhibiting neuroinflammation associated
with depressive states in SS (Crupi et al., 2012).
Research continues into anti-BAFF drugs for anxiety and
selective serotonin reuptake inhibitors for depression, given their
potential roles in the inflammatory processes associated with SS-
related fatigue (Schlesinger et al., 2011;Vivino et al., 2016;Bodewes
et al., 2019). Additionally, contemporary research is exploring the
impact of Chinese medicine on anxiety, depression, and overall
quality of life in patients with pSS (Wu and Li, 2020).
3.6 Hypergammaglobulinemia and
hypogammaglobulinemia
Hypergammaglobulinemia is common in patients with SS and is
presented in almost half of the patients (Ramos-Casals et al., 2002;
Yang et al., 2018). It can manifest as either polyclonal or
monoclonal. The presence of hypergammaglobulinemia is closely
associated with the presence of anti-Ro/SSA and anti-La/SSB
antibodies and RF (Alexander et al., 1983;Ramos-Casals et al.,
2002). Hypogammaglobulinemia is less prevalent than
hypergammaglobulinemia, and may also develop in patients with
established SS as a sign of underlying lymphoma (Anderson and
Talal, 1972).
Patients with SS can also experience Monoclonal gammopathies
(MG). Monoclonal IgG proteins are the most frequently detected
class, followed by IgM. When SS is complicated by MG, patients
often exhibit a higher incidence of abnormal urine NAG, higher
levels of ESR, ESSDAI, and Clinical ESSDAI (ClinESSDAI) scores
(Yang et al., 2018). Multivariate analysis revealed that the disease
activity, assessed by either ESSDAI or ClinESSDAI, was the sole
independent risk factor for the presence of MG (Yang et al., 2018).
3.7 Exploring alternative approaches
Recent clinical trials have explored novel treatments in pSS,
encompassing experimental drugs like Lanraplenib (spleen tyrosine
kinase inhibitor), Filgoinib (Janus kinase-1 inhibitor), Tirabrutinib
(Bruton’s tyrosine kinase inhibitor), CDZ173 (PI3K inhibitor), and
Dazodalibep (CD40L antagonist and Tn3 fusion protein) (Mæland
et al., 2021). However, neither Lanraplenib, Filgotinib, nor
Tirabrutinib demonstrated significant differences from placebo in
improve the clinical SS-related symptoms, ESSPRI and ESSDAI
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scores (Price et al., 2022). Conversely, Dazodalibep showed a
significant reduction in disease activity measured by the
improvement in ESSDAI score (St et al., 2023). Contemporary
research aims to assess the impact of Chinese medicine on
anxiety, depression, and overall quality of life in pSS patients
(Wu and Li, 2020). Current pharmaceutical strategies, including
hydroxychloroquine, RTX, and TNF-αinhibitors, consistently show
significant improvements in extraglandular symptoms like fatigue.
Ongoing explorations of anti-BAFF drugs for anxiety and selective
serotonin reuptake inhibitors for depression are underway,
considering factors like IL-1, IL-36α, and humoral autoimmunity
in SS-related fatigue (Schlesinger et al., 2011;Vivino et al., 2016;
Bodewes et al., 2019), with recent studies revealing an inverse
correlation between fatigue intensity and pro-inflammatory
cytokines, including IFN-γ, TNF-α, lymphotoxin α, and CXCL10
(Davies et al., 2019).
In SS, the functionality of the salivary glands is frequently
substantially diminished. Consequently, in the treatment of
patients with this dry syndrome, the restoration of salivary gland
function should be a top priority. However, current therapeutic
approaches primarily target glandular inflammation and may be
insufficient to address the restoration of salivary gland function
(Gueiros et al., 2019). In the existing studies, the inhibition with anti-
BAFF, anti-APRIL, anti-IL-6R antibodies, Janus kinases1/3 (JAK1/
3) inhibitor, or hydroxychloroquine did not exhibit any inhibitory
effect on active B lymphocytes in SGECs. In contrast, leflunomide,
BTK, or PI3K inhibitors all demonstrated favorable effects (Rivière
et al., 2020).
4 Biologic therapies in SS
4.1 B Cell targeting approach
4.1.1 Mechanism
The escalating interest in biologic therapies is grounded in the
recognition of B cell hyperactivity as a central facet of SS
pathogenesis. SS is distinguished by heightened B cell activity
contributing to autoimmune-mediated glandular impairment,
with approximately 35%–40% of patients manifesting
hypergammaglobulinemia, thereby presenting symptoms of
xerophthalmia and xerostomia (Nocturne and Mariette, 2018;Du
et al., 2021). B cells are crucial for producing autoantibodies
associated with SS, including ANA, anti-SSA, and anti-SSB
antibodies, which are central to the autoimmune responses
observed in the syndrome. In pSS, the activation of B cells can
lead to the overproduction of κand λlight chains, which are then
secreted into the serum as free light chains (FLC). Serum FLC levels
in pSS are associated with IgG, RF, and systemic disease activity,
indicating their potential as biomarkers for monitoring the disease.
Additionally, chronic activation of B cells may heighten the risk of
developing lymphomas, particularly mucosa-associated lymphoid
tissue-lymphoma (MALT-L) (Du et al., 2021).
CD20, expressed on B cell precursors, is pivotal in B cell
activation, proliferation, and differentiation, making it a rational
target for addressing the B cell dysfunction underpinning SS. In this
context, RTX, a chimeric monoclonal antibody directed against
CD20, emerged as a prospective therapeutic option (Gurcan
et al., 2009). Furthermore, B cells are responsible for the
secretion of a myriad of cytokines that contribute to the
pathogenesis and advancement of SS, including but not limited
to IL-4, IL-6, IL-10, and various others (Ohyama et al., 1996;van
Woerkom et al., 2005).
4.1.2 Application of rituximab in SS
Rituximab (RTX), a chimeric monoclonal antibody directed
against CD20, that achieves therapeutic effects by reducing the
number of circulating B cells (Beers et al., 2010) and modulating
T cell responses in autoimmune diseases (Ciccia et al., 2013;Ciccia
et al., 2014), has emerged as a frontrunner in alleviating symptoms
such as fatigue and oral dryness. The application of RTX in SS aims
to modulate aberrant B cell responses (Meijer et al., 2010). The
combination of RTX with bendamustine has been evaluated in
MALT-L complicating pSS. Several studies have demonstrated its
efficacy and safety in low-grade B-cell lymphomas, including mantle
cell lymphomas and extra gastric MALT-L (Rummel et al., 2013;
Salar et al., 2014). These investigations have yielded a spectrum of
outcomes, with variable improvements observed in measures such as
fatigue, salivary flow rates, and joint pain (Dass et al., 2008;Meiners
et al., 2012;Gottenberg et al., 2013). However, the outcomes have
not been consistently uniform, and several trials have failed to meet
their primary endpoints (Chen et al., 2021), with concerns about
safety and long-term efficacy (Table 1). According to current RCTs,
RTX demonstrated no significant differences compared to the
placebo in terms of pain, fatigue, and dry mouth (Devauchelle-
Pensec et al., 2014;Bowman et al., 2017). As a result, we do not
recommend the use of RTX for the treatment of ocular dryness, pain,
or fatigue (Ramos-Casals et al., 2020). Recent studies indicate that
patients with elevated levels of B-cell infiltration in the parotid
glands tend to exhibit a more favorable response to RTX. This
implies that, in the future, we may be able to tailor drug treatments
more precisely for individual patients (Delli et al., 2016).
4.1.3 Limitations
The effectiveness of RTX in SS has faced limitations due to the
heterogeneous nature of the disease and varying responses among
patients. Some autoimmune patients have developed autoimmunity
against RTX itself. The intricate interplay of factors influencing SS
pathogenesis adds complexity to assessing RTX’s effectiveness in
diverse patient profiles. Additionally, understanding the long-term
impact of RTX on disease progression and the underlying immune
dysregulation requires further investigation. Some studies suggest
that the use of RTX is associated with an increased likelihood of
adverse events, primarily respiratory infections (Fox et al., 2021).
4.1.4 Exploring alternative approaches
B-cell activating factor (BAFF) and a proliferation-inducing
ligand (APRIL) significantly influence B cell maturation,
proliferation, and survival (Chen et al., 2021). Multiple studies
consistently highlight BAFF’s substantial involvement in SS
pathogenesis, emphasizing its critical role (Lavie et al., 2008;
Yoshimoto et al., 2011;Loureiro-Amigo et al., 2021). Therapeutic
interventions aimed at inhibiting B-cell activation through BAFF
disruption have been the subject of extensive research. Notable
agents in this context include belimumab, an antibody that
targets BAFF (Mariette et al., 2015b), and atacicept or
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TABLE 1 Summary of Sjögren’s Syndrome therapeutic targets and biologics treatments.
Target Duration Evaluation criterion Study
type
Treatment No. of
subjects
Finding Refs
B cell
CD20 48 weeks The count of IL-22+ cells in
pSS patients’SG.
L RTX 10 pSS RTX in pSS reduces salivary
gland IL-22, potentially
affecting lymphoma
progression
Bernacchi et al.
(2004), Ciccia et al.
(2013)
52 weeks SG expression of IL-17, IL-
23p19, and p-STAT3
L RTX 15 pSS RTX globally reduces IL-17
and specifically depletes mast
cells in pSS.
Bernacchi et al.
(2005), Ciccia et al.
(2014)
48 weeks Primary: Stimulated saliva flow RCT RTX vs. placebo 30 pSS RTX effectively and safely
improves the primary and
secondary outcomes
Meijer et al. (2010),
Katayama (2016)
Secondary: B cell and RF levels,
MFI scores, VAS scores for
sicca symptoms, and
extraglandular issues
26 weeks Primary: Fatigue
reduction>20%
RCT RTX vs. placebo 17 pSS RTX improved fatigue and
showed potential benefits in
social functioning and mental
health in pSS.
Grisius et al.
(1997), Dass et al.
(2008)
Secondary: Changes in SF-36
social functioning and trend
for SF-36 mental health scores
CD20 35 months ESSDAI, corticosteroid
reduction, and adverse
reactions
O RTX vs. RTX + ISx 78 pSS RTX reduces disease activity
and corticosteroid dosage in
systemic pSS treatment
Manoussakis et al.
(2007), Gottenberg
et al. (2013)
60 weeks ESSPRI and ESSDAI. O RTX 28 pSS ESSPRI and ESSDAI detect pSS
treatment changes, with
ESSDAI more responsive in
rituximab-treated patients
Meiners et al.
(2012), Fogel et al.
(2018)
CD22 52 weeks Primary: Efficacy and safety of
epratuzumab
RCT (p) Epratuzumab vs.
placebo
113 sSS-SLE Epratuzumab enhanced
disease activity and hastened
B cell/IgM reduction in
sSS-SLE.
Chalifoux et al.
(2017), Gottenberg
et al. (2018)
Secondary: B cell count and
IgM level
CD38 6 months ESSDAI and ESSPRI. L Daratumumab 2 refractory
pSS
ESSDAI decreased in both pSS
patients, and ESSPRI remained
stable
Trevisani et al.
(2022), Nocturne
et al. (2023)
BAFF 28 weeks Primary: reduction in dryness,
fatigue, pain scores, b cell
activation biomarker, and
systemic activity
RCT BEL 30 pSS 60% met the primary endpoint,
showing notable reductions in
the ESSDAI and improvements
in dryness, while salivary flow
and Schirmer’s test remained
unchanged
Mariette et al.
(2015b), Mæland
et al. (2021)
Secondary: ESSDAI and
ESSPRI.
BAFF 68 weeks ESSDAI and B cell depletion C&L BEL + RTX vs. BEL
vs. RTX vs. placebo
86 pSS Combined BEL + RTX
induced enhanced salivary
gland B cell depletion
Manoussakis et al.
(1999), Mariette
et al. (2022)
24 weeks SG quality assessed by
ultrasound
RCT Ianalumab 27 pSS Ianalumab treatment
improved gland quality,
reduced inflammation, and
altered perfusion and stiffness
versus placebo
Diekhoff et al.
(2020), Posada
et al. (2021)
BAFF/
APRIL
24 weeks ESSDAI, MFI-20, and serum
immunoglobulin level
RCT Telitacicept vs.
placebo
42 pSS The Telitacicept group reduced
MFI-20 and immunoglobulin
levels, but there was no change
in the ESSDAI score
Mariette et al.
(2015a), Xu et al.
(2023)
T-B cell interaction
CD40 12 weeks ESSDAI, adverse events RCT Iscalimab vs.
placebo
44 pSS Only intravenous iscalimab
resulted in a significant
reduction in ESSDAI.
Crupi et al. (2012),
Clarke (2020)
(Continued on following page)
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TABLE 1 (Continued) Summary of Sjögren’s Syndrome therapeutic targets and biologics treatments.
Target Duration Evaluation criterion Study
type
Treatment No. of
subjects
Finding Refs
20 weeks Primary: Efficacy and safety of
iscalimab
RCT Iscalimab vs.
placebo
82 pSS Subcutaneous iscalimab did
not significantly differ from
placebo, yet intravenous
treatment notably reduced the
ESSDAI score
Schlesinger et al.
(2011), Fisher et al.
(2020)
Secondary: ESSDAI.
T cell
CD80/86 48 weeks Primary: ESSDAI, ESSPRI. L Abatacept 15 pSS Abatacept treatment decreased
the ESSDAI, ESSPRI, RF, and
IgG levels, and improved
fatigue, health-related quality
of life, and disease activity. But
the gland function did not
change
van Woerkom et al.
(2005), Meiners
et al. (2014)
Secondary: RF and IgG levels,
fatigue, gland function, adverse
events
CD80/86 52 weeks Primary: the remission rate as
measured by SDAI.
O Abatacept 68 sSS-RA Abatacept increased the SDAI
remission, ameliorated
glandular, extraglandular
involvements, systemic disease
activities, and patient-reported
outcomes
Beers et al. (2010),
Tsuboi et al. (2023)
Secondary: Saxon’s test,
Schirmer’s test, ESSDAI,
ESSPRI, adverse events
169days Primary: ESSDAI. RCT Abatacept vs.
placebo
187 pSS Abatacept decreased the
disease-relevant biomarkers
(including IgG, IgA, IgM- RF),
but there was no change in the
clinical efficacy
Ciccia et al. (2013),
Baer et al. (2021)
Secondary: ESSPRI, SWSF,
b cell activation biomarker,
immune cell phenotypes
TNF
TNFα22 weeks Primary: improvement of
disease activity
RCT Infliximab vs.
placebo
103 pSS Infliximab did not significantly
differ from placebo in both
primary and secondary
endpoints
Mariette et al.
(2004), Gottenberg
et al. (2013)
Secondary: the level of CRP,
ESR, the number of tender and
swollen joints, gland function,
and life quality
TNFα12 weeks Primary: Clinical assessments
of disease activity
RCT Etanercept vs.
placebo
28 SS Etanercept did not significantly
differ from placebo in the
primary clinical outcomes, and
can’t decrease the markers of
immune activation, frequency
of cell subpopulations, and
aberrant cytokine profile levels
Moutsopoulos
et al. (2008),
Meiners et al.
(2012)
Secondary: Peripheral blood
distribution of T cells, B cells,
monocytes, expression of their
activation markers, systemic
cytokine levels
ILs
IL-6 44 weeks ESSDAI, VNS. RCT Tocilizumab vs.
placebo
110 pSS Tocilizumab did not improve
systemic involvement and
symptoms compared with
placebo
Vincent et al.
(2014), Felten et al.
(2021b)
IL-17 3 months ESSDAI, fatigue, headache, the
levels of ESR, globulins, and
serum viscosity
L Bortezomib 1 refractory
pSS
Bortezomib can improve the
general symptoms, particularly
fatigue, also decrease serum
globulin levels and serum
viscosity
Brignole et al.
(2000),
Jakez-Ocampo
et al. (2015)
IL-12/23 3 years The levels of autoimmune
antibody, ESR, CRP, gland
function, and extraglandular
issues
L Ustekinumab 1 refractory
sSS- psoriatic
Ustekinumab can improve
psoriasis and joint pain in SS
patients with psoriatic
Chimenti et al.
(2015), Clarke
(2020)
(Continued on following page)
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telitacicept, a soluble wild-type extracellular domain Fc fusion
protein that strongly inhibits BAFF and weakly inhibits APRIL
signaling (Samy et al., 2017;Shi et al., 2021;Xu et al., 2023). It is
important to note that the sustained use of BAFF antagonists
effectively reduces disease activity but may not impact certain
parameters such as salivary flow rate, Schirmer’s test, and lesion
scores in salivary gland biopsies (Mariette et al., 2015b).
The BAFF/APRIL system comprises not only these two ligands
but also three receptors: BAFF receptor (BAFF-R), also known as
B-lymphocyte stimulator receptor 3 (BR3), B-cell maturation
antigen (BCMA), and transmembrane activator and cyclophilin
ligand interactor (TACI) (Vincent et al., 2014). Both BAFF and
APRIL can interact with BCMA and TACI, while BAFF exclusively
binds to BAFF-R (Vincent et al., 2012). These receptors also play a
pivotal role in the survival, maturation, and regulation of B cells
(Vincent et al., 2013). Presently, there is ongoing research on drugs
targeting these receptors, Ianalumab, a novel BAFF-R targeting
antibody, demonstrated favorable therapeutic effects in primary
SS patients, affecting ESSDAI score, gland quality, inflammation,
perfusion, and stiffness (Diekhoff et al., 2020;Bowman et al., 2022).
In the pursuit of diversified therapeutic strategies, novel avenues
have been explored (Table 1). A notable focus lies in targeting CD22,
a protein on B cell surfaces, exemplified by epratuzumab, a
humanized IgG1 anti-CD22 antibody. In contrast to the
depletion approach of RTX, epratuzumab modulates B cell
activity, potentially offering an alternative means to mitigate B
cell-mediated autoimmune responses (Giltiay et al., 2017).
Epratuzumab enhanced disease activity and hastened B cell/IgM
reduction in systemic lupus erythematosus (SLE) patients with SS
(Gottenberg et al., 2018). However, further research is required to
establish its effectiveness. CD38, a glycoprotein found on plasma
cells, acts as an adhesion molecule, ectoenzyme, and receptor for
activation or proliferation signals. CD38 antibodies can directly
interfere with plasma cells through calcium disruption and signal
transduction, or Fc-dependent immune-effector mechanisms
(complement-dependent cytotoxicity, antibody-dependent cellular
cytotoxicity, and antibody-dependent cellular phagocytosis).
Daratumumab, a monoclonal antibody targeting CD38 on
multiple myeloma cells and immune cells, is being explored for
potential applications in autoimmune diseases such as SS (Nocturne
et al., 2023). Its mechanism of action in modulating the autoimmune
response shows promise, but rigorous clinical trials are essential to
establish its safety and efficacy in these specific conditions.
Iguratimod, by reducing Immunoglobulins production and
suppressing B cell proliferation, proved effective and well-
tolerated in a 24-week clinical trial with 66 pSS patients. It
ameliorated dryness symptoms and disease activity, concurrently
decreasing BAFF levels and plasma cell proportions (Li et al., 2019).
CD40 has been identified as involved in a spectrum of cell-mediated
responses and has been implicated in the pathogenesis of chronic
inflammatory disorders (Dimitriou et al., 2002) Studies have shown
elevated CD40 expression in salivary gland and conjunctival cells of
SS patients, indicating its involvement in the disease. CD40 has also
been found to be upregulated in the conjunctival cells of SS patients
with dry eyes (Brignole et al., 2000). Recently, Iscalimab, an anti-
CD40 monoclonal antibody, exhibited preliminary efficacy in
treating pSS in a phase II clinical trial (Clarke, 2020;Fisher et al.,
2020). The intricate nature of SS underscores the need for ongoing
research into these therapeutic modalities to optimize their clinical
application and address the complexities of autoimmune
pathogenesis.
Remibrutinib is a selective, covalent inhibitor of Bruton’s
tyrosine kinase (BTK). By inhibiting BTK activity, it reduces
B-cell-mediated inflammation and autoimmune responses. A
recent Phase II RCT demonstrated that remibrutinib significantly
improved the ESSDAI scores compared to placebo. Additionally, it
enhanced salivary flow rates. These findings substantiate the
potential of remibrutinib as a therapeutic option for SS and
TABLE 1 (Continued) Summary of Sjögren’s Syndrome therapeutic targets and biologics treatments.
Target Duration Evaluation criterion Study
type
Treatment No. of
subjects
Finding Refs
JAK
JAK1/2 6 months ESSDAI, ESSPRI, PGA scores,
IgG and ESR level, remission of
organ manifestations
L Baricitinib 11 pSS Baricitinib decreased the
ESSDAI, ESSPRI, and PGA,
improved the symptoms of
arthritis, skin rash, and ILD in
patients with SS.
Giltiay et al. (2017),
Bai et al. (2022)
JAK1 52 weeks Primary: week-12 proportion
of patients fulfilling protocol-
specified improvement criteria
(based on CRP, SS-related
symptoms)
RCT Filgotinib vs.
lanraplenib vs.
tirabrutinib vs.
placebo
150 SS Filgotinib reduced Type I IFN
signature activity. There were
no changes in primary and
secondary endpoints
Felten et al.
(2021a),Price et al.
(2022)
Secondary: ESSDAI, ESSPRI,
adverse events
L, longitudinal study; RCT, randomized, placebo-controlled trial; O, prospective observational study; C, cross-sectional study; RCT (p), post hoc analysis of rendomized, placebo-controlled trial;
Primary, primary endpoint; Secondary, secondary endpoint; BAFF, B-cell activating factor; APRIL, a proliferation-inducing ligand; TNF, tumour necrosis factor; IFN, interferon; STAT, signal
transducer and activator of transcription; IL, interleukin; JAK, janus kinases; SS, Sjögren’s syndrome; pSS, primary Sjögren’s syndrome; sSS, secondary Sjögren’s syndrome; SLE, systemic lupus
erythematosus; RA, rheumatoid arthritis; ILD, interstitial lung disease; sSS-SLE, SLE, with associated SS; sSS-RA, SS, associated with RA; sSS- psoriatic, SS, associated with psoriatic; RTX,
rituximab; ISx, immunosuppressant; BEL, belimumab; SG, salivary gland; MFI, multidimensional fatigue inventory; VAS, visual analog scale; SF-36, 36-item Short-Form Health Survey; ESSPRI,
the EULAR, Sjögren’s Syndrome Patient Reported Index; ESSDAI, the EULAR, Sjögren’s Syndrome Disease Activity Index; SWSF, stimulated whole salivary flow; SDAI; the Simplified Disease
Activity Index; VNS, visual numeric scale; PGA, physician global assessment; RF, rheumatoid factor; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; wks, weeks; mos, months; vs.,
verse.
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provide a rationale for further drug development and extended-
duration trials (Dörner et al., 2024).
4.1.5 Exploring B Cell targeted approaches and
potential synergies
Biologic therapies targeting B cell dysregulation continue to
evolve in the management of SS. While RTX’s clinical outcomes
show variability, ongoing research endeavors aim to optimize its
application. Simultaneously, alternative strategies like
CD22 targeting and BAFF interference hold promise in reshaping
the treatment landscape. Currently, two considerations underlie the
diverse clinical outcomes associated with the use of RTX: the
reconstitution of B cells and the increased levels of BAFF after
B-cell depletion.
The restoration of peripheral blood B cells following B-cell
depletion with RTX mirrors the developmental process of B cells
and typically begins between 6 and 12 months after the last infusion.
B-cell reconstitution has been widely described in numerous
autoimmune diseases, such as Sjögren’s Syndrome (SS), systemic
lupus erythematosus (SLE), rheumatoid arthritis (RA), immune
thrombocytopenia (ITP) (Abdulahad et al., 2011;Crickx et al.,
2020). The second hypothesis posits that, upon depletion of
B cells, the diminished B cell count leads to increased unbound
BAFF levels, fostering a microenvironment conducive to B cell
regeneration (Zhang et al., 2023). This hypothesis is supported
by an experimental setting, serum analysis of five patients,
including two with SS, who underwent RTX treatment, revealed
an early elevation in BAFF levels (Lavie et al., 2007).
Given the current circumstances, it is worthwhile to further
explore the potential of combining anti-B cell and anti-BAFF
therapies for synergistic treatment of SS. Encouragingly, clinical
trials investigating the combination of RTX and belimumab for the
treatment of pSS are currently underway, providing fertile ground
for further therapeutic advancements in the field (De Vita et al.,
2014;Gandolfo and De Vita, 2019). Presently, data from a phase II
clinical trial demonstrate that the combination of belimumab and
RTX induces a more pronounced depletion of B cells in the salivary
glands compared to monotherapies, potentially resulting in
improved clinical outcomes (Mariette et al., 2022). Furthermore,
in this experimental setting, the sequential treatment protocol begins
with the administration of Belimumab, followed by the subsequent
addition of RTX. This strategy aims to preemptively disrupt the
environment conducive to B cell growth before commencing the
depletion of B cells, with the potential of achieving enhanced
therapeutic efficacy.
4.2 T cell-targeted therapies in SS
4.2.1 Mechanism
B cells have long been considered critical in the pathogenesis of
SS, yet studies indicate that their hyperactivity is influenced by
T cells (Verstappen et al., 2021a). Furthermore, T lymphocytes and
the cytokines they release, including IL-17, IL-22, and various other
factors, occupy a pivotal role in the initiation and perpetuation of
inflammatory infiltrates within the salivary glands of individuals
affected by SS (Katsifis et al., 2007;Ciccia et al., 2012). Particularly in
the early stages of the disease, CD4
+
T cells are the primary
lymphocytes infiltrating the salivary and lacrimal glands.
Consequently, investigating the pathological mechanisms of
T cells in SS is as vital as studying the B cells.
Current research indicates that various Th cell types formed
after the differentiation of CD4
+
T cells produce different signaling
factors. Notably, studies have detected aberrant expression of the IL-
22 receptor in mantle cell lymphoma (MCL), which may promote
cell growth in MCL by modulating various cellular signaling
pathwaysThis observation leads to the hypothesis that patients
with increased IL-22/IL-22R pathway expression might be at a
higher risk for lymphoma (Gelebart et al., 2011). T-cell immune
responses involve the formation of specialized junctions between
T cells and antigen-presenting cells mediated by adhesion molecules.
In SS, autoantigens on endothelial cells trigger T-cell migration to
exocrine tissue, leading to activation and increased B-cell
autoantibody production (Zhou et al., 2020). This mechanism
has spurred interest in developing drugs that target adhesion
molecules to modulate T-cell responses in SS.
4.2.2 Application of abatacept in SS
Current research suggests that CD4
+
T cells are the primary
lymphocytes infiltrating the salivary and lacrimal glands during the
initial stages of pSS. Additionally, elevated levels of T cell-associated
cytokines have been observed in pSS patients who present with skin
manifestations. These findings support the early consideration of T
cell-targeted therapies, especially for patients with dermatological
symptoms. Such therapies, exemplified by abatacept, have gained
prominence due to their critical role in the complex pathogenesis of
SS, as outlined in Table 1. Abatacept, a fusion protein consisting of
the extracellular domain of human cytotoxic T-lymphocyte-
associated antigen 4 and a modified Fc portion of human IgG1,
is approved for rheumatoid arthritis (RA). It interferes with the
CD80/86-CD28 co-stimulatory pathway, thereby inhibiting T-cell
activation. Studies have shown that abatacept reduces the number of
circulating follicular helper T (Tfh) cells and the expression of the
T-cell surface activation marker ICOS in the peripheral blood of pSS
patients. This reduction in activated Tfh cells contributes to
suppressing the hyperactivity of Tfh cell-dependent B cells
(Verstappen et al., 2017). Additionally, human cytotoxic
T-lymphocyte-associated antigen 4 has been demonstrated to
regulate CD4
+
T cell proliferation and reduce T cell activation in
SS (Manoussakis et al., 1999).
Initially, abatacept was found to lessen inflammation and
enhance saliva production in SS (Meiners et al., 2014), with
subsequent ROSE and ROSE II trials confirming improvements
in various outcomes, including glandular, extraglandular, and
systemic manifestations (Tsuboi et al., 2023). However, despite
these biological effects on biomarkers and immune cells, a phase
III trial in active primary SS indicated that abatacept did not achieve
significant clinical efficacy compared to placebo (Baer et al., 2021;
van N et al., 2020).
4.2.3 Limitations and alternatives
While the targeting of T cell activation through adhesion
molecule interactions has gained attention, concerns regarding
adverse effects persist. For instance, alefacept, a drug designed to
target T cells binding to CD2, has shown promise in achieving long-
term remission in psoriasis but comes with apprehensions due to
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substantial T cell depletion. Similarly, efalizumab, a humanized
monoclonal antibody that interferes with T cell activation,
reactivation, and migration, faced safety issues in SS, leading to
its discontinuation, including potential risks like progressive
multifocal leukoencephalopathy.
T cell-targeted therapies have emerged as a promising avenue in
SS treatment, exemplified by the potential benefits of abatacept in
addressing glandular inflammation and promoting saliva
production. However, the delicate balance between efficacy and
safety remains a challenge, as evidenced by the limitations of
alefacept and efalizumab. Given the intricate interplay between
T cell dysregulation and autoimmune pathogenesis, there is a
continuous need for exploring innovative therapeutic strategies
that effectively modulate T cell responses while mitigating
potential risks.
Lately, in a Phase II clinical trial, Dazodalibep, an antagonist of
the CD40 ligand, significantly improved patients’ESSDAI and
ESSPRI scores compared to placebo. These improvements were
sustained over time, demonstrating positive effects in alleviating
symptoms of the disease such as dryness, fatigue, and pain (St et al.,
2023). Dazodalibep emerges as a promising new therapeutic
candidate for managing systemic disease activity in patients with
SS. To substantiate its clinical efficacy, further extensive and large-
scale clinical studies are warranted.
4.3 Anti-TNF-α-targeted therapies in SS
4.3.1 Mechanism
TNF-α, secreted by glandular T cells, is implicated in promoting
glandular epithelial apoptosis and the induction of inflammation
through Fas induction (Matsumura et al., 2000). In SS patients,
TNF-αis notably elevated in the acinar and ductal cells of the
salivary glands (Sisto et al., 2010). In a mouse model engineered to
express high levels of TNF-α, researchers observed severe
inflammation in the salivary glands, along with acinar cell
atrophy, fibrosis, and ductal dilation (Limaye et al., 2019). This
observation is particularly significance due to the heightened
production of TNF-αwithin glandular lesions. Inhibiting TNF-α
can also suppress the production of matrix metalloproteinase-9
induced by it, thereby preventing the destruction of alveolar cells
and the extracellular matrix. Therefore, mechanistically, anti-TNFα
therapy should have a beneficial effect on SS (Azuma et al., 2000;
Mignogna et al., 2005). However, current research indicates that this
treatment has not achieved the anticipated outcomes.
4.3.2 The efficacy and challenges of Anti-TNF
therapies in SS
Infliximab, the first anti-TNF therapy explored in SS, initially
demonstrated statistical improvement in clinical and functional
parameters in a pilot trial (Steinfeld et al., 2013). However,
subsequent larger RCTs failed to establish any beneficial effects
(Mariette et al., 2004). Trials investigating etanercept also yielded
negative outcomes (Moutsopoulos et al., 2008). Challenges such as
achieving therapeutic concentrations in salivary glands and
overcoming inflammation-associated fibrosis could have
contributed to this treatment failure (Table 1). Therefore, anti-
TNF therapies are not recommended for the treatment of SS.
4.3.3 Limitations and insights from animal models
The outcomes of clinical trials partially align with insights from
animal models. TNF appears to attenuate T cell autoreactivity and
inflammation, and its absence leads to the accumulation of reactive
CD4
+
T cells. Emerging data from these models suggest a protective
role of TNF in SS, as TNF deficiency exacerbates SS-like disease, the
absence of TNF in certain models associated with inflammation
within salivary glands and altered marginal B cell compartments,
which might contributes to lymphoid tumors resembling MALT-L
(Nocturne et al., 2021).
Anti-TNF-α-targeted therapies in SS face significant challenges,
and their efficacy is questioned based on clinical trials and insights
from animal models. The efficacy of anti-TNF therapies, despite
their success in other autoimmune conditions, remains equivocal in
the context of SS, potentially attributed to the complex and
multifaceted role of TNF in the disorder’s pathogenesis (Azuma
et al., 1997). The exploration of the discrepancies between the
pathological mechanisms and the actual therapeutic efficacy of
TNF therapy presents an interesting research direction.
4.4 IFN and anti-IFN-targeted therapies in SS
4.4.1 Mechanism
Interferon (IFN) proteins exhibit significant immunomodulatory
and antiviral properties. In the context of SS, an in-depth analysis of
gene expression profiles has unveiled distinctive activation signatures
associated with the IFN pathway in peripheral blood leukocytes and
minor salivary gland biopsies (Båve et al., 2005;Kimoto et al., 2011;
Bodewes et al., 2018). Type I interferons play a pivotal role in promoting
inflammatory responses by activating peripheral blood mononuclear
cells among other immune cells. Numerous studies have documented
the overexpression of Type I IFN in these cells, a phenomenon known
as the ‘Type I IFN signature.’This observation is intricately linked to the
onset of systemic extra-glandular manifestations, accompanied by a
notable production of autoantibodies and inflammatory cytokines (Del
Papa et al., 2021). Furthermore, Type I interferons are crucial in
inducing B cells to produce autoantibodies, such as anti-SSA and
anti-SSB, which are hallmark features of autoimmune responses in
SS. IFN-γ, a canonical cytokine, induces the activation of T and NK cells
and plays dual roles in immunomodulation (Zeng et al., 2022), also
enhancing the class switching of immunoglobulins in B cells, thereby
further promoting the production of autoantibodies.
In a recent study, the activity of Type I (IFN-I) and Type II (IFN-
II) interferons in patients with SS was investigated, along with their
relationship to clinical features. Patients were categorized into three
groups: those with no IFN activation, those with IFN-I activation,
and those with both IFN-I and IFN-II activation. The findings
indicated no significant differences among the groups in terms of
ESSPRI, fatigue, or dryness. However, the groups with active IFN
showed higher ESSDAI scores and lower pain scores. Consequently,
in future clinical trials targeting the IFN pathway, the ESSDAI score
may serve as a more sensitive indicator (Bodewes et al., 2018).
4.4.2 Application of IFN-αagonists in SS
IFN pathway activation signatures in SS have sparked interest in
harnessing IFN-αagonists for therapeutic benefit. Early-phase trials
suggest the potential for improving sicca symptoms and saliva
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production (Del Papa et al., 2021). A Phase III clinical trial
demonstrated that low doses of oral IFN increase unstimulated
salivary output. Oro-mucosal administration of IFN-αis believed to
enhance saliva secretion by up-regulating aquaporin 5 transcription,
without disrupting the autoimmune process (Cummins et al., 2003).
However, larger double-blind, placebo-controlled RCTs involving a
substantial number of patients failed to establish significant
differences in oral dryness or stimulated salivary flow. Notably,
an increase in unstimulated salivary flow was observed in treated
groups, indicating potential therapeutic effects. Despite these
findings, the clinical benefits of IFN-αagonists for SS patients
remain uncertain. Thus, the IFN-αtherapy is presently not
recommended for treating SS.
4.4.3 Limitations and anti-IFN-αmAbs
Considering IFN-α′s pro-inflammatory role, efforts have been
directed towards targeting it. Two monoclonal antibodies (mAbs)
directed against IFN-α, namely, rontalizumab and sifalimumab,
have been explored. Rontalizumab demonstrated safety but
lacked efficacy in a phase II trial (Kalunian et al., 2016).
Sifalimumab also exhibited a favorable safety profile, but its
efficacy in improving SS-related symptoms and markers of
disease activity remained modest. Furthermore, it is worth noting
that anti-IFN-αtherapy has been linked with gastrointestinal
adverse effects in SS (Choudhary et al., 2023). These results
suggest that the development of anti-IFN-αmAbs offers an
alternative approach, despite their potential, anti-IFN-αmAbs
may face limitations in achieving substantial clinical benefits,
which underscore the complexity of targeting IFN pathways in
SS. Continued research and refinement of therapies are essential
to unravel the intricate interplay of IFN and its modulation in the
context of SS.
4.5 Therapies targeting ILs in SS
4.5.1 Mechanism
Elevated levels of IL-6 observed in the serum, saliva, and tears of
SS patients serve as a compelling indicator of the cytokine’s pivotal
and integral role within the pathophysiological framework of SS
(Ohyama et al., 1996;Grisius et al., 1997;Yoshimoto et al., 2011). IL-
6 is a key factor in B cell activation, and T cell differentiation, and is
associated with fatigue. Tocilizumab, a monoclonal antibody,
effectively inhibits IL-6 signaling by blocking the IL-6 receptor.
4.5.2 Application of tocilizumab in SS
Although tocilizumab is routinely used to treat rheumatoid
arthritis, it is not yet approved for SS. However, given its ability
to disrupt IL-6-mediated inflammatory processes, it presents a
promising avenue for intervention in SS. While limited clinical
data are available, a single case report has documented the
beneficial effects of tocilizumab in a patient with neuromyelitis
optica spectrum disorder complicated by SS (Komai et al., 2016).
Additionally, a phase III RCT led by French investigators is
comparing tocilizumab to placebo in SS patients. However, this
trial failed to provide the efficacy of tocilizumab in systemic
involvement and symptoms compared with placebo (Table 1)
(Felten et al., 2021b).
4.5.3 Limitations and future prospects
The elevation of IL-6 in SS highlights its potential as a
therapeutic target. Tocilizumab, known for its efficacy in
disrupting IL-6-mediated pathways, has shown promise.
Although a single case report offers encouraging evidence, a
large-scale Phase III study in France did not confirm
tocilizumab’s effectiveness in addressing systemic involvement or
alleviating symptoms in SS. Therefore, the role of targeting IL-6 in
the treatment of SS remains a subject worthy of further investigation.
Moreover, elucidating the broader impacts of targeting IL-6 in SS,
including its potential impact on fatigue and autoimmune
mechanisms, remains a topic of interest and ongoing research.
4.6 Therapies targeting JAK/STAT in SS
4.6.1 Mechanism
The Janus kinases (JAK)-signal transducers and activators of the
transcription (STAT) pathway assume a central role in
autoimmunity and systemic inflammation, governing the
production of inflammatory cytokines, including ILs, TNFs,
granulocyte-macrophage colony-stimulating factors, and IFN-γ
(Morris et al., 2018). Data concerning JAK and STAT expression
within pSS-afflicted salivary glands remain sparse. However,
research by Aota et al. has shed light on robust JAK1 and
JAK2 expression in ductal and acinar cells of minor salivary
gland biopsies from pSS patients (Aota et al., 2021). Elevated
expression of STAT1 and STAT3 in minor salivary gland
biopsies from pSS patients, as well as in their blood samples, has
been correlated with activation triggered by a range of immune
mediators, including IFN-α, IFN-γ, IL-6, IL-17, and IL-22
(Wakamatsu et al., 2006;Ciccia et al., 2012).
4.6.2 Application of JAK inhibitors in SS
JAK inhibitors, approved for immune disorders and under
investigation in autoimmune diseases, offer a promising
therapeutic approach in rheumatology by competitively binding
to ATP and modulating critical molecular and biological processes,
with potential applications in pSS. In the context of the complex
cytokine landscape characterizing pSS, numerous JAK inhibitors,
including baricitinib, filgotinib, tofacitinib, oclacitinib, and
upadacitinib, have found applications in the treatment of
autoimmune diseases (Tanaka et al., 2022). In a recent pilot trial
of 11 active pSS patients, the JAK1 and JAK2 inhibitor, baricitinib,
showed promise in reducing immune cell infiltration and improving
clinical manifestations, although controlled trials are needed for
validation (Bai et al., 2022). Filgotinib, a JAK1 inhibitor, has shown
potential in reducing IFN-related genes and BAFF in pSS. A clinical
trial, while not meeting primary and secondary endpoints, might
suggests promise for filgotinib in subgroups of pSS patients with
biomarker guidance, stabilizing salivary and tear production and
reducing IFN activity (Price et al., 2022). The overall safety and
tolerability profile is encouraging, indicating the need for more
targeted approaches in pSS clinical trials (Table 1).
4.6.3 Limitations and future prospects
Notable, promising research by Renaudineau and colleagues
suggests that JAK1/2 inhibitors, AG490 and ruxolitinib, may reverse
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specific pathways implicated in pSS pathogenesis (McCoy et al.,
2022). Tofacitinib, a JAK1 and JAK3 inhibitor, has the potential to
treat pSS by restoring autophagy and mitigating inflammation,
particularly by targeting IL-6 expression (Barrera et al., 2021).
Additionally, JAK1/2 inhibitors can counteract ROS-induced ten-
eleven translocation 3 production and IFNα-mediated DNA
hydroxymethylation, suggesting promise for pSS treatment
(Charras et al., 2019;Charras et al., 2020).
Recent discoveries have unveiled the engagement of STAT3 in
epigenetic DNA methylation and hydroxymethylation processes
within pSS, impacting genes regulated by IFN-α, IFN-γ, and
oxidative stress pathways (Table 1)(Charras et al., 2020). The
promise of JAK-STAT inhibition in treating immune-mediated
disorders, including pSS, is underscored by the intricate cytokine
landscape and the key role of IFN pathways in pSS. While existing
data are encouraging, further research is needed to fully grasp the
implications of JAK-STAT pathway inhibition in pSS, extending
beyond inflammation control to restoring salivary gland
epithelium functions.
4.7 Unexplored potential therapies in SS
4.7.1 Cytokine blockade therapies
In the landscape of SS treatment, a host of cytokines have shown
promise in other autoimmune conditions, yet their potential in SS
remains untapped. Cytokine blockade strategies have demonstrated
efficacy in diseases like psoriasis, RA, multiple sclerosis, and
inflammatory bowel disease. For instance, the blockade of IL-12
and IL-23 using briakinumab and ustekinumab has yielded success
in various autoimmune disorders. Similarly, Fontolizumab, an IFN-
γblocker, is being evaluated for Crohn’s disease. IL-17 inhibition,
employed in conditions such as inflammatory bowel disease, dry eye,
psoriatic arthritis, and RA, presents another avenue worth exploring.
Furthermore, the perturbation of IL-1, implicated in SS
pathogenesis, has shown promise in ameliorating fatigue.
Although these cytokine-targeting therapies bear potential for SS
treatment, their direct investigation in the context of SS is yet to be
undertaken.
Ongoing clinical trials are investigating various approaches to
target SS (Table 1). A case report describes the significant efficacy of
bortezomib, a proteasome inhibitor typically used in the treatment
of multiple myeloma, in improving patient fatigue and overall
quality of life (Jakez-Ocampo et al., 2015). Similarly, trials are
exploring monoclonal antibodies against IL-23, including
ustekinumab (Chimenti et al., 2015), briakinumab, and
tildrakizumab, which are currently used in the treatment of other
autoimmune diseases (Markham, 2018;Verstockt et al., 2023).
Additionally, there are ongoing clinical trials aimed at targeting
interferons, exemplified by NCT05383677. These trials represent
continued efforts to advance our understanding and treatment of SS.
4.7.2 Targeting toll-like receptors
The intricate interplay exhibited by Toll-like receptors (TLRs) in
orchestrating the initiation of both innate and adaptive immune
responses highlights their innovative and promising role as
therapeutic targets (Zheng et al., 2010;Guerrier et al., 2012;
Karlsen et al., 2017;Shimizu et al., 2019). TLR dysregulation is
linked to salivary gland inflammation in SS. Inhibition of TLR-7 by
IRS-954 demonstrated in a SLE murine model, could hold promise
for SS intervention. Furthermore, the overexpression of TLR-9 in SS
salivary glands and peripheral blood mononuclear cells is
noteworthy (Zheng et al., 2010;Guerrier et al., 2012), potentially
influencing aberrant B cell differentiation, and opens a path for
therapeutic exploration, though its specific role remains to be
elucidated.
4.7.3 Chemokine-mediated lymphocyte trafficking
Chemokines, orchestrators of lymphocyte trafficking and
lymphoid structure formation, bear significance in SS due to the
presence of ectopic lymphoid structures in affected glandular tissues.
These structures are notably characterized by the overexpression of
chemokines, including CXCL13 and CXCL21 (Amft et al., 2001;
Barone et al., 2005;Lee et al., 2017;Loureiro-Amigo et al., 2021). The
regulation of lymphocyte behavior by these chemokines suggests
their therapeutic potential. However, despite their relevance, no
treatment targeting these chemokines has been investigated in
SS to date.
4.7.4 Exploring diverse molecular targets
Additional molecules with implications in SS manifestations and
complications hold therapeutic promise. Serum fms-like tyrosine
kinase 3 ligand, linked to lymphoma risk in SS, presents itself as a
potential biomarker and therapeutic target (Tobón et al., 2013).
Elevated CD6 expression on B and T cells in SS-affected salivary
glands opens the door for itolizumab, an anti-CD6 monoclonal
antibody, as an immune activation inhibitor (Alonso et al., 2010;Le
Dantec et al., 2013). Furthermore, the inhibition of the lymphotoxin
βreceptor in a murine SS model suggests its viability as a molecular
target. However, a phase II trial showed that the baminercept, a
lymphotoxin βreceptor IgG fusion protein, blocks lymphotoxin β
receptor signaling while failing to significantly improve glandular
and extraglandular disease in patients with primary SS (St Clair
et al., 2018).
While numerous cytokines and molecular targets have displayed
efficacy in other autoimmune conditions, their potential in SS is a
largely unexplored terrain. Cytokine blockade, TLR inhibition,
chemokine modulation, and exploration of diverse molecules
hold promise for revolutionizing SS treatment. However, rigorous
investigation, encompassing controlled trials and mechanistic
studies, is essential to unravel their therapeutic potential and
translate them into effective therapies for SS patients.
5 Advancing biologic therapies in SS:
navigating complexity and
embracing promise
Biologic therapies have revolutionized the landscape of SS
management, providing potential treatments and advancing our
understanding of immune dysregulation. Recent large-scale studies
have classified patients with SS from various perspectives, including
immunological patterns, clinical symptoms, and histological
phenotypes. These investigations have revealed significant
heterogeneity among patients with SS. Research involving
extensive cases of SS, multi-omics analyses, and detailed clinical
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parameters has facilitated the development of personalized
treatment approaches.
The intricate interplay of Th1, Th17, and B cells in persistent
inflammation and autoantibody production in SS is highlighted in a
review, with IL-6 emerging as a central orchestrator. Notably, T cell-
targeted interventions exhibit limited efficacy, emphasizing the
crucial role of autonomous B cells in driving cytokine
production. Varied outcomes in B cell depletion therapies’trials
underscore the need for nuanced patient selection, especially
favoring those in early stages with active extraglandular
involvement.
While the horizon of biologic therapies for SS is replete with
potential, the journey is not devoid of challenges. The ongoing trials
investigating IL-6 and 17 targeting agents, along with agents
targeting BAFF, attest to the evolving landscape of SS
therapeutics. Given the intricate heterogeneity in SS patient
presentations and the intricate immune responses at play,
predicting individual responses to biologic therapies remains a
formidable challenge.
Moving forward, nuanced approaches to patient selection for
biologic therapy, targeting IL-6, IL-17, and BAFF, show promise.
However, predicting individual responses to biologic therapies
remains challenging, given the intricate heterogeneity in SS
patient presentations. Comprehensive RCTs combining diverse
therapeutic targets and patient profiles will play a pivotal role,
providing evidence-based insights into the superiority of biologic
therapies over conventional treatments.
In conclusion, the ongoing refinement in SS management
involves navigating the complex immunological landscape,
patient diversity, and a rapidly evolving therapeutic frontier.
Meticulous research, strategic clinical trials, and insights from the
European study collectively contribute to the promise of innovative
therapies, marking a significant step towards a brighter future for
SS patients.
6 Conclusion
The pursuit of biologic therapies holds the promise of
ameliorating symptoms and thwarting the progression of SS. As
scientific understanding of SS mechanisms advances and tailored
therapeutic interventions are charted, judicious consideration of
patient heterogeneity and empirically grounded treatments is
paramount. The ongoing exploration through clinical trials and
innovative research endeavors heralds a promising trajectory for
individuals grappling with SS, promising improved quality of life
and enhanced management of this intricate autoimmune affliction.
The future of pSS treatment may involve gene, stem-cell, and tissue-
engineering therapies. This review offers insights into advancing pSS
management through innovative biologic interventions.
Author contributions
XL: Writing–original draft, Writing–review and editing. MM:
Writing–review and editing. QT: Writing–review and editing. WH:
Writing–review and editing. YL: Writing–review and editing. ZL:
Writing–review and editing. YW: Writing–review and editing. YZ:
Writing–review and editing. XC: Writing–review and editing. RC:
Writing–review and editing. YT: Writing–review and editing. SY:
Writing–original draft, Writing–review and editing.
Funding
The author(s) declare financial support was received for the
research, authorship, and/or publication of this article. This project
was supported by the Guangdong Basic and Applied Basic Research
Foundation of Guangdong Province, China (Grant No.
2019A1515011094); the Guangdong Basic and Applied Basic
Research Foundation of Guangdong Province, China (Grant No.
2022A1515010471); the Guangzhou Science and Technology
Planning Project of Guangdong Province, China (Grant
No.202102010139); Science and technology project of Guangzhou
(No. 202201010778).
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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Nomenclature
ACPA Anti-citrullinated peptide antibodies
APRIL a proliferation-inducing ligand
BAFF-R BAFF receptor
BCMA B-cell maturation antigen
BLyS/BAFF B lymphocyte stimulator/B-cell activating factor
BR3 B-lymphocyte stimulator receptor 3
ClinESSDAI Clinical ESSDAI
CXCL C-X-C motif chemokine ligand
ESSDAI the EULAR Sjögren’s Syndrome disease activity index
ESSPRI the EULAR Sjögren’s Syndrome Patient Reported Index
HCQ hydroxychloroquine
HPA hypothalamic-pituitary-adrenal
IFN interferon
IL interleukin
ILD interstitial lung disease
ITP immune thrombocytopenia
JAK Janus kinases
mAbs monoclonal antibodies
LELs lymphoepithelial lesions
MALT-L mucosa-associated lymphoid tissue-lymphoma
MCL mantle cell lymphoma
MMF mycophenolate mofetil
MTX methotrexate
NLR neutrophil-to-lymphocyte ratio
NSIP non-specific interstitial pneumonitis
PGA patient global assessment
PBC primary biliary cholangitis
pSS Primary Sjögren’s Syndrome
RA rheumatoid arthritis
RCTs randomized controlled trials
RF rheumatoid factor
RTX rituximab
SS Sjögren’s Syndrome
SLE systemic lupus erythematosus
STAT signal transducers and activators of the transcription
TACI transmembrane activator and cyclophilin ligand interactor
Tfh follicular helper T
TNF tumour necrosis factor
TLRs Toll-like receptors
Th cell T helper cell
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