Related Experiment Video
Updated: Jul 10, 2026
04:50
Preliminary Study on Acupuncture Combined with Grain-sized Moxibustion for Treating Rheumatoid Arthritis with Finger Joint Pain
Published on: May 16, 2025
How does leflunomide modulate the immune response in rheumatoid arthritis?
R I Fox1, M L Herrmann, C G Frangou
1Division of Rheumatology, Scripps Memorial and Research Institutes, La Jolla, California 92037, USA. bobfox@adnc.com
Summary
Leflunomide, a disease-modifying antirheumatic drug (DMARD), effectively treats rheumatoid arthritis by inhibiting pyrimidine synthesis in lymphocytes. Its active metabolite, A77-1726, targets dihydro-orotate dehydrogenase (DHO-DH), impacting lymphocyte proliferation.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- Leflunomide is a newly approved disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis treatment.
- Clinical trials demonstrated leflunomide's efficacy comparable to methotrexate and sulfasalazine, with superiority over placebo.
- Both leflunomide and methotrexate demonstrated disease-modifying properties by retarding radiological progression.
Purpose of the Study:
- To elucidate the mechanism of action of leflunomide in rheumatoid arthritis.
- To investigate the role of dihydro-orotate dehydrogenase (DHO-DH) inhibition in leflunomide's immunomodulatory effects.
- To understand how leflunomide affects lymphocyte proliferation and cell cycle progression.
Main Methods:
- In vitro studies assessing the inhibition of human dihydro-orotate dehydrogenase (DHO-DH) by leflunomide's active metabolite, A77-1726.
- Analysis of pyrimidine synthesis pathways (de novo and salvage) in lymphoid and non-lymphoid cells.
- Proposed mechanism involving p53 and interference with cell cycle progression.
Main Results:
- Leflunomide's active metabolite, A77-1726, inhibits DHO-DH at concentrations relevant to rheumatoid arthritis treatment.
- Inhibition of DHO-DH leads to reduced uridine monophosphate (rUMP) production, crucial for lymphocyte proliferation.
- Non-lymphoid cells exhibit less toxicity due to their reliance on the salvage pyrimidine pathway.
Conclusions:
- Leflunomide acts as an immunomodulatory drug by inhibiting de novo pyrimidine synthesis via DHO-DH.
- This mechanism selectively targets activated lymphocytes, preventing their expansion and autoimmune responses.
- The differential utilization of pyrimidine synthesis pathways explains leflunomide's relative safety profile in non-lymphoid cells.
Related Concept Videos
01:24T Cell Types and Functions
When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
Crohn's disease is an inflammatory bowel disorder marked by chronic inflammation of the GI tract. Various treatment strategies for Crohn's disease are employed, such as immunomodulatory agents, glucocorticoids, and biologics or anti-TNF therapy. Azathioprine (Imuran), a commonly used immunomodulatory drug for Crohn's disease, is converted in the body to mercaptopurine, which inhibits purine biosynthesis and cell proliferation. Both are utilized in severe cases of Inflammatory Bowel Disease...
01:19Antiasthma Drugs: Leukotriene Modifiers
Leukotriene modifiers, or cysteinyl leukotriene receptor antagonists, are medications used to manage chronic asthma. These agents target specific inflammatory mediators produced during arachidonic acid metabolism, an essential process in generating inflammation in the body.
Leukotriene modifiers work through two distinct mechanisms:
Leukotriene modifiers work through two distinct mechanisms:
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab (Humira),...
01:28Inflammatory Response
An inflammatory response is a localized, nonspecific immune reaction that occurs when a tissue is injured. It is characterized by redness, swelling, heat, and pain, which are commonly called the cardinal signs and symptoms of inflammation. Inflammation can sometimes result in a loss of function.
Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...
Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...