Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience

Yocum, David E.; Fürst, Daniel E.; Bensen, W.; Burch, Francis X.; Borton, Mary Ann; Mengle-Gaw, L.; Schwartz, Benjamin D.; Wisememandle, W; Mekki, Qais

doi:10.1093/rheumatology/keh155

Cited by 74 publications

(61 citation statements)

References 22 publications

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“…The response of patients with RA to tacrolimus treatment is normally investigated about 1-2 months after initiation of such treatment [19][20][21][22][23][24][25] . In our study, however, we noted that some patients responded …”

Section: Discussionmentioning

confidence: 99%

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Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

et al. 2010

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ABSTRACT. Objective. Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. Methods. One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio).Results. The disease activity of enrolled patients was 5.8 ± 1.2 (mean ± SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. Conclusion. Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment. (First Release Jan 15 2010;

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Section: Discussionmentioning

confidence: 99%

“…Studies indicate that the clinical effects of tacrolimus on RA appear after 1-2 months of treatment [19][20][21][22][23][24][25] . In our study, we report rapid improvement in clinical symptoms and laboratory tests after 2-week treatment with tacrolimus.…”

Section: Rheumatologymentioning

confidence: 99%

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

et al. 2010

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“…Tacrolimus has been shown to be efficacious in patients with RA resistant to or intolerant of MTX [7] or DMARDs [8,9,80], on the basis of criteria defined by the American Vol. 54,2005 A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis 5 [11 -13, 15 -19] Vol.…”

Section: Discussionmentioning

confidence: 99%

A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis

2005

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Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.

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“…In some studies, 3 mg/day of TAC improved the disease activity and had minimal adverse effects in patients with RA. But at this dose, the ACR 20 response rate is limited to 34-66 % of patients [7][8][9]. In one of these studies, although 5 mg/day of TAC was more effective than 3 mg/day, discontinuation due to creatinine elevation occurred more often in the 5 mg TAC group than in the 3 mg group [9].…”

Section: Introductionmentioning

confidence: 99%

Long-term therapeutic effects and safety of tacrolimus added to methotrexate in patients with rheumatoid arthritis

et al. 2012

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To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.

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Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience

Abstract: This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.

Cited by 74 publications

References 22 publications

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis

Long-term therapeutic effects and safety of tacrolimus added to methotrexate in patients with rheumatoid arthritis

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