Leflunomide for the treatment of rheumatoid arthritis

Osiri, Manathip; Shea, Beverley; Welch, Vivian; Suarez‐Almazor, María E.; Strand, Vibeke; Tugwell, Peter; Wells, George A.

doi:10.1002/14651858.cd002047

Cited by 98 publications

(95 citation statements)

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“…Leflunomide is a synthetic, low molecular weight isoxazole derivative that is clinically applied for the treatment of rheumatoid arthritis (RA) due to its potent antiinflammatory and immunosuppressive properties (1)(2)(3). Furthermore, it is currently being evaluated for the treatment of inflammatory bowel disease (4) and as a novel immunosuppressive agent for the amelioration of chronic allograft rejection (5).…”

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confidence: 99%

Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Zeyda

Poglitsch

Geyeregger

et al. 2005

Arthritis & Rheumatism

105

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Objective. Leflunomide, a potent diseasemodifying antirheumatic drug of the isoxazole class, exhibits antiinflammatory, antiproliferative, and immunosuppressive effects by largely unknown mechanisms, although alterations of pyrimidine synthesis have been proposed. Successful immune responsiveness requires T cell activation by interaction with antigen-presenting cells (APCs), and integrin activation and formation of an immunologic synapse (IS). In this study, we evaluated the impact of the active leflunomide metabolite teriflunomide on T cell integrin activation, evolution of the IS, and antigen-specific formation of stable T cell/ APC conjugates.Methods. Effects of pharmacologic concentrations of teriflunomide on CD3/CD28-and lymphocyte function-associated antigen 1-induced signal transduction and activation of primary human T cells were investigated. Furthermore, T cells were stimulated with superantigen-and antigen-pulsed APCs to study relocalization of molecules to the IS and T cell/APC conjugate formation.Results. Teriflunomide inhibited T cell receptor (TCR)/CD3-mediated calcium mobilization, but other critical T cell signaling events, including activation of MAPK and NF-B, remained unaltered. In contrast, inhibition of TCR/CD3-triggered ␤1,2 integrin avidity and integrin-mediated costimulation (outside-in signaling) by teriflunomide revealed a striking interference with integrin function that was independent of altered pyrimidine synthesis. Moreover, teriflunomide abolished molecule relocalization to the IS and induction of T cell/APC conjugates.Conclusion. These data show that the active metabolite of leflunomide prevents the interaction of T cells with APCs to form an IS. Since IS formation is crucial for eliciting an immune response, this novel mechanism could underlie the beneficial effects of leflunomide in immune-mediated disorders such as rheumatoid arthritis.

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confidence: 99%

Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Zeyda

Poglitsch

Geyeregger

et al. 2005

Arthritis & Rheumatism

105

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“…Although many randomized controlled trials to this point proved that LEF safety and efficacy profiles were comparable to MTX [18][19][20][21][22], other studies showed serious concerns regarding LEF hepatotoxicity that still needs clarification [22,23]. Several previous findings have suggested a greater toxicity (up to 5 fold increased incidence of LFT abnormalities) with LEF + MTX combination over MTX monotherapy [24] or increased risk of fibrosis when using this combination [25].…”

Section: Resultsmentioning

confidence: 99%

Safety and efficacy of Methotrexate Monotherapy Vs Methotrexate Plus Leflunomide Combination Therapy in Early Active Rheumatoid Arthritis Patients

Boshra¹,

Ahmed²,

Salem³

et al. 2016

Med-Science

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“…The most common side effects detected by clinical studies were diarrhea, dyspepsia, nausea, abdominal pain, oral ulcers, impaired liver function tests, increased risks of seconder infections, weight loss and hypertension [8] . We have to claim that stopping of Leflunomide and potassium replacement was at the same time prevent to make a concise diagnosis about hypokalemia etiology, but, there was no other reasons for hypokalemia at that time, and her potassium levels were in normal range during follow up after stopping leflunomide.…”

Section: Resultsmentioning

confidence: 99%

A treatment resistant hypokalemia case associated with leflunomide

Aktaş

Karacay²,

Özmen³

et al. 2014

CRIM

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Introduction: Leflunomide is a disease-modifying antirheumatic drug which is used in the treatment of rheumatoid arthritis. The most common side effect of leflunomide is diarrhea, however, hypokalemia may also develop during treatment with this drug. Here, we present a case with treatment resistant hypokalemia in a patient who has been on leflunomide treatment for approximately 8 weeks for treatment of rheumatoid arthritis.Case report: Fifty six years old woman was admitted to internal medicine outpatient clinic with complaints of weakness, constipation, loss of appetite, abnormal weight loss (approximately 10 kilograms) and arthralgias for 3 weeks. Laboratory analyse revealed hypokalemia on admission (serum potassium: 2.3 mmol/L). Potassium chloride was infused in isotonic solutions with close monitoring; a potassium value of 4.5 mmol/L was achieved on the fifth day of treatment. Her complaints such as nausea, constipation, lack of appetite were decreased with normalization of serum potassium. Conclusion:We suggest close electrolyte monitoring is important if leflunomide treatment was planning especially in patients whose treatment regimens include multiple medications.

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Leflunomide for the treatment of rheumatoid arthritis

Abstract: Cochrane Database of Systematic Reviews Analysis 9.13. Comparison 9 Changes of CRP (mg/dl), Outcome 13 Lef/lef+MTX vs Plc/lef+MTX, at 48 weeks.

Cited by 98 publications

References 50 publications

Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Safety and efficacy of Methotrexate Monotherapy Vs Methotrexate Plus Leflunomide Combination Therapy in Early Active Rheumatoid Arthritis Patients

A treatment resistant hypokalemia case associated with leflunomide

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