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 telitacicept in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled, phase 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of telitacicept in adult patients with primary SS (pSS) in a phase II randomized double-blind placebo-controlled trial. METHODS: Patients with pSS with positive anti-SSA antibody and ESSDAI ≥ 5 were randomly assigned, in a 1:1:1 ratio, to receive weekly subcutaneous telitacicept 240 mg, 160 mg, or placebo for 24 weeks. The primary end point was the change from baseline in the ESSDAI at week 24. Safety was monitored. RESULTS: A total of 42 patients were enrolled and randomized (n = 14 per group). Administration of telitacicept 160 mg resulted in a significant reduction in ESSDAI score from baseline to week 24 compared with placebo (P < 0.05). The placebo-adjusted least-squares mean change from baseline was -4.3 (95% CI -7.0, -1.6; P = 0.002). While, mean change of ESSDAI in telitacicept 240 mg was -2.7(-5.6-0.1) with no statistical difference when compared that in placebo group (P = 0.056). In addition, MFI-20 and serum immunoglobulins decreased significantly (P < 0.05) at week 24 in both telitacicept groups compared with placebo. No serious adverse events were observed in the telitacicept treating group. CONCLUSION: Telitacicept showed clinical benefits and good tolerance and safety in the treatment of pSS. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04078386.

Longitudinal study of patients with antimelanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease.

OBJECTIVES: To describe the 8-year longitudinal study and long-term prognosis of a large inception cohort of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (MDA5+) DM-interstitial lung disease (ILD) patients. METHODS: In total, 216 patients diagnosed with MDA5+ DM-ILD were enrolled and followed up to analyse long-term survival rate. Demographic and clinical variables were collected at baseline and each temporal end point. Seventy patients who survived the first year were analysed for the long-term serological and respiratory outcomes. RESULTS: A total of 85 patients (39.3%) died during the follow-up period up to 96 months, with 89% of the deaths occurring in the first year after diagnosis. Long-term outcome was reported in 70 patients. Serological markers including anti-MDA5 antibody showed significant improvement with time. Radiographic findings and pulmonary function also improved notably in the follow-up period, especially in rapidly progressive ILD group, as measured by high-resolution computed tomography imaging scores, the estimated forced vital capacity, estimated diffusing capacity of lung carbon monoxide and dyspnoea scores. Early application of anti-fibrosis therapy helped to improve long-term pulmonary function. CONCLUSIONS: MDA5+ DM-ILD patients had a high mortality rate despite aggressive treatment. Patients who survived the first year usually showed a significant improvement in serological markers and pulmonary function during the long-term follow-up.

Leflunomide versus azathioprine for maintenance therapy of lupus nephritis: a prospective, multicentre, randomised trial and long-term follow-up.

OBJECTIVES: Previous studies have compared mycophenolate mofetil and azathioprine as maintenance therapy for lupus nephritis (LN). Leflunomide is an immunosuppressant widely used in the treatment of rheumatoid arthritis. The aim of this investigator-initiated study was to compare the efficacy and safety of leflunomide versus azathioprine as maintenance therapy for LN. METHODS: 270 adult patients with biopsy-confirmed active LN from 7 Chinese Rheumatology Centres were enrolled. All patients received induction therapy with 6-9 months of intravenous cyclophosphamide plus glucocorticoids. Patients who achieved complete response (CR) or partial response (PR) were randomised to receive prednisone in combination with leflunomide or azathioprine as maintenance therapy for 36 months. The primary efficacy endpoint was the time to kidney flare. Secondary outcomes included clinical parameters, extrarenal flare and adverse effects. RESULTS: A total of 215 patients were randomly allocated to the leflunomide group (n=108) and azathioprine group (n=107). Kidney flares were observed in 17 (15.7%) leflunomide-treated patients and 19 (17.8%) azathioprine-treated patients. Time to kidney flare did not statistically differ (leflunomide: 16 months vs azathioprine: 14 months, p=0.676). 24-hour proteinuria, serum creatinine, serum albumin, serum C3 and serum C4 improved similarly. Extrarenal flare occurred in two patients from the azathioprine group and one patient from the leflunomide group. The incidence of adverse events was similar in the 2 groups: leflunomide 56.5% and azathioprine 58.9%. CONCLUSIONS: The efficacy and safety profile of leflunomide are non-inferior to azathioprine for maintenance therapy of LN. Leflunomide may provide a new candidate for maintenance therapy in patients with LN. TRIAL REGISTRATION NUMBER: NCT01172002.

Prognostic values of anti-Ro52 antibodies in anti-MDA5-positive clinically amyopathic dermatomyositis associated with interstitial lung disease.

OBJECTIVE: Anti-Ro52 antibody often co-occurs with anti-Jo1 antibody in antisynthetase syndrome and their co-occurrence correlates with a more aggressive clinical phenotype and poorer prognosis. The strong association of anti-Ro52 antibody with anti-melanoma differentiation-associated protein-5 (anti-MDA5) antibody has been indicated in juvenile myositis. The aim of this study was to assess the clinical significance of anti-Ro52 antibody in a cohort of adult patients with anti-MDA5-positive clinically amyopathic dermatomyositis with interstitial lung disease (CADM-ILD). METHODS: We assessed a cohort of 83 consecutive patients with anti-MDA5-positive CADM-ILD. Anti-MDA5 antibodies and anti-Ro52 antibodies were detected in immunoblotting and semi-quantitatively analysed by densitometry. Clinical features and the 24 month survival were compared between anti-MDA5-positive patients with and without anti-Ro52 antibodies. RESULTS: Anti-Ro52 antibodies were found in 74.7% of anti-MDA5-positive CADM-ILD patients and were associated with an increased frequency of rapidly progressive interstitial lung disease (RP-ILD; 54.8% vs 23.8%; P = 0.014) and cutaneous ulcerations (27.4% vs 4.8%; P = 0.033). The cumulative 24 month survival rate tended to be lower in patients with anti-Ro52 antibodies than patients without (59.9% vs 85.7%; P = 0.051). The combination of anti-Ro52 antibody status and anti-MDA5 antibody levels further stratified patients' survival rates, showing that the survival rate of patients who were dual positive for anti-MDA5 antibody and anti-Ro52 antibody was significantly lower than patients with mild positive anti-MDA5 antibody alone (59.9% vs 100%; P = 0.019). CONCLUSION: Anti-Ro52 antibody is highly prevalent in anti-MDA5-positive CADM-ILD patients and their coexistence correlates with a subgroup of patients with more aggressive phenotypes. The combination of anti-MDA5 antibody levels and anti-Ro52 antibody status could help to predict patients' prognosis and guide risk-based therapy.

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.

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.

Baricitinib in patients with rheumatoid arthritis with inadequate response to methotrexate: results from a phase 3 study.

OBJECTIVES: This study evaluated the efficacy and safety of baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) therapy. METHODS: In this phase 3, double-blind, 52-week, placebo-controlled study, 290 patients with moderately to severely active RA and inadequate response to MTX were randomly assigned 1:1 to placebo or baricitinib 4-mg once daily, stratified by country (China, Brazil, Argentina) and presence of joint erosions. Primary endpoint measures included American College of Rheumatology 20% response (ACR20) at week 12. Secondary endpoints included changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease Activity Score for 28-joint counts (DAS28)-high-sensitivity C-reactive protein (hsCRP), Simplified Disease Activity Index (SDAI) score ≤3.3, mean duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS 0-10), worst tiredness NRS, and worst joint pain NRS at week 12. RESULTS: Most patients (approximately 80%) were from China. More patients achieved ACR20 response at week 12 with baricitinib than with placebo (58.6% vs. 28.3%; p<0.001). Statistically significant improvements were also seen in HAQ-DI, DAS28-hsCRP, morning joint stiffness, worst tiredness, and worst joint pain in the baricitinib group compared to placebo at week 12. Through week 24, rates of treatment-emergent adverse events, including infections, were higher for baricitinib compared to placebo, while serious adverse event rates were similar between baricitinib and placebo. CONCLUSIONS: In patients with RA who had an inadequate response to MTX, baricitinib was associated with significant clinical improvements as compared with placebo.

Urine Metabolic Fingerprints Encode Subtypes of Kidney Diseases.

Metabolic fingerprints of biofluids encode diverse diseases and particularly urine detection offers complete non-invasiveness for diagnostics of the future. Present urine detection affords unsatisfactory performance and requires advanced materials to extract molecular information, due to the limited biomarkers and high sample complexity. Herein, we report plasmonic polymer@Ag for laser desorption/ionization mass spectrometry (LDI-MS) and sparse-learning-based metabolic diagnosis of kidney diseases. Using only 1 µL of urine without enrichment or purification, polymer@Ag afforded urine metabolic fingerprints (UMFs) by LDI-MS in seconds. Analysis by sparse learning discriminated lupus nephritis from various other non-lupus nephropathies and controls. We combined UMFs with urine protein levels (UPLs) and constructed a new diagnostic model to characterize subtypes of kidney diseases. Our work guides urine-based diagnosis and leads to new personalized analytical tools for other diseases.

Lupus-associated atypical memory B cells are mTORC1-hyperactivated and functionally dysregulated.

OBJECTIVES: A population of atypical memory B cells (AtMs) are greatly expanded in patients with active lupus, but their generation and pathophysiological roles are poorly defined. The aim of this study was to comprehensively characterise lupus AtMs with a purpose to identify therapeutic clues to target this B cell population in lupus. METHODS: Peripheral B cell subsets were measured by flow cytometry. Sorting-purified B cell subsets were subject to RNA sequencing and functional studies. Plasma cytokines and secreted immunoglobulins were detected by Luminex or ELISA. In situ renal B cells were detected by multiplexed immunohistochemistry. RESULTS: CD24-CD20hi AtMs were strongly increased in two Chinese cohorts of patients with treatment-naïve lupus. Gene expression profile indicated that B cell signalling and activation, lipid/saccharide metabolism and endocytosis pathways were abnormally upregulated in lupus AtMs. In addition, the mammalian target of rapamycin complex 1 (mTORC1) pathway was remarkably activated in lupus AtMs, and blocking mTORC1 signalling by rapamycin abolished the generation of T-bet+ B cells and terminal differentiation of lupus AtMs. Furthermore, lupus AtMs displayed a dysfunctional phenotype, underwent accelerated apoptosis, poorly co-stimulated T cells and produced proinflammatory cytokines. Interestingly, lupus AtMs were in a paradoxically differentiated status with markers pro and against terminal differentiation and enriched with antinucleosome reactivity. Finally, AtMs were accumulated in the kidneys of patients with lupus nephritis and associated with disease severity. CONCLUSIONS: These findings demonstrated that mTORC1-overactivated lupus AtMs are abnormally differentiated with metabolic and functional dysregulations. Inhibiting mTORC1 signalling might be an attractive option to target AtMs and to improve therapeutic effectiveness in patients with lupus.

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.

Serum KL-6 level is a prognostic marker in patients with anti-MDA5 antibody-positive dermatomyositis associated with interstitial lung disease.

OBJECTIVE: This study aimed to investigate the clinical significance of Krebs von den Lungen-6 (KL-6) serum levels in patients with anti-MDA5 antibody-positive dermatomyositis (anti-MDA5+ DM) having interstitial lung disease (ILD), especially in the amyopathic DM phenotype. METHODS: The serum KL-6 level was measured using a chemiluminescence enzyme immunoassay (CLEIA) in patients with anti-MDA5+ DM, including clinically amyopathic dermatomyositis (CADM)-ILD and classic DM-ILD, and healthy donors. The baseline and post-treatment serum KL-6 levels were determined in 39 patients with CADM-ILD who experienced remission or acute exacerbation. The association between laboratory findings, high-resolution computed tomography (HRCT) scores, pulmonary function tests (PFTs), and the predictive value of baseline KL-6 level for death was analyzed. RESULTS: The serum KL-6 levels were significantly higher in patients with CADM-ILD (1339 ± 1329 U/mL) compared with DM-ILD (642.3 ± 498.4 U/mL) and healthy donors (162.4 ± 54.01 U/mL). The KL-6 levels correlated positively with chest HRCT scores, serum lactate dehydrogenase, serum ferritin levels, and PFTs, but not with erythrocyte sedimentation rate. During follow-up, the post-treatment serum KL-6 levels significantly reduced in the remission/stable group, but increased in the acute exacerbation group. Higher levels of ferritin and KL-6 and HRCT scores were independently associated with poor prognosis. The 1-year survival rate was significantly lower in patients with high KL-6 level than in those with low KL-6 level. CONCLUSION: The serum KL-6 levels may be a useful marker for predicting and monitoring ILD in Chinese patients with anti-MDA5+ DM, especially amyopathic DM phenotype.

Deficiency of ß-arrestin1 ameliorates collagen-induced arthritis with impaired TH17 cell differentiation.

Rheumatoid arthritis (RA) is an inflammatory disease in which interleukin 17 (IL-17)-producing T helper 17 (T(H)17) cells have been critically involved. We show that in patients with RA, the expression of a multifunctional regulator ß-arrestin1 was significantly up-regulated in peripheral and synovial CD4(+) T cells, which correlated well with active phases of RA. In collagen-induced arthritis, deficiency of ß-arrestin1 ameliorated disease with decreased T(H)17 cell differentiation, proinflammatory cytokine production, synovitis, and cartilage and bone destruction. Further mechanistic study reveals that ß-arrestin1 promoted signal transducer and activator of transcription 3 (STAT3) activation required for T(H)17 cell differentiation through scaffolding the interaction of Janus kinase 1 and STAT3. These findings indicate a critical role for ß-arrestin1 in the pathogenesis of collagen-induced arthritis and T(H)17 cell differentiation and suggest ß-arrestin1 as a potential diagnostic biomarker and therapeutic target for RA.

Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: results of a randomised, controlled trial.

BACKGROUND AND OBJECTIVES: Efficacy of adalimumab for ankylosing spondylitis (AS) has been established for Western populations but not in the Chinese population. This study is the first to evaluate the efficacy and safety of adalimumab in Chinese patients with AS. METHODS: Chinese adults with active AS who had an inadequate response or were intolerant to ≥1 non-steroidal anti-inflammatory drugs were randomised to adalimumab 40 mg (N=229) or matching placebo (N=115) subcutaneously every other week (EOW) for 12 weeks, followed by a 12-week open-label adalimumab 40 mg EOW phase. The primary efficacy endpoint was the percentage of patients meeting the Assessment in Spondyloarthritis International Society (ASAS20) response criteria at week 12. The recently developed AS Disease Activity Score (ASDAS), as well as efficacy measures of spinal mobility, disease activity, physical function and quality of life were evaluated. RESULTS: At week 12, adalimumab treatment resulted in a significantly greater percentage of ASAS20 responders than placebo (67.2% versus 30.4%, respectively; p<0.001). Differences in ASAS20 were observed as early as week 2 (42.8% vs 6.1%, respectively; p<0.001). The percentages of patients achieving ASAS40, ASAS 5/6 and ASDAS inactive disease were significantly greater with adalimumab than placebo at week 12 (all p<0.001). Tuberculosis was reported in one patient. No cases of malignancy, lymphoma, demyelinating disease or lupus-like syndrome were reported during the study. CONCLUSIONS: Adalimumab significantly reduced the signs and symptoms, improved physical function and quality of life of Chinese patients with active AS, and was generally safe and well tolerated in this population.

Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of golimumab in Chinese patients with active AS. METHODS: Two hundred and thirteen patients were randomized in a 1:1 ratio to receive either s.c. injections of placebo from weeks 0 to 20 followed by golimumab 50 mg from weeks 24 to 48 (group 1, n = 105) or golimumab 50 mg from weeks 0 to 48 (group 2, n = 108), both every 4 weeks. Placebo crossover occurred at week 24, while early escape was at week 16. The primary endpoint was an improvement of at least 20% in the Assessment of SpondyloArthritis international Society (ASAS20) criteria at week 14. Major secondary endpoints included week 24 ASAS20 response and week 14 change scores for BASFI and BASMI. RESULTS: Golimumab treatment elicited significantly better responses than placebo in week 14 ASAS20 response [49.1% (53/108) vs 24.8% (26/105), respectively, P < 0.001], week 24 ASAS20 response (50.0% vs 22.9%, P < 0.001) and mean improvements in BASFI (-1.26 vs 0.11, P < 0.001) and BASMI (-0.42 vs -0.19, P = 0.021) scores at week 14. Additionally, golimumab treatment led to significant improvements in the mental and physical components of health-related quality of life (HRQoL) and sleep problems at week 24, all of which were further improved through week 52. During the 16-week placebo-controlled study period, 31.4% and 30.6% of patients had adverse events (AEs) in groups 1 and 2, respectively; similar AE reporting rates were observed through week 24 (34.3% and 32.0%) and among the golimumab-treated patients through week 56 (41.2%). CONCLUSION: Golimumab significantly reduced clinical symptoms/signs and improved physical function, range of motion and HRQoL in Chinese patients with active AS without unexpected safety concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01248793.

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.

[The efficacy and safety of tocilizumab combined with disease-modifying anti-rheumatoid drugs in the treatment of active rheumatoid arthritis: a multi-center, randomized, double-blinded, placebo-controlled trial].

OBJECTIVE: To evaluate the efficacy and safety of human anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) in combination with disease-modifying anti-rheumatoid drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) patients with moderate to severe activity and inadequate response to DMARDs. METHODS: The present study was a multi-center, randomized, double-blinded, placebo controlled trial. Eligible patients were randomized (tocilizumab:Placebo = 2:1) to one of two groups: tocilizumab 8 mg/kg group or placebo group. The drug was administered every 4 weeks by infusion along with stable dose of DMARDs. The primary analysis evaluated at week 24 included: the proportion of patients with American College of Rheumatology (ACR)20, ACR50 and ACR70 response; the average changes of ACR core components from baseline; the proportion of patients with disease activity score (DAS28) ≤ 3.2 and DAS28 < 2.6. Patients who completed double-blinded phase could choose to enter 24-week open-label therapy with tocilizumab 8 mg/kg infusion every 4 weeks. RESULTS: Totally 139 patients from tocilizumab group and 69 patients from placebo group completed the 24-week double-blinded period respectively with comparable baseline characteristics. The proportion of patients with ACR20, ACR50 and ACR70 in tocilizumab group was significantly higher than that in placebo group: 69.8% vs 24.6% (P < 0.05), 38.8% vs 10.1% (P < 0.05) and 12.9% vs 2.9% (P < 0.05) respectively. ACR core components change, proportion of patients with DAS28 ≤ 3.2 and DAS28 < 2.6 were all better in tocilizumab group than those in the placebo group. Decreased level of biomarkers C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3) and N-terminal propeptide of type IIA collagen (PIIANP) were observed in patients with tocilizumab treatment, indicating its positive effects on bone metabolism. A total of 202 patients received tocilizumab treatment in the study with the longest duration as 48 weeks, and all the indexes were improved further with the elongation of the treatment time. During the doubled blind phase, 42.4% of patients in the tocilizumab group had ≥ 1 adverse event (AE), compared with 27.9% of patients in the control group. The most common AE was infection, and most of the AEs were mild to moderate. Serious AEs occurred in 0.7% and 5.9% of patients in the tocilizumab and control groups, respectively. More patients in the tocilizumab group had higher percentage of increased alanine transaminase and aspartate transaminase (12.9% and 9.4%) compared to the placebo group (4.4% and 4.4%). Increase of total cholesterol, high density lipoprotein, low density lipoprotein, and triacylglycerol were observed in the tocilizumab group, but no increase of occurrence of cardiac events. No additional safety signals were found during the extension phase. CONCLUSION: The study showed that tocilizumab combined with DMARDs was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to DMARDs.

Healthcare Costs and Utilization for Patients With Systemic Lupus Erythematosus in China: A National Claims Database Study.

OBJECTIVES: This study aimed to describe the healthcare resource utilization (HCRU) and healthcare costs associated with systemic lupus erythematosus (SLE) management in China from the patient's and the payer's perspective. METHODS: HCRU and medical costs (2017 US dollar [USD]) between January 1 and December 31, 2017, were extracted from the national medical insurance claims database, China Health Insurance Research Association (consisting of claims from all public health insurance schemes in China), for adults with ≥ 1 SLE-related claim. The main analysis group comprised all adults with an SLE diagnosis and claim during 2017 (overall group); the annual subgroup (SLE diagnosis and claim in January 2017) informed annual HCRU and costs. RESULTS: The overall group consisted of 3645 adults with ≥ 1 SLE-related claim. Outpatient visits constituted 86.9% of healthcare visits. SLE-related healthcare outpatient costs were USD 433 per outpatient, and inpatient costs were USD 2072 per inpatient. Medication costs accounted for 75.0% (USD 42/56) of total costs for outpatient visits and 44.3% (USD 456/1030) for inpatient hospitalizations. Notably, 35.4% of patients had a severe SLE flare; mean SLE-related cost per severe flare was USD 1616. HCRU and costs were similar in the annual subgroup. Female sex, SLE flares, tertiary hospitals, renal involvement, and utilization of anti-infective drugs were associated with higher SLE-related patient costs. CONCLUSIONS: SLE in China is associated with considerable HCRU and medical costs, especially for patients experiencing severe SLE flares. Preventing organ involvement, infections, flares, and associated hospitalizations may reduce the burden on patients and healthcare providers in China.