Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. METHODS AND FINDINGS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). TRIAL REGISTRATION: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).

The role of inflammatory biomarkers in the association between rheumatoid arthritis and depression: a Mendelian randomization study.

BACKGROUND: Inflammation may mediate the co-pathogenesis of rheumatoid arthritis (RA) and depression because inflammatory cytokines are associated with RA and depression. However, traditional observational research was not able to address problems with residual confusion and reverse causality. METHODS: We summarized and retrieved 28 inflammatory cytokines associated with RA, depression, or RA with depression through a literature search. The summary statistics from genome-wide association studies for RA, inflammatory biomarkers, broad depression, and major depression disease phenotypes were used. Mendelian randomization was performed to assess the causal association between RA and inflammatory biomarkers, as well as the effects of inflammatory biomarkers on depression. Bonferroni correction was used to reduce the possibility of false positive results. RESULTS: The study found that evidence for associations of genetically predicted RA was associated with higher levels of interleukin (IL)-9 (OR = 1.035, 95%CI = 1.002-1.068, P = 0.027), IL-12 (OR = 1.045, 95%CI = 1.045-1.014, P = 0.004), IL-13 (OR = 1.060, 95%CI = 1.028-1.092, P = 0.0001), IL-20 (OR = 1.037, 95%CI = 1.001-1.074, P = 0.047), and IL-27 (OR = 1.017, 95%CI = 1.003-1.032, P = 0.021). The level of IL-7 (OR = 1.029, 95%CI = 1.018-1.436, P = 0.030) was significantly related to RA. Only the analysis results between RA and IL-13 were satisfied with the statistical significance threshold corrected by Bonferroni (P < 0.002). However, a causal effect was not found between inflammatory biomarkers and depression. CONCLUSIONS: In the current study the inflammatory cytokines associated with RA comorbid depression may not be the mediators that directly lead to the co-pathogenesis of RA and depression.

Nutrients and rheumatoid arthritis: From the perspective of neutrophils.

Neutrophils are considered as core immune cells involve in the early stage of rheumatoid arthritis (RA) and participate in the disease progression. The underlining mechanisms include the elevated chemotaxis and infiltration of neutrophils, the increase in the reactive oxygen species and the promotion of neutrophil extracellular traps formation. Accumulating studies demonstrated the important role of nutrients intake played in the initiation and progression of RA. This study summarized the effects of several macronutrients and micronutrients on regulating RA through the modulation of activated neutrophils and appealed for a healthy diet in RA-risk individuals as well as RA patients.

Radiological Characteristics of Patients With Anti-MDA5-Antibody-Positive Dermatomyositis in 18F-FDG PET/CT: A Pilot Study.

Objective: To elucidate the 18F-fluorodeoxyglucose (FDG) PET/CT characteristics and its prognostic value in the patients with anti-melanoma differentiation associated protein 5 antibody positive (anti-MDA5+) dermatomyositis (DM). Methods: This retrospective cross-sectional study included 26 patients with anti-MDA5+ DM and 43 patients with anti-MDA5 negative (anti-MDA5-) idiopathic inflammatory myopathy (IIM) who were examined by 18F-FDG PET/CT from January 1, 2017 to December 31, 2020. The maximum standardized uptake value (SUVmax) of multiple organs and other clinical characteristics of the patients were measured and analyzed. Results: Compared with the anti-MDA5- group, the patients in the anti-MDA5+ group showed higher bilateral lung SUVmax (p = 0.029), higher SUVmax of spleen (p = 0.011), and bone marrow (p = 0.048). Significant correlations between the spleen SUVmax and serum ferritin levels (r = 0.398, p < 0.001), erythrocyte sedimentation rate (ESR) (r = 0.274, p = 0.023), platelet count (r = -0.265, p= 0.028), myositis disease activity assessment score (r = 0.332, p = 0.005), bone marrow SUVmax (r = 0.564, p < 0.001), and bilateral lung SUVmax (r = 0.393, p < 0.001) were observed. Conclusion: 18F-FDG PET/CT was found valuable in quantifying the pulmonary focal inflammation and potentially unveil the distinctive characteristics and pathophysiological mechanisms in the patients with anti-MDA5+ DM.

The Salivary Microbiota, Cytokines, and Metabolome in Patients with Ankylosing Spondylitis Are Altered and More Proinflammatory than Those in Healthy Controls.

The pathogenesis of ankylosing spondylitis (AS) remains unclear but appears to be associated with heredity and the environment. The mouth links the external environment to the gut and lungs. In the present study, compared to that observed in healthy controls (HCs), AS saliva was depleted of Bacilli such as Streptococcus, enriched with Clostridia such as Veillonellaceae, and enriched with opportunistic pathogens from Proteobacteria such as Brucella spp. and Campylobacter concisus. AS saliva was enriched with 16 cytokines related to inflammation, such as soluble IL-6 receptor α (sIL-6Rα), interleukin 2 (IL-2), IL-10, IL-11, IL-12p40, IL-12p70, IL-20, IL-26, IL-27, IL-28A, IL-29, alpha 2 interferon (IFN-α2), IFN-ß, and matrix metalloproteinase 3 (MMP-3). AS saliva was also enriched with hazardous compounds, such as cadaverine and putrescine. AS-altered salivary bacteria, compounds, and cytokines are closely linked with disease indicators. Oral cleaning reduced the levels of proinflammatory cytokines and hazardous compounds in AS saliva compared with HC saliva. AS saliva induced the production of more proinflammatory cytokines, such as IL-12p70 and IL-8, by THP-1 monocyte-derived macrophages, than did HC saliva. The results highlight the importance of salivary microbes, cytokines, and compounds in the development and treatment of AS and provide new ideas for the pathogenesis and treatment of AS. IMPORTANCE Ankylosing spondylitis (AS) affects as much as 0.32% of the population in some districts and causes work disability in one-third of these patients. Microbes are considered to play important roles in AS pathogenesis, and the mouth links the environment to the lungs and the gut. Our results showed that opportunistic pathogens such as Brucella and Campylobacter are enriched in the saliva of AS patients with ankylosing spondylitis. In addition, proinflammatory cytokines and hazardous materials such as putrescine were also enriched in the saliva of AS patients.[AQ1 sentence edit] Interestingly, the opportunistic pathogens and hazardous materials detected in the saliva of AS patients were associated with disease indexes. The saliva of AS patients was shown to induce immune cells to secrete proinflammatory cytokines in vitro. Reducing the levels of salivary microbes can significantly reduce the hazardous materials present in the saliva of AS patients. Our results provide a new perspective on the potential role of salivary microbes, cytokines, and hazardous compounds in the pathogenesis and treatment of AS.

Features and Outcomes of Elderly Rheumatoid Arthritis: Does the Age of Onset Matter? A Comparative Study From a Single Center in China.

INTRODUCTION: The aim of this work is to investigate the clinical and radiological characteristics of elderly rheumatoid arthritis and compare the outcomes between the two subgroups, elderly- and young-onset rheumatoid arthritis (EORA and YORA, respectively). METHODS: We conducted a retrospective case-control study on the elderly rheumatoid arthritis patients in our medical center. EORA was defined as the patient whose onset age was above 60. RESULTS: A total of 142 elderly rheumatoid arthritis patients were admitted, with 79 patients in EORA and 63 in YORA group. Inflammatory parameters including C-reactive protein, D-dimer, serum ferritin, and platelet count levels were all higher in the EORA group than those in YORA. EORA patients showed a higher score of health assessment questionnaire's disability index (p = 0.01) and patient global health assessment (p = 0.049), but a lower status of modified total sharp score (p = 0.001). Bivariate logistic regression analysis revealed that elderly onset of the disease (OR 2.30, 95% CI [1.45-3.77]), age (OR 2.04, 95% CI [1.22-3.41]), high disease activity (OR 1.90, 95% CI [1.17-3.32]), and red blood cell distribution width (OR 1.81, 95% CI [1.03-3.19]) were independent prognostic factors of disability. Age (OR 0.25, 95% CI [0.07-0.91]), disease duration (OR 2.73, 95% CI [0.97-7.70]), and co-morbid diabetes mellitus (OR 118.10, 95% CI [3. 50-3985.57]) independently contributed to radiographic joint damage in the elderly population. EORA patients showed increased death incidents and worse prognosis than YORA. Cox regression analysis reveals that comorbid hypertension (HR 12.02, 95% CI [1.08-133.54]), interstitial lung disease (ILD) (HR 85.04, 95% CI [4.11-1759.19]), and compressive fracture (HR 85.04, 95% CI [4.11-1759.19]) are independent predictors of mortality, and that ILD (HR 50.21, 95% CI [5.56-335.33]) and pulmonary hypertension (HR 25.37, 95% CI [3.03-265.81]) are independent predictors of no disease remission in the EORA patients. CONCLUSIONS: The distinct features of EORA patients make EORA a unique entity different from "classic rheumatoid arthritis". EORA patients develop an upgraded systemic inflammatory status, more declined life quality, and worse prognosis than the elderly YORA. Better control of the comorbidities like ILD and diabetes mellitus may benefit the management of elderly rheumatoid arthritis. Further investigation regarding the pathogenesis and therapeutic strategies of EORA is urgently warranted.

Overproduced bone marrow neutrophils in collagen-induced arthritis are primed for NETosis: An ignored pathological cell involving inflammatory arthritis.

OBJECTIVES: Bone marrow edema is a universal manifestation of rheumatoid arthritis (RA), and its pathological essence is a bone marrow lesion (BML) formed by various bone marrow (BM) immune cells. Neutrophils play an important role in inflammatory arthritis, but the role and mechanism of neutrophils in BML are not clear. MATERIALS AND METHODS: Granulocyte colony-stimulating factor (G-CSF) -/- mice and wild type (WT) C57BL/6 mice were immunized for collagen-induced arthritis (CIA). Histological scores of arthritis were evaluated. Immunohistochemistry staining with anti-Ly6G was conducted. Neutrophil extracellular traps (NETs) in joint sections were determined by immunofluorescence staining. BM neutrophils were isolated for flow cytometry and NETosis induction in vitro. RESULTS: Histological study showed significant neutrophil infiltrations in BML of CIA mice. Inhibition of BM neutrophil production by G-CSF knock out can obstruct the induction of BML and CIA. In addition to abundant infiltrated NETs intra-articular, remarkable NETosis primed BM neutrophils were infiltrated in BML of CIA mice, which was positively related to bone erosion. Neutrophils derived from G-CSF-/- mice have diminished ability of NETs formation in vitro, while G-CSF induction can enhance its capacity of NETs formation. CONCLUSIONS: We propose for the first time that the overproduced BM neutrophils in CIA mice are primed for NETosis in a G-CSF dependent manner, and these pathogenic cells may have an important role in inflammatory arthritis. Blocking this pathological process could be a potential strategy for the treatment of RA.

Circulating microRNA let­7e is decreased in knee osteoarthritis, accompanied by elevated apoptosis and reduced autophagy.

Knee osteoarthritis (KOA) is a major cause of leg disability in the elderly population. Recently, the expression levels of circulating microRNA (miRNA) let­7e have been reported to be significantly reduced in KOA. The aims of the present study were to assess the feasibility of let­7e as a serum marker for detecting KOA and to explore the underlying mechanisms of its involvement. Based on previous studies and bioinformatics analysis, let­7e may regulate apoptosis and autophagy of articular chondrocytes. A total of 10 patients with KOA and 10 patients with trauma without KOA were recruited to examine the levels of let­7e in peripheral blood. Subsequently, KOA rat models were established, and the levels of let­7e in the cartilage and serum were examined, the expression of apoptotic proteins and autophagy­related proteins in the cartilage were investigated, and apoptotic and autophagic activities of primary cultured chondrocytes were also detected. In patients with KOA, let­7e levels in the peripheral serum were significantly decreased compared with the control group, and this result was confirmed in the peripheral serum and cartilage of KOA rats. In addition, the expression levels of proteins involved in the apoptotic pathway were increased in the cartilage of KOA rats, and apoptotic activity was increased. The expression of autophagy­related proteins beclin 1 and microtubule associated protein 1 light chain 3 ß (LC3B) II/LC3BI in the articular cartilage of KOA rats was lower compared with the controls, and autophagy was decreased. Si­Miao­San (SMS) treatment restored the expression of let­7e and reversed the changes in apoptosis and autophagy. Therefore, the present study provided additional evidence that circulating let­7e may be a potential serum biomarker for the diagnosis and treatment of KOA. Elevated apoptosis levels and decreased autophagy levels of cartilage tissue are involved in KOA, and treatment with SMS may reverse these effects.

Hemophagocytic Lymphohistiocytosis: Prevalence, Risk Factors, Outcome, and Outcome-related Factors in Adult Idiopathic Inflammatory Myopathies.

OBJECTIVE: To clarify the prevalence, risk factors, outcome, and outcome-related factors of hemophagocytic lymphohistiocytosis (HLH) in patients with dermatomyositis (DM), polymyositis (PM), or clinically amyopathic dermatomyositis (CADM). METHODS: Data of patients with DM, PM, or CADM who were admitted to the First Affiliated Hospital of Zhejiang University from February 2011 to February 2019 were retrospectively collected. Patients diagnosed with HLH constituted the case group. A 1:4 case-control study was performed to identify risk factors for HLH in patients with DM, PM, or CADM through comparison, univariate, and multivariate logistic regression analysis. Intragroup comparison was made among patients with HLH to identify factors influencing unfavorable short-term outcome. RESULTS: HLH was a rare (4.2%) but fatal (77.8%) complication in patients with DM, PM, or CADM. The retrospective case-control study revealed that higher on-admission disease activity (p = 0.008), acute exacerbation of interstitial lung disease (AE-ILD, p = 0.002), and infection (p = 0.002) were risk factors for complication of HLH in patients with DM, PM, or CADM. The following intragroup comparison showed that higher on-admission disease activity (p = 0.035) and diagnosis of CADM (p = 0.039) might influence the short-term outcome of patients with HLH. However, no risk factor was identified after false discovery rate correction. CONCLUSION: In this study, secondary HLH was a fatal complication, with higher on-admission disease activity, AE-ILD, and infection working as risk factors. The underlying role of infection and autoimmune abnormality in HLH in connective tissue disease was subsequently noted. Clinical factors influencing the short-term outcome of patients with secondary HLH require further study.

Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes.

OBJECTIVE: Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). METHODS: The proliferation of RA-FLSs was assessed by 5-ethynyl-2'-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. RESULTS: Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. CONCLUSIONS: Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs.

PKM2: A Potential Regulator of Rheumatoid Arthritis via Glycolytic and Non-Glycolytic Pathways.

Immunometabolism provides a new perspective on the pathogenesis of rheumatoid arthritis (RA). In recent years, there have been investigations focusing on the role of intracellular glucose metabolism in the pathogenesis of RA. Previous studies have shown that glycolysis of synovial tissue is increased in RA patients, while glycolysis inhibitors can significantly inhibit synovitis. Pyruvate kinase (PK) is a key enzyme in glycolysis, catalyzing the final rate-limiting step in the process. An isoform of PK, PKM2, provides favorable conditions for the survival of tumor cells via its glycolytic or non-glycolytic functions and has become a potential therapeutic target in tumors. RA synovium has the characteristic of tumor-like growth, and, moreover, increased expression of PKM2 was identified in the synovial tissue of RA patients in recent studies, indicating the underlying role of PKM2 in RA. PKM2 has potential value as a new therapeutic target or biomarker for RA, but its exact role in RA remains unclear. In this review, the properties of PKM2 and existing research concerning PKM2 and RA are thoroughly reviewed and summarized, and the possible role and mechanism of PKM2 in RA are discussed.

Combined immunosuppressive treatment (CIST) in lupus nephritis: a multicenter, randomized controlled study.

OBJECTIVES: The standard strategy for treating lupus nephritis comprises glucocorticoids together with either intravenous cyclophosphamide or oral mycophenolate mofetil, but the low remission rate is still a challenge in practice. This study was aimed to seek higher remission rate of lupus nephritis using a combined strategy. METHOD: A 24-week trial was conducted in 17 rheumatology or nephrology centers in China. A total of 191 lupus nephritis patients were randomized to follow a combined immunosuppressive treatment (CIST) with intravenous cyclophosphamide, an oral immunosuppressive agent, namely mycophenolate mofetil, azathioprine or leflunomide, and hydroxychloroquine (n = 95), or receive intravenous cyclophosphamide alone (n = 96) for 24 weeks. Glucocorticoid was given to both groups. The primary end point was a complete remission with a most stringent standard as proteinuria < 150 mg per 24 h, normal urinary sediment, serum albumin, and renal function at 24 weeks. The secondary end point was treatment failure at 24 weeks. RESULTS: At week 24, both the rate of complete remission (39.5%) and total response (87.2%) was higher in the combined group, compared with CYC group (20.8% and 68.8%, p < 0.05). The cumulative probability of complete remission was also higher in the combined group (p = 0.013). In addition, the combined treatment was superior to routine CYC with less treatment failure (12.8% vs.31.2%, p < 0.001). No difference was found between the incidences of severe adverse events in the two arms: 3.2% (3/95 combined group) vs.4.2% (4/96 CYC group). CONCLUSION: Treatment with a combined immunosuppressive agent is superior to routine CYC only therapy in lupus nephritis.

Whether innate immune together with genetic factor are involved in leukemic arthritis?: A case report and review of the literature.

We report a case of leukemic arthritis (LA) of monocytic differentiation, which presented with spondyloarthritis-like symptoms and a positive human leukocyte antigen-B27, and discuss its potential mechanisms.The patient was admitted because of pain in her right knee and lower back for 18 months. Magnetic resonance imaging showed diffuse hyperintense signal in the bilateral liac bones and bone marrow edema and synovitis in the right knee.The diagnosis of acute monocytic leukemia and LA were concluded by bone marrow aspiration and flow cytometry of the synovial fluid.The patient had poor response to nonsteroidal anti-inflammatory drugs. One week after she received chemotherapy, the symptoms were dramatically relieved.For 5-year follow-up, she got clinical remission without suffering pain of the right knee and the lower back.Leukemic arthritis is a rare manifestation of leukemia with unknown mechanism and may be the initial presentation of leukemia. The problem whether abnormal immune response of the neoplasitc monocytes together with hereditary factors contribute to the pathogenesis of LA in adult is raised from this case, which worth further research.

Acute lymphocytic leukemia mimicking spondyloarthritis in an adolescent: A case report and review of the literature.

The present study describes the case of an 18-year-old adolescent male exhibiting acute lymphocytic leukemia (ALL), complicated by the onset of the symptom of sacroiliitis mimicking spondyloarthritis. Atypical features including an enlarged spleen, poor effects of non-steroidal anti-inflammatory drug therapy, low levels of hemoglobin, a low platelet count, a low neutrophil count and increased levels of monocytes, indicated the possibility of hematological malignancy. Bone marrow examination confirmed the diagnosis of ALL. The patient received chemotherapy and the symptoms were dramatically relieved. To the best of our knowledge, the current study reports the second published case of a patient with ALL presenting with sacroiliitis. Sacroiliitis as an onset manifestation of ALL may result in misdiagnosis, therefore, a differential diagnosis is essential when atypical features are present.

Local and Systemic IKKε and NF-κB Signaling Associated with Sjögren's Syndrome Immunopathogenesis.

The activated NF-κB signaling pathway plays an important role in pathogenesis of primary Sjögren's syndrome (pSS). The inhibitor of κB (IκB) kinase (IKK) family such as IKKα, IKKß, IKKγ, and IKKε, is required for this signaling. Our aim was to investigate the role of IKKα/ß/γ/ε in patients with untreated pSS. In minor salivary glands from pSS patients, phosphorylated IKKε (pIKKε), pIκBα, and pNF-κB p65 (p-p65) were highly expressed in ductal epithelium and infiltrating mononuclear cells by immunohistochemistry, compared to healthy individuals. pIKKα/ß and pIKKγ were both negative. And pIKKε positively related to expression of p-p65. Furthermore, pIKKε and p-p65 expression significantly correlated with biopsy focus score and overall disease activity. Meanwhile, in peripheral blood mononuclear cells from pSS patients, pIKKε, total IKKε, pIKKα/ß, and p-p65 were significantly increased by western blot, compared to healthy controls. However, there was no difference in IKKγ and IκBα between pSS patients and healthy individuals. These results demonstrated an abnormality of IKKε, IκBα, and NF-κB in pSS, suggesting a potential target of treatment for pSS based on the downregulation of IKKε expression and deregulation of NF-κB pathway.