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

Alfaro-Lara, Roberto; Espinosa-Ortega, Fabricio; Arce-Salinas, César Alejandro

doi:10.1016/j.reuma.2017.07.020

Cited by 51 publications

(29 citation statements)

References 32 publications

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“…For grade ≥3 symptoms, higher dosages of 40-60 mg/day of prednisone equivalents may be required (LE: 1 184 185 ). ► Treatments for patients with inflammatory arthritis that requires long-term treatment or does not respond to corticosteroids may include TNF-α inhibitors (eg, infliximab), methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, or IL-6 receptor (IL-6R) inhibitors (eg, tocilizumab), depending on the circumstances (LE: 1 [186][187][188][189][190] ). Decisions regarding this medication selection depend on severity, comorbidities, and anticipated time to efficacy, and should be managed by a rheumatologist.…”

Section: Inflammatory Arthritis and Pmrmentioning

confidence: 99%

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

Brahmer

Abu-Sbeih

Ascierto

et al. 2021

J Immunother Cancer

412

392

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Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.

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Section: Inflammatory Arthritis and Pmrmentioning

confidence: 99%

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

Brahmer

Abu-Sbeih

Ascierto

et al. 2021

J Immunother Cancer

412

392

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“…Lef is an agent with a long track record of safety that has been used in autoimmune disorders such as rheumatoid arthritis 8 . In autoimmune disease, Lef aims to mitigate the immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of the pyrimidine synthesis pathway can sensitize cancer cells to genotoxic chemotherapy agents 7 . Leflunomide (LEF), an agent with a long history of safety and efficacy in the treatment and prevention of autoimmune disorders and allograft rejection, targets de novo pyrimidine synthesis via inhibition of dihydroorotate dehydrogenase (DHODH) 8 , 9 . DHODH is the rate-limiting enzyme in the synthesis chain of uridine and is a critical enzyme in this pathway 10 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer

Phan¹,

Nguyen²,

Buettner³

et al. 2021

Int. J. Biol. Sci.

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Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis. De Novo pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer. Methods: MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells in vitro . An in vivo heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling. Results: Lef inhibits KPC cell growth and synergizes with Gem in vitro (P<0.05; Combination Index 0.44 (<1 indicates synergy). In vivo , Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits de novo pyrimidine synthesis both in vitro (p<0.0001) and in vivo (p<0.05). Conclusions: In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits de novo pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.

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“…Leflunomide has a similar infection risk to methotrexate. 24 Azathioprine is used for the management of vasculitis, CTDs and as a steroid sparing agent. It is associated with an increased risk of SI including CMV viraemia.…”

Section: Conventional Disease Modifying Anti-rheumatic Drugs (Dmards)mentioning

confidence: 99%

Identifying rheumatic disease patients at high risk and requiring shielding during the COVID-19 pandemic

et al. 2020

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Rheumatology teams care for patients with diverse, systemic autoimmune diseases who are often immunosuppressed and at high risk of infections. The current COVID-19 pandemic has presented particular challenges in caring for and managing this patient group. The office of the chief medical officer (CMO) for England contacted the rheumatology community to provide expert advice on the identification of extremely vulnerable patients at very high risk during the COVID-19 pandemic who should be 'shielded'. This involves the patients being asked to strictly self-isolate for at least 12 weeks with additional funded support provided for them to remain at home. A group of rheumatologists (the authors) have devised a pragmatic guide to identifying the very highest risk group using a rapidly developed scoring system which went live simultaneous with the Government announcement on shielding and was cascaded to all rheumatologists working in England.

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

Cited by 51 publications

References 32 publications

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer

Identifying rheumatic disease patients at high risk and requiring shielding during the COVID-19 pandemic

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