Effects of leflunomide: A Synthesis of Findings from 25 Studies

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Original Abstract of the Article

Major Research Findings

Leflunomide is an immunomodulatory drug used to treat rheumatoid arthritis. Multiple studies have shown that leflunomide can influence various pathways involved in cell proliferation and inflammation.

A771726, the active metabolite of leflunomide, significantly inhibited the expression of CD147, MMP-2, and MMP-9 in PMA-differentiated THP-1 cells. 23 This suggests that leflunomide may help suppress inflammatory responses in rheumatoid arthritis.

A rat model study indicated that leflunomide may cause gastrointestinal side effects. 6 Leflunomide increased the expression of TNF-α, IL-1β, and IL-6 in the intestines of rats.

Leflunomide reduced the severity of arthritis in DBA/1 mice with collagen-induced arthritis by modulating the balance of Th17/Treg cells. 10 Leflunomide reduced the number of Th17 cells and inhibited the expression of ROR-γt and IL-21 mRNA.

Leflunomide inhibited the proliferation of renal carcinoma cells, induced cell cycle arrest, and triggered autophagy. 7 At higher concentrations, leflunomide inhibited the canonical WNT signaling pathway by promoting the degradation of β-catenin.

Leflunomide suppressed inflammation and fibrosis in a rat model of bleomycin-induced pulmonary fibrosis. 17

Leflunomide reduced the number of CD4(+)CD25(+)Foxp3(+) Treg cells in mice receiving allogeneic bone marrow transplantation. 22

Combining leflunomide and benazepril provided superior protection against diabetic nephropathy in streptozotocin-induced diabetic nephropathy rat models compared to monotherapies. 14

Leflunomide is widely used to treat rheumatoid arthritis, but studies also show its antiviral effects in in vitro and/or in vivo experiments. 1

Supplementation of vitamin D, infliximab, and leflunomide in rats undergoing atorvastatin therapy showed alterations in serum testosterone concentrations. 4

Carvedilol and crocin demonstrated a hepatoprotective effect against leflunomide-induced liver injury. 2

Leflunomide showed protective effects in Lewis rats with experimental autoimmune uveitis. 8

Topical delivery of leflunomide resulted in the local deposition of teriflunomide and anti-inflammatory effects in an arthritis rat model. 11

Leflunomide exhibited immunosuppressive effects in human dendritic cells infected with dengue virus. 24

Nimesulide enhanced the symptomatic and disease-modifying effects of leflunomide in collagen-induced arthritis mouse models. 13

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a novel ester derivative of paeoniflorin, which has been shown to have synergistic pharmacodynamic effects with leflunomide (LEF). 3 CP-25 affected the pharmacokinetics of LEF in rats, promoting TER excretion and reducing its content in many tissues and organs, especially the liver.

β-caryophyllene showed an anti-arthritic effect and ameliorated methotrexate and/or leflunomide-induced side effects in arthritic rats. 5

Leflunomide protected renal lesions in a rat model of diabetic nephropathy. 9 Leflunomide reduced the increase in urine volume, protein, creatinine, and urea nitrogen levels in diabetic rats.

Leflunomide may play a role in cytomegalovirus disease prophylaxis in addition to its antirheumatic effects. 15

Leflunomide (A771726) protected the expression of podocalyxin, NF-κB, and MMP-9 in podocytes exposed to a high glucose environment. 18

A771726, the active metabolite of leflunomide, influenced the cytoskeleton of podocytes exposed to high glucose conditions. 19

Double filtration plasmapheresis (DFPP) combined with leflunomide and methotrexate (MTX) showed effects on inflammatory changes detected by magnetic resonance imaging (MRI) in patients with early rheumatoid arthritis. 21

Leflunomide is an immunosuppressant with multiple effects on T cell function. 16

UTL-5b (GBL-5b) is a novel leflunomide analog that demonstrated anti-inflammatory and anti-arthritic effects. 25 UTL-5b showed better anti-inflammatory effects compared to leflunomide and its metabolite in a carrageenan-induced edema study in rats.

The effects of Leflunomide may differ in treating patients with rheumatoid arthritis with different Chinese medical syndrome patterns. 20

The combination of LiCl and A771726, the active metabolite of leflunomide, affected viral-induced interleukin 6 production and EV-A71 replication. 12

Benefits and Risks

Benefit Summary

Leflunomide is a potentially effective immunosuppressant for treating rheumatoid arthritis. 16 Multiple studies have shown that leflunomide can suppress inflammation and slow down joint destruction. 10 Furthermore, leflunomide may enhance the effectiveness of other antirheumatic drugs when used in combination. 13 Additionally, leflunomide may be beneficial in treating dengue virus infections. 24

Risk Summary

Leflunomide may cause gastrointestinal side effects. 6 Leflunomide increased the expression of TNF-α, IL-1β, and IL-6 in the intestines of rats. 6 Furthermore, leflunomide may be hepatotoxic. 2

Comparison of Studies

Commonalities

Numerous studies have demonstrated the effectiveness of leflunomide in treating rheumatoid arthritis. 10 Leflunomide has been shown to suppress inflammation and slow joint destruction. 16 Furthermore, leflunomide may enhance the effectiveness of other antirheumatic drugs when used in combination. 13

Differences

The research findings regarding leflunomide side effects vary. Some studies suggest that leflunomide may cause gastrointestinal side effects. 6 Other studies indicate that leflunomide may also be hepatotoxic. 2

Consistency and Contradictions of Results

There is consistency in the research results regarding the effectiveness and side effects of leflunomide. Many studies have shown leflunomide to be effective in treating rheumatoid arthritis. 10 However, the research findings regarding leflunomide side effects can vary across studies. 6 2

Implications for Everyday Life

Leflunomide is a potentially effective immunosuppressant for treating rheumatoid arthritis. 10 However, leflunomide may cause side effects in the gastrointestinal system and liver. 6 2 Therefore, when considering the use of leflunomide, it is crucial to consult a physician and understand the risks and benefits involved.

Limitations of Current Research

Many studies on leflunomide have been conducted using animal models. 10 6 Therefore, further research is needed to determine the effects of leflunomide on humans.

Future Research Directions

Further research is necessary to determine the effects and side effects of leflunomide in humans. 10 6 Additionally, research on the combined effects of leflunomide with other drugs is needed. 13

Conclusion

Leflunomide has the potential to be an effective immunosuppressant for treating rheumatoid arthritis. 10 However, leflunomide may cause side effects in the gastrointestinal system and liver. 6 2 It is essential to consult with a physician and fully understand the risks and benefits before considering the use of leflunomide.

Literature analysis of 25 papers
Positive Content
24
Neutral Content
0
Negative Content
1
Article Type
1
0
0
1
25
1.

Leflunomide: Traditional immunosuppressant with concurrent antiviral effects.

Author: ZhengKunyu, ChenYiran, LiuSuying, HeChengmei, YangYunjiao, WuDi, WangLi, LiMengtao, ZengXiaofeng, ZhangFengchun

Leflunomide antiviral effects
Leflunomide immunoregulatory effects

Leflunomide, a disease-modifying anti-rheumatic drug, has both immunosuppressive and antiviral properties. It may be a valuable treatment option for autoimmune and autoinflammatory disorders, balancing anti-inflammatory effects with infection control.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

8.

[Effects of leflunomide on experimental autoimmune uveitis in Lewis rats].

Author: FangChengbo, ZhouDexi, ZhanShuxiang, HeYong, LinZhen, HuangCheng, LiJun

EAU treatment

Leflunomide was found to effectively suppress IRBP-induced uveitis in rats, suggesting that it may be protective against experimental autoimmune uveitis (EAU).

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : Chinese

11.

Topical delivery of leflunomide for rheumatoid arthritis treatment: evaluation of local tissue deposition of teriflunomide and its anti-inflammatory effects in an arthritis rat model.

Author: BaeJoonho, ParkJin Woo

Effective for rheumatoid arthritis
None mentioned

Topically applied leflunomide can be delivered effectively and deposited as teriflunomide in an arthritic joint, potentially improving compliance in rheumatoid arthritis patients by avoiding leflunomide's side effects.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

12.

The combination effects of licl and the active leflunomide metabolite, A771726, on viral-induced interleukin 6 production and EV-A71 replication.

Author: HungHui-Chen, ShihShin-Ru, ChangTeng-Yuan, FangMing-Yu, HsuJohn T-A

Enterovirus 71 treatment

LiCl, a GSK3β inhibitor, effectively suppressed enterovirus 71 (EV-A71) replication, apoptosis, and inflammatory cytokine production in infected cells. The combination of LiCl and an immunomodular agent showed synergistic effects in suppressing EV-A71 replication, highlighting potential new treatment regimens for this viral infection.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

13.

Nimesulide improves the symptomatic and disease modifying effects of leflunomide in collagen induced arthritis.

Author: Al-AbdAhmed M, Al-AbbasiFahad A, NofalSalwa M, KhalifaAmani E, WilliamsRichard O, El-ErakyWafaa I, NagyAyman A, Abdel-NaimAshraf B

Rheumatoid arthritis treatment

This study investigated the effects of nimesulide (a COX-2 inhibitor) and leflunomide (an anti-pyrimidine) on rheumatoid arthritis in mice. Nimesulide alone only provided temporary symptom relief, while leflunomide alone provided moderate symptom relief and slowed disease progression. Combining nimesulide and leflunomide significantly improved symptoms and slowed disease progression.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

14.

Synergistic effects of leflunomide and benazepril in streptozotocin-induced diabetic nephropathy.

Author: JinHua, PiaoShang Guo, JinJi Zhe, JinYing Shun, CuiZhen Hua, JinHai Feng, ZhengHai Lan, LiJin Ji, JiangYu Ji, YangChul Woo, LiCan

Body weight gain
DN prevention
Reduced proteinuria

LEF treatment lessens DN, and combined treatment with LEF and benazepril provides synergistic effects in preventing DN.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

15.

Can leflunomide play a role in cytomegalovirus disease prophylaxis besides its antirheumatic effects?

Author: LuCheng-Hsun, TsaiJia-Huei, WuMu-Zon, YuChia-Li, HsiehSong-Chou

CMV prophylaxis
Leflunomide effectiveness
CMV disease

Leflunomide, a disease-modifying antirheumatic drug, has shown potential for CMV prophylaxis and pre-emptive therapy in high-risk patients. This case report describes two patients who developed CMV disease after receiving low-dose leflunomide, highlighting the importance of monitoring for this potential complication.

Case ReportsIn the medical field, a report that describes in detail a unique case, an unusual medical condition, or the effect of a treatment. Provides new insights and possibilities for treatment through individual patient cases.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

18.

[Effects of leflunomide on podocytes exposed to high glucose condition and its mechanism].

Author: ZhaoXing, YuWei-min, LiRong-shan, RenXiao-jun

Protective for podocytes

Leflunomide has protective effects on podocytes in high glucose, possibly due to a lowered expression of matrix metalloproteinase-9 (MMP-9) through an inhibition of NF-κB activation.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : Chinese

19.

[Effects of leflunomide on high glucose-induced podocyte cytoskeleton and its mechanism].

Author: ChaiWei-xia, YuWei-min, LiRong-shan, XueJin-jie, ZhaoXing

Podocyte protection

The active metabolite of leflunomide, A771726, protected podocytes from high glucose-induced damage by blocking the NF-κBp65 signaling pathway. This was demonstrated by decreased p-NF-κBp65 protein expression and reduced TRPC6 expression, while nephrin expression was increased.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : Chinese

20.

[Effects of leflunomide in treating patients with rheumatoid arthritis of different Chinese medical syndrome patterns].

Author: WangZhi-Ming, WuYan, LiWei-Qing

Significant effects in treating RA
None

Leflunomide showed significant effects in treating rheumatoid arthritis, with better outcomes in the heat-dampness blocking collateral type, cold-dampness blocking collateral type, and stagnant blood blocking collateral type compared to the Shen-qi deficiency cold type and Gan-Shen yin deficiency type.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : Chinese

21.

Effects of double filtration plasmapheresis, leflunomide, and methotrexate on inflammatory changes found through magnetic resonance imaging in early rheumatoid arthritis.

Author: YuXiaoxia, WangLixin, XuPing, LuWeiwei, LanGuobin, PingLifeng, WangXiaolei, TianJunge, LiuJunlan

Inflammation suppression
RA treatment

This randomized study compared the effects of double filtration plasmapheresis (DFPP) in combination with leflunomide and methotrexate (MTX) to leflunomide plus MTX alone in 60 patients with early rheumatoid arthritis (RA). DFPP significantly reduced MRI-detected synovitis and bone edema, leading to greater ACR responses and DAS28 remission rates. DFPP enabled rapid and more complete suppression of inflammation, with nearly half the patients achieving both clinical and imaging remission.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

22.

The effects of leflunomide on CD4(+)CD25 (+)Foxp3 (+) T regulatory cells in mice receiving allogeneic bone marrow transplantation.

Author: JinDi, DuanKaizhong, ZhangLianjun, PengJianxia, ZhaoYong

Autoimmune disease treatment
Graft rejection prevention

Leflunomide, a drug for rheumatoid arthritis, was found to affect Treg cells in a mouse model of allogeneic bone marrow transplantation.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

23.

Inhibiting effects of Leflunomide metabolite on overexpression of CD147, MMP-2 and MMP-9 in PMA differentiated THP-1 cells.

Author: HuangJian-lin, WuShi-yao, XieXu-jing, WangMing-xia, ZhuShangling, GuJie-ruo

Rheumatoid arthritis treatment

A771726, the active metabolite of leflunomide, significantly inhibited CD147 expression and gelatinolytic activity of MMP-2 and MMP-9 in activated THP-1 cells. This suggests that leflunomide may have a therapeutic effect in rheumatoid arthritis by modulating CD147 and MMPs.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

24.

Immunosuppressive effects and mechanisms of leflunomide in dengue virus infection of human dendritic cells.

Author: WuWan-Lin, HoLing-Jun, ChenPei-Chih, TsaiYi-Ting, HsuSeng-Ting, ChangDeh-Ming, LaiJenn-Haung

DENV infection treatment
Immunosuppressive effects

Leflunomide, a drug commonly used to treat arthritis, was found to inhibit the activation of dengue virus (DENV)-stimulated monocyte-derived dendritic cells (mo-DCs). This suggests that leflunomide may be a potential therapeutic option for DENV infection.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

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