Targeting pathogenic fibroblast-like synoviocyte subsets in rheumatoid arthritis.

Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid arthritis (RA). FLSs are emerging as promising new therapeutic targets in RA. However, fibroblasts perform many essential functions that are required for sustaining tissue homeostasis. Direct targeting of general fibroblast markers on FLSs is challenging because fibroblasts in other tissues might be altered and side effects such as reduced wound healing or fibrosis can occur. To date, no FLS-specific targeted therapies have been applied in the clinical management of RA. With the help of high-throughput technologies such as scRNA-seq in recent years, several specific pathogenic FLS subsets in RA have been identified. Understanding the characteristics of these pathogenic FLS clusters and the mechanisms that drive their differentiation can provide new insights into the development of novel FLS-targeting strategies for RA. Here, we discuss the pathogenic FLS subsets in RA that have been elucidated in recent years and potential strategies for targeting pathogenic FLSs.

Seronegative primary Sjögren's syndrome, a distinct subtype of primary Sjögren's syndrome in Chinese patients.

BACKGROUND: To investigate the clinical and immune characteristics of patients with primary Sjögren's syndrome (pSS) who were negative for anti-Sjögren's-syndrome-related antigen A antibodies (anti-SSA) and anti-Sjögren's-syndrome-related antigen B antibodies (anti-SSB) in Chinese population. METHODS: A retrospective study were performed and 232 patients with pSS were analyzed. Patients positive for anti-SSA or/and anti-SSB were termed as seropositive pSS, and these negative for both anti-SSA and anti-SSB (non-antinuclear antibodies) as seronegative pSS. Clinical manifestations and laboratory findings were compared between the two groups. RESULTS: Among the 232 patients with pSS, 192 (82.8%) were seropositive pSS and 40 (17.2%) were seronegative pSS. Compared to seropositive pSS, seronegative pSS were older and with higher percentage of low disease activity (ESSDAI < 5), xerostomia and xerophthalmia, with higher platelet count and level of creatine kinase. This subgroup was with lower levels of gamma globulin, immunoglobulin G, immunoglobulin A and autoantibodies including rheumatoid factor and antinuclear antibody in serum, and less immunoglobulin G deposition in labial gland. CONCLUSION: Seronegative pSS was a distinct subtype of pSS different from seropositive pSS. Clinical manifestations in seronegative pSS subgroup were restricted to exocrine gland and less B lymphocyte activation, while seropositive pSS were prone to present with systemic involvement and high disease activity. Specific underlying pathogenesis mechanisms and therapeutic strategies in this subgroup needed to be further studied.

Circulating cell-free DNA correlate to disease activity and treatment response of patients with radiographic axial spondyloarthritis.

Microdamage and its related inflammation contribute to the development of radiographic axial spondyloarthritis (r-axSpA). Inflammation and cell death in damaged tissues are associated with cell-free DNA (cfDNA) release. Here we investigated whether circulating cfDNA could be a potential biomarker for evaluating disease activity and treatment response in r-axSpA. Circulating cfDNA was detected in the discovery and validation cohort with 79 and 60 newly diagnosed r-axSpA patients respectively and 42 healthy controls using the Quant-iT PicoGreen dsDNA reagent and kit. As a result, cfDNA levels were significantly higher in r-axSpA patients compared with healthy controls in the discovery and validation cohort. Moreover, cfDNA levels were positively correlated with CRP, ASDAS-CRP and neutrophil counts. Additionally, non-steroid anti-inflammatory drugs (NSAIDs) combined with disease-modifying anti-rheumatic drugs or tumor necrosis factor inhibitors but not NSAIDs alone could reduce cfDNA levels. Moreover, a decrease of cfDNA levels after treatment was associated with an effective therapeutic response. Intriguingly, patients with higher levels of cfDNA at diagnosis responded better to combination therapy rather than NSAIDs. However, patients with lower levels of cfDNA displayed similar responses to combination or mono-NSAID treatment. In conclusion, circulating cfDNA levels showed a significant correlation with disease activity as well as treatment efficacy in patients with r-axSpA. Moreover, cfDNA at diagnosis might predict the response to different therapy. Consequently, cfDNA may serve as a useful biomarker of inflammation in r-axSpA.

Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).

Exploring the role of LIAS-related cuproptosis in systemic lupus erythematosus.

BACKGROUND: Cuproptosis is a novel mode of cell death, which is strongly related to energy metabolism in mitochondria and regulated by protein lipoylation. Currently, the molecular mechanisms of cuproptosis-related genes (CRGs) involved in systemic lupus erythematosus (SLE) largely remained unclear, our study is aimed to explore the mechanisms of cuproptosis and CRGs involved in SLE. METHODS: Bulk RNA-seq datasets were collected to display the expressions of CRGs in peripheral blood mononuclear cells (PBMCs) of SLE and healthy individuals, and then ROC analysis was used to establish the diagnostic models of CRGs. Next, the immune infiltration analyses were applied to reveal the difference of immune cells infiltration in LIAS-low and LIAS-high group. Additionally, WGCNA analysis was performed to find the gene modules significantly correlated with the LIAS expression level. We also performed the functional enrichment analyses for LIAS-related gene modules to determine the potential pathways involved in the development of SLE. Finally, scRNA-seq dataset was used to cluster immune cell subsets, reveal the activated pathways, and study cell-cell interactions in LIAS-low and LIAS-high cells. RESULT: We found CDKN2A was significantly increased and LIAS was significantly decreased in SLE patients compared with healthy individuals. The AUC score showed that LIAS had a great diagnostic value than other CRGs. Additionally, the results of immune infiltration analyses showed that immune cells proportion were diverse in LIAS-low and LIAS-high samples. The gene sets related to LIAS expression level were involved in dephosphorylation of JAK1 by SHP1, phosphorylation of STAT2, cytokine signaling in immune system, expression of interferon-alpha and beta, inhibition of JAK kinase activity by SOCS1/3, and so on. Finally, the results of cell-cell communication showed that CCL- (CCL5 + CCR1) and ANNEXIN- (ANXA1 + FPR1) might play an essential role in the communication network between LIAS-low and LIAS-high cells. CONCLUSION: Above findings inferred that LIAS-mediated cuproptosis might involve in a comprehensive cellular and molecular mechanism to cause the occurrence and development of SLE.

Gαq-PKD/PKCµ signal regulating the nuclear export of HDAC5 to induce the IκB expression and limit the NF-κB-mediated inflammatory response essential for early pregnancy.

Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a successful pregnancy in human. Here, we demonstrated that knockout of Gαq lead to an aberrantly enhanced inflammatory state during decidualization. Furthermore, we showed that deficiency of Gαq resulted in over-activation of nuclear factor (NF)-κB signaling, due to the decreased expression of NFκBIA, which encode the IκB protein and is the negative regulator for NF-κB. Mechanistically, Gαq deficiency decreased the Protein kinase D (PKD, also called PKCµ) phosphorylation levels, leading to attenuated HDAC5 phosphorylation and thus its nuclear export. Aberrantly high level of nuclear HDAC5 retarded histone acetylation to inhibit the induced NFκBIA transcription during decidualization. Consistently, pharmacological activation of the PKD/PKCµ or inhibition of the HDAC5 restored the inflammatory state and proper decidual response. Finally, we disclosed that over-active inflammatory state in Gαq-deficient decidua deferred the blastocyst hatching and adhesion in vitro, and the decidual expression of Gαq was significantly lower in women with recurrent pregnancy loss compared with normal pregnancy. In brief, we showed here that Gαq as a key regulator of the inflammatory cytokine's expression and decidual homeostasis in response to differentiation cues, which is required for successful implantation and early pregnancy.

Phosphorylated signal transducer and activator of transcription proteins 1 in salivary glandular tissue: an important histological marker for diagnosis of primary Sjögren's syndrome.

OBJECTIVES: The pathological diagnostic criteria for primary Sjögren's syndrome (SjS) have certain limitations. We first explored the key pathogenic pathways of SjS through a bioinformatics approach, and then evaluated the diagnostic value of the important biomarker in SjS. METHODS: Transcriptome data from non-SjS controls and patients with SjS were analysed using integrated bioinformatics methods. In a case-control study, phosphorylated signal transducer and activator of transcription proteins 1 (p-STAT1), a key biomarker for the activation of interferon (IFN) pathway, was selected to evaluate its diagnostic value by immunohistochemical analyses in salivary gland (SG) tissues. RESULTS: The IFN-related pathways were aberrantly activated in patients with SjS. Positive staining of p-STAT1 was detected in the SjS group, but not in non-SjS control group. There was a significant difference in the integrated optical density values of p-STAT1 expressions between the controls and the SjS groups, as well as between the controls and the SjS lymphatic foci-negative groups (p<0.05). The area under the curve of the receiver operating characteristic curve for p-STAT1 was 0.990 (95% CI 0.969 to 1.000). There was a significant difference in both accuracy and sensitivity of p-STAT1 compared with the Focus Score (p<0.05). The Jorden index for p-STAT1 was 0.968 (95% CI 0.586 to 0.999). CONCLUSIONS: The IFN pathway is the key pathogenic pathway in SjS. p-STAT1 may serve as an important biomarker, in addition to lymphocytic infiltration, to diagnose SjS. Particularly in SG samples with negative lymphatic foci, p-STAT1 confers pathological diagnostic value.

Regulatory Fibroblast-Like Synoviocytes Cell Membrane Coated Nanoparticles: A Novel Targeted Therapy for Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLS) are the main cell component in the inflamed joints of patients with rheumatoid arthritis (RA). FLS intimately interact with infiltrating T cells. Fibroblasts have potent inhibitory effects on T cells, leading to the resolution of inflammation and immune tolerance. However, this "regulatory" phenotype is defect in RA, and FLS in RA instead act as "proinflammatory" phenotype mediating inflammation perpetuation. Signals that orchestrate fibroblast heterogeneity remain unclear. Here, it is demonstrated that different cytokines can induce distinct phenotypes of FLS. Interferon-gamma (IFN-γ) is pivotal in inducing the regulatory phenotype of FLS (which is termed FLSreg ) characterized by high expressions of several inhibitory molecules. Rapamycin enhances the effect of IFN-γ on FLS. Based on the characteristics of FLSreg , a novel biomimetic therapeutic strategy for RA is designed by coating cell membrane derived from FLSreg induced by IFN-γ and rapamycin on nanoparticles, which is called FIRN. FIRN show good efficacy, stability, and inflammatory joint targeting ability in an RA mouse model. The findings clarify how fibroblast phenotypes are modulated in the inflammatory microenvironment and provide insights into novel therapeutic designs for autoimmune diseases based on regulatory fibroblasts.

Association between antinuclear antibody and female infertility: A meta-analysis.

Autoimmunity is reported involving in reproductive failures, and antinuclear antibody (ANA) positivity has been regarded as a typical feature of autoimmunity. Published studies on the association of ANA with reproductive failures including infertility are controversial. The aim of this meta-analysis was to analyse whether the presence of ANA positivity increases the risk of infertility in women. We searched the PubMed and Embase databases for relevant literature without any restrictions prior to April 28, 2021. All analyses were performed using the RevMan 5.3 software. Twelve studies with 2734 participants, including 1482 patients with infertility, met the inclusion and exclusion criteria. The total positivity rate of ANA was 23.8% (353/1482) in all infertile patients and 8.5% (107/1252) in the control group. Infertile females had a significantly higher ANA positivity rate than the control group (odds ratio [OR] = 2.90, 95% confidence interval [CI]: 1.72-4.87, I2 = 65%, P < .0001). Several subgroup analyses were performed to reduce the heterogeneity. ANA positivity was associated with female infertility in studies either performed by indirect immunofluorescence (OR = 2.26, 95% CI:1.67-3.06, P < .00001) or by ELISA (OR = 10.76, 95% CI:1.82-63.64, P < .00001). ANA was significantly associated with increased risk of women infertility either after the definite exclusion of individuals with autoimmune diseases (AID) or without exclusion [(OR = 1.99, 95% CI:1.29-3.06, P = .002), (OR = 2.76, 95% CI:1.56-4.88, P = .0005), respectively]. This meta-analysis provides a comprehensive overview of the prevalence of antinuclear antibodies (ANA) in infertile women and suggests that ANA positivity increases the risk of infertility.

Expression of CFTR, a hallmark gene of ionocytes, is downregulated in salivary glands of Sjögren's syndrome patients.

INTRODUCTION: The autoimmune exocrinopathy, Sjögren's syndrome (SjS), is associated with secretory defects in salivary glands. The cystic fibrosis transmembrane conductance regulator (CFTR) of the chloride channel is a master regulator of fluid secretion, but its role in SjS has not been investigated. Our research found a link between CFTR and SjS at the genetic and protein levels, as well as through clinical data. METHODS: We used single-cell RNA sequencing to identify the presence of CFTR in glandular epithelial cells of the human salivary gland (scRNA-seq) and confirmed the difference using immunofluorescence tests in labial glands and clinical data statistics from 44 non-SjS and 36 SjS patients. RESULTS: The changes of CFTR expression in salivary glands of SjS patients was assessed at both mRNA and protein levels. According to the scRNA-seq analyses, CFTR was the hallmark gene of ionocytes. We firstly identified that SjS had a lower level of CFTR expression in the labial glands than non-SjS at mRNA level. Using immunofluorescence assays, we also found that CFTR expression was decreased in SjS patients compared to non-SjS. The results of the clinical statistics revealed that CFTR expression was adversely correlated with feelings of dry mouth, lymphocyte infiltration in the labial glands, and certain autoantibodies in serum (antinuclear antibody, anti-Ro/SSA, and anti-La/SSB antibodies). CONCLUSION: Those findings above proved an obviously downregulated expression of CFTR in salivary glands of SjS patients and its clinical significance. Dysfunction in CFTR or ionocytes may contribute to SjS pathogenesis and represents a promising therapeutic target.

High-fat diet-induced intestinal dysbiosis is associated with the exacerbation of Sjogren's syndrome.

Environmental factors are believed to influence the evolution of primary Sjögren's syndrome (pSS). The aims of this study were to investigate the association of pSS with a high-fat diet (HFD) and to relate HFD-induced gut dysbiosis to pSS exacerbation. Male Wild Type (WT) and IL-14α transgenic mice (IL-14α TG) were fed a standard diet (SD) and HFD for 11 months. We found an increase in the autoantibody level, more severe dry eye, severe dry mouth symptoms, and an earlier presence of systemic features in the IL-14α TG mice treated with HFD. These data suggest that HFD can promote the process of pSS in the IL-14α TG mice. In addition, an HFD leads to a decrease in the richness of gut microbiota of IL-14α TG mice treated with HFD. The abundance of Deferribacterota was significantly enriched in the IL-14α TG mice treated with HFD compared with other groups. Through the mental test between gut microbiota and clinical parameters, we found that HFD-induced dysbiosis gut microbiota were associated with pSS clinical parameters. In conclusion, HFD results in the aggravation of pSS progression, likely due to the increase of potentially pathogenic microorganisms.

The serum uric acid is longitudinally related to patients global assessment of disease activity in male patients with axial spondyloarthritis.

OBJECTIVES: To investigate longitudinal relationship between serum uric acid (SUA) and disease activity among Chinese males with axial spondyloarthritis (axSpA). METHODS: Two-year data from the NASA study cohort of male patients with axial spondyloarthritis were analyzed. Patients global assessment of disease activity (PtGA), BASDAI, ASDAS-CRP, BASFI, and SF-36 were used as the outcomes. The autoregressive Generalized Estimation Equation (GEE) model was used to investigate the longitudinal relationship between SUA and the above outcomes. Age and gender and symptom duration were tested as effect modifiers or confounders. RESULTS: In total, 102 male axSpA patients were included, 33.3% of who were hyperuricemia at baseline. Over time,serum uric acid levels associated with the global assessment of patient global assessment of disease activity (PtGA)[P=0.041, ß=-2.059,95%CI(-4.032, -0.086)], SF-36: Vitality (VT) [P=0.01, ß=1.751, 95%CI (0.415,3.087)], SF-36: Social Functioning (SF)[P=0.002, ß= 2.968,95%CI (1.067,4.869)]). And these relationgships were independent of age, symptom duration, baseline uric acid levels, and medication use. CONCLUSIONS: In summary, SUA levels is longitudinally related to PtGA and mental health assessment. Age, gender and symptom duration do not have an impact on the relationships.

Abnormal Changes of Monocyte Subsets in Patients With Sjögren's Syndrome.

Background: Recent studies have proven the existence of distinct monocyte subsets, which play a significant role in the development of some rheumatic diseases such as systemic lupus erythematosus (SLE). This study was performed to define the changes of monocyte subsets in patients with Sjögren's Syndrome (SjS). Methods: Single cell RNA-sequencing (scRNA-seq) data of monocytes from SjS patients and controls were analyzed. The transcriptomic changes in monocyte subsets between SjS and controls were identified and potential key functional pathways involved in SjS development were also explored. Results: A total of 11 monocyte subsets were identified in the scRNA-seq analyses of monocytes. A new monocyte subset characterized by higher expression of VNN2 (GPI-80) and S100A12 (Monocyte cluster 3) was identified, and it was increased in SjS patients. Compared with controls, almost all monocyte subsets from SjS patients had increased expression of TNFSF10 (TRAIL). Moreover, interferon (IFN)-related and neutrophil activation-associated pathways were main up-regulated pathways in the monocytes of SjS patients. Conclusion: This study uncovered the abnormal changes in monocyte subsets and their transcriptomic changes in SjS patients, and identified TNFSF10 high/+ monocytes as a potential key player in SjS pathogenesis and a promising target for SjS treatment.

Meibomian gland alteration in patients with systemic lupus erythematosus.

PURPOSE: To investigate meibomian gland (MG) alteration in patients with systemic lupus erythematosus (SLE). METHODS: This study included 23 SLE patients evaluated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and 21 healthy controls (HCs). All the subjects were evaluated with Ocular Surface Disease Index (OSDI) questionnaire, and the eyes were performed examinations of tear meniscus height (TMH), non-invasive keratographic tear film break-up time (NIKBUT), Schirmer I Test, MG eyelid score, meibography score, and in vivo confocal microscopy (IVCM) on the meibomian gland. RESULTS: There was no significant difference between the SLE patients and the HCs in the TMH, NIKBUT, and Schirmer I Test. However, the SLE patients had higher MG eyelid scores and meibography scores on both upper eyelid and lower eyelid than the HCs. Through meibography observation, 34.8% of the SLE patients presented MG deficiency in Grade 3, whereas that of all the HCs were less than Grade 3. The SLE patients were found to have significant MG atrophy and vascular enrichment around the meibomian glands (MGs). The SLE patients were also found to have excessive inflammatory cell infiltration around the MGs, especially the typical lymph node-like foci of inflammatory cell infiltration. CONCLUSIONS: MG alteration can be found in the SLE patients. Examinations of the MGs can help diagnose or infer ocular diseases at an early stage of SLE.

Abnormal Histones Acetylation in Patients with Primary Sjögren's Syndrome.

INTRODUCTION: Aberrant histone acetylation is increasingly thought to play important roles in the pathogenesis of autoimmune diseases. However, there are very few data on histone acetylation in primary Sjögren's syndrome (pSS). We aimed to investigate whether there was abnormal histones acetylation in patients with pSS. METHODS: We investigated the expressions of histone acetyltransferase (HAT) genes (p300, CREBBP and PCAF) by real-time PCR in the peripheral blood mononuclear cells (PBMCs) of pSS patients. HAT activity and histone H3/H4 acetylation activity were measured by activity kit, and histone H3/H4 acetylation was verified by Western blot (WB). Spearman test was utilized to analyze the association between HAT activity levels and clinical parameters of pSS patients. RESULTS: The mRNA expressions of p300, CREBBP and PCAF in PBMCs from pSS patients were decreased in comparison with healthy controls (P < 0.05). HAT activity and histone H3/H4 acetylation were reduced in PBMCs from pSS patients (P < 0.05). We found that HAT activity was negatively correlated with CRP (P = 0.040) and TNF-α (P = 0.012), and was positively correlated with C4 (P = 0.041). CONCLUSIONS: Histone hypoacetylation is observed in patients with pSS and is involved in the pathogenesis of pSS. KEY POINTS: • The mRNA expressions of p300, CREBBP and PCAF in PBMCs from pSS patients were decreased in comparison with HCs. • HAT activity and histone H3/H4 acetylation were reduced in PBMCs from pSS patients. • HAT activity was correlated with disease characters. • We show for the first time that the histone hypoacetylation may be involved in the pathogenesis of pSS.

Fine Comparison of the Efficacy and Safety Between GB242 and Infliximab in Patients with Rheumatoid Arthritis: A Phase III Study.

INTRODUCTION: This phase III trial (NCT04178850) evaluated the efficacy, safety, and immunogenicity of GB242, an infliximab biosimilar, vs. infliximab (Remicade®) reference product in patients with moderate-to-severe active rheumatoid arthritis (RA) combination with methotrexate (MTX) therapy. METHODS: Patients were randomized in a 1:1 ratio to receive either GB242 or INF (3 mg/kg). Therapeutic equivalence of clinical response according to the American College of Rheumatology 20% (ACR20) response rate at week 30 was declared if the two-sided 95% CI for the treatment difference was within ± 14%. The comparison of GB242 with INF also included the proportion of patients achieving a week 30 ACR 50 response, ACR70 response, change in Disease Activity Score 28 (DAS28), as well as safety and immunogenicity. RESULTS: A total of 570 subjects were randomized into GB242 (N = 285) or INF (N = 285) and 283 subjects in each group were analyzed. At week 30, the ACR20 was 62.54% for the GB242 group (95% CI 56.62-68.20%) and 56.89% for the INF group (95% CI 50.90-62.74%). The difference between the two groups was 5.65% with a 95% CI of - 2.48 to 13.74. ACR50 response was 37.12% for GB242 and 32.86% for INF at week 30. ACR70 response was 19.79% for GB242 and 16.96% for INF at week 30, respectively. The incidence of treatment-emergent adverse events was comparable (77.4% in GB242 vs. 80.2% in INF) and detection of antidrug antibodies (ADA) to infliximab up to week 30 (60.8% in GB242 vs. 59.4% in INF) was comparable. CONCLUSIONS: GB242 demonstrated equivalent efficacy to INF at week 30. Moreover, GB242 was well tolerated, with a similar immunogenicity and safety profile comparable to INF.

Targeted Therapy for Primary Sjögren's Syndrome: Where are We Now?

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy characterized by dryness symptoms. This review briefly describes recent advances in the targeted therapies for pSS. Biologics evaluated for pSS treatment mainly include B cell-depleting agents, inhibitors of B cell activation, and agents that target co-signaling molecules or proinflammatory cytokines. Small molecule inhibitors that target signaling pathways have also been evaluated. However, current evidence for the efficacy of targeted therapies in pSS is still sparse. Although ianalumab (an anti-B cell-activating factor [BAFF]-receptor antibody) and iscalimab (an anti-CD40 antibody) are promising biologics for pSS, their efficacy still needs to be evaluated in larger clinical trials. For other biologics, clinical trials have found no differences versus placebo in the change from baseline in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score and fatigue score. Possible causes of the disappointing outcomes mainly include the inefficacy of those evaluated biologics in treating pSS, the high heterogeneous nature of pSS, irreversible exocrine glandular failure at advanced disease stages, inappropriate recruitment strategy in clinical trials, and outcome measures. Early diagnosis and glandular function-centered outcome measures may help to improve the current situation in the systemic therapy of pSS.