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.

Short-term, low-dose etoposide in refractory adult-onset Still's disease-associated macrophage activation syndrome.

INTRODUCTION: In this study, we modified the classical regimen of the hemophagocytic lymphohistiocytosis-04 protocol and evaluated the efficacy and safety of short-term, low-dose etoposide in patients with refractory macrophage activation syndrome (MAS) associated with adult-onset Still's disease (AOSD). METHODS: A total of 17 patients with refractory AOSD-associated MAS were enrolled and received short-term, low-dose etoposide (100 mg twice a week for four times). Another 11 patients, who were not treated with etoposide, were included as historical controls. Patient information, such as clinical manifestations, laboratory results, treatments, and short-term prognosis, were recorded and analyzed. RESULTS: In this case series, 88.24% of the patients with MAS who were treated with short-term, low-dose etoposide had a favorable response in 3 weeks, which was significantly higher (p = 0.017) than that in the patients with MAS who were treated without etoposide (45.45%). The 90-day survival rate after the onset of MAS was significantly higher (p = 0.0029) among the patients in the short-term etoposide group (16/17, 94.12%) than in the control group (5/11, 45.45%). CONCLUSION: The regimen of short-term (2 weeks), low-dose etoposide was highly effective in the treatment for patients with refractory AOSD-associated MAS with an acceptable safety profile. Key Points • There is no high level evidence to guide the management of refractory MAS-associated AOSD patients. • This study was the first to propose and confirm the efficacy and safety of short-term, low-dose etoposide in the treatment of refractory MAS-associated AOSD patients.

[Preliminary study on the efficacy and safety of oral sildenafil in pulmonary arterial hypertension in China].

OBJECTIVE: Sildenafil has been shown to be effective in pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH has been under-investigated in China. The aim of the present study was to evaluate the efficacy and safety of oral sildenafil in PAH patients in China. METHODS: In this prospective, open-label and multi-center study, 90 patients were recruited from 14 centers to receive oral sildenafil (75 mg/d) for 12 weeks. They underwent a six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of 12 weeks. The primary endpoint was the changes in exercise capacity as assessed by SMWT. And the secondary endpoints included assessment of functional class, evaluation of cardiopulmonary hemodynamics and clinical deterioration (defined as death, transplantation and re-hospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: There were 19 males and 71 females with an average age of 32.5 ± 12.1 years old (range: 18 - 61). Their etiologies were idiopathic (n = 15), related with congenital heart disease (n = 60), or related with connective tissue disease (n = 9) and chronic thromboembolic pulmonary hypertension (n = 6). Oral sildenafil significantly increased the SMWT distances [(342 ± 93) m vs. (403 ± 88) m, P < 0.001]. There was also remarkable improvement in Borg dyspnea score (2.9 ± 2.6 vs. 2.4 ± 2.0, P = 0.005). Furthermore, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also found (mean pulmonary artery pressure, P < 0.001; cardiac index, P < 0.001; pulmonary vascular resistance, P < 0.001). Side effects were mild and consistent with other reports. CONCLUSION: This study confirms and extends previous studies. Oral sildenafil is both safe and effective for the treatment of adult PAH patients in China.

A double-blind, double-dummy, randomized controlled, multicenter trial of 99Tc-methylene diphosphonate in patients with moderate to severe rheumatoid arthritis.

BACKGROUND: Clinical observational studies revealed that 99Tc-methylene diphosphonate (99Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA. METHODS: Eligible patients with moderate to severely active RA were randomized to receive 99Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or 99Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48. RESULTS: At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%) (P = 0.03 for MTX + 99Tc-MDP vs. MTX, and MTX + 99Tc-MDP vs.99Tc-MDP, respectively). The participants in the MTX + 99Tc-MDP group and the 99Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + 99Tc-MDP vs. MTX: P = 0.03, 99Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed. CONCLUSIONS: This study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of 99Tc-MDP therapy in patients with RA are warranted. TRIAL REGISTRATION: Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.

Rapid Onset of Efficacy of Baricitinib in Chinese Patients with Moderate to Severe Rheumatoid Arthritis: Results from Study RA-BALANCE.

INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.

[The relationship of vitamin D endocrine system and estrogen receptor expression with bone mineral density in initial systemic lupus erythematosus].

OBJECTIVE: To study the incidence of osteopenia in patients with initial systemic lupus erythematosus (SLE). Investigate the levels of the vitamin D (VitD) endocrine system in peripheral blood of SLE patients and its relation to bone mineral density (BMD). Analyse the relationship between the estrogen receptor (ER) and BMD and evaluate the role of ER in the pathogenesis osteopenia. METHODS: Serum levels of 25-OH VitD(3) and 1,25-(OH)(2) VitD(3) were detected by enzyme linked immunosorbent assay. The gene expression levels of VitD receptor (VDR) and ER were determined by real-time PCR. BMD measurements in the lumbar spine (L1-L4) and left proximal femur (femoral neck) were performed using dual X-ray absorptiometry before treatment. RESULTS: The initial SLE patients had significantly lower BMD values, and higher frequency of bone loss at both sites of measurement compared with normal controls (P < 0.05). The levels of 25-OH VitD(3) and 1,25-(OH)(2) VitD(3) were lower in the initial SLE patients than normal controls (P < 0.01 both). There is no difference in the levels of 25-OH VitD(3) and 1,25-(OH)(2) VitD(3) between the osteopenia SLE group and the normal BMD SLE group (P > 0.05, P > 0.05). There are no correlations between the VitD and BMD in initial SLE patients (P > 0.05 both). The expressions of VDR gene were significantly increased in the initial SLE patients compared with the normal controls (P < 0.01). There was no difference in VDR gene expression between osteopenia SLE group and normal BMD SLE group (P > 0.05). The VDR gene expression does not correlate with the bone mass (P > 0.05). The levels of ER-beta gene expression are higher in the initial SLE group than the normal controls (P < 0.01). CONCLUSIONS: The incipient SLE patients may have lower BMD than expected. SLE patients present abnormal VitD endocrine system and higher ER-beta mRNA expression than those in normal controls, but these weren't concerned with osteopenia.

Efficacy and Safety of Baricitinib in Chinese Rheumatoid Arthritis Patients and the Subgroup Analyses: Results from Study RA-BALANCE.

INTRODUCTION: Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2, which has demonstrated significant efficacy in patients with moderately to severely active rheumatoid arthritis (RA). This analysis aims to describe the efficacy and safety of baricitinib in Chinese RA patients with an inadequate response to methotrexate (MTX-IR), and to analyze the effects of baseline characteristics on the efficacy of baricitinib treatment. METHODS: In this 52-week, randomized, double-blind, placebo-controlled study, 231 Chinese patients with moderately to severely active RA who had MTX-IR were randomly assigned to placebo (n = 115) or baricitinib 4 mg once daily (n = 116). The primary endpoint was American College of Rheumatology 20% (ACR20) response at week 12. Other efficacy measures included ACR50, ACR70, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, patient's assessment of pain, Disease Activity Score in 28 joints using high-sensitivity C-reactive protein, remission and low disease activity rates according to Simplified Disease Activity Index or Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, and mean duration and severity of morning joint stiffness, worst tiredness and worst joint pain were analyzed. Additionally, subgroup analyses were performed across baseline characteristics. RESULTS: Statistically significant improvement in ACR20 response was achieved with baricitinib at week 12 (53.4 vs. 22.6%, p = 0.001) in Chinese patients, compared to placebo. Most of the secondary objectives were met with statistically significant improvements. Efficacy of baricitinib was irrespective of patient demographics and baseline characteristics. Safety events were similar between the baricitinib and placebo groups. CONCLUSIONS: The efficacy of baricitinib 4 mg in Chinese patients with moderately to severely active RA and prior MTX-IR was clinically significant compared to placebo regardless of baseline characteristics. Baricitinib was well tolerated with an acceptable safety profile during the full study period. TRIAL REGISTRATION: NCT02265705.

Degeneration of normal articular cartilage induced by late phase osteoarthritic synovial fluid in beagle dogs.

OBJECTIVE: To investigate the pathogenesis of late phase osteoarthritic (OA) synovial fluid (SF) on normal articular cartilage in vivo and provide an understanding of degenerative cartilage extending in OA joint. METHODS: A random knee, each of 8 beagle dogs, received anterior cruciate ligament transection (ACLT) and was confirmed to have late phase OA degenerative changes at 24 weeks after operation. Thereafter, one random elbow of each canine was injected with autologous late phase OA knee SF. The contralateral elbow was injected with normal saline (NS) of the same volume as SF aspirated from ACLT knee. These two groups of elbows were labeled "SF" and "NS". 8 other beagle dogs were left intact and placed in Group Control. After aseptic arthrocentesis was performed weekly on both elbows for 24 weeks, morphological changes were observed in the cartilage of the elbows, and expressions of 7 biological etiological factors of chondrocytes of the elbows were determined in Group SF, Group NS and Group Control, respectively. RESULTS: Morphological changes were observed in articular cartilage of the elbows in Group SF. Levels of unit area of collagen type I in the noncalcified, calcified and full zones of articular cartilage of the elbows in Group SF increased significantly. Level of unit area of collagen type III in the calcified zone of articular cartilage of the elbows in Group SF remained unchanged. Meanwhile, expressions of MMP-1 and MMP-3 of chondrocytes of the elbows in Group SF increased significantly. There was almost no difference between articular cartilage in Group NS and Group Control. CONCLUSION: Based on these results, we conclude that OA degeneration of normal articular cartilage can be independently induced by late phase OA SF. Endogenous OA biological etiological factor may be one of the reasons causing degenerative cartilage extending in OA joint.

Evaluation of risk factors that contribute to high prevalence of premature atherosclerosis in Chinese premenopausal systemic lupus erythematosus patients.

OBJECTIVE: To evaluate the prevalence of atherosclerosis in Chinese premenopausal women with systemic lupus erythematosus (SLE) and study possible associations between traditional and nontraditional risk factors with premature atherosclerosis. METHODS: We evaluated 111 premenopausal women with SLE and 40 healthy controls without clinical cardiovascular disease. B-mode ultrasound was used to measure carotid plaque and intima-media wall thickness (IMT). The frequency of risk factors for atherosclerosis in patients and controls was compared, and the relationship between the patients' clinical characteristics and carotid plaque was examined. At the same time, we used B-mode ultrasound to measure flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) in the brachial artery to assess for difference in endothelial function between SLE patients and controls. RESULTS: Carotid plaque was more frequent in patients with lupus (16 of 111 patients) than in control subjects (0 of 40 subjects) (P = 0.007). The mean IMT was significantly higher in patients than in controls. Compared with controls, SLE patients were found to have a significantly higher prevalence of hypertension (P = 0.001), hypercholesterolemia (P = 0.022), and hypertriglyceridemia (P < 0.001). As compared with patients without plaque, patients with plaque were significantly older, had longer disease duration, higher body mass index, raised blood pressure, shorter prothrombin time, raised C-reactive protein, higher Systemic Lupus International Collaborating Clinics damage index score, higher cumulative prednisone dose, used less hydroxychloroquine, had higher mean IMT, lower FMD, and NMD. In logistic regression analysis, older age, higher body mass index, and higher Systemic Lupus International Collaborating Clinics damage index score were independently related to the presence of plaque. Using multiple regression analysis, we found SLE (P = 0.003) to be significantly associated with impaired FMD. CONCLUSION: In our Chinese SLE group, patients presented a higher prevalence of carotid atherosclerosis plaque than healthy controls. SLE patients have significant endothelial dysfunction. We found that risk factors identified in other SLE populations were associated with atherosclerosis in our Chinese group.

[Adalimumab plus methotrexate for the treatment of rheumatoid arthritis: a multi-center randomized, double-blind, placebo-controlled clinical study.].

OBJECTIVE: To investigate the efficacy and safety of adalimumab plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). METHODS: This is a multi-center, randomized, double-blind, parallel-group, and placebo-controlled clinical study, included a total of 302 cases of active rheumatoid arthritis, randomized into three groups of observation: 40 mg adalimumab (121 cases), 80 mg adalimumab (121 cases), or placebo (60 cases). Upon enrollment, all subjects had been previously treated with MTX for at least 3 months, and their doses of drug had remained stable for at least 28 days. The double-blind phase lasted for 12 weeks, during which the subjects were administered with adalimumab or placebo subcutaneously every other week. Then the subjects entered into another 12 weeks of open-label study, which included subcutaneous injection of 40 mg adalimumab every other week. In both the double-blind and the open-label periods, all subjects were maintained concomitantly with MTX that had already been used before this study. The primary efficacy variables were evaluated on basis of American College of Rheumatology (ACR)20 response rate at week 12. The secondary efficacy variables included: ACR20 response rate at week 24; ACR50 and ACR70 response rates at weeks 12 and 24; and changes at weeks 12 and 24 compared with baseline observations for tender and swollen joint counts, as well as the assessment of pain with visual analog scale (VAS), the physician's and the patient's global assessment of disease activity (VAS), and the analysis on health assessment questionnaire (HAQ) and health related quality of life (HRQL) measured by Short Form-36 (SF-36); The safety variables mainly included adverse events (AE). RESULT: During the double-blind period, subjects treated with 40 mg of adalimumab, 57.0% achieved ACR20 response at week 12 (P = 0.004 versus placebo), and subjects treated with 80 mg of adalimumab, 51.2% achieved ACR20 response at week 12 (P = 0.026 versus placebo), and only 35.0% of subjects treated with placebo achieved ACR20 response at week 12. On the other hand, 32.2% of subjects receiving 40 mg of adalimumab achieved ACR50 response (P = 0.009 versus placebo), and 15.7% achieved ACR70 response (P = 0.007 versus placebo) at week 12. Subjects treated with 40 mg of adalimumab got a better result versus placebo at week 12 for tender joint count, swollen joint count, and improvement in C-reactive protein; and subjects treated with 80 mg of adalimumab were also seen an amelioration versus placebo at week 12 for swollen joint count, and improvement in C-reactive protein; all of these findings were statistically significant in differences. During the open-label period all subjects received 40 mg of adalimumab, and response rates for ACR20, ACR50, and ACR70 in the two treatment groups of 40 mg and 80 mg adalimumab were maintained or improved from week 12 to week 24 (being 73.1%, 40.3% and 17.6% respectively for 40 mg group; 71.1%, 39.5% and 17.5% respectively for 80 mg group); while response in the original placebo group (being 67.8%, 44.1% and 18.6%) increased during the 12-week open-label period to match that of the original adalimumab treatment groups. While for changes in tender and swollen joint counts, VAS, HAQ, SF-36, a significant improvement was seen at week 24 when compared with baseline and week 12 values. Throughout the double-blind and open-label period, adverse events reported in >/= 5% of subjects at least possibly associated with the study drug were upper respiratory tract infection, nasopharyngitis, and injection site itching, mostly being mild to moderate in severity. There were 3 cases of tuberculosis reported during this study. And 3 cases of serious adverse event (SAE) were reported among the adalimumab subjects during the double-blind period, which were determined as unrelated or probably unrelated to the study drug. And 8 cases (2.7%) of SAE were seen among the adalimumab subjects during the open-label period, 3 of which were at least possibly unrelated with the study drug. All SAEs reported were consistent to those seen in other adalimumab trials. No other unexpected safety signals were reported. CONCLUSION: Adalimumab plus MTX is better than single MTX in efficacy for the treatment of RA. Being generally safe and well tolerated, adalimumab plus MTX can significantly increase the response rate, continuously reduce the arthritic signs, symptoms and the inflammatory factors in patients, and also be helpful for reducing disabilities and improving the global quality of life for the patients.

[Efficacy and safety of infliximab in patients with rheumatoid arthritis].

OBJECTIVE: To investigate the efficacy and safety of Infliximab (IFX) plus methotrexate (MTX) combination therapy in patients with rheumatoid arthritis (RA). METHODS: Prospectively observe refractory RA patients who were treated with combination therapy of MTX and IFX. IFX was infused at the dosage of 3 mg/kg, in week 0, 2, 6, and then every 8 weeks. During treatment, clinical variables, disease activity and adverse effects were evaluated. RESULTS: After treatment, 69.8%, 52.4%, 29.5% and 7.2% RA patients achieved ACR20, ACR50, ACR70 and ACR90 respectively. There were significant statistical differences in the changes of swollen joint counts, tender joint counts, VAS scale, patient' s global assessment, and physician's global assessment before and after therapy. CONCLUSION: Infliximab plus MTX achieved significant efficacy and safety in refractory RA patients.

Glycogen storage disease manifested as gout and myopathy: three case reports and literature review.

Glycogen storage diseases (GSDs) are a group of congenital inherited metabolic diseases. They may present the symptoms of muscle and joint which may be misdiagnosed with some rheumatic diseases. We report three cases of GSDs in order to have a more clear recognition of the disease and to discuss the differential diagnosis.

Safety and efficacy of T-614 in the treatment of patients with active rheumatoid arthritis: a double blind, randomized, placebo-controlled and multicenter trial.

BACKGROUND: A novel anti-rheumatic drug, T-614, has been shown to have an anti-inflammatory effect and to improve abnormal immunological findings in rheumatoid arthritis (RA). To assess the safety and efficacy of T-614 versus placebo in patients with active RA we conducted a 24-week clinical study in 280 Chinese patients. METHODS: In a multicenter, randomized, double blind, placebo controlled study, 280 patients were randomly assigned to receive placebo (n = 95) or T-614 at 50 mg (n = 93) or 25 mg (n = 92) daily. Active disease was defined by 4 of the following 5 criteria: >or= 5 tender joints, >or= 3 swollen joints, morning stiffness lasting for >or= 60 minutes, and Westergren erythrocyte sedimentation rate (ESR) >or= 28 mm/h, the assessment of pain at the rest by patient as moderate or severe. Clinical and laboratory parameters were analyzed at baseline, 2, 4, 6, 12, 18 and 24 weeks. The primary efficacy variable at week 24 was the American College of Rheumatology (ACR) response rate using the intent-to-treat population. RESULTS: The ACR response rate was significantly higher in the T-614 treatment group compared with the placebo group within 8 weeks after the initiation of treatment. After 24 weeks, the 25 mg/d and 50 mg/d dosage groups and the placebo group showed 39.13%, 61.29% and 24.21% in ACR20 and 23.91%, 31.18% and 7.37% in ACR50, respectively. A time-response in ACR response was observed, with clear superiority for the 25 mg/d and 50 mg/d dosage groups compared to placebo (P < 0.0001), and the 50 mg/d dose compared to the 25 mg/d dose (P < 0.05) when using the ACR response analyses after 24 weeks. ESR and c-reactive protein (CRP) were significantly different in the treatment groups after 24 weeks. The incidence of adverse events (AEs) was not significantly higher with T-614 than with placebo, but upper abdominal discomfort, leucopenia, elevated serum alanine aminotransferase (sALT), skin rash and/or pruritus were more common in the 50 mg and 25 mg dosage groups. CONCLUSION: T-614, a new slow-acting drug, is effective in treatment of rheumatoid arthritis and is well tolerated.

Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. METHODS: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. RESULTS: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. CONCLUSIONS: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. CLINICAL TRIAL IDENTIFIER: NCT00856544 and NCT00413699.

Clinical features, prognostic and risk factors of central nervous system infections in patients with systemic lupus erythematosus.

The purpose of this study is to describe the etiology, characteristics and outcomes of central nervous system (CNS) infections in patients with systemic lupus erythematosus (SLE), while also identifying prognostic and risk factors. Thirty-eight SLE patients with CNS infections were identified from review of all charts of patients with SLE hospitalized from January 1995 to June 2005. These patients were divided into 3 groups, i.e., Mycobacterium tuberculosis (TB), non-TB bacterial and fungal infection groups. Of the 38 SLE cases with CNS infections, TB was identified in 19 patients, Listeria monocytogenes in 3 patients, Klebsiella pneumoniae in 1 patient, Staphylococcus aureus in 1 patient, Gram's stain positive bacteria in 1 patient, Cryptococcus neoformans in 12 patients, and Aspergillus fumigatus in 1 patient. The rate of unfavorable outcome in patients with fungal infection was lower than in patients with TB (P=0.028) and non-TB bacterial CNS infections (P=0.046). SLE patients with TB or fungal CNS infections had a more insidious or atypical clinical presentation. Compared to SLE patients without CNS infections, those with CNS infections were more likely to have low serum albumin levels (P=0.048) and have been receiving higher doses of prednisolone at the onset of CNS infection (P=0.015) or higher mean doses of prednisolone within the previous year (P=0.039). In conclusion, low levels of serum albumin and higher doses of received prednisolone are important risk factors for the development of CNS infections in SLE patients.

Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study.

The aim of the study was to investigate the characteristics of adult clinically amyopathic dermatomyositis (CADM) with rapid progressive interstitial lung disease (ILD). Hospitalized patients with dermatomyositis (DM) and polymyositis (PM) between 1998 and 2005 in the Shanghai Renji Hospital were retrospectively studied. One hundred and forty-five patients were classified into CADM, classic DM or PM according to the modified Sontheimer's definition or Bohan-Peter's classification criteria. They were further stratified based on the presence or absence of clinical ILD. The Kaplan-Meier survival analysis and COX regression were performed. The predictive factors for ILD and other clinical properties of CADM-ILD were explored. The presence of clinical ILD was a significant risk factor for the poor outcome of DM/PM (OR = 4.237, CI 95%: 1.239-14.49, p = 0.021). Other risk factors are the presence of rashes and elevated urea nitrogen. Patients with DM/PM complicated by ILD had different clinical courses. Patients with CADM-ILD showed a rapidly progressive pattern with 6-month survival rate of 40.8%. The DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively. Better preserved muscle strength, elevated erythrocyte sedimentation rate, and hypoalbuminemia may herald ILD in DM/PM. Patients with CADM-ILD who later died had lower PO(2), higher lactate dehydrogenase, and prominent arthritis/arthralgia compared with those who survived. The presence of antinuclear antibody seems to be protective. Rapid progressive CADM-ILD is refractory to conventional treatment. ILD is a common complication in over 40% of our hospitalized DM/PM cohort and is also a prominent prognostic indicator. CADM is a special phenotype of DM/PM. CADM-ILD, which is usually rapidly progressive and fatal, requires further investigation.

[Effects of RNAi on cyclooxygenase-2 expression and biologic activity of human rheumatoid arthritis synovial fibroblasts].

OBJECTIVE: To screen highly efficient small interfering RNA (siRNA) targeting human cyclooxygenase-2 (hCOX-2) mRNA on human rheumatoid arthritis synovial fibroblasts (RASF) and to further study the impact there on prostaglandin E2 (PGE2) and cytokines, such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), timorous necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor (VEGF). METHODS: 4 lines of COX-2 mRNA siRNA (1(#) - 4(#) siRNA) were designed and transfected into the fibroblasts from the synovial membrane of a patient with rheumatoid arthritis (RASF). Phorbol ester was added 4 hours later. A scrambled line (NC) group and a blank control (CTL) group were used. RT-PCR and Western blot ting were used to detect the mRNA and protein expression of COX-2 36 and 48 hours after transfection. The levels of PGE2, IL-1beta, IL-6, TNF-alpha, and VEGF were measured by ELISA. RESULTS: RT-PCR showed that the absorbance ratios of the positively interfering groups, NC, and 1(#) - 3(#) siRNA groups, to CTL group were 0.72, 0.3, 0.25, 0.4, and 0.04 respectively. The ratios of the positively interfering groups to CTL group were 1.04, 0.52, 0.39, 0.9, and 36 h after transfection and 1.05, 0.52, 0.51, 0.9, and 0.15 respectively 48 h after transfection. The levels of PGE2, IL-1beta, IL-6, TNF-alpha, and VEGF in the culture supernatant were lower in the 4(#) siRNA group than in other groups 24, 36, and 48 h after transfection. The death rates of RASF of all trial groups were within the range of 9% - 11% and there were not statistically significant differences between the CTL group and the siRNA groups or between the 4(#) siRNA and other siRNA groups. CONCLUSION: 4(#) siRNA effectively inhibits the expression of COX-2 mRNA and protein the level of PGE2, IL-1beta, IL-6, TNF-alpha, and VEGF in the clear supernatant of the 4(#) group is lowest.

[Clinical significance of neuro-reactive autoantibodies in neuro-psychiatric systemic lupus erythematosus].

OBJECTIVE: To investigate the clinical significance of specific/non-specific neuro-reactive autoantibodies in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Samples of serum and cerebrospinal fluid (CSF) were collected from 25 NPSLE patients, 11 patients with SLE complicated with central nervous system (CNS) infection (control group 1), and 10 SLE patients without CNS infection (non-NPSLE, control group 2)) were detected, Indirect immunofluorescence technique was used to detect the anti-nuclear antibody (ANA) based on the slides with human epithelium cell of laryngocarcinoma of the line Hep-2 or on the slides with cerebellum and peripheral nerve of monkey, he type of immunofluorescence were assayed. RESULTS: The percentages of ANA positive serum of the NPSLE, SLE control 1, and SLE control 2 groups were 92% (23/25), 100% (11/11), and 100% (10/10) respectively without significant differences between any 2 groups (all P > 0.05). The percentage of ANA positive CSF of the NPSLE was 60% (15/25), significantly higher than that of the SLE control group 1 (27%, 3/11, P < 0.01). There was no significant correlation between the titer of serum ANA and the titer of CSF ANA (P > 0.05). The positive rate of neuro-reactive autoantibodies was 40% (10/25), significantly higher than those of the 2 control groups (both 0, both P > 0.001). CONCLUSION: (1) The ANA positivity in the CSF of the NPSLE group is associated with the disease activity and CNS involvement, the higher the titer of autoantibodies the severe the clinical manifestations. (2) The neuro-reactive autoantibodies in the serum may associate with NPSLE with still unknown mechanism.

Efficacy and safety of loxoprofen hydrogel patch versus loxoprofen tablet in patients with knee osteoarthritis: a randomized controlled non-inferiority trial.

This study is aimed at comparing the efficacy and safety of loxoprofen sodium hydrogel patch (LX-P) with loxoprofen sodium tablet (LX-T) in patients with knee osteoarthritis (OA). One hundred sixty-nine patients were enrolled in a randomized, controlled, double-blind, double-dummy, multicenter, non-inferiority trial of LX-P. Patients were randomly assigned to either LX-P or LX-T groups for a 4-week treatment. The primary efficacy endpoint was the proportion of patients with an overall improvement of ≥50%, and the secondary efficacy endpoint was the proportion of patients with an improvement of ≥25% from baseline in each of the seven main symptoms. The non-inferiority trial was based on a power of 80% and significance level of 2.5% with a non-inferiority margin of -10%. In both intention-to-treat (ITT) and per-protocol (PP) analyses, LX-P was as effective as LX-T in regard to the primary endpoint. In the ITT analysis, the difference between the two groups was 12.6% [95% confidence interval, -1.7 to 26.9%]. No significant differences were found between the two groups in any of the secondary efficacy outcomes. A lower incidence of adverse events was observed in LX-P group; however, the difference was not statistically significant. No serious adverse events were reported in the LX-P group, whereas one case was reported in LX-T group. Based on the present study, topical loxoprofen patch was non-inferior to oral loxoprofen in patients with knee osteoarthritis.