Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist.

Ketone α-alkylation at the more-hindered site.

Control of the regioselectivity of α-alkylation of carbonyl compounds is a longstanding topic of research in organic chemistry. By using stoichiometric bulky strong bases and carefully adjusting the reaction conditions, selective alkylation of unsymmetrical ketones at less-hindered α-sites has been achieved. In contrast, selective alkylation of such ketones at more-hindered α-sites remains a persistent challenge. Here we report a nickel-catalysed alkylation of unsymmetrical ketones at the more-hindered α-sites with allylic alcohols. Our results indicate that the space-constrained nickel catalyst bearing a bulky biphenyl diphosphine ligand enables the preferential alkylation of the more-substituted enolate over the less-substituted enolate and reverses the conventional regioselectivity of ketone α-alkylation. The reactions proceed under neutral conditions in the absence of additives, and water is the only byproduct. The method has a broad substrate scope and permits late-stage modification of ketone-containing natural products and bioactive compounds.

Divergent Copper-salt-controlled Reactions of Donor-Acceptor Cyclopropanes and N-Fluorobenzene Sulfonimide: Access to the 1,3-Haloamines and Aminoindanes.

We herein report a method for divergent copper salt controlled reactions of donor-acceptor cyclopropanes and N-fluorobenzene sulfonimide (NFSI). Specifically, in the presence of CuX2 (X=Cl, Br), the cyclopropanes underwent formal umpolung 1,3-aminohalogenation bifunctionalization via a free radical mediated ring-opening process to afford 1,3-aminochlorination and 1,3-aminobromination products in moderate to good yields. In addition, by using CuI as a catalyst, we synthesized various aminoindane derivatives via 1,3-aminoarylation cyclization of D-A cyclopropanes, the reactions involved a free radical mediated ring-opening and subsequent ring expansion via C-H bond activation.

Automatic Time Picking for Weak Seismic Phase in the Strong Noise and Interference Environment: An Hybrid Method Based on Array Similarity.

The extraction of travel-time curve of seismic phase is very important for the subsequent inference of the structural properties of underground media in seismology. In recent years, with the increase in the amount of data, manual processing is facing significant challenges, and automatic signal processing has gradually become the mainstream. According to the similarity of array signals and considering the elimination of outliers, we propose an improved multi-channel cross-correlation method using the L1 norm measure to obtain preliminary results, which builds on a new controllable measurement mode. Then, the post-correction step is carried out in combination with the signal gain property of beamforming technique. Based on these two methods, this paper proposes a new scheme of automatic arrival time picking. We apply the scheme to actual data to verify the effects of the two methods step by step. The entire scheme achieves fine results: direct water waves, seismic waves refracted by the crust and seismic waves reflected by the upper mantle are automatically detected. In addition, compared with the two traditional methods, the scheme proposed in this paper has a better overall effect and a reasonable computation cost.

A clinical practice guideline for the screening and assessment of enthesitis in patients with spondyloarthritis.

Objective: The aim of this review is to provide guidance on the selection of approaches to the screening and assessment of enthesitis in patients with spondyloarthritis (SpA). Methods: Twenty-four questions regarding the approaches to the screening and assessment of enthesitis and the implementation details were devised, followed by a systemic literature review. The Grading of Recommendations Assessment, Development, and Evaluation methodology was employed in the development of this guideline, with modifications to evaluate non-interventional approaches under comprehensive consideration of costs, accessibility, and evidence strength. A consensus from the voting panel was required for the inclusion of the final recommendations and the strength of each recommendation. Results: Seventeen recommendations (including five strong recommendations) were included in this guideline. The voting panel expressed unequivocal support for the necessity of screening and assessment of enthesitis in patients with SpA. It was agreed unanimously that symptom evaluation and physical examination should serve as the initial steps to the recognition of enthesitis, whereas Maastricht Ankylosing Spondylitis Enthesitis Score is a reliable tool in both clinical trials and daily medical practice. Ultrasound examination is another reliable tool, with power Doppler ultrasound as an informative addition. Notwithstanding its high resolution, MRI is limited by the costs and relatively low accessibility, whereas radiographs had low sensitivity and therefore should be rendered obsolete in the assessment of enthesitis. PET/CT was strongly opposed in the detection of enthesitis. Conclusion: This guideline provides clinicians with information regarding the screening and assessment of enthesitis in patients with SpA. However, this guideline does not intend on dictating choices, and the ultimate decisions should be made in light of the actual circumstances of the facilities.

Corporate climate risk and stock market reaction to performance briefings in China.

This study aims to enrich our understanding of the valuation consequence of climate risk in financial markets. The primary focus of our study is on the stock price reaction to firms' climate-risk-related information. We employ transcripts of Chinese listed firms' performance briefings to capture the climate risk at the firm level. Using a sample of Chinese listed firms between 2009 and 2021, we find that greater corporate climate risks lead to negative market reactions over a short time window, consistent with the market quickly comprehending corporate climate risks. This result holds for a series of robustness checks. We further find that the negative impact of corporate climate risk on the stock price reaction operates through the increased market trading activities, greater investor attention, and reduced positive media coverage. Finally, we demonstrate that industry carbon emission, local abnormal temperature, state ownership, institutional shareholding, and dividend payout are important moderators that shape the association of the corporate climate risk and the adverse market reaction. Our evidence suggests that disclosures of climate-related information can help the stock market to price climate risk more efficiently.

Acid Sphingomyelinase and Acid ß-Glucosidase 1 Exert Opposite Effects on Interleukin-1ß-Induced Interleukin 6 Production in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Acid sphingomyelinase (ASM) and acid ß-glucosidase 1 (GBA1) catalyze ceramide formation through different routes, and both are involved in rheumatoid arthritis (RA) pathogenesis as well as IL-6 production. However, whether ASM and GBA1 regulate IL-6 production in RA remains unknown. Serum ASM, GBA1, and ceramide levels were measured in RA patients and healthy controls by enzyme-linked immunosorbent assay, and their correlations with clinical indicators of patients were evaluated. Pharmacologic inhibitors or small hairpin RNAs of ASM and GBA1 were employed to explore the roles of ASM and GBA1 in IL-6 production, cell behavior, and MAPK signaling in fibroblast-like synoviocytes from RA patients (RAFLS). ASM, GBA1, and ceramide serum levels were significantly elevated in patients with RA. GBA1 and ceramide serum levels were negatively and positively correlated with IL-6 serum level in RA patients, respectively. ASM inhibitor or knockdown of ASM abolished IL-1ß-induced IL-6 expression and secretion. Functionally, ASM inhibitor suppressed IL-1ß-induced cell proliferation, migration, and invasion in RAFLS. Mechanistically, ASM inhibitor or knockdown of ASM effectively countered IL-1ß-induced activation of p38 MAPK signaling. The pharmacologic inhibitor or knockdown of GBA1 exhibited the opposite effects. Importantly, p38 inhibitor blocked IL-1ß-induced IL-6 production in RAFLS. ASM plays a pathogenic role in RA, whereas GBA1 plays a protective role in RA possibly by regulating IL-6 production in RAFLS at least partially via p38 signaling, serving as potential therapeutic targets in RA treatment.

Safety and Efficacy of Prefilled Liquid Etanercept-Biosimilar Yisaipu for Active Ankylosing Spondylitis: A Multi-Center Phase III Trial.

INTRODUCTION: The aim of this work is to examine the efficacy and safety of prefilled liquid etanercept-biosimilar Yisaipu versus lyophilized Yisaipu in active ankylosing spondylitis (AS) patients. METHODS: This double-blind, phase III trial with non-inferiority design randomized adult patients with active AS in a 3:1:1 ratio to receive twice-weekly 25-mg prefilled liquid Yisaipu for a total of 48 injections (group I, n = 330), once-weekly 50-mg prefilled liquid Yisaipu for 24 injections (group II, n = 110), or twice-weekly 25-mg lyophilized Yisaipu for 48 injections (group III, n = 110). Both physicians and patients who received 25-mg twice-weekly lyophilized or liquid Yisaipu were blinded to treatment assignment while patients who received 50-mg once-weekly liquid Yisaipu received treatment in an open-label design. In addition, 90 patients in the PK/PD study were randomized in a 1:1:1 ratio to each group. The primary outcome was the proportion of patients who achieved ASAS20 at week 24. RESULTS: A total of 640 subjects were enrolled. The proportion of patients who attained ASAS20 at week 24 was 85.56% in group I, 85.71% in group II, and 83.45% in group III (group I vs. III, P = 0.545; group II vs. III, P = 0.605). The difference between group I and III was 2.10% (95% CI - 5.06%, 9.27%) and 2.26% (95% CI - 6.21%, 10.73%) between group II and III, meeting the non-inferiority threshold (Δ = - 15%) (P < 0.001). Except for a statistical difference between group I (75.83%) and group III at week 8 (64.75%, P = 0.011), there was no statistical difference in the ASAS20 attainment rate among the three groups at other time points. The incidence of serious adverse events was comparable among the three groups (group I, 2.50%, II, 2.86% and III, 1.43%; P > 0.05). No deaths were reported. CONCLUSIONS: Once-weekly 50-mg or twice-weekly 25-mg prefilled liquid Yisaipu is safe and non-inferior to twice-weekly 25-mg lyophilized Yisaipu. TRIAL REGISTRATION: CTR20130124 and NCT04345458.

Acute effects of air pollution on lupus nephritis in patients with systemic lupus erythematosus: A multicenter panel study in China.

Air pollution may trigger systemic lupus erythematosus (SLE). However, few studies have investigated the associations between air pollution and complications of SLE, such as lupus nephritis (LN). In this study, multicenter longitudinal data from 13 hospitals in China, including 8552 SLE patients with 24,762 visits, were used. Based on the generalized estimating equation (GEE) model, we assessed the associations of LN occurrence with short-term exposures to different air pollutants including particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). We identified 2672 LN patients, and about half of them were from east China. Our results based on the entire data set showed that PM2.5 and NO2 were risk factors for LN within one month after exposure, with odds ratio of 1.16 (95% confidence interval (CI), 1.08-1.19) at lag 18 day and 1.19 (95% CI, 1.12-1.26) at lag 16 day relative to an interquartile range (IQR) increase in PM2.5 and NO2, respectively. This positive association between LN and NO2 was also observed for south, west, and east China. In addition, we found that the short term exposure to CO and O3 was not generally associated with LN. Finally, the negative associations of LN with SO2 were found for the entire region and east China. Our results implied that SLE patients may gain the health benefits of air quality improvement in China. Our work also provided evidence that short-term variations in air pollution may trigger LN, and further studies are needed to confirm these findings and the potential pathogenic mechanisms should be explored.

2018 Chinese Guidelines for the Diagnosis and Treatment of Rheumatoid Arthritis.

A multidisciplinary guideline development group was established to formulate this evidence-based diagnosis and treatment guidelines for rheumatoid arthritis (RA) in China. The grading of recommendations, assessment, development, and evaluation (GRADE) system was used to rate the quality of the evidence and the strength of recommendations, which were derived from research articles and guided by the analysis of the benefits and harms as well as patients' values and preferences. A total of 10 recommendations for the diagnosis and treatment of RA were developed. This new guideline covered the classification criteria, disease activity assessment and monitoring, and the role of disease modifying antirheumatic drugs (DMARDs), biologics, small molecule synthetic targeting drugs, and glucocorticoids in the treat-to-target approach of RA. This guideline is intended to serve as a tool for clinicians and patients to implement decision-making strategies and improve the practices of RA management in China.

Stereospecific Synthesis of cis-2,5-Disubstituted Pyrrolidines via N,O-Acetals Formed by Hydroamination Cyclization-Hydroalkoxylation of Homopropargylic Sulfonamides in HFIP.

We reported a novel two-step stereoselective synthesis of functionalized pyrrolidines from homopropargylic sulfonamides and nucleophiles via an isolable N,O-acetal intermediates. This reaction features mild conditions and good scope of substrates. In addition, the use of hexafluoroisopropanol, acting as a solvent, an additive, a weak nucleophile, and a good leaving group, is pivotal to the success of the method. Moreover, reactions of chiral homopropargylic sulfonamides afford only 2,5-cis-disubstituted pyrrolidines with high diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to >99% ee). The overall reaction constitutes a formal 1,1-bifunctionalization of terminal alkynes, which has hitherto been reported only rarely. Additionally, this method provides efficient access to pharmaceutical intermediate and to carry out postmodification of natural products.

IL-38 restrains inflammatory response of collagen-induced arthritis in rats via SIRT1/HIF-1α signaling pathway.

OBJECTIVE: To observe the restraining effect of IL-38 on inflammatory response in collagen-induced arthritis rats (CIA), and to explore the regulatory mechanism of SIRT1/HIF-1α signaling pathway. METHODS: 40 SD rats were randomly divided into Control group, CIA group, CLL group and CLH group, with 10 rats in each group; CIA rat model was established. The effects of IL-38 on arthritis index, inflammatory response, osteogenic factor and angiogenic factor were observed by methods including HE staining, ELISA, immunohistochemical and immunofluorescence. Human synoviocytes were cultured in vitro, and SIRT1 inhibitors were added to detect the expression for relating factors of SIRT1/HIF-1α signaling pathway by Western blot. RESULTS: IL-38 could alleviate CIA joint damage and restrain inflammatory response, could up-regulate the expression of OPG in CIA rats and could down-regulate the expression of RANKL and RANK. IL-38 could restrain the expression of VEGF, VEGFR1, VEGFR2 and HIF. Moreover, we found that IL-38 could up-regulate the SIRT1 expression and down-regulate the HIF-1α, TLR4 and NF-KB p65 expression in CLL and CLH groups. From the treatment of synoviocytes to simulate the CIA model and the treatment of SIRT1 inhibitors, we demonstrated that the inhibitory effect of IL-38 on inflammatory factors and regulation of SIRT1/HIF-1α signaling pathway-related proteins were inhibited. CONCLUSION: IL-38 can restrain the inflammatory response of CIA rats, can promote the expression of osteogenic factors, can inhibit neovascularization, and can alleviate joint damage in rats. The mechanism may be related to the regulation of SIRT1/HIF-1α signaling pathway.

Anti-cyclic citrullinated peptide antibody predicts the development of rheumatoid arthritis in patients with undifferentiated arthritis.

BACKGROUND: Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development. METHODS: We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression. RESULTS: A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001). CONCLUSION: As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.

Efficacy and Safety of Loxoprofen Hydrogel Transdermal Patch Versus Loxoprofen Tablet in Chinese Patients with Myalgia: A Double-Blind, Double-Dummy, Parallel-Group, Randomized, Controlled, Non-Inferiority Trial.

BACKGROUND AND OBJECTIVE: Loxoprofen (LOX) is a nonsteroidal anti-inflammatory drug (NSAID). Although oral administration of LOX has been widely prescribed, clinical guidelines for osteoarthritis generally recommend topical rather than oral NSAIDs in specific patients. However, there is limited information on the effects of loxoprofen sodium oral (LOX-O) versus loxoprofen sodium hydrogel transdermal patch (LOX-T) in myalgia patients. Hence, this non-inferiority study was designed to compare the efficacy and safety of LOX-O versus LOX-T in Chinese patients with myalgia. METHODS: In this double-blind, double-dummy, parallel-group, randomized controlled trial, 182 Chinese patients were enrolled and randomized equally to either LOX-T or LOX-O treatment for 2 weeks. Patients in the LOX-T group applied one sheet of the active LOX-T once a day on the affected site and took one placebo tablet three times a day immediately after meals, whereas patients in the LOX-O group applied one sheet of the placebo patch once a day and took one active LOX-O three times a day. Primary endpoint was the proportion of patients with 50% overall improvement or higher at the final visit. The cutoff value of a non-inferiority difference was set as - 10%. RESULTS: In the full analysis set, the primary endpoint of final efficacy rate was 81.3% (n = 91) in the LOX-T group and 72.2% (n = 88) in the LOX-O group. The difference between the two groups was 9.1% [95% confidence interval (CI) - 3.1 to 21.3%], which showed that LOX-T was non-inferior compared with LOX-O. No serious adverse events occurred in either group. CONCLUSIONS: This trial showed the non-inferiority of LOX-T compared with LOX-O in efficacy and safety in Chinese patients with myalgia. Also, the characteristic features of topical LOX-T, such as better compliance and lower risk-benefit ratio, make it more favorable for clinical practice. TRIAL REGISTRATION: The study was registered in the isrctn.com registry (ISRCTN trial ID: ISRCTN16227145).

Causes of death in hospitalized patients with systemic lupus erythematosus: a 10-year multicenter nationwide Chinese cohort.

To estimate the mortality and describe the causes of death in a large multicenter cohort of hospitalized patients with SLE in China. This was a retrospective study of a nationwide SLE cohort (10 centers, 29,510 hospitalized patients) from 2005 to 2014 in China. Standardized mortality ratios (SMRs) were calculated for all death and were stratified by sex and age. Chi-square test was used to determine whether the major causes of death vary in age, sex, duration of SLE, disease activity, or medications. Comparison between dead patients and survival controls was used to identify the risk factors for mortality. Logistic regression analysis was used to evaluate the risk factors for mortality. A total of 360 patients died during the study period, accounting for 1.22%. The overall SMR was 2.13 (95% CI 1.96, 2.30), with a particularly high SMR seen in subgroups characterized by younger age. Infection (65.8%) was the most common cause of death, followed by lupus nephritis (48.6%), hematological abnormality (18.1%), neuropsychiatric lupus/NPSLE (15.8%), and interstitial pneumonia (13.1%). Cardiovascular disease and malignancy contributed little to the causes of death. Infection, in particular severe pulmonary infection, emerged as the foremost risk factor for mortality, followed by lupus encephalopathy. However, lupus nephritis and hematological abnormalities occurred more frequently in survival patients. SLE patients at a younger age of diagnosis have a poorer prognosis. Infection dominated the causes of death in recent China. Ethnicity and medications might account for the differences in causes of death compared with western populations.

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.

IBI303, a biosimilar to adalimumab, for the treatment of patients with ankylosing spondylitis in China: a randomised, double-blind, phase 3 equivalence trial.

BACKGROUND: China approved adalimumab for the treatment of ankylosing spondylitis in 2013. However, the cost of the standard dose regimen exceeds ¥15 000 (around US$2250) per month, which is well beyond affordability for most Chinese patients. No biosimilars of adalimumab are available in China; IBI303 is a monoclonal antibody against TNFα that is currently in development. This study aimed to assess the clinical equivalence of IBI303 to adalimumab in patients with ankylosing spondylitis. METHODS: This phase 3, multicenter, double-blind, parallel, randomised controlled equivalence trial was done in 20 centers across China. Patients were randomly assigned in a 1:1 ratio to receive either 40 mg of IBI303 or 40 mg of adalimumab as a subcutaneous injection every 2 weeks until week 22. Patients were eligible for inclusion if they were between 18 and 65 years old, fulfilled the 1984 Modified New York Criteria for ankylosing spondylitis, were non-responders, inadequate responders, or intolerant to treatment with NSAIDs for 4 or more weeks, and had active ankylosing spondylitis defined by two or more indicators of disease severity. The investigators, site staff, patients, sponsors, and the contract research organisation were masked to treatment allocation. The primary outcome was the proportion of patients who met the Assessment of SpondyloArthritis international Society (ASAS) Response Criteria for a 20% improvement (ASAS20) at week 24 after treatment. Equivalence was established if the 95% CI of the difference in responses between groups was between -15% and 15%. Efficacy analyses were done in the full analysis population and in the per-protocol population. Safety analyses were done in all randomly assigned patients who received at least one drug dose. This trial is registered with ClinicalTrials.gov, number NCT02893254. FINDINGS: Between Sept 22, 2016, and May 11, 2018, 438 patients were randomly allocated either to the biosimilar IBI303 group (n=220) or the adalimumab group (n=218). In the full analysis population, 165 (75%) of 220 patients in the IBI303 group (95% CI 68·7-80·6) and 158 (72%) of 218 patients in the adalimumab group (66·0-78·3) reached the primary outcome of ASAS20 at week 24. The difference between the two groups was 2·3% with a 95% CI of -5·9 to 10·6, which fell within the pre-specified equivalence boundaries at week 24 (-15 to 15). In the per-protocol population, 163 (80%) of 203 patients in the IBI303 group reached ASAS20 at week 24 (95% CI 74·1-85·5), compared with 150 (80%) of 188 patients in the adalimumab group (73·3-85·3%). The difference between the groups was 0·6% with a 95% CI of -7·4 to 8·6%, which also fell within the pre-specified equivalence boundaries at week 24. Safety and tolerability profiles were similar between the two groups; 174 (79%) of 220 patients in the IBI303 group and 178 (82%) of 218 patients in the adalimumab group had treatment-emergent adverse events. INTERPRETATION: This trial showed therapeutic equivalence of IBI303 and adalimumab in the treatment of ankylosing spondylitis. The efficacy, safety, and immunogenicity of both drugs are highly similar. IBI303 could be an alternative treatment option for patients with ankylosing spondylitis in China. FUNDING: Innovent Biologics, National Major Scientific and Technological Special Project for "Significant New Drugs Development".

KLF15 Regulates the Expression of MMP-3 in Human Chondrocytes.

Imbalance of metabolism on catabolic and anabolic molecules in chondrocytes has been associated with the cartilage damage in osteoarthritis (OA). Matrix metalloproteinase-3 (MMP-3), one of the most important catabolic factors, acts as a cartilage-degrading enzyme, which is associated with the degradation of type II collagen and aggrecan. Kruppel-like factor 15 (KLF15), an important member of the KLFs family, possesses a variety of biological functions. However, the physiological roles of KLF15 in chondrocytes and the pathological progression of OA remain unknown. In the current study, we report that KLF15 is expressed in primary chondrocytes as well as ATDC5 and SW1353 chondrogenic cell lines. Interestingly, KLF15 expression was significantly lower in chondrocytes from OA patients compared with those from normal subjects. Also, we found that tumor necrosis factor α (TNF-α) treatment reduced the expression of KLF15 mediated by p53 in human chondrocytes. Notably, it was shown that KLF15 reduced TNF-α-induced expression of MMP-3 at the transcriptional level. Mechanistically, the chromatin immunoprecipitation assay displayed that KLF15 could bind to the promoter region of MMP-3. Our results suggest that KLF15 might be a novel therapeutic target of OA.

Increased frequency of CCR7+CD4+ T cells from patients with primary Sjögren's syndrome: An indicator of disease activity rather than of damage severity.

Expression of CCR7 on T cells has been reported to be associated with the lymphocytic migration and infiltration, which is recognized as a vital part of the pathogenesis of Primary Sjögren's syndrome (pSS). Here, we compared the expression of CCR7 on CD4+T cells between pSS patients and control groups, including healthy donors (HD) and patients with systemic lupus erythematosus (SLE) and examined correlations with disease activity and damage severity, which were evaluated by EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and Sjogren's Syndrome Disease Damage Index (SSDDI), respectively. Peripheral blood mononuclear Cells (PBMC) were obtained from patients and controls and expressions of CCR7 were evaluated by flow cytometry. CCR7 was selectively and frequently expressed on CD4+T cells, but less on CD8+ T cells of patients with pSS. In contrast, this phenomenon was neither seen in normal subjects nor in patients with SLE. The expression level of CCR7 in the peripheral blood CD4+ T cells is closely correlated with ESSDAI, but not SSDDI. Correspondently, the chemotactic index (CI) of CD4+T cells was higher than CD8+T cells in patients with pSS. Furthermore, the CI of CD4+T cells is also higher than that of other controls, which is correlated with ESSDAI. All the findings suggested that CCR7 might play an important role in the development of pSS by mediating the migration of CD4+cells. Thus, the expression of CCR7 in CD4+ T cells is probably a useful biomarker to evaluate and monitor disease activity. CCR7 can also potentially be a novel target for the therapy of pSS.

Remission assessment of rheumatoid arthritis in daily practice in China: a cross-sectional observational study.

The objective of this study is to evaluate the remission rate and describe the current use of medication in a large cohort of rheumatoid arthritis (RA) patients under routine clinical care in China. RA patients were recruited from 40 large teaching hospitals nationwide in China. Data regarding RA disease activity, medication treatment, and adverse events were recorded using a standardized clinical data questionnaire. RA remission was evaluated by the 28 Joint Disease Activity Score DAS28-ESR Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria. A total of 1945 patients with RA were included in the study. The proportions of patients who fulfilled the DAS28-ESR, CDAI, SDAI, and ACR/EULAR remission criteria were 10.90%, 6.17%, 5.04% , and 1.75%, respectively. Most patients had taken at least one disease-modifying anti-rheumatic drug (DMARD), and the most common prescriptions included leflunomide (LEF) and methotrexate (MTX). DMARD combined with botanics were the most common and dominant strategy for RA management (29.16%). Overall, 433 patients (22.27%) had at least one adverse event. Gastrointestinal adverse events (41.27%) were the most frequently reported events. The incidence of side effects in patients using biologics DMARDs (bDMARDs) was significantly lower than that in those taking MTX, LEF, or sulfasalazine (SSZ). The remission rate of RA disease activity, as assessed in Chinese clinical practice, was very low. Adverse effects of the medicine occurred in approximately one in five RA patients, with bDMARDs were demonstrated to be the medication with the lowest side effects.