Efficacy of leflunomide combined with ligustrazine in the treatment of rheumatoid arthritis: Prediction with network pharmacology and validation in a clinical trial

Chi Zhang, Daogang GUAN, Miao Jiang, Chao LIANG, Li Li, Ning Zhao, Qinglin Zha, Wandong Zhang, Cheng Lu, Ge ZHANG*, Jian Liu, Aiping LYU

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background: Leflunomide (LEF) is a first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA). However, there are still a few nonresponders. It is logical to suggest that employing combinations including LEF that produce synergistic effects in terms of pharmacological activity is a promising strategy to improve clinical outcomes. Methods: We propose a novel approach for predicting LEF combinations through investigating the potential effects of drug targets on the disease signaling network. We first constructed an RA signaling network with disease-associated driver genes. Thousands of available FDA-approved and investigational compounds were then selected based on a drug-RA network, which was generated using an algorithm model named synergistic score that combines chemical structure, functional prediction and target pathway. We then validated our predicted combination in a prospective clinical trial. Results: Ligustrazine (LIG), a key component of the Chinese herb Chuanxiong and an approved drug in China, ranked first according to synergistic score. In the clinical trial, after 48 weeks, the American College of Rheumatology (ACR) 20 response rate was significantly lower (P < 0.05) in the LEF group [58.8% (45.4%, 72.3%)] than in the LEF + LIG group [78.7% (68.5%, 89.0%)]. Consistently, the erosion score was lower in patients treated with LEF + LIG than in those treated with LEF (0.34 ± 0.20 vs 1.12 ± 0.30, P < 0.05). Conclusions: Our algorithm combines structure and target pathways into one model that predicted that the combination of LEF and LIG can reduce joint inflammation and attenuate bone erosion in RA patients. To our knowledge, this study is the first to apply this paradigm to evaluate drug combination hypotheses.

Original languageEnglish
Article number26
JournalChinese Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 2 Aug 2019

Scopus Subject Areas

  • Pharmacology
  • Complementary and alternative medicine

User-Defined Keywords

  • Leflunomide
  • Ligustrazine
  • Rheumatoid arthritis

Fingerprint

Dive into the research topics of 'Efficacy of leflunomide combined with ligustrazine in the treatment of rheumatoid arthritis: Prediction with network pharmacology and validation in a clinical trial'. Together they form a unique fingerprint.

Cite this