Characteristics of patients with psoriatic arthritis in Korea: focusing on axial involvement.

BACKGROUND/AIMS: We aimed to clarify the clinical characteristics of psoriatic arthritis (PsA) in Korean patients focusing on PsA with axial involvement. METHODS: A retrospective medical chart review was performed to identify PsA patients at a single tertiary center. Cases of AS patients with psoriasis were recruited from a prospective AS registry of the same center. Demographics, laboratory findings, and radiologic characteristics were assessed. RESULTS: A total of 69 PsA patients were identified. In PsA patients, spondylitis (46.4%) was the most common form. Compared to AS patients with psoriasis, PsA patients with radiographic axial involvement were older (50.9 vs. 32.4 years; p < 0.001) and showed greater peripheral disease activity (peripheral arthritis 78.1 vs. 12.5%, p < 0.001; enthesitis 50.0 vs. 6.3%, p = 0.003). AS patients with psoriasis presented a higher rate of HLA-B*27 positivity (81.3 vs. 17.2%; p < 0.001) and a more frequent history of inflammatory back pain (100.0 vs. 75.0%; p = 0.039) than PsA patients with radiographic axial involvement. Significant proportions of PsA patients with radiographic axial involvement had cervical spine involvement (10/18, 55.6%) and spondylitis without sacroiliitis (10/23, 43.5%). CONCLUSION: We demonstrate that axial involvement is common in Korean PsA patients, and its characteristics can be distinct from those of AS.

Comparative effectiveness of JAK inhibitors and biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

BACKGROUND/AIMS: We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. METHODS: A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)-28- erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). RESULTS: Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. CONCLUSION: Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

Mesenchymal Stem/Stromal Cell-Based Therapies in Systemic Rheumatic Disease: From Challenges to New Approaches for Overcoming Restrictions.

Systemic rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, are chronic autoimmune diseases affecting multiple organs and tissues. Despite recent advances in treatment, patients still experience significant morbidity and disability. Mesenchymal stem/stromal cell (MSC)-based therapy is promising for treating systemic rheumatic diseases due to the regenerative and immunomodulatory properties of MSCs. However, several challenges need to be overcome to use MSCs in clinical practice effectively. These challenges include MSC sourcing, characterization, standardization, safety, and efficacy issues. In this review, we provide an overview of the current state of MSC-based therapies in systemic rheumatic diseases, highlighting the challenges and limitations associated with their use. We also discuss emerging strategies and novel approaches that can help overcome the limitations. Finally, we provide insights into the future directions of MSC-based therapies for systemic rheumatic diseases and their potential clinical applications.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Can whole spine magnetic resonance imaging predict radiographic progression and inflammatory activity in axial spondyloarthritis?

OBJECTIVE: To investigate whether initial whole spine magnetic resonance imaging (MRI) predicts radiographic progression and inflammatory activity in patients with axial spondyloarthritis (axSpA). METHODS: A retrospective analysis of spine MRI and X-rays from 70 axSpA patients was conducted. The number of affected discovertebral units was determined according to the definition of pathologic lesions on spine MRI set down by the ASAS/OMERACT group. Radiographic progression was defined as an increase in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) of≥2 compared with baseline. The association of spine MRI with radiographic progression, cumulative C-reactive protein (CRP), and cumulative erythrocyte sedimentation rate (ESR) was investigated. RESULTS: The axSpA-relevant lesions on spine MRI at baseline were independent predictors of radiographic progression. Arthritis of the costovertebral and costotransverse joints on MRI showed the highest odds ratio at 3years (OR [95% CI]: 2.54 [1.29-5.02]). Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) for radiographic progression at 2years was 0.89 [95% CI: 0.81-0.96] for structural lesions and 0.83 [95% CI: 0.72-0.94] for inflammatory lesions. Notably, subgroup analysis of 26 patients with mSASSS=0 showed that fatty metaplasia on MRI were highly predictive of radiographic progression at 3years (AUC [95% CI]: 0.87 [0.61-1.00]). Moreover, 3-year cumulative ESR and CRP values increased in proportion to the extent of inflammatory lesions on initial MRI. CONCLUSION: Initial MRI assessment of the whole spine may predict radiographic progression and subsequent systemic inflammatory burden in axSpA patients, particularly those without axSpA-relevant abnormalities on spine X-rays.

Chronic kidney disease in Korean patients with lupus nephritis: over a 35-year period at a single center.

INTRODUCTION: Chronic kidney disease (CKD) is a major risk factor for overall morbidity and mortality even in lupus nephritis (LN) patients. However, less attention has been paid to the development of CKD in patients with LN. The objective of this study was to identify predictors for CKD with 35-year experience depending on newly revised guidelines for patients with LN. METHODS: We conducted a retrospective cohort study for 401 patients who visited Seoul St. Mary's Hospital between January 1985 and December 2019. We analyzed clinical and laboratory indices, treatment response, the final renal function, and biopsy findings. The timing and cumulative risk of developing CKD were identified by Kaplan-Meier methods. Independent risk factors for developing CKD were examined by Cox proportional hazard regression analyses. RESULTS: The median follow-up time after the diagnosis of LN was 131 months. CKD occurred in 15.5% of patients within 10 years after the diagnosis of LN. The development of CKD was associated with delayed-onset LN, acute renal dysfunction at onset of LN, and failure to reach complete response (CR) at 6 or 12 months rather than histopathological findings or the severity of proteinuria at onset of LN. Cumulative incidence of progression to CKD was significantly higher in patients with the three predictors mentioned above. CONCLUSION: Ten-year cumulative incidence of CKD was about 15%. Our results showed that delayed-onset LN, acute renal dysfunction at the onset of LN, and inadequate treatment response assessed at 6 or 12 months after treatment were predictors for the development of CKD in LN. Key Points • CKD is a major risk factor for overall morbidity and mortality in LN patients. • Ten-year cumulative incidence of CKD was about 15% • Delayed-onset LN, acute renal dysfunction at the onset of LN, and inadequate treatment response assessed at 6 or 12 months after treatment were predictors for the development of CKD in LN.

B Cell-Specific Deletion of CR6-Interacting Factor 1 Drives Lupus-like Autoimmunity by Activation of Interleukin-17, Interleukin-6, and Pathogenic Follicular Helper T Cells in a Mouse Model.

OBJECTIVE: CR6-interacting factor 1 (CRIF1) is a nuclear transcriptional regulator and a mitochondrial inner membrane protein; however, its functions in B lymphocytes have been poorly defined. This study was undertaken to investigate the effects of CRIF1 on B cell metabolic regulation, cell function, and autoimmune diseases. METHODS: Using mice with B cell-specific deletion of CRIF1 (Crif1ΔCD19 mice), we assessed the relevance of CRIF1 function for lupus disease parameters, including anti-double-stranded DNA (anti-dsDNA), cytokines, and kidney pathology. RNA sequencing was performed on B cells from Crif1ΔCD19 mice. The phenotypic and metabolic changes in immune cells were evaluated in Crif1ΔCD19 mice. Roquinsan/+ mice crossed with Crif1ΔCD19 mice were monitored to assess the functionality of CRIF1-deficient B cells in lupus development. RESULTS: Crif1ΔCD19 mice showed an autoimmune lupus-like phenotype, including high levels of autoantibodies to dsDNA and severe lupus nephritis with increased mesangial hypercellularity. While loss of CRIF1 in B cells showed impaired mitochondrial oxidative function, CRIF1-deficient B cells promoted the production of interleukin-17 (IL-17) and IL-6 and was more potent in helping T cells develop into follicular helper T cells. In a mouse model of autoimmune lupus, depletion of CRIF1 in B cells exacerbated lupus severity, and CRIF1 overexpression prevented lupus development in roquinsan/san mice. CONCLUSION: These results demonstrated that CRIF1 negatively correlates with disease severity and that overexpression of CRIF1 ameliorates disease development. Our findings suggest that CRIF1 is essential for preventing lupus development by maintaining B cell self tolerance.

Postnatal regulation of B-1a cell development and survival by the CIC-PER2-BHLHE41 axis.

B-1 cell development mainly occurs via fetal and neonatal hematopoiesis and is suppressed in adult bone marrow hematopoiesis. However, little is known about the factors inhibiting B-1 cell development at the adult stage. We report that capicua (CIC) suppresses postnatal B-1a cell development and survival. CIC levels are high in B-1a cells and gradually increase in transitional B-1a (TrB-1a) cells with age. B-cell-specific Cic-null mice exhibit expansion of the B-1a cell population and a gradual increase in TrB-1a cell frequency with age but attenuated B-2 cell development. CIC deficiency enhances B cell receptor (BCR) signaling in transitional B cells and B-1a cell viability. Mechanistically, CIC-deficiency-mediated Per2 derepression upregulates Bhlhe41 levels by inhibiting CRY-mediated transcriptional repression for Bhlhe41, consequently promoting B-1a cell formation in Cic-null mice. Taken together, CIC is a key transcription factor that limits the B-1a cell population at the adult stage and balances B-1 versus B-2 cell formation.

Hypergammaglobulinaemia predicts glandular and extra-glandular damage in primary Sjögren's syndrome: results from the KISS cohort study.

OBJECTIVES: To investigate whether temporal changes in immunoglobulin (Ig) levels and persistent hypergammaglobulinaemia cause glandular and extra-glandular damage in patients with primary Sjögren's syndrome (pSS). METHODS: Cumulative demographics and clinical and serological data from pSS patients in the Korean Initiative pSS cohort were evaluated. Persistent hypergammaglobulinaemia was defined as mean IgG levels of ≥1600 mg/dL over 3 years. Salivary gland damage was assessed by measuring salivary flow impairment, and lacrimal gland damage was assessed by examining ocular structural abnormalities. Solid organ damage included neurological and pleuropulmonary damage, renal impairment and lymphoproliferative disease. Independent predictors of glandular and extra-glandular damage in the third year were identified by logistic regression. RESULTS: Of 256 patients with pSS (median age, 55 years; 98% female), 47% had hypergammaglobulinaemia at baseline. IgG levels fell during the first 2 years in patients with hypergammaglobulinaemia at baseline, but not in those with normal IgG levels. Changes in IgG levels were associated with hydroxychloroquine and glucocorticoids. In the third year of follow-up, salivary flow impairment and solid organ damage were present in 71% and 9% of patients, respectively. After adjusting for age and medication use, persistent hypergammaglobulinaemia was associated with salivary flow impairment and solid organ damage in the third year. Patients in whom IgG fell by more than 80 mg/dL from baseline over 2 years showed less solid organ damage. CONCLUSIONS: Persistent hypergammaglobulinaemia was associated with salivary gland and solid organ damage. Decreased IgG may attenuate progression to solid organ dysfunction.

Programmed Death-Ligand 1 Expression Potentiates the Immune Modulatory Function Of Myeloid-Derived Suppressor Cells in Systemic Lupus Erythematosus.

Multiple studies have explored the potential role of programmed death-ligand 1 (PD-L1) as a mediator of Myeloid-derived suppressor cells (MDSCs) effects in various cancers. However, the role PD-L1 expression in MDSCs on autoimmune disease is still largely unknown.This study was undertaken to whether MDSC expressing PD-L1 have more potent immunoregulatory activity and control autoimmunity more effectively in two murine models of lupus (MRL/lpr mice and Roquinsan/san mice). The populations of MDSC were increased in peripheral blood of lupus patients. The mRNA levels of immunosuppressive molecules were profoundly decreased in MDSCs from lupus patients and mice. Co-culture with splenocytes showed that PD-L1 expressing MDSCs from control mice expand both Treg cells and regulatory B cells more potently. Infusion of PD-L1 expressing MDSCs reduced autoantibody levels and degree of proteinuria and improved renal pathology of two animal models of lupus. Moreover, PD-L1 expressing MDSCs therapy can suppress double negative (CD4-CD8-CD3+) T cells, the major pathogenic immune cells and follicular helper T cells in MRL/lpr mice, and podocyte damage. Our results indicate PD-L1 expressing MDSCs have more potent immunoregualtory activity and ameliorate autoimmunity more profoundly. These findings suggest PD-L1 expressing MDSCs be a promising therapeutic strategy targeting systemic autoimmune diseases.

Four-year follow-up of atherogenicity in rheumatoid arthritis patients: from the nationwide Korean College of Rheumatology Biologics Registry.

OBJECTIVE: This study aimed to evaluate the impact of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) on lipid profile and atherogenic index of plasma (AIP) in rheumatoid arthritis (RA) patients and to compare the occurrence of dyslipidemia between patients using bDMARDs, tsDMARDs, or conventional DMARDs (cDMARDs). METHODS: Data on lipid profile, AIP, and occurrence of dyslipidemia were collected from the Korean College of Rheumatology BIOlogics registry. A comparison was conducted between patients using bDMARDs (tumor necrosis factor (TNF)-α inhibitor, tocilizumab, abatacept), Janus kinase inhibitors (JAKis), and cDMARDs. The Kaplan-Meier method was used to compare the occurrence of dyslipidemia between groups, and hazard ratios (HR) were calculated using the cox proportional hazard method. RESULTS: The data of 917, 826, 789, 691, and 520 RA patients were eligible for analysis at the baseline, 1-year, 2-year, 3-year, and 4-year follow-ups, respectively. Baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were higher in the cDMARDs group, whereas AIP was comparable. During the 4-year follow-up, AIP was comparable between the groups. The occurrence of dyslipidemia did not show a significant difference when comparing the bDMARDs/tsDMARDs and cDMARDs groups (P=0.06) or the TNF-α inhibitor, tocilizumab, abatacept, JAKi, and cDMARD user groups (P=0.3). In the multivariate cox proportional hazard model, older age (HR=1.03, P=0.005) and concomitant hypertension (HR=2.21, P=0.013) were significantly associated with dyslipidemia occurrence. CONCLUSION: Long-term use of bDMARDs and tsDMARDs is relatively safe with regard to lipid profile, AIP, and the occurrence of dyslipidemia in RA patients. Key Points • The use of bDMARDs and tsDMARDs did not increase the risk of dyslipidemia than cDMARDs use in patients with RA. • AIP was comparable between bDMARDs user, tsDMARDs user, and cDMARDs user group in 4-year follow-up data. • Based on the present study, the long-term use of bDMARDs or tsDMARDs did not significantly deteriorate atherogenic lipid profile nor an increased risk of dyslipidemia in patients with RA.

Type I Interferon Increases Inflammasomes Associated Pyroptosis in the Salivary Glands of Patients with Primary Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic and systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine glands. In SS, type I IFN has a pathogenic role, and recently, inflammasome activation has been observed in both immune and non-immune cells. However, the relationship between type I IFN and inflammasome-associated pyroptosis in SS has not been studied. We measured IL-18, caspase-1, and IFN-stimulated gene 15 (ISG15) in saliva and serum, and compared whether the expression levels of inflammasome and pyroptosis components, including absent in melanoma 2 (AIM2), NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, gasdermin D (GSDMD), and gasdermin E (GSDME), in minor salivary gland (MSG) are related to the expression levels of type I IFN signature genes. Expression of type I IFN signature genes was correlated with mRNA levels of caspase-1 and GSDMD in MSG. In confocal analysis, the expression of caspase-1 and GSDMD was higher in salivary gland epithelial cells (SGECs) from SS patients. In the type I IFN-treated human salivary gland epithelial cell line, the expression of caspase-1 and GSDMD was increased, and pyroptosis was accelerated in a caspase-dependent manner upon inflammasome activation. In conclusion, we demonstrate that type I IFN may contribute to inflammasome-associated pyroptosis of the SGECs of SS patients, suggesting another pathogenic role of type I IFN in SS in terms of target tissue -SGECs destruction.

Male patients with primary Sjögren's syndrome: A distinct clinical subgroup?

AIM: Because the clinical and immunologic phenotypes of male primary Sjögren's syndrome (pSS) patients have not been fully elucidated, we aimed to investigate the clinical characteristics of male patients with pSS in Korea. METHODS: We retrospectively evaluated the medical records of male patients with pSS, who visited Seoul St. Mary's Hospital, a tertiary referral center in Korea, between January, 2015 and December, 2019. Of a total of 1107 patients with pSS, 33 were male, which is a prevalence of 2.9%. These 33 were compared with 353 female patients as a control group, whose records were extracted from the database of the Korean Initiative of Primary Sjögren's Syndrome, our nationwide pSS database. Various clinical aspects were assessed, including secretory functions, extra-glandular manifestations (EGM), disease activity-measuring indices, and hematological and serological variables. RESULTS: Male patients were less likely to complain of xerophthalmia and xerostomia and presented with fewer patient-reported disease outcomes and glandular dysfunctions as compared with female patients. White blood cell and neutrophil counts and the seropositivity of anti-ribonucleoprotein antibody were higher in male patients than in their female counterparts, whereas anti-Ro/SSA antibody and rheumatoid factor were less concentrated in sera from male patients. Pulmonary involvement and lymphoma were seen more frequently in male patients. Among other EGMs, female patients had a higher prevalence of autoimmune thyroid diseases. CONCLUSIONS: Male patients with pSS present less severe glandular dysfunctions, better patient-reported disease outcomes, and a higher prevalence of pulmonary involvement and lymphoma compared to females, suggesting distinct clinical phenotypes of pSS.

Positive histopathologic assessment in salivary glands shows little impact on clinical features of established primary Sjögren's syndrome in a Korean population.

OBJECTIVES: The presence and severity of focal lymphocytic sialadenitis in minor salivary glands is a pathognomonic feature in primary Sjögren's syndrome (pSS). However, it has not been determined whether performing minor salivary gland biopsy (MSGB) in a setting of serologically and clinically established pSS provides additional clinical value. Therefore, we aimed to investigate the necessity of MSGB in established pSS patients with anti-Ro/SSA antibodies. METHODS: We extracted 185 patients with anti-Ro/SSA antibody-positive pSS from the Korean Initiative of pSS study, a prospective cohort study. We assigned them into two groups, 161 patients with focus scores ≥1 and another 24 with focus scores <1. The two groups were compared in various clinical aspects, including the severity of glandular dysfunction, systemic disease activity, extra- glandular manifestations, and other clinical indices and laboratory values. We also evaluated the relationship between focus scores and clinically important variables in pSS. RESULTS: Between the two groups, there were no significant differences in the severity of secretory dysfunction, the frequency of extra-glandular manifestations, systemic disease activity represented by various clinical indices, and laboratory findings possibly predicting the risk for lymphoma. Rather, theSjögren's syndrome disease damage index was higher in the group with focusscores <1. Among all variables, only serum immunoglobulin G levels were correlated with focus scores. CONCLUSIONS: Given the little influence on clinical phenotypes, routine MSGB could be omitted for serologically and clinically established pSS patients, especially in low-risk areas for lymphoproliferative diseases.

Cytokine clusters as potential diagnostic markers of disease activity and renal involvement in systemic lupus erythematosus.

OBJECTIVE: To describe interactions among cytokines and to identify subgroups of systemic lupus erythematosus (SLE) patients based on cytokine levels using principal component analysis and cluster analysis. METHODS: Levels of 12 cytokines were measured using sensitive multiplex bead assays and associations with SLE features including disease activity and renal involvement were assessed. RESULTS: In a group of 203 SLE patients, strong correlations were observed between interleukin (IL)6 and interferon (IFN)γ levels (r = 0.624), IL17 and IFNγ levels (r = 0.768), and macrophage inflammatory protein (MIP)1α and MIP1ß levels (r = 0.675). Cluster analysis revealed two distinct patient groups characterized by high levels of IL8, MIP1α, and MIP1ß (group 1) or of IL2, IL6, IL10, IL12, IFNγ, and tumor necrosis factor α (group 2). Active disease was more common in group 1 (49/88, 55.7%) than in group 2 (40/115, 34.8%). More patients in group 2 had renal involvement (42/115, 36.5%) than in group 1 (22/88, 25%). CONCLUSIONS: Assessment of cytokine profiles can identify distinct SLE patient subgroups and aid in understanding clinical heterogeneity and immunological phenotypes.

Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus.

OBJECTIVES: Mesenchymal stem cells (MSCs) are considered potential therapeutic agents for treating autoimmune disease because of their immunomodulatory capacities and anti-inflammatory effects. However, several studies have shown that there is no consistency in the effectiveness of the MSCs to treat autoimmune disease, including SLE. In this study, we investigated whether metformin could enhance the immunoregulatory function of MSCs, what mechanism is relevant, and whether metformin-treated MSCs could be effective in an animal lupus model. METHODS: Adipose-derived (Ad)-MSCs were cultured for 72 h in the presence of metformin. Immunoregulatory factors expression was analysed by real-time PCR and ELISA. MRL/lpr mice weekly injected intravenously with 1 × 106 Ad-MSCs or metformin-treated Ad-MSCs for 8 weeks. 16-week-old mice were sacrificed and proteinuria, anti-dsDNA IgG antibody, glomerulonephritis, immune complex, cellular subset were analysed in each group. RESULTS: Metformin enhanced the immunomodulatory functions of Ad-MSCs including IDO, IL-10 and TGF-ß. Metformin upregulated the expression of p-AMPK, p-STAT1 and inhibited the expression of p-STAT3, p-mTOR in Ad-MSCs. STAT1 inhibition by siRNA strongly diminished IDO, IL-10, TGF-ß in metformin-treated Ad-MSCs. As a result, metformin promoted the immunoregulatory effect of Ad-MSCs by enhancing STAT1 expression, which was dependent on the AMPK/mTOR pathway. Administration of metformin-treated Ad-MSCs resulted in significant disease activity improvement including inflammatory phenotype, glomerulonephritis, proteinuria and anti-dsDNA IgG antibody production in MRL/lpr mice. Moreover, metformin-treated Ad-MSCs inhibited CD4-CD8- T-cell expansion and Th17/Treg cell ratio. CONCLUSION: Metformin optimized the immunoregulatory properties of Ad-MSCs and may be a novel therapeutic agent for the treatment of lupus.

Interleukin-21-mediated suppression of the Pax3-Id3 pathway exacerbates the development of Sjögren's syndrome via follicular helper T cells.

Sjögren's syndrome (SS) is a systemic autoimmune disease with severe dysfunction of glandular secretory function mediated by T and B lymphocyte infiltration into the exocrine glands, including the salivary and lacrimal glands. Follicular helper T (Tfh) cells exacerbate the disease by causing B cell hyperactivity. Inhibitor of DNA binding 3 (Id3) deficiency causes activation of Tfh cells and is known to be a clinical manifestation of human SS disease. In this study, we investigated the mechanism of action of Pax3, which is reduced in SS and can interact with Id3, in NOD/ShiLtJ mice as an animal model of SS. Treatment with interleukin (IL)-21, a major cytokine secreted from Tfh cells, suppressed Pax3 and Id3 expression via STAT3 in splenic T cells in vitro. Administration of pCMV14-3xFlag PAX3 vector improved the severity of SS by reducing the number of Tfh cells in NOD/ShiLtJ mice. Application of IL-21R-Fc increased the number of Pax3- and Id3-positive cells in the salivary glands, while reducing the proportion of Tfh cells and IL-17-producing T cells in NOD/ShiLtJ mice. The salivary glands from SS patients showed decreased levels of Pax3 or Id3 expression compared with healthy controls. Our findings regarding reinforcement of the Pax3-Id3 signal pathway may facilitate the development of novel therapeutic strategies for SS.

Effects of birth months on rheumatic diseases in South Korea: a nationwide case-control study.

OBJECTIVES: Birth month/season impacts the development of certain diseases. However, the effect of birth month/season on the development of rheumatic diseases has not been thoroughly investigated. Thus, the objective of this study was to determine whether birth month/season might affect the development of rheumatic diseases. METHODS: Birth month patterns of patients with various rheumatic diseases were compared with those of the general population. The dataset included 17,247,458 individuals from the health insurance review and assessment service database of Korea. RESULTS: Among 24 rheumatic diseases, the development of Crohn's disease, ulcerative colitis (UC), rheumatoid arthritis, Sjögren's syndrome, polymyalgia rheumatica, ankylosing spondylitis (AS), gout, and fibromyalgia (FM) was significantly associated with birth month/season. UC and AS were more prevalent in individuals born in February/winter. On the contrary, those who were born in June or July/summer were at a higher risk of gout and FM. CONCLUSIONS: Seasonal variations in infectious agents, sun exposure, and food ingestion during gestation or early infancy seem to explain the association between birth month/season and development of rheumatic diseases.

Impact of TNF-α inhibitor on lipid profile and atherogenic index of plasma in axial spondyloarthritis: 2-year follow-up data from the Catholic Axial Spondyloarthritis COhort (CASCO).

To evaluate the influence of TNF-α inhibitor on lipid profile and atherogenic index of plasma (AIP) in axial spondyloarthritis (axSpA) patients with long-term use of stable dose TNF-α inhibitor. AxSpA patients were enrolled in the Catholic Axial Spondyloarthritis COhort (CASCO). We collected their data annually and analyzed their lipid profile and AIP. Comparison was conducted between TNF-α inhibitor user group and non-user group. Additionally, lipid profile and AIP of TNF-α inhibitor user group were compared over 2 years. A total of 238 axSpA patients were enrolled for the present study, including 132 TNF-α inhibitor users and 106 non-users. Changes of total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL-C), and HDL-C over 2 years did not show significant difference between TNF-α inhibitor user group and non-user group. When baseline data and 2-year follow-up data were compared within the TNF-α inhibitor user group, there was no significant increase in TG, LDL-C, HDL-C, or AIP. Only TC level was slightly increased in the 2-year follow-up data for the TNF-α inhibitor user group (177.86 ± 28.73 vs. 183.08 ± 29.82, P = 0.019). Long-term use of stable dose TNF-α inhibitor did not increase atherogenic lipid profile or AIP compared to the control group. Furthermore, atherogenic lipid profile or AIP was not increased significantly in the TNF-α inhibitor user group over the 2-year follow-up. Therefore, using TNF-α inhibitor for a long term might not affect atherosclerosis of axSpA.Key Points• Managing risk factors of cardiovascular disease (CVD) such as dyslipidemia in axSpA is important because axSpA patients have increased risk of CVD.• Using TNF-α inhibitor for 2 years with stable dose did not deteriorate atherogenic lipid profile or AIP as predictor of atherosclerosis.• Maintaining stable dose of TNF-α inhibitor for long-term in axSpA may be relatively safe for managing atherogenic lipid.