Despite advances in approaches to treatment for patients with systemic sclerosis (SSc), the effects have been modest at best. This investigator-initiated study aimed to evaluate the therapeutic benefit, safety and the genetic characteristics related to effect of baricitinib in SSc. In this 24-week study, eligible SSc patients were randomised to baricitinib 4 mg, 2 mg or control group. The primary outcome was the change in modified Rodnan skin score (mRSS) from baseline to week 12. Secondary outcomes included changes in the American College of Rheumatology Combined Response Index in Systemic Sclerosis (ACR-CRISS) score, forced vital capacity (FVC), Systemic Sclerosis Score, tender and swollen joint counts, digital ulcers, EQ5D (EuroQol five-dimensions) and safety at week 12 and 24. Transcriptome differences in blood samples from patients before and after baricitinib treatment were compared. Gene Ontology enrichment analysis was performed to identify potential biological functions and canonical pathways. Between April 2021 to January 2022, 48 patients were randomly assigned to three groups. Mean change in mRSS score from baseline to week 12 was - 8.9 in 4 mg group, - 3.8 in 2 mg group, and - 3.6 in control group (P = 0.019). At week 12, the ACR-CRISS scores were 0.5 and 0.3 in baricitinib 4 mg and 2 mg group, as compared with 0.2 among those in control group (P = 0.171). FVC (

目的 探讨趋化因子受体2(CXCR2)抑制剂在急性痛风小鼠模型中的作用.方法 小鼠急性痛风足掌模型:12只6～8周龄C57BL/6雄性小鼠随机分为3组,每组4只,对照组:小鼠右后足掌注射生理盐水;实验组:小鼠右后足掌注射单钠尿酸盐(MSU)建立急性痛风足掌模型;干预组:小鼠右后足掌注射MSU及CXCR2抑制剂SB225002.于注射8 h后测量3组小鼠右/左后足掌厚度比值,采用苏木素?伊红(HE)染色评估小鼠足掌关节炎症程度,采用蛋白质免疫印迹法(Western blot)检测足掌组织白细胞介素(IL)?1β水平.小鼠急性痛风腹腔模型:9只6～8周龄C57BL/6雄性小鼠随机分为3组,每组3只.对照组:小鼠腹腔注射生理盐水;实验组:小鼠腹腔注射MSU建立急性痛风腹腔模型;实验组:小鼠腹腔注射MSU及CXCR2抑制剂SB225002.于MSU注射4 h后收取腹腔灌洗液检测中性粒细胞密度及比例、IL?1β及趋化因子水平.结果 在小鼠急性痛风足掌模型中,实验组小鼠右/左后足掌厚度比值高于对照组,干预组低于实验组(P<0.05);与对照组比较,实验组小鼠足掌关节炎症细胞浸润程度明显增加;与实验组比较,干预组小鼠足掌关节炎症细胞浸润程度明显下降;实验组足掌组织IL?1β水平高于对照组,干预组低于实验组.在小鼠急性痛风腹腔模型中,实验组小鼠腹腔灌洗液中中性粒细胞密度和比例均高于对照组,干预组上述指标均低于实验组(P<0.001或P<0.05);实验组小鼠腹腔灌洗液中IL?1β、CXCL1、CXCL2、CXCL8水平均高于对照组,干预组小鼠腹腔灌洗液中CXCL1、CXCL2、CXCL8水平均低于实验组(P<0.05).结论 抑制CXCR2可减轻小鼠急性痛风炎症反应,CXCR2可能成为急性痛风治疗中抑制急性炎症的可行靶点.

Gout is a common arthritis caused by deposition of monosodium urate crystals. Macrophage is crucial in the process of monosodium urate (MSU)-induced inflammation. Although it has been reported that adrenocorticotropic hormone (ACTH) in nature can be used to cure urarthritis, the mechanism concerning macrophage is still not clear. However, gout patients manifest other complications, such as hypertension, diabetes, chronic kidney disease, and hormone intolerance, which limit efficacy of some of these first-line drugs. Therefore, this study aims to explore how natural ACTH can alleviate urarthritis through functional changes in macrophage. We analyzed the variations in VAS pain scores of five patients, knowing the time of action and detecting the level of cortisol and ACTH in patients 24 hours after the application of ACTH. The effect of natural ACTH on joint inflammation and the level of cortisol in blood in the mouse model was evaluated by studies in vivo. In vitro studies, we evaluated the effect of natural ACTH on macrophages and revealed different functions of ACTH and dexamethasone on macrophages in the transcriptional level. In patients with acute gout, natural ACTH can quickly alleviate pain and does not affect the level of cortisol and ACTH. Natural ACTH is able to ease the swelling and inflammatory cell infiltration caused by arthritis, without changing the level of cortisol. Besides, natural ACTH in vitro can alleviate acute gouty inflammation by regulating phagocytosis and polarization of macrophage, which also exerts different effects on the transcription of some related genes. Natural ACTH is able to alleviate acute gouty inflammation by regulating macrophage, and this effect differs from that of dexamethasone at the transcriptional level.

OBJECTIVE:Interleukin (IL)-37 is a natural suppressor of inflammation. Macrophages play an important role in acute gout flare by dominating the inflammation and spontaneous relief. We have reported that IL-37 could limit runaway inflammation in gout. Here we focus on whether IL-37 inhibits gouty inflammation by altering macrophage functions, and how it does so. METHODS:Macrophage functions were evaluated in terms of phagocytosis, pyroptosis, polarization and metabolism. Phagocytosis and polarization of macrophages were detected by side scattering and double-labelling induced nitrogen monoxide synthase (iNOS)/arginase-1 (Arg-1) using flow cytometry, respectively. Transcription of pyroptosis-related molecules was detected by qPCR. Metabolomics was performed by liquid chromatograph mass spectrometer. Human IL-37 knock-in mice and a model with point mutation (S9A) at mouse Gsk3b locus were created by CRISPR/Cas-mediated genome engineering. MSU was injected into the paws and peritoneal cavity to model acute gout. Vernier calliper was used to measure the thickness of the paws. The mice paws and human synovium tissues or tophi were collected for pathological staining. Peritoneal fluid of mice was used to enrich macrophages to detect polarization. RESULTS:IL-37 promoted non-inflammatory phagocytic activity of macrophages by enhancing phagocytosis of MSU, reducing transcription of pyroptosis-related proteins and release of inflammatory cytokines, protecting mitochondrial function, and mediating metabolic reprogramming in MSU-treated THP-1 cells. These multifaceted roles of IL-37 were partly depended on the mediation of glycogen synthase kinase-3β (GSK-3β). CONCLUSIONS:Our study revealed that IL-37 could shape macrophages into a 'silent' non-inflammatory phagocytic fashion. IL-37 may become a potentially valuable treatment option for patients of chronic gout, especially for those with tophi.

Objective To investigate bone mineral density (BMD), bone metabolism-related factors, and microRNA-218 in Chinese ankylosing spondylitis (AS) patients and to identify their correlation with disease activities and the treatment with TNF-alpha inhibitors. Methods A total of 89 AS patients were enrolled in the study. Patients' information and laboratory examination results were collected. BMD of the anteroposterior lumbar spine (L2-L4), left femoral neck, and whole body were measured and T-scores were calculated. MicroRNA-218 was extracted from PBMCs of AS patients and detected by RT-PCR. Bone metabolism-related factors were detected using protein chips and flow cytometer. Results Out of 86 patients undergoing whole-body BMD measurement, 14 had osteopenia and 72 had normal BMD without osteoporosis or high BMD. Compared with short- (disease duration <= 3 years) and long-term groups (disease duration >= 10 years), medium-term group (disease duration ranges from 3 to 10 years) showed lowest BMD. Patients with onset age <= 20 years old had significantly lower BMD than the other groups (p < 0.05). The BMD of femoral neck had negative correlation with CRP (p < 0.05) and no correlation with BASDAI or ESR. Both whole-body BMD and femoral neck BMD were negatively correlated with BASMI (p < 0.05). Dickkopf-1 (DKK-1), platelet-derived growth factor-BB (PDGF-BB), and receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) were significantly increased, while Osteopontin (OPN) was significantly decreased in AS patients. Expression of microRNA-218 in PBMC of AS patients was low and was positively correlated with BASMI (p < 0.05), but it was not correlated with the duration of disease, age of onset, BASDAI, ESR, or BMD. Conclusion Loss of bone mass mainly occurred at the inflammatory sites in AS patients, depending on the severity of inflammation. The alleviation of inflammation can improve loss of bone mass and bone metabolism disorders. Anti-inflammatory treatment is critical for the treatment of secondary osteoporosis caused by AS.

To the Editor: Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive skin and visceral fibrosis, microvasculopathy, and autoimmunity. Circulating auto-antibodies (AAbs) are detectable in 90% to 95% of patients with SSc.[1] It is reported that 60% to 80% of SSc patients are positive for anti-topoisomerase I antibody (ATA), anti-centromere antibody (ACA), and anti-RNA polymerase III antibody (ARA).[2] These three AAbs are the most prevalent SSc-associated AAbs, with high specificity for the diagnosis of SSc; so they have been included in the classification criteria for SSc defined by the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) in 2013. Currently, SSc-associated AAbs have been widely used in clinical practice, and the research on the clinical significance of AAbs is still in progress. In our present study, we analyzed the correlations between the SSc-associated auto-antibody profile and clinical manifestations in a well-characterized Chinese SSc cohort. One hundred and forty-four patients enrolled between June 2018 and August 2020 in our center were included in this cross-sectional study. The inclusion criteria were as follows: (1) patients diagnosed with SSc according to 2013 ACR/EULAR classification criteria; (2) patients who had undergone chest high-resolution computed tomography (HRCT) scan; and (3) patients tested for ATA, ACA, and AAbs to nuclear-ribonuclear-protein (nRNP). This research was conducted according to the Declaration of Helsinki, and all procedures involving study participants were approved by the ethics committee of Huashan Hospital, Fudan University (No. 2019-191). Each participant signed an informed consent form before the research. Through careful medical history inquiry and physical examination, we collected patient demography (age at onset, sex, smoking history, and disease duration) and clinical characteristics (disease subset, Raynaud's phenomenon [RP], digital ulcer, telangiectasia, puffy finger, arthralgia, and myalgia). The onset of disease was defined as the time when the first non-RP symptom of SSc (skin thickening, sclerodactyly, puffy finger, digital ulcer, or organ involvement) appeared. The skin fibrosis was scored according to the modified Rodnan skin thickness score (mRSS), a widely used clinical assessment of skin thickness where the examining rheumatologist records the degree of skin thickening on a scale of 0 (no involvement) to 3 (severe thickening) in 17 body areas (total score range: 0–51). Interstitial lung disease (ILD) was defined by HRCT. Pulmonary arterial hypertension (PAH) was defined as mean systolic pulmonary arterial pressure ≥40 mmHg detected by echocardiography. Scleroderma renal crisis (SRC) was defined as the acute deterioration of renal function accompanied by hypertension or corresponding renal biopsy results. All patients were classified into four disease subsets, including diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), overlap syndrome (overlap) subsets based on the classification of LeRoy et al, and SSc sine scleroderma subset characterized by typical visceral involvement, vasculopathy, and serologic abnormalities without skin alterations. AAbs were tested by immunoblotting. All the patients were tested for ATA, ACA, and AAbs to Ku, nRNP, and polymyositis (PM)-Scl. Sixty-four patients were also tested for ARA and AAbs to fibrillarin, Th/To, NOR90, and platelet-derived growth factor receptor (PDGFR). Of the 64 patients, those positive for any of the above-mentioned ten AAbs were defined to be AAb-positive SSc (SSc-AAbs [+]) patients, whereas the patients who were negative for the above-mentioned ten AAbs were defined to be AAb-negative SSc (SSc-AAbs [−]) patients. Data were analyzed by GraphPad Prism (version 8.0.2 for Windows, GraphPad Software, San Diego, California, USA). Quantitative data were analyzed using t test, Welchtest, and Mann–Whitney test where appropriate. The Chi-squared test or Fisher's exact test was used to evaluate categorical data. P value < 0.05 was considered statistically significant. A total of 144 patients were included in our SSc cohort with a mean age at onset of 47.8 ± 13.9 years. Of all, 117 (93.5%) were female and 27 (6.5%) were male. SSc disease duration from RP onset and non-RP onset was 4.0 (1.5– 9.6) and 2.0 (1.0–5.0) years, respectively. The mean mRSS was 6.0 (2.0–12.0). There were 58 (41.1%), 61 (42.4%), 8 (5.6%), and 17 (11.8%) patients diagnosed as dcSSc, lcSSc, SSc sine scleroderma, and overlap, respectively. Ninety-three patients (64.6%) were determined with ILD. The patients with SSc-associated AAbs in our cohort is as follows in the order: ATA 61 (42.4%), ACA 34 (23.6%), ARA 11/64 (17.2%), anti-nRNP 15 (10.6%), anti-NOR90 6/64 (9.4%), anti-fibrillarin 4/64 (6.3%), anti-Ku 5 (3.5%), anti-Th/To 2/64 (3.1%), anti-PM-Scl 3 (2.8%), and anti-PDGFR 0/64 (0%). In addition, 11/64 (17.2%) of the patients were SSc-AAbs (–) [Supplementary Table 1, https://links.lww.com/CM9/A875 and Supplementary Figure 1, https://links.lww.com/CM9/A875]. Due to the limited number of anti-fibrillarin, anti-NOR90, anti-Th/To, anti-PDGFR, and anti-PM-Scl subgroups (n< 10), the correlation analysis may not be convincing. Therefore, clinical associations were analyzed only among the SSc patients positive for ATA, ACA, ARA, anti-nRNP and SSc-AAbs (–) subgroups. In our cohort, compared with the patients negative for the corresponding antibodies, patients with ATA had earlier disease onset (P = 0.02), higher mRSS level (P = 0.003), and higher proportions of ILD (P < 0.0001); patients with ACA had lower mRSS level (P = 0.005), lower proportions of male (P = 0.04), myalgia (P = 0.02), and ILD (P < 0.0001) or overlap (P < 0.0001); patients with ARA had later disease onset (P = 0.04); and patients with anti-nRNP had lower mRSS level (P = 0.009). Patients who are negative for SSc-AAbs manifested as more dcSSc than lcSSc (P = 0.009); patients who are positive for ACA manifested as more lcSSc than dcSSc (P < 0.0001) or overlap (P < 0.0001); and patients who are positive for anti-nRNP manifested as more overlap than dcSSc (P = 0.0003) or lcSSc (P = 0.001). No significant correlations were found between SSc-associated AAbs and disease duration, RP, digital ulcer, arthralgia, puffy finger, telangiectasia, PAH, or SRC [Table 1, Supplementary Figure 2, https://links.lww.com/CM9/A875 and Supplementary Tables 1–3, https://links.lww.com/CM9/A875]. Table 1 - Correlations of quantitative clinical variables with SSc-associated AAbs. Quantitative data Positive Negative N+ N– P values Age at onset (years), mean ± SD ATA 44.8 ± 13.3 50.0 ± 14.0 61 83 0.020∗ ACA 50.9 ± 10.3 46.8 ± 14.8 34 110 ns∗ ARA 56.0 ± 13.4 45.9 ± 15.0 11 53 0.040† Anti-nRNP 45.6 ± 15.5 48.0 ± 13.8 15 129 ns SSc-AAbs (+) 47.4 ± 15.8 48.8 ± 11.8 53 11 ns† mRSS, median (IQR) ATA 8.0 (4.0–18.0) 4.0 (2.0–10.3) 57 64 0.003∗ ACA 3.0 (2.0–8.0) 7.0 (3.0–14.5) 29 92 0.005∗ ARA 9.0 (4.0–16.0) 6.0 (2.0–10.3) 11 48 ns∗ Anti-nRNP 2.0 (0.5–4.0) 7.0 (2.0–12.8) 11 110 0.009∗ SSc-AAbs (+) 6.0 (2.0–11.0) 8.5 (5.0–11.5) 51 8 ns∗ Disease duration (years), median (IQR) RP disease duration ATA 4.0 (1.1–7.9) 3.5 (1.5–9.9) 59 82 ns∗ ACA 4.0 (1.5–10.0) 3.0 (1.4–8.0) 33 108 ns∗ ARA 8.0 (0.7–12.0) 2.5 (1.0–7.0) 11 53 ns∗ Anti-nRNP 4.0 (2.0–9.2) 3.0 (1.0–9.5) 14 127 ns∗ SSc-AAbs (+) 3.0 (1.0–9.0) 2.0 (0.6–4.5) 53 11 ns∗ Non-RP disease duration ATA 2.0 (0.8–5.0) 2.0 (1.0–5.0) 61 83 ns∗ ACA 2.9 (1.0–5.0) 2.0 (0.9–5.0) 34 110 ns∗ ARA 0.8 (0.7–2.8) 2.0 (1.0–5.0) 11 53 ns∗ Anti-nRNP 2.0 (0.6–3.5) 2.0 (1.0–5.0) 15 129 ns∗ SSc-AAbs (+) 1.5 (1.0–5.0) 1.0 (0.8–2.0) 53 11 ns∗ ∗t test.†Mann–Whitney test. N+ = The number of positive group patients; N– = The number of negative group patients. AAbs: Auto-antibodies; ACA: Anti-centromere antibody; ARA: Anti-RNA polymerase III antibody; ATA: Anti-topoisomerase I antibody; IQR: Interquartile range; mRSS: Modified Rodnan skin score; ns: Not significant; RP: Raynaud's phenomenon; SD: Standard deviation; SSc: Systemic sclerosis; SSc-AAbs (+): AAb-positive-SSc. The present study compared the prevalence of SSc-associated AAbs in a well-described Chinese cohort and analyzed the associations between SSc-associated AAbs and clinical features, such as disease subsets and critical organ involvement. Considering that fibrosis is one of the most important characteristics of SSc, we applied various ways to evaluate the degree of fibrosis in patients, including mRSS, disease subsets according to the extent of skin fibrosis and ILD. In our study, the proportion of lcSSc in ACA-positive patients was much higher than that of dcSSc and overlap; also, the mRSS was significantly lower in the patients who are positive for ACA than in those who are negative for ACA. We also found that mRSS was higher in ATA-positive patients and that the subset of dcSSc was more frequently seen in SSc patients who are positive for ATA. The proportion of ILD was higher in ATA-positive patients and lower in ACA-positive patients. Since ILD is one of the major causes of death in SSc at present, and normally indicative of severer disease and worse prognosis, our findings confirmed the view that early screening for ILD is highly recommended in ATA-positive patients.[3] Importantly, it was found in our cohort that among SSc-AAbs (-) patients, the proportion of dcSSc was higher and that of lcSSc was lower, which appeared even more remarkable than in ATA-positive patients. We speculated that there could be some existing but still unknown AAbs underlying, which could be the direction of our further research. In summary, we have applied different methods to analyze the correlation between SSc-associated auto-antibody profile and fibrosis, and gotten consistent results, which may provide supportive and supplementary data for the previous similar study in a Chinese SSc cohort.[4] Besides the correlation with fibrosis, we also found other clinical correlations of SSc-associated AAbs in our cohort. We found that the onset age of ATA-positive patients was relatively earlier in our cohort and that ACA was more commonly seen in females, consistent with the findings of Mierau et al.[5] In terms of musculoskeletal involvement, we found that myalgia is less common in ACA-positive patients, and another study[5] also reported that ACA-positive patients had less musculoskeletal involvement. In the future, we need to add more detailed musculoskeletal parameters (such as myodynamia, electromyography, muscle biopsy, and creatine kinase level) to obtain more thorough observation on the clinical relationship between AAbs and muscle involvement. ARA-positive patients had later disease onset. None of the ARA-positive patients in our cohort developed renal crisis so far, although ARA was reported to be highly correlated with SRC.[1] Since the number of ARA-positive patients was relatively small (n = 15), these findings may need further observation in a larger cohort. Anti-nRNP is usually associated with SSc overlap,[1] which was also confirmed in our cohort. The limitation of our current study mainly lies in the limited sample size in this cohort. A well-described cohort with larger sample size from multiple centers may help us to study the clinical associations with AAbs more comprehensively and thoroughly. Acknowledgments The authors appreciate and acknowledge all members of the Division of Rheumatology of Huashan Hospital; they made considerable effort in the evaluation of the patient's condition, data collection, statistical analysis, etc. The authors thank the patients for their cooperation in providing descriptions of their conditions and blood samples. Funding This work was supported by grants from the Youth Program of National Natural Science Foundation of China (No. 81501391), and medical and health research projects from Shanghai Baoshan Science and Technology Commission (No. 20-E-3). Conflicts of interest None.

Background Ultrasound is a useful tool to evaluate and quantify skin lesions. Few studies have assessed the criterion validity of skin ultrasound in systemic sclerosis (SSc). The aims of the study were to investigate skin thickness and stiffness using ultrasound and shear wave elastography (SWE) in SSc and to validate skin ultrasound measurements against histological skin thickness. Methods A total of 22 patients with diffuse cutaneous SSc (dcSSc), 22 with limited cutaneous SSc (lcSSc), and 22 age- and gender-matched healthy controls were enrolled. Skin thickness and stiffness were measured by B-mode ultrasound with SWE imaging on the bilateral fingers and hands. Additional ultrasound evaluation was carried out in 13 patients (9 dcSSc and 4 lcSSc) on their dorsal forearms, followed by skin biopsy conducted in the same skin areas. Correlations between ultrasound measurements and histological skin thickness and modified Rodnan skin score (mRSS) were investigated using Spearman’s correlation. Results Compared with controls, ultrasound-measured skin thickness and skin stiffness were significantly higher in patients with SSc ( p < 0.001) and even higher in those with dcSSc. No clear correlation could be established between ultrasound-determined skin thickness and stiffness at the same site. Ultrasound-measured skin thickness correlated well with histological skin thickness ( r = 0.6926, p = 0.009). A weaker association was also observed between histological skin thickness and local mRSS ( r = 0.5867, p = 0.050). Conclusions Ultrasound is a reliable tool for quantifying skin involvement in SSc. Ultrasound-measured skin thickness showed good agreement with histological skin thickness.

痛风是尿酸代谢异常引起的炎症性疾病,与肥胖诱发的代谢异常相关. 随着人们生活水平的提高,过去20年间痛风患者的发病率增加了1倍,痛风相关的并发症相应增加,其中肥胖症由20年前的10％增加到现在的29％[1].

Gouty arthritis is an inflammatory disease that is triggered by abnormal uric acid metabolism, which is usually attributed to obesity, a risk factor of hyperuricemia and gout attack. A high level of leptin in plasma is a marker of individuals with obesity. Population studies show that leptin promotes obesity-related arthritis, such as osteoarthritis, but it is unknown whether leptin contributes to gouty arthritis, another form of obesity-related arthritis. Our present study showed that the levels of leptin and leptin receptor in patients with active gouty arthritis were elevated. Leptin facilitates the stimulation of human synoviocytes, mouse peritoneal macrophages, and HL-60 cells induced by monosodium urate, leading to higher levels of acute gout-related proinflammatory factors. Leptin obviously exacerbates the inflammation of monosodium urate-induced acute gouty arthritis in wild-type mice, whereas that in leptin-deficient C57BL6/J(ob/ob) mice is markedly alleviated. The proinflammatory effect of leptin in acute gouty arthritis is partly mediated by mTORC1 signaling pathway. Our study reveals that leptin may serve as a novel prevention and treatment target in acute gouty arthritis.

目的:建立一种临床适用的系统性红斑狼疮(SLE)肾脏损害风险评估模型.方法:通过建立Logistic回归模型,回顾性分析SLE患者不同起病年龄、补体水平和性别间产生肾脏损害的风险.结果:383名SLE患者中88.0％为女性,35.5％有肾脏受累;肾脏受累组的初诊年龄和C3均显著低于无肾脏受累组(P=0.034和P<0.001).仅26～36岁患者组肾脏受累的风险显著升高2.890倍(P=0.001),其中女性患者的风险升高2.589倍(P=0.005),男性患者升高9.880倍(P=0.034).随着C3的降低,女性患者的肾脏受累风险逐渐升高.结论:26～36岁起病且C3<0.51 g/L的女性患者,肾脏受累的风险将显著升高;该年龄段的男性患者狼疮性肾炎的风险也显著提高且明显高于女性患者,但因例数限制,尚需进一步研究证实.

BACKGROUND:Functional variants of the B cell gene, B cell scaffold protein with ankyrin repeats 1 (BANK1) contribute to rheumatoid arthritis (RA) susceptibility, but their influences on B cell responses are unclear. Moreover, the function of induced T regulatory cells (iTregs) in the inflammatory milieu in a collagen-induced arthritis (CIA) model is unknown. This study was performed to investigate the roles of BANK1 in CIA and the interaction between B cells and iTregs.METHODS:The changes in BANK1 mRNA and protein levels and their correlation with disease severity in CIA were determined. Next, the antigen-presenting function and autoantibody production in B cells were evaluated by co-culture with effector T cells and iTregs, respectively, both in vitro and in vivo. Then, the mechanisms underlying these interactions were studied by adding neutralizing antibodies or transwell inserts and by adoptive transfer to B-cell-depleted CIA mice.RESULTS:The BANK1 level decreased in the peripheral blood, spleen and lymph nodes of CIA mice, particularly during the acute stage of arthritis, and exhibited negative correlation with disease severity and autoantibody production. B cell responses were enhanced by this decrease. B cells from CIA mice (CIA-B cells) promoted iTreg differentiation, proliferation and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) expression. Meanwhile, BANK1 expression in CIA-B cells increased after co-culture with iTregs, limiting B cell responses. All these interactions depended on cell contact with CTLA-4-overexpressing iTregs but were independent of CTLA-4 cytokine.CONCLUSION:Decreased BANK1 expression promotes B cell responses, resulting in an increased antigen presentation ability and autoantibody production that subsequently influences the communication between B cells and iTregs through a cell-contact-dependent and CTLA-4- cytokine-independent mechanism in CIA mice.

消化系统是系统性硬化症除皮肤外最常见的受累器官,从口腔到直肠肛门均可受累,范围非常广泛.系统性硬化症患者消化系统受累症状不一,但消化系统受累的危害却不容小觑,症状明显者严重影响患者的生存质量.本文对硬皮病消化系统受累的临床表现,评估方法和治疗进行详细综述,以帮助风湿科、消化科或其他科室医生能早期识别硬皮病消化道受累的表现,能够让患者早诊断、早治疗,改善生存质量.

系统性硬化症(Systemic sclerosis,SSc)是一种累及皮肤及多脏器的自身免疫性疾病,血管病变在SSc发病中起重要作用.本文综述了系统性硬化症血管病变诊治进展.

Background: The Acute Physiology and Chronic Health Evaluation II (APACHE II) score is used to determine disease severity and predict outcomes in critically ill patients. However, the prognostic significance of APACHE after acute paraquat (PQ) poisoning remains unclear. The meta-analysis was aimed to study the value of APACHE II in predicting mortality in PQ-exposed Chinese and Korean patients. Methods: Databases that included PubMed, Embase, Cochrane Library, and the Chinese National Knowledge Infrastructure were searched through August 2016. Studies using APACHE II to predict mortality in PQ-poisoned patients were selected. The odds ratio and weighted mean difference (WMD) were used to pool binary and continuous data. Additionally, we aggregated sensitivity, specificity, and other measures of accuracy. Statistical analyses were made using the Stata V.13.0 software. Results: This study included 29 studies, and 25 studies evaluated APACHE II scores on admission. Pooled data showed that survivors had significantly lower total scores than nonsurvivors (WMD = –7.29, and I2 = 98.2%, both P <.05). The pooled sensitivity of an APACHE II score ≥5 for predicting mortality was 75% and the pooled specificity was 86%. The positive likelihood ratio (PLR) was 5.3 and the negative likelihood ratio (NLR) was 0.29. The pooled sensitivity of an APACHE II score ≥10 for predicting mortality was 88% and the pooled specificity was 84%. The pooled PLR and NLR was 5.5 and 0.15, respectively. Conclusion: This study showed PQ-poisoned nonsurvivors had significantly higher APACHE II score than did survivors. APACHE II scores satisfactorily predicted mortality.

Background:The Acute Physiology and Chronic Health Evaluation II (APACHE II) score is used to determine disease severity and predict outcomes in critically ill patients. However, the prognostic significance of APACHE after acute paraquat (PQ) poisoning remains unclear. The meta-analysis was aimed to study the value of APACHE II in predicting mortality in PQ-exposed Chinese and Korean patients. Methods:Databases that included PubMed, Embase, Cochrane Library, and the Chinese National Knowledge Infrastructure were searched through August 2016. Studies using APACHE II to predict mortality in PQ-poisoned patients were selected. The odds ratio and weighted mean difference (WMD) were used to pool binary and continuous data. Additionally, we aggregated sensitivity, specificity, and other measures of accuracy. Statistical analyses were made using the Stata V.13.0 software. Results:This study included 29 studies, and 25 studies evaluated APACHE II scores on admission. Pooled data showed that survivors had significantly lower total scores than nonsurvivors (WMD=-7.29, and I-2=98.2%, both P<.05). The pooled sensitivity of an APACHE II score >= 5 for predicting mortality was 75% and the pooled specificity was 86%. The positive likelihood ratio (PLR) was 5.3 and the negative likelihood ratio (NLR) was 0.29. The pooled sensitivity of an APACHE II score >= 10 for predicting mortality was 88% and the pooled specificity was 84%. The pooled PLR and NLR was 5.5 and 0.15, respectively. Conclusion:This study showed PQ-poisoned nonsurvivors had significantly higher APACHE II score than did survivors. APACHE II scores satisfactorily predicted mortality.

OBJECTIVES:New interleukins (ILs), especially members of IL-1 and IL-12 families, have recently been reported to be involved in the development and regulation of autoimmune and inflammatory diseases. In this study, we aimed to explore the impact of these new ILs in psoriasis (Ps) and psoriatic arthritis (PsA).METHODS:Forty PsA patients, 20 Ps patients, and 20 healthy controls (HCs) were recruited. Blood samples were obtained for detecting the levels of ILs, IL-12/23p40, and tumor necrosis factor α (TNF-α). The severity of skin lesions was assessed by the Psoriasis Area and Severity Index (PASI). Arthritis activities of PsA patients were assessed by the PsA Joint Activity Index. For PsA patients, circulating osteoclastogenesis-related cytokines (osteoprotegerin and receptor activator of nuclear factor-κB ligand) and numbers of osteoclast precursors were evaluated. Radiographic features of affected joints in these patients were scored for erosion, joint-space narrowing, osteolysis, and new bone formation. Correlations among levels of these ILs, Ps, and PsA disease activities and bone erosions were studied.RESULTS:Ps and PsA patients had higher serum levels of TNF-α, IL-12/23p40, and IL-33. Serum levels of IL-34 and IL-35 were higher in PsA patients than in Ps patients and HCs. Patients with pustular Ps had higher serum levels of IL-36α and IL-38 than patients with Ps vulgaris or HCs. Increased serum levels of IL-36α were positively correlated with PASI.CONCLUSION:Certain ILs were elevated in the circulation of patients with Ps and PsA, which might contribute to the pathogenesis of skin lesions and arthritis.

BACKGROUND:Interleukin (IL)-37 has emerged as a fundamental inhibitor of innate immunity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. In the current study, we assessed the preventive and therapeutic effect of recombinant human IL-37 (rhIL-37) in human and murine gout models.METHODS:We investigated the expression of IL-37 in patients with active and inactive gouty arthritis and assessed the effect of rhIL-37 in human and murine gout models: a human monocyte cell line (THP-1) and human synovial cells (containing macrophage-like and fibroblast-like synoviocytes) exposed to MSU crystals, a peritoneal murine model of gout and a murine gouty arthritis model. After inhibition of Mer receptor tyrosine kinase (Mertk), levels of IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL-2) were detected by ELISA and expression of mammalian homologs of the drosophila Mad gene 3 (Smad), suppressor of cytokine signaling 3 (SOCS3), NACHT-LRR-PYD-containing protein 3 (NLRP3), and IL-8R of THP-1 were assessed by qPCR and western blot to explore the molecular mechanisms.RESULTS:Our studies strongly indicated that rhIL-37 played a potent immunosuppressive role in the pathogenesis of experimental gout models both in vitro and in vivo, by downregulating proinflammatory cytokines and chemokines, markedly reducing neutrophil and monocyte recruitment, and mitigating pathological joint inflammation. In our studies, rhIL-37 suppressed MSU-induced innate immune responses by enhancing expression of Smad3 and IL-1R8 to trigger multiple intracellular switches to block inflammation, including inhibition of NLRP3 and activation of SOCS3. Mertk signaling participated in rhIL-37 inhibitory pathways in gout models. By inhibition of Mertk, the anti-inflammatory effect of rhIL-37 was partly abrogated, and IL-1R8, Smad3 and S​OCS3 expression were suppressed, whereas NLRP3 expression was reactivated.CONCLUSIONS:Our studies reveal that IL-37 limits runaway inflammation initiated by MSU crystal-induced immune responses, partly in a Mertk-dependent fashion. Thus, rhIL-37 has both preventive and therapeutic effects in gouty arthritis.

Objective To observe hepatitis B virus (HBV) reactivation in 12 patients with rheumatic disease undergoing immunosuppressive therapy and to evaluate whether preemptive antiviral therapy is necessary for patients receiving disease-modifying anti-rheumatic drugs (DMARDs).Methods From January 2008 to March 2012,a total of 12 HBV-infected patients with rheumatic diseases were consecutively enrolled into this long-term follow-up study.Liver function and serum levels of HBV DNA were tested during the follow-up.Results The medium duration of follow-up was 41 months (range 16-48).Four patients received steroid treatment,and among them two patients without pre-emptive antiviral therapy developed HBV reactivation.After administr-ation of LAM or ETV,HBV replication was controlled in both patients.Five patients were treated with disease-modifying anti-rheumatic drugs and the other three patients received tumor necrosis factor-alpha-blocking agents.None of these patients received pre-emptive antiviral therapy.HBV reactivation did not occur in any of them.Conclusion HBV reactivation does occur in HBV-infected patients with rheumatoid diseases after immunosuppressive therapy.Pre-emptive antiviral therapy should be administered in patients who are receiving steroid therapy for rheumatic diseases.In contrast,DMARDs and TNFBA are relatively safe for HBV-infected patients with rheumatic diseases.Close monitoring of HBV DNA and ALT levels is necessary to the mana-gement of HBV reactivation.

With the continuous improvement of living standards, the prevalence of gout and hyperuricemia has been increasing these years. Diet is closely related to gout and hyperuricemia. Diet management is an essential part in the management of gout and hyperuricemia. The relationship of diet with gout and hyperuricemia is reviewed in this article.

The aims of this paper are to report hepatitis B virus reactivation in 12 patients with rheumatic disease undergoing immunosuppressive therapy and to evaluate whether pre-emptive antiviral therapy is necessary in patients receiving disease-modifying anti-rheumatic drugs. From January 2008 to March 2012, a total of 12 HBV-infected patients with rheumatic diseases were consecutively enrolled in the long-term follow-up. Liver function, HBV DNA, and serum aminotransferase level were tested during the follow-up. We also reviewed the published reports and summarized the clinical characteristics of HBV reactivation during immunosuppressive therapy in patients with rheumatic diseases. The medium duration of follow-up was 41 months (range 16–48). Patients were treated with prednisone, disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis factor-alpha-blocking agents (TNFBA). HBV reactivation was only documented in two patients treated with prednisone without pre-emptive antiviral therapy. One hundred patients from literature review were identified as having HBV reactivation; 20.8 % of the patients receiving prednisone experienced HBV reactivation compared to only 4.46 and 9.52 % of patients treated with DMARDs or TNFBA, respectively. This long-term follow-up of serial cases suggests that pre-emptive antiviral therapy should be administered in patients receiving prednisone therapy for rheumatic disease. In contrast, DMARDs and TNFBA are relatively safe to HBV-infected patients with rheumatic diseases. Close monitoring of HBV DNA and ALT levels is necessary in the management of HBV reactivation.