Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).

Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricaemia: a randomized controlled phase II study.

OBJECTIVE: To evaluate the efficacy and safety of SHR4640, a highly selective urate transporter 1 inhibitor, in Chinese subjects with hyperuricaemia. METHODS: This was a randomized double-blind dose-ranging phase II study. Subjects whose serum uric acid (sUA) levels were ≥480 µmol/l with gout, ≥480 µmol/l without gout but with comorbidities, or ≥540 µmol/l were enrolled. Subjects were randomly assigned (1:1:1:1:1) to receive once daily 2.5 mg, 5 mg, 10 mg of SHR4640, 50 mg of benzbromarone or placebo, respectively. The primary end point was the proportion of subjects who achieved target sUA level of ≤360 µmol/l at week 5. RESULTS: 99.5% of subjects (n = 197) were male and 95.9% of subjects had gout history. The proportions of subjects who achieved target sUA at week 5 were 32.5%, 72.5% and 61.5% in the 5 mg, 10 mg SHR4640 and benzbromarone groups, respectively, significantly higher than the placebo group (0%; P < 0.05 for 5 mg and 10 mg SHR4640 group). The sUA was reduced by 32.7%, 46.8% and 41.8% at week 5 with 5 mg, 10 mg SHR4640 and benzbromarone, respectively, vs placebo (5.9%; P < 0.001 for each comparison). The incidences of gout flares requiring intervention were similar among all groups. Occurrences of treatment-emergent adverse events (TEAEs) were comparable across all groups, and serious TEAEs were not reported. CONCLUSIONS: The present study indicated a superior sUA-lowering effect and well tolerated safety profile after 5-week treatment with once-daily 5 mg/10 mg of SHR4640 as compared with placebo in Chinese subjects with hyperuricaemia. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03185793.

Inhibiting role of long non-coding RNA LINC01197 in inflammation in rheumatoid arthritis through the microRNA-150/THBS2 axis.

PURPOSE: Rheumatoid arthritis (RA) is a commonly diagnosed systemic autoimmune disease. Aberrant expression of long non-coding RNAs (lncRNAs) is closely linked to the development of RA. This study was conducted to explore the functions of the lncRNA LINC01197 in RA progression. METHODS: Differentially expressed lncRNAs/microRNAs/mRNAs in patients with RA were analyzed using RNA microarrays. A mouse model with RA was established and RA-fibroblast-like synoviocytes (RA-FLS) were acquired for in vitro experiments. The function of LINC01197 in inflammation and RA progression in mice and its role in the viability of RA-FLS were determined by experiments involving its overexpression or suppression. The sub-cellular localization of LINC01197 was determined and the downstream molecules involved in LINC01197-mediated events were identified. RESULTS: LINC01197 was poorly expressed in the synovial tissues in the RA model mice. Overexpression of LINC01197 reduced RA severity in mice and inhibited proliferation and inflammatory responses as well as promoted apoptosis in RA-FLS. Online predictions and dual luciferase reporter gene assays suggested that LINC01197 could bind to miR-150 and further regulate THBS2 expression. LINC01197 promoted THBS2 expression through miR-150 sponging and inactivated the TLR4/NF-κB signaling pathway, thus alleviating RA inflammation. CONCLUSION: The current study suggested that LINC01197 sponged miR-150 to promote THBS2 expression, leading to TLR4/NF-κB inactivation, and ameliorated RA inflammation. These findings may offer new insights into RA treatment.

Validation of new classification criteria of rheumatoid arthritis in an international multicentre study.

OBJECTIVES: Early identification of patients with rheumatoid arthritis (RA) is essential to allow prompt therapy. In this study, we aimed to evaluate the performance of the newly proposed ERA criteria, compared to the 1987 ACR and 2010 ACR/EULAR criteria in an international multicentre study. METHODS: A total of 606 patients with disease duration ≤2 years and age ≥16 years who were diagnosed as RA or non-RA were enrolled from China, Sweden and India. The clinical and laboratory parameters were recorded. We compared the sensitivity, specificity, predictive value, likelihood ratio (LR), and the area under the ROC curve (AUC) of three criteria in these cohorts. Concordance between the three criteria was calculated with the Kappa coefficient. RESULTS: Three hundred and twelve RA and 294 non-RA patients were included. The Early Rheumatoid Arthritis (ERA) criteria had significantly higher specificity compared to the 2010 ACR/ EULAR criteria (83.7% vs. 78.2%, p=0.02) and sensitivity were similar (79.2% vs. 78.5%, p=0.883). In comparison with the 1987 ACR criteria, the ERA criteria had higher sensitivity (79.2% vs. 54.5%, p<0.001) but lower specificity (83.7% vs. 89.1%, p<0.001), and the AUC of the ERA criteria (0.878) was comparable to the 2010 ACR/EULAR criteria (0.849) and higher than the 1987 ACR criteria (0.791, p<0.0001). Patients from the three countries, seronegative and very early arthritis cohorts yielded consistent results. CONCLUSIONS: The ERA criteria demonstrate a better performance across ethnics in early RA diagnosis, and is more feasible in daily practice.

4-O-methylhonokiol protects against diabetic cardiomyopathy in type 2 diabetic mice by activation of AMPK-mediated cardiac lipid metabolism improvement.

Diabetic cardiomyopathy (DCM) is characterized by increased left ventricular mass and wall thickness, decreased systolic function, reduced ejection fraction (EF) and ultimately heart failure. The 4-O-methylhonokiol (MH) has been isolated mainly from the bark of the root and stem of Magnolia species. In this study, we aimed to elucidate whether MH can effectively prevent DCM in type 2 diabetic (T2D) mice and, if so, whether the protective response of MH is associated with its activation of AMPK-mediated inhibition of lipid accumulation and inflammation. A total number of 40 mice were divided into four groups: Ctrl, Ctrl + MH, T2D, T2D + MH. Five mice from each group were sacrificed after 3-month MH treatment. The remaining animals in each group were kept for additional 3 months without further MH treatment. In T2D mice, the typical DCM symptoms were induced as expected, reflected by decreased ejection fraction and lipotoxic effects inducing lipid accumulation, oxidative stress, inflammatory reactions, and final fibrosis. However, these typical DCM changes were significantly prevented by the MH treatment immediately or 3 months after the 3-month MH treatment, suggesting MH-induced cardiac protection from T2D had a memory effect. Mechanistically, MH cardiac protection from DCM may be associated with its lipid metabolism improvement by the activation of AMPK/CPT1-mediated fatty acid oxidation. In addition, the MH treatment of DCM mice significantly improved their insulin resistance levels by activation of GSK-3ß. These results indicate that the treatment of T2D with MH effectively prevents DCM probably via AMPK-dependent improvement of the lipid metabolism.

4-O-methylhonokiol ameliorates type 2 diabetes-induced nephropathy in mice likely by activation of AMPK-mediated fatty acid oxidation and Nrf2-mediated anti-oxidative stress.

Diabetic nephropathy (DN) is one of the most serious long-term complications of type 2 diabetes (T2D). 4-O-methylhonokiol (MH) is one of the biologically active ingredients extracted from the Magnolia stem bark. In this study, we aim to elucidate whether treatment with MH can ameliorate or slow-down progression of DN in a T2D murine model and, if so, whether the protective response of MH correlates with AMPK-associated anti-oxidant and anti-inflammatory effects. To induce T2D, mice were fed normal diet (ND) or high fat diet (HFD) for 3 months to induce insulin resistance, followed by an intraperitoneal injection of STZ to induce hyperglycemia. Both T2D and control mice received gavage containing vehicle or MH once diabetes onset for 3 months. Once completing 3-month MH treatment, five mice from each group were sacrificed as 3 month time-point. The rest mice in each group were sacrificed 3 months later as 6 month time-point. In T2D mice, the typical DN symptoms were induced as expected, reflected by increased proteinuria, renal lipid accumulation and lipotoxic effects inducing oxidative stress, and inflammatory reactions, and final fibrosis. However, these typical DN changes were significantly prevented by MH treatment for 3 months and even at 3 months post-MH withdrawal. Mechanistically, MH renal-protection from DN may be related to lipid metabolic improvement and oxidative stress attenuation along with increases in AMPK/PGC-1α/CPT1B-mediated fatty acid oxidation and Nrf2/SOD2-mediated anti-oxidative stress. Results showed the preventive effect of MH on the renal oxidative stress and inflammation in DN.

Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate-inadequate responder Chinese patients with active rheumatoid arthritis: 24-week results from a randomised, double-blind, placebo-controlled phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.

Maintenance of effect of duloxetine in Chinese patients with pain due to osteoarthritis: 13-week open-label extension data.

BACKGROUND: The objectives of this study were to assess the maintenance of effect of duloxetine 60 mg once-daily (QD) in Chinese patients with chronic pain due to osteoarthritis (OA) of the knee or hip and to provide additional long-term safety data. METHODS: This was an open-label, extension phase of a randomized, double-blind, placebo-controlled clinical trial. Eligible patients were outpatients who met the American College of Rheumatology clinical and radiographic criteria for OA with a rating ≥4 on Brief Pain Inventory (BPI) 24-h average pain. After completing the 13-week placebo-controlled phase, patients originally assigned to placebo were titrated to duloxetine 60 mg QD (PLA_DLX), whereas patients originally assigned to duloxetine 60 mg QD remained on the same dose of duloxetine (DLX_DLX) for another 13 weeks. The maintenance effect of duloxetine 60 mg QD during the extension phase was evaluated by a 1-sided 97.5% confidence interval (CI) of the baseline-to-endpoint change in the extension phase for patients who took duloxetine and reported ≥30% reduction in BPI average pain at the end of placebo-controlled phase (placebo-controlled phase duloxetine responders). Other BPI severity and interference items, as well as safety and tolerability, were assessed. RESULTS: Of 342 patients entering the extension phase, 162 (97.6%) DLX_DLX-treated patients and 157 (89.2%) PLA_DLX-treated patients completed this phase. Most patients (76.0%) were female. Mean age was 60.6 years. Mean BPI average pain was 5.5 at baseline of the placebo-controlled phase. Among 113 placebo-controlled phase duloxetine responders, mean change in BPI average pain during the extension phase was - 0.59 (from 2.47 to 1.88); the upper bound of the 1-sided 97.5% CI was - 0.31 and less than the pre-specified non-inferiority margin of a 1.5-point increase (p < 0.001). Significant within-group improvements in all BPI items were observed for both PLA_DLX and DLX_DLX groups during the extension phase (all p < 0.01). No deaths or suicide-related events occurred. Seven (4.0%) PLA_DLX-treated patients and no DLX_DLX-treated patients discontinued due to an adverse event. CONCLUSION: The analgesic effect of duloxetine 60 mg QD among treatment responders was maintained for the entire duration of the extension phase. Duloxetine 60 mg QD was well tolerated during the extension phase. TRIAL REGISTRATION: ClinicalTrials.gov identification number NCT01931475 . Registered 29 August 2013.

Chinese lupus treatment and research group (CSTAR) registry: X. family history in relation to lupus clinical and immunological manifestations.

OBJECTIVES: This study aimed to examine the associations between family history and clinical manifestations and immunologic characteristics of lupus in China. METHODS: Based on their family history, lupus patients from the Chinese lupus treatment and research group (CSTAR) registry were categorised: familial lupus (FL), family history of other rheumatic disorders (RD), and sporadic lupus (SL). Demographic data, clinical manifestations, and laboratory data were compared among these three groups. RESULTS: A total of 2,104 patients from CSTAR were included, with 34 (1.6%) in the FL group, 50 (2.4%) in the RD group, and 2,020 (96.0%) in the SL group. There were no significant differences in age or gender among these groups (p=0.36 and p=0.75, respectively). The prevalence of discoid rash and positivity of anti-RNP antibodies differed significantly among the three groups. Photosensitivity and neurological disorder were marginally significantly different among the three groups (p=0.05). No statistical differences were observed in other clinical manifestations or laboratory results. In the FL group, first-degree relatives (25/34, 73.5%) had higher susceptibility to lupus. Rheumatoid arthritis (RA) (35/50, 70.0%) was the most frequent non-lupus rheumatic disorder in the RD group. CONCLUSIONS: Among lupus patients, the rate of familial lupus was lower in Chinese patients than among other ethnicities. Familial lupus cases are found mainly among their first-degree relatives. A family history of lupus did not significantly affect clinical phenotypes, except for higher frequency of discoid rash and anti-RNP in the FL group, and more anti-RNP positivity in the RD group.

Irreversible electroporation for the treatment of rabbit VX2 breast cancer.

Irreversible electroporation (IRE) is considered predominantly as a non-thermal ablative technique that uses electrical fields to permeabilize cell membranes and lead to cell death. In this study, we evaluated the efficacy of IRE in the rabbit VX2 breast cancer model. Thirty-five female New Zealand white rabbits were inoculated against VX2 breast cancer cells. The rabbits were randomly divided into two groups: a control group of 15 rabbits and an IRE treatment group of 20 rabbits. Treatment and treatment outcome were evaluated by computerized tomography (CT) scan (plain or contrast enhanced), tumor growth curves and pathological examination including H&E, TUNEL, PCNA and CD31 staining. All rabbits in the IRE treatment group experienced successful IRE without obvious complications except for thoracic major muscle injury. A focused, complete and well-defined ablation zone where tumor cells have been thoroughly eradicated was detected by H&E staining, along with increasing TUNEL staining. The expression of PCNA and CD31 was down-regulated at the periphery of the ablation region. As of the last follow-up, 10 rabbits (67%) in IRE group demonstrated disease is under control; 2 rabbits (13%) are in stable condition; 3 rabbits (20%) suffered from disease progression; the remaining 5 rabbits were sacrificed for pathological examination halfway through the study. Overall, the efficacy of IRE was demonstrated by the creation of a complete ablation region, with increased apoptosis in the ablation zone and decreased proliferation and microvessel density of tumor tissue at the periphery. IRE is a promising local treatment for breast cancer.

Association of Serum Interleukin-28B with Clinical Features, Laboratory Values and Radiographic Score in Rheumatoid Arthritis Patients.

BACKGROUND: Interleukin-28B (IL-28B) is a member of the interferon lambda family (also known as type III interferons), it has already been studied in many diseases, but it has almost never been studied in rheumatoid arthritis (RA). With this background, we determined the serum levels of IL-28B in RA patients and investigated its clinical significances. METHODS: IL-28B levels were measured by enzyme-linked immunosorbent assay (ELISA) in 80 RA patients and 80 healthy controls. Radiographs were scored for total Sharp score (TSS). RESULTS: Serum IL-28B levels were significantly lower in the RA than in the control (p = 0.02). Anticyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were negatively correlated with serum IL-28B levels. There was no association between serum IL-28B levels and TSS at baseline, but there was a significant difference in change of IL-28B during 6 months follow up between progressors and non-progressors. The disease activity of RA patients decreased, but no difference was observed in serum IL-28B levels between before and after disease-modifying anti-rheumatic drugs (DMARDs) therapy. CONCLUSIONS: These findings indicated a role of IL-28B in RA and it may contribute to avoiding osteoclasia in RA patients.

Rutin Attenuates Oxidative Stress and Proinflammatory Cytokine Level in Adjuvant Induced Rheumatoid Arthritis via Inhibition of NF-κB.

The present study was intended to elucidate the effect of rutin, a flavonoid, on arthritis in complete Freund's adjuvant-induced arthritic rats. The present study showed that more pronounced effect has been observed in the case of 15 mg/kg dose of rutin, with significant reduction in paw diameter together with positive modulation of hematological parameters as compared to 2 other tested doses. A significant upsurge in the level of superoxide dismutase, glutathione peroxidase and glutathione were observed together with decrease in the level of malondialdehyde after treatment with rutin in a dose-dependent manner. Furthermore, the effect of rutin on the tumor necrosis factor-α and interleukin-1ß in arthritic rats showed does-dependent lowering of these cytokines with maximum benefit at 15 mg/kg dose and the level of both NF-κB p65 and NF-κBp65 (Ser536) has been significantly reduced in the presence of rutin. Histopathological examination showed that the inflammatory cells infiltration, synovial hyperplasia, pannus formation and cartilage and bone erosion had considerably improved on administration of rutin. In conclusion, our paper strongly demonstrated the protective effect of rutin against the rheumatoid arthritis involved via suppression of NF-κB p65 protein expression.

Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity.

The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/ß production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of self-antigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.

Classification criteria of early rheumatoid arthritis and validation of its performance in a multi-centre cohort.

OBJECTIVES: To develop classification criteria for early rheumatoid arthritis (ERA) based on a large cohort of early inflammatory arthritis patients and to evaluate the performance of these criteria. METHODS: The study population comprised a cohort of early inflammatory arthritis patients with symptom duration less than one year. Classification criteria of ERA were developed by incorporating the most sensitive or specific variables. Performance of the ERA criteria, 1987 ACR and 2010 ACR/EULAR criteria were evaluated. RESULTS: A total of 803 patients were enrolled in this study. By the end of the one year follow-up, 514 patients were diagnosed with RA, 251 with other rheumatic diseases, and 38 patients with undifferentiated arthritis. The ERA criteria are as follows: 1) morning stiffness ≥30 minutes; 2) arthritis of 3 or more joint areas; 3) arthritis of hand joints; 4) positive RF; 5) positive anti-CCP antibody. Rheumatoid arthritis is defined by the presence of 3 or more of the criteria. The sensitivity (84.4%) of the ERA classification criteria was much higher than the 1987 ACR criteria (58.0%). In a validation cohort of early inflammatory arthritis patients, the area under the ROC curves (AUC) showed a better performance for the ERA criteria (0.906, 95%CI 0.866 to 0.945) than the 1987 ACR criteria (0.786, 95%CI 0.725 to 0.848) and the 2010 ACR/EULAR criteria (0.745, 95%CI 0.677 to 0.814). CONCLUSIONS: A set of ERA classification criteria has been developed with good performance for early RA. It is applicable in clinical practice and research.

A randomized, double-blind, and placebo-controlled multicenter clinical trial of a novel cytotoxic T-lymphocyte antigen-4 fusion protein, Leining, in Chinese active rheumatoid arthritis patients with an inadequate response to methotrexate.

To assess the clinical efficacy as well as safety profiles of Leining, a novel cytotoxic T-lymphocyte antigen-4 fusion protein, versus placebo in the treatment of Chinese active rheumatoid arthritis (RA) patients with an inadequate clinical response to methotrexate (MTX). In this 24-week, randomized, double-blind, placebo-controlled multicenter study, a total of 440 Chinese patients with active RA with an inadequate response to MTX were randomly assigned to receive Leining (10 mg/kg) or placebo. Clinical response was assessed using the American College of Rheumatology 20 % improvement criteria ACR20, ACR50, and ACR70, with ACR20 as the primary major endpoints. Disease activity scores in 28 joints with erythrocyte sedimentation rate assessment (DAS28-ESR) were used to evaluate disease activity. After 24 weeks of treatment, significantly more patients in Leining group achieved ACR20 response than those in placebo group (70.61 vs. 46.36 %; p < 0.001). Similarly, ACR50 and ACR70 responses of Leining group were significantly higher than those of placebo group (40.30 vs. 22.73 %; p < 0.001 and 16.67 vs. 7.27 %; p < 0.05, respectively). DAS28-ESR in Leining group was significantly reduced compared to that in placebo group, with greater clinically meaningful (>1.2 unit) improvement (54.85 vs. 29.09 %, p < 0.05). Both the rates of remission (DAS28-ESR < 2.6) and low disease activity (DAS28-ESR < 3.2) were greater in the Leining group than those in the placebo group (12.42 vs. 2.73 %; p < 0.05 and 15.45 vs. 2.73 %; p < 0.05 respectively). The overall incidence of adverse events was similar in both Leining and placebo groups. No neutralizing antibodies were detected. Leining demonstrated clinically meaningful efficacy compared with placebo in Chinese patients with active RA despite MTX therapy. Administration of Leining in combination with MTX for 24 weeks was well tolerated.

Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis.

BACKGROUND: Bicarbonate has recently been identified as a crucial factor affecting peptidylarginine deiminase (PAD) activity; however, the mechanism underlying its role in rheumatoid arthritis (RA) remains unclear. Iguratimod (IGU), a small-molecule disease-modifying anti-rheumatic drug, requires further investigation. This study aimed to explore the mechanism by which bicarbonate affects citrullination and inflammation in RA and identify new targets for IGU. METHODS: We enrolled 20 patients with RA in the study. Sodium bicarbonate cotransporter 2 (NBCe2) was detected in the peripheral blood neutrophils and peripheral blood mononuclear cells (PBMCs) of these patients. The effects of varying concentrations of IGU, methotrexate (MTX), dexamethasone (DXM), and S0859 (an NBCe2 inhibitor) on NBCe2, PAD2, PAD4, and citrullinated histone H3 (cit-H3) levels in, migration ability of, and cytokine production from neutrophils and PBMCs were examined. RESULTS: Our findings showed that in patients with RA, citrullinated protein production by peripheral blood neutrophils instead of PBMCs, which showed higher NBCe2 expression levels, increased with an increase in the bicarbonate concentration. In addition, tumor necrosis factor-alpha (TNF-α) promoted NBCe2 expression in neutrophils from patients with RA. Furthermore, we revealed that the inhibitory effects of IGU on neutrophil NBCe2 and cit-H3 levels, degrees of inhibition of neutrophil and PBMC migration, and suppression of interleukin 6, TNF-α, and metalloproteinase-9 secretion from neutrophil-like differentiated HL-60 cells did not substantially differ from those of MTX, DXM, and S0859 at specific doses. CONCLUSIONS: Bicarbonate promotes protein citrullination and inflammation in RA via NBCe2, and IGU can downregulate NBCe2.

Determinants of brachial-ankle pulse wave velocity in Chinese patients with rheumatoid arthritis.

OBJECTIVE: To investigate the relationship between Brachial-ankle pulse wave velocity (baPWV), and its associated risk factors in Chinese patients with RA. METHODS: 138 Chinese RA patients and 150 healthy subjects were included. baPWV of all the participants was measured. RA related factors were determined, as well as traditional cardiovascular risk factors. RESULTS: baPWV was significant higher in RA group (1705.44 ± 429.20 cm/s) compared to the healthy control group (1386.23 ± 411.09 cm/s) (P < 0.001). Compared with low baPWV group, high baPWV group patients were significantly older (P = 0.008) and taller (P = 0.033). Serum cholesterol (P = 0.035), triglycerides (P = 0.004), and LDL level (P = 0.006) were significantly higher in high baPWV group patients compared with low baPWV group patients. The baPWV of RA patients was positively correlated with age (r = 0.439, P < 0.001), and serum cholesterol level (r = 0.231, P = 0.035), serum triglycerides level (r = 0.293, P < 0.001), serum LDL level (r = 0.323, P = 0.003). Meanwhile, baPWV negatively correlated with the height of RA patients (r = -0.253, P = 0.043). Multivariate regression analysis showed that baPWV of RA group was independently associated with age and serum triglycerides level. CONCLUSIONS: The old age and high level of serum triglycerides may be the major determinants of arterial stiffness in Chinese RA patients.

The transient receptor potential channels in rheumatoid arthritis: Need to pay more attention.

Rheumatoid arthritis (RA) is characterized by the augment of vascular permeability, increased inflammatory cells infiltration, dysregulated immune cells activation, pannus formation and unbearable pain hyperalgesia. Ca2+ affect almost every aspect of cellular functions, involving cell migration, signal transduction, proliferation, and apoptosis. Transient receptor potential channels (TRPs) as a type of non-selective permeable cation channels, can regulate Ca2+ entry and intracellular Ca2+ signal in cells including immune cells and neurons. Researches have demonstrated that TRPs in the mechanisms of inflammatory diseases have achieved rapid progress, while the roles of TRPs in RA pathogenesis and pain hyperalgesia are still not well understood. To solve this problem, this review presents the evidence of TRPs on vascular endothelial cells in joint swelling, neutrophils activation and their trans-endothelial migration, as well as their bridging role in the reactive oxygen species/TRPs/Ca2+/peptidyl arginine deiminases networks in accelerating citrullinated proteins formation. It also points out the distinct functions of TRPs subfamilies expressed in the nervous systems of joints in cold hyperalgesia and neuro-inflammation mutually influenced inflammatory pain in RA. Thus, more attention could be paid on the impact of TRPs in RA and TRPs are useful in researches on the molecular mechanisms of anti-inflammation and analgesic therapeutic strategies.

New insights into MAIT cells in autoimmune diseases.

Mucosal-associated invariant T (MAIT) cells are resident T cells that express semi-invariant TCR chains and are restricted by monomorphic major histocompatibility complex (MHC) class I-related molecules (MR1). MAIT cells can be activated by microbial-specific metabolites (MR1-dependent mode) or cytokines (MR1-independent mode). Activated MAIT cells produce chemokines, cytotoxic molecules (granzyme B and perforin), and proinflammatory cytokines (IFN-γ, TNF-α, and IL-17), to clear pathogens and target infected cells involved in the pro-inflammatory, migratory, and cytolytic properties of MAIT cells. MAIT cells produce pro-inflammatory cytokines in the target organs of autoimmune diseases and contribute to the development and progression of autoimmune diseases. This article reviews the biological characteristics, activation mechanism, dynamic migration, and dual functions of MAIT cells, and focuses on the mechanism and potential application of MAIT cells in the early diagnosis, disease activity monitoring, and therapeutic targets of autoimmune diseases, to lay a foundation for future research.

Efficacy and Safety of CMAB008 Compared with Innovator Infliximab in Patients with Moderate-to-Severe Rheumatoid Arthritis Receiving Concomitant Methotrexate: A Randomized, Double-blind, Multi-center, Phase III Non-inferiority Study.

OBJECTIVES: The aim of this work is to verify the non-inferior efficacy and safety of CMAB008 compared with innovator infliximab in rheumatoid arthritis patients combined with methotrexate. METHODS: We conducted a randomized, double-blinded, parallel, positive control design, multicenter study, with a stable dose of methotrexate. Patients were enrolled randomly with a ratio of 1:1 to receive intravenously CMAB008 3 mg/kg or innovator infliximab 3 mg/kg at weeks 0, 2, 6, 14, 22 and 30. The primary efficacy endpoint was American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 30. The non-inferiority was established if the lower limit of the one-sided 97.5% confidence interval (CI) for the difference was more than - 15% and the equivalence was established if the two-sided 95% CI was within ± 15% in an exploratory equivalence analysis. The secondary endpoints included other efficacy assessment parameters, as well as immunogenicity, safety, and pharmacokinetics. RESULTS: In the full analysis population (FAS), 110 (57.6%) of 191 patients in the CMAB008 group and 120 (62.2%) of 193 patients in the innovator infliximab group reached the primary outcome of ACR20 at week 30. The differences of the rates were - 4.6% and the lower limit of one-sided 97.5% confidence interval was - 14.29%, not less than the lower limit of the non-inferiority margin (- 15%); so CMAB008 was non-inferior to innovator infliximab. Further, CMAB008 was equivalent to innovator infliximab both in FAS (difference - 4.6%, 95% CI - 14.29% to 5.12%) and PPS (difference - 3.3%, 95% CI - 13.18% to 6.62%). The efficacy, safety, immunogenicity, and pharmacokinetics are highly similar between CMAB008 and innovator infliximab. CONCLUSIONS: Non-inferior efficacy of CMAB008 to innovator infliximab is illustrated with similar early and lasting therapeutic effects, and the equivalence is further demonstrated. CMAB008 is well tolerated and has semblable safety compared with the innovator infliximab. TRIAL REGISTRATION NUMBER: NCT03478111.