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Objectives To explore the relationship of tumour-associated antigens (TAAs) with the clinical manifestations and serological markers of SLE. Methods This was a retrospective study. Clinical data of SLE patients were extracted from the electronic medical records, including serum levels of TAAs such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, CA125, CA15-3 and cytokeratin 19-fragments (CYFRA21-1). TAA positivity was defined as serum level exceeding the upper limit of the corresponding reference range. Results A total of 149 SLE patients (SLE group) and 149 age- and sex-matched healthy subjects (control group) were enrolled. Compared with healthy controls, the SLE group had higher positivity rates for CA19-9 and CYFRA21-1, and elevated serum levels of CA125, CA15-3 and CYFRA21-1. SLE patients with TAA positivity were older, had a higher prevalence of serous effusion, pericardial effusion, albuminuria and thrombocytopenia, and lower positivity rate for anti-dsDNA than patients without TAA positivity. The levels of serum creatinine (SCR), blood urea nitrogen, glutamic oxalate transaminase and 24-h urinary protein were also higher in SLE patients with TAA positivity, but platelet count and serum albumin levels were lower. On logistic regression, thrombocytopenia and SCR levels were identified as independent risk factors for TAA positivity. CA125 positivity rate and serum levels of CA125 were associated with SLE disease activity. Conclusion The positivity rates and serum levels of some TAAs were elevated in SLE, and thrombocytopenia and SCR levels were independent risk factors for TAA positivity.

AimTo evaluate the diagnostic performance of the American College of Rheumatology (ACR)-1997, the Systemic Lupus International Collaborating Clinics (SLICC)-2012, and the European League against Rheumatism (EULAR)/ACR-2019 classification criteria in adult patients with systemic lupus erythematosus (SLE).MethodsPubMed, Embase, Web of Science and Cochrane Library databases were searched for literature comparing the three classification criteria of ACR-1997, SLICC-2012 and EULAR/ACR-2019, which took clinical diagnosis as reference. Meta-analysis was used to evaluate and compare the sensitivity, specificity and diagnostic odds ratio of ACR-1997, SLICC-2012 and EULAR/ACR-2019. To assess the early diagnosis capability of the classification criteria, subgroups of patients with disease duration < 3 years and < 1 year were selected for comparison of sensitivity and specificity based on the inclusion of the original study. The sensitivity and specificity of each item in three sets of classification criteria were evaluated. In addition, the clinical and immunological characteristics of patients who did not meet the three classification criteria were compared.ResultsNine original studies were included in the analysis, including 6404 SLE patients and 3996 controls. Results showed that the diagnostic odds ratios (95% confidence interval) of the SLICC-2012 [136.35 (114.94, 161.75)] and EULAR/ACR-2019 [187.47 (158.00, 222.42)] were higher than those of the ACR-1997 [67.53 (58.75, 77.63)]. Compared with ACR-1997[(0.86 (0.82, 0.89)], SLICC-2012[(0.96 (0.93, 0.97)] and EULAR/ACR-2019[(0.95 (0.92, 0.97)] had higher sensitivity. The specificity of the three classification criteria was similar: ACR-1997, SLICC-2012, and EULAR/ACR-2019 were 0.93 (0.89, 0.95), 0.86 (0.79, 0.91), and 0.91 (0.85, 0.95), respectively. The sensitivity of SLICC-2012 and EULAR/ACR-2019 were higher than that of ACR-1997 in early-course subgroups. Patients who did not meet ACR-1997 had more hypocomplementemia, patients who did not meet SLICC-2012 had more cutaneous lupus and photosensitivity, and patients who did not meet EULAR/ACR-2019 had more cutaneous lupus and leucopenia.ConclusionsSLICC-2012 and EULAR/ACR-2019 have better diagnostic ability than the ACR-1997, and the sensitivity of the former two criteria is also higher than that of the latter; Moreover, the SLICC-2012 and EULAR/ACR-2019 for patients in the early stages of disease performed equally excellent.

Introduction The characteristics of leukopenia in patients with systemic lupus erythematosus (SLE) in different studies are different, which may be related to region, race, and sample size. Moreover, the extent of leukocyte count decline remains to be studied. This study aimed to analyze the clinical characteristics of leukopenia in patients with SLE of Han ethnicity in China. Methods A single-center, retrospective, cross-sectional study was conducted in Chinese Han patients with SLE from June 2013 to August 2020. Results A total of 125 patients with SLE were included in the study, and 104 age- and sex-matched healthy controls were recruited. The prevalence of leukopenia, neutropenia, and lymphopenia was 40.0, 20.8, and 55.2%, respectively. The median leukocyte count in the leukopenia group was 2.80 × 109/l, the median neutrophil count in the neutropenia group was 1.40 × 109/l, and the median lymphocyte count in the lymphopenia group was 0.60 × 109/l, which was 47.06, 40.58, and 30.00% of the median of the healthy control group, respectively. The lymphocyte count of SLE patients without lymphopenia was also lower than that of healthy controls, and the lymphocyte count was negatively correlated with the SLE disease activity index 2000 score in all patients with SLE. Independent risk factors for neutropenia include decreased platelet count and lymphocyte count, as well as the presentation of cylindruria. For lymphopenia, the independent risk factors were positivity for anti-dsDNA antibody and Coombs’ test, decreased platelet count, and cylindruria. Conclusions In Han Chinese patients with SLE, leukopenia, neutropenia, and lymphopenia are common clinical manifestations, and the degree of reduction in blood cell count was also remarkable. Lymphopenia is associated with disease severity in patients with SLE. The correlation between Coombs’ test results and lymphopenia deserves further study. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00336-6.

Leixi Xue,1,* Yi Zhang,1,* Jiajun Xu,1 Wentian Lu,1 Qing Wang,1 Jinxiang Fu,2 Zhichun Liu1 1Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhichun LiuDepartment of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Sanxiang Road No. 1055, Suzhou, Jiangsu, 215004, People’s Republic of ChinaTel +86 13771994276Email liuzhichun5190@163.comJinxiang FuDepartment of Hematology, The Second Affiliated Hospital of Soochow University, Sanxiang Road No. 1055, Suzhou, Jiangsu, 215004, People’s Republic of ChinaTel +86 13962525217Email fjx3000@126.comPurpose: Current studies on the mechanism of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis (LN) mainly focus on the inflammatory pathway. Herein, we aimed to determine whether TWEAK could promote the progression of renal interstitial fibrosis by regulating peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) expression and intervening in lipid metabolism in LN.Materials and Methods: MRL/lpr mice, an animal model of lupus, were treated with the anti-TWEAK antibody or co-treated with adeno-associated virus-mediated PGC-1α short hairpin RNA (shRNA). In addition, human proximal tubular epithelial cells (HK2 cells) were treated with recombinant human TWEAK (rhTWEAK) or ammonium pyrrolidine dithiocarbamate (PDTC) in vitro.Results: The renal contents of free fatty acids and triglycerides were higher in MRL/lpr mice than in MRL/MpJ mice; however, these contents were decreased by treatment with the anti-TWEAK antibody. Based on immunofluorescencestaining, the expression of PGC-1α was markedly more in the renal tubules of MRL/MpJ mice than in the glomeruli. However, treatment with anti-TWEAK antibody increased the levels of PGC-1α and its downstream target genes, which were remarkably lower in MRL/lpr mice than in MRL/MpJ mice. Anti-TWEAK antibody effectively eased renal interstitial fibrosis, which manifested as a decrease in the deposition of collagen fibers and the inhibition of type I collagen and fibronectin expression. However, the therapeutic effects of the anti-TWEAK antibody were abolished by PGC-1α shRNA. Treatment with rhTWEAK decreased PGC-1α expression in both dose- and time-dependent manners in HK2 cells in vitro. PDTC, an inhibitor of IκBα phosphorylation, suppressed the decrease in the PGC-1α protein level induced by rhTWEAK treatment.Conclusion: Our results suggest that TWEAK prevents renal tubular PGC-1α expression by promoting NF-κB activation, resulting in a deficiency in lipid metabolism and the progress of renal interstitial fibrosis. The upregulation of renal tubular PGC-1α expression to improve lipid metabolism is one of the mechanisms employed by the anti-TWEAK antibody to treat renal interstitial fibrosis.Keywords: TWEAK, lupus nephritis, renal interstitial fibrosis, PGC-1α, lipid metabolism

Objective: To explore the value of the quantitative parameter of intravoxel incoherent motion diffusion (IVIM-DWI) at 3.0 T MRI of the sacroiliac joint in differentiating different disease activity statuses of ankylosing spondylitis (AS) and to compare it with traditional diffusion-weighted imaging (DWI) and Spondyloarthritis Research Consortium of Canada (SPARCC) score. Methods: 56 AS patients (active group, inactive group) and 24 healthy controls were included. Clinical data, quantitative parameters of IVIM-DWI MR images and the SPARCC scores were collected. The Kruskal–Wallis test was used to compare the differences between the groups. Receiver operating characteristic (ROC) curve analysis of histogram data and the SPARCC scores identified the efficacy of the three groups. The Spearman correlation coefficients were used to analyse the correlation between the quantitative IVIIM-DWI parameters and the SPARCC score. Results: The f (10th percentile) and SPARCC score of the active group were significantly higher than those of the inactive group. The f (10th, 25th, 50th percentiles), Dslow (average, entropy, 10th ~ 90 th percentiles), Dfast (kurtosis, skewness), ADC (average, 10th ~ 90 th percentiles) and the SPARCC score of the active group were significantly higher than the control group (p < 0.05). The AUC of the SPARCC score was the highest (0.799) in the identification between the active and inactive groups, and the sensitivity and specificity were 69.23 and 82.35%, respectively, at the cut-off value of 12. The SPARCC score was positively correlated with each percentile and the average value. Conclusions: Quantitative IVIIM-DWI parameters are helpful for the identification of different AS disease activity levels and are superior to traditional DWI. IVIM-DWI quantitative parameters had a good correlation with the SPARCC score. Advances in knowledge: A new MR technology-quantitative parameters of IVIM-DWI contribute to the identification of AS disease activity. IVIM-DWI quantitative parameters were well correlated with the SPARCC score.

Background and aimsSeveral different versions of classification criteria, including the American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and European Alliance of Associations for Rheumatology (EULAR)/ACR-2019 classification criteria, have been launched in the past decades. The current study aimed to investigate the performance of these three classification criteria for diagnosing patients with SLE in a Chinese cohort.Methods352 patients with SLE and 385 controls with other diseases who had the detection results of ANA were enrolled into the study. Various clinical parameters were estimated, such as demographics variables, clinical characteristics and other variables related to three criteria.ResultsThe current study demonstrated great diagnostic ability of the three criteria; and the receiver operating characteristic curve and the area under curve (AUC) were used to evaluate the diagnostic ability of three criteria: ACR-1997 (AUC=0.972), SLICC-2012 (AUC=0.986) and EULAR/ACR-2019 (AUC=0.983). Despite lower specificity of the SLICC-2012 and EULAR/ACR-2019 classification criteria, their sensitivity is significantly improved than ACR-1997. Of note, we also compared the median time interval between the appearance of the earliest item and fulfilment of the three sets of criteria, suggesting the SLICC-2012 and EULAR/ACR-2019 could achieve earlier diagnosis. Adjusting the thresholds of the EULAR/ACR-2019 criteria from 10 to 12, the specificity and accuracy significantly increased.ConclusionThe SLICC-2012 and EULAR/ACR-2019 performed well in Chinese patients with SLE and showed better early diagnosis ability. In addition, by adjusting the classification threshold, the accuracy of the EULAR/ACR-2019 classification criteria was improved.

Aim: In clinical practice, an anechoic signal was often exhibited between the volar plate (VP) of the proximal interphalan - geal joint (PIPJ) (PIPJVP) and the flexor digitorum tendon (FDT) on ultrasound, which suggests the presence of effusions (PIPJVP-FDT effusions). The purpose of this study was to investigate the prevalence of PIPJVP-FDT effusions and to explore the possible mechanism preliminarily. Material and methods: A single-center, cross sectional study in hand osteoarthritis (HOA) patients, rheumatoid arthritis (RA) patients and healthy controls was conducted. Ultrasound examination was per - formed by the same real-time scanner with 18-MHz linear array transducer. Bilateral interphalangeal joints (IPJs) of the thumb, 2 ed , 3 rd , 4 th and 5 th PIPJs were examined. The PIPJVP-FDT effusions was defined as an anechoic signal between the PIPJVP and FDT in two perpendicular ultrasound planes. Results: In total, 200 patients with HOA, 78 patients with RA and 101 healthy controls were eligible for the study. 37.6% of healthy controls and 35.0% of HOA patients showed PIPJVP-FDT effusions, while only 11.5% of RA patients had PIPJVP-FDT effusions (p

Supplemental material, sj-pdf-1-tab-10.1177_1759720X21999564 for Comparative efficacy and safety of Janus kinase inhibitors and biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and network meta-analysis by Chenghua Weng, Leixi Xue, Qing Wang, Wentian Lu, Jiajun Xu and Zhichun Liu in Therapeutic Advances in Musculoskeletal Disease

Background: Renal interstitial fibrosis (RIF) is one of the main poor prognostic factors of lupus nephritis (LN). Here, we tested whether iguratimod could inhibit RIF in LN. Methods: MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney was evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor β1 (TGF-β1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3 and p-p38 MAPK in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence. Results: In MRL/lpr mice, iguratimod eased the renal interstitial deposition of collagen fibers, further confirmed by decreased expression of COL-I after iguratimod treatment. Moreover, upstream pathological processes of RIF, including IgG deposition along the tubular basement membrane, infiltration of inflammatory cells into renal interstitium and tubular injury, were also prevented effectively by iguratimod treatment. Furthermore, iguratimod suppressed the expression of FSP-1 and raised the expression of E-cadherin in renal tubular epithelial cells, suggesting that iguratimod reversed the process of tubular epithelial-to-mesenchymal transition (EMT). In HK2 cells induced by TGF-β1, co-treatment with iguratimod not only reversed cellular morphologic change, but also prevented down-regulation of E-cadherin and up-regulation of fibronectin. Finally, iguratimod blocked TGF-β1-induced phosphorylation of Smad2/3 and p38 MAPK in HK2 cells. Conclusions: Our results suggest that iguratimod shows an inhibitory effect on the progress of RIF in vivo and in vitro, so iguratimod may be a potential drug for the treatment of RIF in LN.

Acute kidney injury (AKI) results in retention of waste products and dysregulation of extracellular volume and electrolytes, thus leading to a variety of complications. Recent advances in long noncoding RNAs suggested their close relationship with disease progression. In the current study, we investigated the role and mechanism of maternally expressed gene 3 (MEG3) on AKI pathogenesis. Real-time polymerase chain reaction found that the expression of MEG3 was significantly increased in both kidney tissues and TKPTS cells induced by lipopolysaccharide (LPS). Western blot assay showed that the expression of apoptosis regulator Bcl-2 was increased in MEG3-inhibited TKPTS cells. Flow cytometry assay confirmed that LPS-induced apoptosis was significantly attenuated after transfection of si-MEG3. The RNAhybrid informatics algorithm predicted that there was a strong binding capacity between miR-21 and MEG3. Luciferase reporter assay confirmed that MEG3 could function as a competing endogenous RNA of miR-21. The antiapoptotic effect of si-MEG3 could be neutralized by a miR-21 inhibitor, demonstrated by the decreased expression of Bcl-2 and flow cytometry results. Further investigation showed that programmed cell death protein 4 (PDCD4), a validated target of miR-21, was highly expressed in both injured kidney tissues and LPS-stimulated TKPTS cells. Meanwhile, the protein expression of PDCD4 was significantly reduced by inhibition of MEG3, but retrieved by coinhibition of MEG3 and miR-21. In conclusion, our results demonstrated that inhibition of MEG3 could attenuate LPS-induced apoptosis in TKPTS cells by regulating the miR-21/PDCD4 pathway, suggesting that the MEG3/miR-21/PDCD4 axis could be developed as a potential therapeutic target of AKI.

This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used forin vivoexperiments and human proximal tubular cells (HK2 cells) were used forin vitroexperiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, andα-SMA proteins.In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2,α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway.

To assess the efficacy of long-term treatment with nonsteroidal antiinflammatory drugs (NSAIDs) on bone marrow oedema (BMO) of the sacroiliac joint in newly diagnosed axial spondyloarthritis (SpA) with a symptom duration of less than 4 years, a single-center, open-label study in a cohort of consecutive patients with newly diagnosed axial SpA was conducted. Eligible patients had magnetic resonance imaging (MRI)-determined BMO of the sacroiliac joint at baseline, had a symptom duration of less than 4 years, and were naive to NSAIDs. After the baseline MRI, an optimal dose of NSAID was administered for 24 or 48 weeks. BMO of sacroiliac joint was quantified by applying the Spondyloarthritis Research Consortium of Canada (SPARCC) system. Disease activity was expressed using the Ankylosing Spondylitis Disease Activity Score (ASDAS). Primary end points were improvement in BMO of sacroiliac joint at week 24 or week 48. Forty-three patients were recruited, and 33 patients eventually completed the study, including 10 patients having follow-up MRI at week 24 and 23 patients having follow-up MRI at week 48. Overall, the mean of SPARCC score decreased from 21.8 ± 16.1 at baseline to 10.2 ± 12.8 at follow-up (p

Objectives Oestrogens have been shown to play key roles in the pathogenesis of SLE. The aim of this study was to investigate the roles and mechanisms of 17β-estradiol (E2) in TNF-like weak inducer of apoptosis (TWEAK) expression in LN. Methods Peripheral blood mononuclear cells (PBMCs) obtained from LN patients were used for in vitro experiments, while female MRL/lpr and MRL/MpJ mice were used for in vivo studies. E2, ICI 182 780 [estrogen receptor (ER)-selective antagonist], methyl-piperidino-pyrazole (MPP, ERα-selective modulator), lentivirus (LV)-TWEAK-short hairpin RNA (shRNA) and LV-control-shRNA treatments were used in this study. Results TWEAK mRNA expression in PBMCs was significantly increased following E2 treatment and downregulated after incubation with ICI 182 780 or MPP. Compared with sham-operated MRL/lpr mice, ovariectomized mice, treated with dimethyl sulphoxide vehicle alone, showed lower expression levels of renal TWEAK mRNA and protein. The expression of both mRNA and protein in ovariectomized mice was upregulated after E2 treatment and downregulated after ICI 182 780 or MPP co-treatment. Severe renal damage was observed in E2-treated ovariectomized mice, as were higher serum levels of IL-6, compared with dimethyl sulphoxide vehicle-treated ovariectomized mice. Co-treatment with LV-TWEAK-shRNA reversed these changes, and LV-control-shRNA treatment had no effect on them. Conclusion Our results demonstrated that E2 plays an important role in the upregulation of TWEAK expression in LN, most likely through an ERα-dependent pathway, causing kidney damage. This provides a novel insight into the mechanisms of the E2-TWEAK signalling pathway in LN.