Leflunomide Group Research Articles

Comparison of Effectiveness of Leflunomide against High Dose Methyl-Prednisolone in Multiple Sclerosis

Background: Leflunomide is a disease-modifying, anti-rheumatic drug, whose active metabolite Teriflu-nomide is licensed drug therapy for reducing progression in Multiple sclerosis. Intravenous high dose Methyl-Prednisolone is an established treatment for acute relapses of multiple sclerosis that escalates reco-very. Intravenous methyl-prednisone also being used anecdotally for the prevention of relapses. Methods: Each patient after enrollment in the study received treatment for 1 year. A total of 30 patients, 15 patients in each group were taken. Patients fulfilling inclusion criteria and giving written informed con-sent were randomly divided into 2 groups (Group A and Group B) using a computer-generated random numbers table. Group A patients received Leflunomide 20mg with a loading dose of 3 tablets for 3 days and then once daily for one year. And group B patients received high-dose intravenous Methyl Prednisolone 1g monthly for a period of one year. Results: Methyl Prednisolone group, 5 (33.3%) had only 1(%) relapse and 10 (66.7%) cases had no relapse. In contrast, Leflunomide group, no relapse was recorded. The frequency of relapse was consequently statistically higher in Methyl Prednisolone group, p-value < 0.05. In respect of, a number of lesions on MRI; Methyl Prednisolone group demonstrated no change in 4 (26.67%) cases and 11 (73.33%) cases had lesions increased from baseline. Whereas, in the Leflunomide group the number of lesions significantly decreased (p-value < 0.05). Significant improvement in Expanded disability status was observed leflunomide group (p-value < 0.05). Conclusion: Leflunomide was more effective in preventing relapses and in decreasing disease activity on MRI, as compared with high dose monthly Methyl-prednisone in patients with Multiple Sclerosis.

Methotrexate (MTX) Plus Hydroxychloroquine versus MTX Plus Leflunomide in Patients with MTX-Resistant Active Rheumatoid Arthritis: A 2-Year Cohort Study in Real World.

PurposeTo compare the efficacy, safety, and cost-effectiveness of methotrexate (MTX) plus hydroxychloroquine (HCQ) vs MTX plus leflunomide (LEF) in established rheumatoid arthritis (RA) with inadequate response to MTX monotherapy in a real-world Chinese cohort.Patients and MethodsA prospective RA cohort (n=549) was screened with eligible patients who had inadequate response (disease activity score in 28 joints using erythrocyte sedimentation rate, DAS28-ESR>3.2) to initial MTX monotherapy and subsequently received either MTX+HCQ or MTX+LEF. Propensity score matching (PSM) was applied to adjust the possible baseline confounders between two groups. The primary outcome was the proportion of patients achieving first remission (DAS28-ESR<2.6) during follow-up by log rank test. Secondary outcomes were changes of DAS28, glucocorticoids (GCs) exposure, safety, cost-effectiveness, sustained remission, and low disease activity (LDA) rate after 24-month follow-up.ResultsOverall, 222 eligible patients were subjected to the aforementioned two treatment protocols (MTX+HCQ, n=102; MTX+LEF, n=120). After PSM adjustment, 97 patients in each group were analyzed. A higher remission rate was observed in the MTX+HCQ group than in the MTX+LEF group (70.1% vs 56.7%, P=0.048). The median time to remission was 11 and 16 months in the two groups, respectively. At the endpoint, more patients achieved remission (46.8% vs 32.5%, P=0.063) and maintained sustained LDA in the HCQ group (53.2% vs 38.6%, P=0.062) and also more patients withdrew GCs in this group (32% vs 16.7%, P=0.053) than those in the LEF group. Safety profiles were non-alarming, with no significant difference between the two groups. The incremental cost-effectiveness ratio yielded by MTX+HCQ over MTX+LEF was $1,111.8 per quality-adjusted life-year (QALY), within the cost-effective threshold set as the per capita gross domestic product (GDP) of China.ConclusionThe MTX+HCQ combination was seemingly superior to MTX+LEF in a real-world cohort of Chinese RA patients with inadequate response to methotrexate monotherapy in respect of the efficacy and cost-effectiveness.

Biological and targeted-synthetic disease-modifying anti-rheumatic drugs with concomitant methotrexate or leflunomide in rheumatoid arthritis: real-life TReasure prospective data

To determine the real-life efficacy, safety, and drug-retention rates of leflunomide (LEF) or methotrexate (MTX) as a synthetic DMARD used in combination with biological DMARDs for rheumatoid arthritis (RA). The TReasure database is a web-based, prospective, observational cohort of RA and spondyloarthritis patients from 17 centres in different regions of Turkey and data entry was enabled since December 2017. Until May 2019, 2556 RA patients on biologic treatment were recorded. Demographic and RA-related data of 1526 patient either received LEF or MTX were compared, efficacy of both drugs compared by RA-disease activity composite indices. Reasons fordrug discontinuation also recorded. Drug retention rates were compared with Kaplan-Meier curves (log-rank test). Of 2556 RA patients 1526 (59.7%) were receiving concomitant LEF (n=646, 42.3%; median follow up 35 months) or concomitant MTX (n=880, 57.3%; median follow-up 32 months) at the time of initiation to their first bDMARDs. The LEF group were older and had longer disease duration, proportion of females and seropositive patients was higher in this group. In the LEF group, non-anti-TNF agents were used in higher rate. Remission rates, changes in composite indices and rate of comorbidities and adverse events were similar in both groups. The retention rate of LEF + non-anti-TNF b/tsDMARDs was higher compared to MTX + anti-TNF bDMARDs (p=0.002, log-rank). Rates of adverse events were similar in both groups. LEF in combination with either anti-TNF or non-anti-TNF drugs appears as an effective and safe therapeutic option at least as MTX.

Traditional Chinese medicine Biqi capsule compared with leflunomide in combination with methotrexate in patients with rheumatoid arthritis: a randomized controlled trial

BackgroundBiqi capsule is a traditional Chinese medicine widely used as a complementary and alternative treatment for rheumatoid arthritis (RA). The objective is to understand the efficacy, safety and mechanism of Biqi combined with methotrexate (MTX) in RA.MethodsWe present a randomized, controlled pilot trial on Biqi combined with MTX against patients with active RA. Seventy patients were randomized 1:1 to receive Biqi + MTX or Leflunomide (LEF) + MTX for 24 weeks, and were assessed at baseline, 4, 12 and 24 weeks. Serum and urine samples were collected for metabolomics.ResultsOverall, 81.2% patients in Biqi group achieved ACR20 at 24 weeks. No statistically significant differences were observed in primary or secondary outcomes between the two groups. A better safety profile was observed for Biqi with significantly fewer adverse effects reported (11.4%) compared to LEF group (40%, P < 0.05). Comparison between treatment responders and non-responders indicated a unique urine metabolic profile of enriched fatty acids and decreased acylcarnitines associated with Biqi responders, indicating a restored energy homeostasis in response to Biqi. The gene targets of these metabolites were significantly enriched in interleukin-4 and interleukin-13 pathways, implying that Biqi could ameliorate Th2-derived inflammatory response. Multivariate network analysis indicated that patient morning stiffness and SJC were key factors associated with metabolomics in Biqi-treated patients, whereas CRP was the main factor in LEF group. Therefore, Biqi and LEF likely work by influencing different patient clinical parameters.ConclusionsOur study suggests that Biqi capsule can be a promising alternative option in combination with MTX for RA treatment, and demonstrates the capability of using metabolomics to interrogate mechanism of action for traditional Chinese medicine.Trial registration This trial is registered with ChiCTR, No. ChiCTR-IPR-16009029. Registered August 15, 2016. http://www.chictr.org.cn/showprojen.aspx?proj=15034

Effectiveness of maintenance therapy with methotrexate compared with leflunomide for patients with RA having achieved disease control with both these drugs: results of a predefined sub-analysis of CareRA, a pragmatic RCT.

Evidence regarding the effectiveness of step-down strategies for patients with well-controlled early rheumatoid arthritis (RA) on a combination of methotrexate (MTX) and leflunomide (LEF) is currently lacking. The Care in early RA (CareRA) trial is a 2-year randomized pragmatic trial comparing different remission induction strategies in treatment-naïve patients with early RA. For this study, we included participants who achieved low disease activity (LDA) (DAS28-CRP ≤ 3.2) between 40 to 52weeks after starting a combination of MTX, LEF, and a prednisone bridging scheme followed by a treat-to-target approach. Patients were re-randomized to a maintenance monotherapy of either MTX 15mg weekly or LEF 20mg daily. Remission rates (DAS28-CRP < 2.6) at week 65 counted from re-randomization, as well as drug retention rates and safety during the 65weeks of follow-up, were compared. Remission rates at week 65 after re-randomization were numerically higher in patients assigned to MTX (29/32; 90.6%) compared with patients on LEF (20/27; 74.1%) (p = 0.091). Of patients assigned to MTX, 60% (19/32) maintained LDA while continuing their assigned monotherapy until week 65 after re-randomization versus 44% (12/27) in the LEF group (p = 0.25). Patients re-randomized to MTX were more frequently in LDA measured by Clinical Disease Activity Index (32/32; 100%) compared with patients on LEF (23/27; 85.2%) (p = 0.024) 65weeks after re-randomization. According to survival analyses, the probability of maintaining MTX monotherapy was higher (81%) than maintaining LEF monotherapy (55%) for 65weeks (p = 0.025) after re-randomization. Safety analysis after re-randomization showed a good safety profile in both groups. MTX monotherapy seems not significantly more efficacious as maintenance treatment compared with LEF monotherapy but has a better retention rate and is well tolerated in early RA patients in LDA after combination therapy with both. Clinical trials NCT01172639 Key points • Methotrexate should be preferred over leflunomide as maintenance therapy after an initial intensive combination of these two drugs. • Methotrexate shows a better retention rate to leflunomide as maintenance therapy in this context.

Effect of Triptolide on Cardiac Function in Arthritic Rats and Its Mechanism

To observe the changes of cardiac function in arthritic rats and the effect of triptolide on it. Forty rats were divided in random into normal control (NC) group, model control (MC) group, leflunomide (LEF) group and triptolide (TP) group. Except for the normal group, rats in the other three groups were injected with Freund's complete adjuvant to create arthritic inflammation in the right hind paws, and the interventional drug was administered on the 12th day after the inflammation. By treating for 30 d, the cardiac function of rats was detected by left ventricular catheterization. The expressions of superoxide dismutase (SOD), malondialdehyde (MDA), reacitve oxygen species (ROS), total antioxidation (T-AOC), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) in serum were measured by enzyme-linked immunosorbent assay. The expressions of keap-like protein 1 ( Keap1), muscular aponeurotic fibrosarcom ( maf) and nuclear factor-E2 related factor2 ( Nrf2) mRNAs in cardiac tissue were detected by real-time PCR. The expressions of Keap1, maf and Nrf2 proteins in heart tissues were detected by Western blot. Comparing with the normal group, the heart rate (HR), heart index (HI), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP) of the model group were significantly increased, whereas the maximum change rate of ventricular pressure rise or decline (±dp/dtmax) was significantly decreased ( P<0.01). SOD, MDA, ROS, T-AOC, and TNF-α were all increased, and IL-10 was significantly decreased ( P<0.01). The mRNA and protein expressions of Keap1, maf and Nrf2 in heart tissues were increased ( P<0.01). Comparing with the model group, HR, HI, LVSP, and LVEDP in the triptolide group were significantly decreased, whereas the ±dp/dtmax was significantly increased ( P<0.01). SOD, MDA, T-AOC, ROS, TNF-α decreased while the IL-10 increased ( P<0.05, P<0.01). The expressions of Keap1, maf and Nrf2 mRNAs and proteins in the heart tissues of the triptolide group were decreased ( P<0.01). Triptolide could improve cardiac function in arthritic rats, and the mechanism may related to its ability of improving the anti-oxidationin cardiomyocytes, reducing oxidative stress damage, and inhibiting abnormal immune inflammatory response.

Efficacy and safety of leflunomide versus cyclophosphamide for initial-onset Takayasu arteritis: a prospective cohort study.

Background:Leflunomide (LEF) has been considered as an alternative treatment for Takayasu arteritis (TA); however, data on its efficacy are still scanty.Objective:To investigate the efficacy and safety of LEF versus cyclophosphamide (CYC) for initial-onset TA.Methods:Initial-onset TA patients with active disease were enrolled in this research. Patients enrolled from 1 January 2009 to 31 December 2015 were treated with glucocorticoids and CYC, while patients enrolled from 1 January 2016 to 31 October 2018 received glucocorticoids and LEF. Treatment response including complete remission (CR), partial remission (PR), and effectiveness rate (ER) and side effects were evaluated at 6 and 12 months.Results and conclusion:In total, 92 patients were enrolled. A total of 47 patients were treated with LEF, while 45 patients were treated with CYC. The CR and ER rates were 75.55%, and 88.89% at 6 months, and 85.37% and 95.12% at 12 months in the LEF group. The CR and ER rates were 39.02% and 70.73% at 6 months, and 56.41% and 82.05% at 12 months in the CYC group. The CR rate was significantly higher in the LEF group than in the CYC group both at 6 months (75.61% versus 38.24%, p < 0.01) and 12 months (77.42% versus 53.33%, p < 0.05) after adjustment for propensity scores. The incidence of side effects in the LEF group was much lower than that in the CYC group (21.28% versus 44.44%). In conclusion, LEF provided a better treatment response, along with lower reproductive toxicity, compared with CYC in initial-onset TA.

Effectiveness and safety of methotrexate versus leflunomide in 12-month treatment for Takayasu arteritis

Aims:The study investigates the effectiveness and safety of methotrexate (MTX) versus leflunomide (LEF) in 12-month treatment of Takayasu arteritis (TAK).Methods:This was a cohort study. Patients diagnosed with TAK between 1 January 2013 and 1 January 2019 were enrolled from First Hospital of China Medical University and Zhongshan Hospital of Fudan University. Patients had active disease and were treated with glucocorticoid combined with LEF or MTX. Treatment response, imaging assessment and side-effects were evaluated during 12-month follow-up.Results:In total, 68 patients were enrolled (40 cases treated with LEF and 28 treated with MTX). At baseline, age, sex, disease duration and disease activity index showed no significant differences between groups. Prevalence of complete remission (CR) at 6 months was significantly higher in the LEF group than that in the MTX group (LEF versus MTX: 72.50% versus 53.57%, p = 0.04), though the CR prevalence at 9 months and 12 months showed no significant differences between groups. At 9 months, the prevalence of treatment resistance was much lower in the LEF group compared with MTX group (5.41% versus 11.54%, p = 0.03). Furthermore, prevalence of disease relapse in the LEF group was lower than that in MTX group at 12 months (7.24% versus 16.67%, p = 0.03). Patients with high baseline C-reactive protein levels (⩾15 mg/L) carried a higher risk of treatment resistance (OR = 1.36, 95% CI 1.07–13.41, p = 0.06) and disease relapse (HR = 2.51, 95% CI 1.36–12.98, p = 0.04).Conclusion:LEF might provide a quicker treatment response with lower prevalence of disease relapse compared with that elicited in MTX during 12 months follow-up for TAK.

Effectiveness and safety of leflunomide compared with cyclophosphamide as induction therapy in Takayasu's arteritis: an observational study.

Aims:The objective of this study was to investigate the outcomes of leflunomide (LEF) compared with those of cyclophosphamide (CYC) as induction against active Takayasu’s arteritis (TA) in Chinese patients.Methods:This was an observational study based on a prospective cohort that included TA patients diagnosed in large third-level first-class general hospitals in East China from January 2009 to September 2018. LEF- or CYC-induced active patients were enrolled for comparative effectiveness analysis. One-to-more paired cohorts of LEF versus CYC were derived by propensity-score matching (PSM). The primary outcome was complete remission (CR) at 9-month follow up, and secondary endpoints included partial remission (PR) and effectiveness rate (ER). Multivariable logistic regression was used to identify statistical significance.Results:A total of 131 enrolled patients with at least 3-months treatment included 53 receiving a regimen of glucocorticoid (GC) and LEF and 78 receiving GC and CYC. Compared with the CYC group, the LEF group showed higher CR rate {LEF versus CYC: 84.6% [95% confidence interval (CI) 74.5–94.8%] versus 59.0% (47.8–70.1%); relative risk (RR) = 0.3 (0.1–0.6), p = 0.002} and lower daily GC dose [10.0 (5.0–12.5) versus 12.5 (10.0–15.0) mg, p = 0.043] at the end of the 9-month induction. In the matched analysis, the LEF group (n = 23) still indicated a higher CR rate than the CYC group (n = 54) after PSM [RR = 0.1 (0.0–0.6), p = 0.003]. Four LEF-treated patients had mild side effects, and one died unrelated to LEF.Conclusion:LEF could be an alternative induction therapy against TA, showing good effectiveness and tolerance compared with CYC.

Evaluation of the clinical and anti-destructive effect of an anti-B cell preparation depending on concomitant therapy with basic anti-inflammatory drugs and glucocorticoids in patients with rheumatoid arthritis

Aim: To evaluate the effectiveness, safety and anti-destructive effect of anti-B-cell therapy (rituximab) in various combinations (RTM-mono, RTM + DMARD, RTM + GK) in patients with rheumatoid arthritis in real clinical practice.Materials and methods: Clinical and radiological evaluation of 110 patients with rheumatoid arthritis who received rituximab therapy (RTM) as monotherapy (group 1), in combination with methotrexate (group 2), leflunomide (group 3), and group 4 with other basic anti-inflammatory drugs.Results: When assessing at 48 weeks of treatment with these regimens, the achievement of remission and a low degree of activity was observed in 22.36% of patients. An X-ray evaluation showed the absence of progression in the total score in 60.9%. When assessing progression in the monotherapy group, there was no progression in 76.92%, in the group of PTM + MT – in 54.29%, in the group of PTM + LEF – 65.0%, in the group of other DMARDs – 50% of patients. When assessing the clinical effect in the group receiving GK – remission and a low degree of activity – 19.67% of patients, in the group without GK – 21.05%. Assessing the radiological dynamics, it was shown that in the group not receiving GK – inhibition by the total score occurred in 54.55%, receiving – 61.54%.Conclusion: This work has demonstrated the high therapeutic efficacy of RTM in real clinical practice. There were no significant differences in the degree of progression depending on the concomitant therapy of DMARDs or GK. In the treatment of RTM, inhibition of articular destruction is possible even against the background of clinical deterioration.

Development and Evaluation of a Water-in-oil Microemulsion Formulation for the Transdermal Drug Delivery of Teriflunomide (A771726).

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying anti-rheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of anti-inflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.

Onset of Hypertension in Leflunamide Treated Low Socioeconomic Rheumatoid Arthritis Patients: An Unseen Iceberg.

To determine the frequency of new-onset hypertension in patients with Rheumatoid arthritis taking leflunomide, in comparison with methotrexate in Asian setting. Perspective case-control study was conducted in 2014 in a tertiary care hospital located in Karachi, Pakistan. Adult patients, having rheumatoid arthritis were randomly prescribed leflunomide or methotrexate. Patients having chronic hypertension, proteinuria and chronic kidney disease were excluded. Patients were monthly followed for blood pressure and heart rate measurements. Hypertension was defined using JNC 7 criteria. Out of 144 patients enrolled, 80 patients received Leflunomide while 64 were started on methotrexate. Mean systolic blood pressure in leflunomide group at the start and at the end of study was 108.5 and 135.4mmHg, respectively while in methotrexate group, mean systolic BP was 109.8 and 110.5 mmhg, respectively. After one year follow up, 33 out of 80 (41%) patients were receiving leflunomide had pre-hypertension or hypertension, while only 3 out of 64 patients (4.7%) were receiving methotrexate had hypertension. Risk of developing hypertension in patient receiving Leflunomide is much higher in Asian population like Pakistan as compared to western population.

Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis

ObjectiveTo assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). MethodsWe performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. ResultsA total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. ConclusionLeflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints.

Efficacy and safety of add‐on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate

To investigate the efficacy and safety of tacrolimus (TAC) versus leflunomide (LEF) when combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients. This was a 24-week multi-center, double-blind, randomized, non-inferiority study targeting RA patients with moderate to severe Disease Activity Score of 28 joints (DAS28>3.2) who showed inadequate response to MTX. Patients were randomized into TAC or LEF (add-on to MTX) groups. Initial daily doses of TAC and LEF were 1.5 and 10mg, respectively, for 4weeks and then doubled until the end of the study. The primary endpoint was DAS28 comparison at 24weeks. Eighty-seven patients were screened in 10 centers and 75 patients were randomized into two groups. Baseline demographics were comparable between TAC+MTX and LEF+MTX groups. The TAC+MTX group was non-inferior to the LEF+MTX group in terms of DAS28 at 24weeks (mean difference of DAS28: -0.1812, 95% confidence interval: -0.8073, 0.4450). There was a greater number of adverse events in the LEF+MTX group (66 in LEF+MTX and 49 in TAC+MTX). Six patients presented with transaminitis in the LEF+MTX group compared with two patients in the TAC+MTX group. The efficacy of TAC combined with MTX was non-inferior to LEF+MTX. It had a reasonable safety profile in RA patients with moderate to severe disease activity (http://cris.nih.go.kr; KCT0000781).

Effect of Miao medicine, Jinwujiangu decoction, on IL- 17/IL-23 inflammatory axis of fibroblast-like synoviocytes in rheumatoid arthritis

Purpose: To explore the influence of the Miao medicine, Jinwujiangu decoction, on the interleukin (IL)- 17/IL-23 inflammatory axis of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA).Methods: Synovial tissue samples were randomly divided into a blank control group, high-dose (0.06mg/mL), medium-dose (0.6mg/mL), and low-dose (6.0mg/mL) groups of Jinwujiangu decoction, a leflunomide group, and a tripterygium glycosides group. Proliferation of RA synovial cells was detected by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Enzyme-linked immunosorbent assay (ELISA) was used to determine the secretion of IL-6, transforming growth factor beta (TGF-β), and IL-17. Real-time polymerase chain reaction was used to evaluate the expression of IL-23R, IL-17R, RAR-related orphan receptor alpha (RORα), RORγt, and signal transducer and activator of transcription (STAT3) mRNA. The protein activities of IL-17R, STAT3 and pSTAT3 were assessed by Western blot assay.Results: Jinwujiangu decoction inhibited the proliferation of RA synovial cells. Treatment with different drug concentrations resulted in downregulation of IL-6, TGF-β, and IL-17 secretion. The expression levels of IL-23R, IL-17R, RORα, RORγt, and STAT3 mRNA in RA-FLS were significantly reduced after intervention with different drugs. Protein expression levels of STAT3, pSTAT3, and IL-17 in the different drug treatment groups were significantly decreased.Conclusion: Jinwujiangu decoction inhibits the secretion of IL-6 and TGF-β in RA-FLS, and intervenes to regulate gene expression of IL-23/IL-17 inflammation axis and suppress immune inflammation. The results of this study provide new evidence for the study of anti-inflammatory mechanism of TCM compound prescription.Keywords: Jinwujiangu decoction, IL-17/IL-23, Fibroblast-like synoviocytes, Rheumatoid arthritis, Ethnomedicine

Synergistic Effect of Leflunomide Combined with Ligustrazine in Treatment of Rheumatoid Arthritis: Predicted with Network Pharmacology and Validated in a Clinical Trial

Background: Leflunomide (LEF) is one of the first-line Disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA). However, there are still a few non-responders. It is logical to suggest that if employing a LEF combination that produces synergistic effect in terms of pharmacological activity is a promising strategy to improve the clinical outcomes. Methods: We propose a novel approach for predicting LEF combinations through investigating potential effects of drug targets on disease signaling network. We first construct a RA signaling network with disease-associated driver genes. Thousands of available FDA-approved and investigational compounds are then selected based on a drug-RA network, which is calculated using an algorithm model named synergistic score which combine chemical structure, functional prediction and targeting pathway. We then validate our predicted combination by using a prospective clinical trial. Findings: Ligustrazine (LIG), a key component of the Chinese Herb Chuanxiong and also approved drug in China, is ranked first according to synergistic score. After 48 weeks, the number of ACR20 responder was 23/55 in the LEF group and 38/57 in the combination group, respectively (P<0.05). Consistently, there was an obvious increase of erosion score from baseline in LEF group during treatment, whereas the erosion score was lower in RA treated with LEF + LIG when compared to LEF patients (0.34 ± 0.20 vs 1.12 ± 0.30, P<0.05 ). Interpretation: Our algorithm puts structure and targeting pathways into one model, and predicted LEF and LIG in combination can reduce joint inflammation and attenuate bone erosion in RA patients. To our knowledge, this is the first study to apply this paradigm to evaluate drug combination hypotheses. Funding: Interdisciplinary Research Matching Scheme of Hong Kong Baptist University, the Hong Kong Baptist University Strategic Development Fund, the Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University, the Faculty Research Grant of Hong Kong Baptist University, and the Natural Science Foundation Council of China Declaration of Interest: No author has any potential conflict to disclose (financial, professional or personal) relevant to the manuscript. Ethical Approval: Informed consents were obtained from all patients and the study was approved by the Ethic Committee of Institute of Basic Research in Clinical Medicine (No 2010031). All patients were provided written informed consent prior to participating in the study.

СРАВНИТЕЛЬНЫЙ АНАЛИЗ И ОЦЕНКА ЭФФЕКТИВНОСТИ ПРИМЕНЕНИЯ МЕТОТРЕКСАТА И ЛЕФЛУНОМИДА У БОЛЬНЫХ АКТИВНЫМ РЕВМАТОИДНЫМ АРТРИТОМ В УСЛОВИЯХ ТЩАТЕЛЬНОГО КОНТРОЛЯ, ОСНОВАННОГО НА ПРИНЦИПАХ СТРАТЕГИИ «TREAT TO TARGET»

Objective: To study and evaluate in a comparative aspect the effectiveness of methotrexate (MT) and leflunomide (LEF) in patients with active rheumatoid arthritis (RA) who have indicators of adverse «Treat to target – T2T» strategy. Methods: Monitoring and comparative evaluation of the effectiveness of therapy of modern basic anti-inflammatory drugs in 104 patients with active RA, which, depending on the character of the therapy was randomized and divided into three groups: I (n=34) – Metoject group (MTJ), II (n=36) – MT group and III (n=34) – LEF group. Results: Against the background of the therapy of MTJ, MT and LEF, the patients surveyed showed a statistically significant decrease in both clinicallaboratory activity indicators of RA and the level of pro-inflammatory cytokines (tumor necrosis factor alpha – TNFα, interleukin-6 – IL-6), the positive results of which were most vividly represented in patients of the MTJ group. By the time the study is completed (after 12 months), most patients have achieved the ultimate goal of therapy – a state of low disease activity/remission – and this figure, for I, II and III groups consisted of 78.2%, 73.1% and 44% respectively. Conclusion: The results of the study show a satisfactory performance/tolerability profile of MTJ, MT and LEF in an intensive mode in conditions of close scrutiny based on T2T strategy. Keywords: Rheumatoid arthritis, metoject, methotrexate, leflunomide, treatment , T2T strategy.

CP-25 combined with MTX/ LEF ameliorates the progression of adjuvant-induced arthritis by the inhibition on GRK2 translocation

ObjectiveCP-25 attenuates arthritis progression in animal models by inhibiting G protein-coupled receptor kinase 2 (GRK2) membrane expression. This study compared groups treated with high-dose methotrexate (MTX)/leflunomide (LEF) and CP-25 combined with low-dose MTX/LEF in an adjuvant-induced arthritis (AA) rat model and investigated possible mechanisms. MethodsAA was induced in rats via complete Freund’s adjuvant. Experimental groups were divided into a normal group; vehicle group; monotherapy groups, including CP-25 (50 mg/kg), MTX (0.25, 0.5 mg/kg), and LEF (5, 10 mg/kg); and CP-25 (50 mg/kg)-combined MTX (0.25 mg/kg)/LEF (5 mg/kg) groups. We measured cytokine levels, phosphorylation and protein expression, and interactions between proteins. The role of GRK2 on phosphorylated extracellular signal-regulated kinase (p-ERK) was determined via GRK2-siRNA using a high content imaging system. ResultsTherapeutic effects, including pathology and cytokine balance, were equivalent between the CP-25-combination groups and the high-dose MTX/LEF groups. P38, ERK, and c-Jun N-terminal kinase (JNK) activation in AA fibroblast-like synoviocytes (FLS) was reduced in the treatment groups; GRK2 expression was only inhibited in the CP-25 group. Interactions between GRK2 and p-ERK decreased in the vehicle group and were restored in the CP-25 group. GRK2 membrane expression and p-ERK nuclear expression increased in FLS pre-treated with tumour necrosis factor alpha and stimulated with prostaglandin E2. Nuclear expression of p-ERK increased in GRK2-siRNA FLS. ConclusionEquivalent therapeutic effects were observed between CP-25-combination groups and high-dose MTX/LEF groups. CP-25 inhibited p-ERK by reducing the membrane expression of GRK2 in FLS from AA rats.

Leflunomide versus cyclophosphamide in the induction treatment of proliferative lupus nephritis in Chinese patients: a randomized trial

ObjectivesA prospective, multi-center, randomized controlled study was conducted to evaluate the efficacy and safety of a 24-week course low-dose leflunomide combined with prednisone in the induction treatment of proliferative lupus nephritis in Chinese patients.MethodPatients (n = 100) with biopsy–proved proliferative lupus nephritis were enrolled in this study. They were randomized into two groups and received either leflunomide or cyclophosphamide in conjunction with prednisone for 24 weeks. Leflunomide was given orally with a loading dose of 40 mg/day for 3 days followed by 20 mg/day. Intravenous cyclophosphamide was administered monthly at a dosage of 0.8–1.0 g. The primary efficacy outcome was the frequency of complete remission and partial remission at week 24. The secondary outcomes included changes of urinary protein excretion, serum albumin, complement 3, anti-dsDNA antibody level, and systemic lupus erythematosus disease activity index (SLEDAI) after 24-week therapy.ResultsOf 100 patients, 48 received leflunomide combined with prednisone and other 52 received cyclophosphamide with concomitant prednisone. There were no statistically significant differences between groups in complete remission rate and partial remission rate. At week 24, 23% of patients in the leflunomide group and 27% of patients in the cyclophosphamide group achieved complete remission (P = 0.64), while 56% of patients in the leflunomide group and 42% of patients in the cyclophosphamide group achieved partial remission at week 24 (P = 0.16). SLEDAI, serum albumin, complement 3, anti-dsDNA antibody level, and urinary protein excretion improved significantly in both groups. No significant difference was seen in the changes of clinical parameters after therapy between the two groups. There was no significant difference in side effects in both groups.ConclusionsCompared with cyclophosphamide, low-dose leflunomide in combination with prednisone showed both effectiveness and safety in the induction therapy of proliferative lupus nephritis in Chinese patients.

A comparison of the effectiveness of cyclophosphamide, leflunomide, corticosteroids, or conservative management alone in patients with IgA nephropathy: a retrospective observational study

To compare the long-term efficacy of corticosteroids (P) alone or in combination with cyclophosphamide (CTX), leflunomide (LEF), or Angiotensin-convertase inhibitors or angiotensin II receptor blockers (ACEI/ARB) in treatment for IgA nephropathy (IgAN), 311 patients with IgAN were identified. Therapeutic effectiveness (including progression, partial remission, complete remission) and combined renal endpoint (defined as 30% reduction in eGFR or ESRD) were compared based on different therapies. After immunosuppressive and ACEI/ARB treatment, the levels of eGFR, proteinuria and albumin were significantly improved at the last follow-up, the extent of improvement of eGFR, proteinuria, and albumin was more notable in P + CTX group and P + LEF group. 41%, 52.2%, 55.3% and 55.2% in P + CTX, P + LEF, P and ACEI/ARB group achieved complete remission, respectively. Multivariate regression analysis indicated that only proteinuria (Relative risk (RR) 0.82(0.72–0.94), P = 0.004) and tubular atrophy/interstitial fibrosis (RR 0.26(0.13–0.57), P = 0.001) were predictors for complete remission. The optimal cutoffs of eGFR was 47.085 ml/min/1.73 m2 predicting renal function recovery in P + CTX therapy. In conclusion, tubular atrophy/interstitial fibrosis and massive proteinuria were poor predictors for complete remission in IgAN, it appears as though patients may have benefited from immunosuppressive treatment but that comparison to a well-matched contemporary control group or, ideally, a randomized controlled clinical trial, would be required to show this.