Tacrolimus is a novel immunosuppressant used in the treatment of a variety of autoimmune diseases.More and more studies have shown that tacrolimus has a certain therapeutic effect on myasthenia gravis (MG).This article reviews the mechanism,clinical researches,adverse reactions,dosage and clinical evaluation of tacrolimus in the treatment of MG.
GOTTERERL, LIY.Maintenance immunosuppression in myasthenia gravis[J]. J Neurol Sci, 2016,369:294-302.
61Therapy for MG is guided by disease severity, antibody status, and comorbidities.61Immunosuppression is needed in most MG patients.61Corticosteroids are first-line and effective in 80% or more of MG patients.61IVIG and PLEX can be used as maintenance therapy in refractory MG.61MuSK-MG is often severe at onset prompting early initiation of immunosuppression.
RAICAM, CIMPEAN AM, RIBATTID, et al.Myasthenia gravis and the thymus gland. A historical review[J]. Clin Exp Med, 2008, 8(2):61-64.
The first report of an association between (MG) and the thymus gland was in 1901. Although the underlying mechanisms are uncertain, thymic abnormalities are clearly associated with MG. This review article summarises, from a historical point of view, our knowledge of these associations, and the surgical and medical treatment of MG, including symptom management, immunosuppression, intravenous immunoglobulin and plasmapheresis.
YUTAKAF, HIROAKIY, KAZUOY, et al.Clinical efficacy and cytokine network-modulating effects of tacrolimus in myasthenia gravis[J]. J Neuroimmunol, 2008, 195(1/2):108-115.
Abstract To clarify the long-term efficacy, safety and the cytokine network-modulating effects of tacrolimus in myasthenia gravis, medical records of 86 newly diagnosed consecutive patients and nine steroid-dependent patients were retrospectively reviewed, and peripheral blood mononuclear cells (PBMC) were cultured for the cytokine profile. Steroid reduction effects were observed by using tacrolimus, and no serious adverse effects were observed. The culture study showed reduced IL-12, IL-17, IFN-gamma, GM-CSF, TNF-alpha and MIP-1beta, and elevated IL-10 in the PBMC from patients who received tacrolimus, which suggests inhibition of T cells and macrophages, and enhancement of type 1 regulatory T cells.
POUCHEL, STOJANOVAJ, MARQUETP, et al.New challenges and promises in solid organ transplantation pharmacogenetics: the genetic variability of proteins involved in the pharmacodynamics of immunosuppressive drugs[J]. Pharmacogenomics,2016,17(3): 277-296.
Abstract Interindividual variability in immunosuppressive drug responses might be partly explained by genetic variants in proteins involved in the immune response or associated with IS pharmacodynamics. On a general basis, the pharmacogenetics of drug target proteins is less known and understood than that of proteins involved in drug disposition pathways. The aim of this review is to facilitate research related to the pharmacodynamics of the main immunosuppressive drugs used in solid organ transplantation. We elaborated a quality of evidence grading system based on a literature review and identified 'highly recommended', 'recommended' or 'potential' candidates for further research. It is likely that a number of additional rare variants might further explain drug response phenotypes in transplantation, and particularly the most severe ones. The advent of next-generation sequencing will help to identify those variants.
MITSUIT, KURODAY, UENOS, et al.FK506 attenuates thymic output in patients with myasthenia gravis[J]. Arch Med Sci, 2013, 9(6): 1090-1096.
Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4(+) T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG.We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants.T-cell receptor excision circle was not significantly different from those in age-matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4(-)CD8(+) cells (p < 0.05), but total cell counts were not significantly changed.These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also na茂ve T-cells.
ZHAO CB, ZHANGX, ZHANGH, et al.Clinical efficacy and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis[J]. Int Immunopharmacol, 2011, 11(4): 519-524.
In this multicenter, open-label pilot study, the efficacy, safety, and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis are assessed. Forty-seven generalized myasthenia gravis (MG) patients were enrolled into this study and given 3mg/day tacrolimus for 24 weeks. The primary efficacy measurements used to monitor response to tacrolimus in MG patients were the Osserman grade, the quantitative MG score (QMGS) recommended by the MGFA, the MG-specific manual muscle testing (MMT) score, and the MG-related activities of daily living (MG-ADL) scale. Also, reduction in steroid doses was used to monitor the effect of tacrolimus. Clinical evaluations were conducted at weeks 4, 8, 12, 16, 20, and 24, while immunological parameters were measured at weeks 4, 12, and 24. Measurements of the Osserman grade, QMGS, MMT, and MG-ADL all suggested improvement in patient health by the fourth week of treatment. Steroid dosage was reduced during the course of the study in 74.2% of the forty-three patients who completed the study. There were thirty-one reported adverse events in the study. Only one was considered serious. We found that tacrolimus reduced levels of the IFN-纬, IL-2, IL-10, and IL-13 cytokines and induced the proliferation of tolerogenic plasmacytoid dendritic cells after treatment. Tacrolimus did not change the population of T cell subtypes but did steadily reduce the population of BAFF-R(+) CD19(+) B cells over the course of the study. Our results show that tacrolimus improves the clinical condition of MG patients and is well tolerated. The decrease in IL-13 and reduction of BAFF-R(+) CD19(+) B cells may be related to the therapeutic effect of tacrolimus.
IMAIT, TSUDAE, HOZUKIT, et al.Early effect of tacrolimus in improving excitation-contraction coupling in myasthenia gravis[J]. Clin Neurophysiol, 2012, 123(9): 1886-1890.
Tacrolimus (FK506) is a macrolide T-cell immunomodulator used to treat myasthenia gravis (MG). Besides immunosuppression, tacrolimus has been reported to have the potential to increase muscle strength by enhancing ryanodine receptor (RyR) function. However, few attempts have been made to demonstrate the early effect of tacrolimus as an RyR enhancer in clinical investigation. In 20 MG patients, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The excitation–contraction (E–C) coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT and bite force were performed before and within 4weeks of tacrolimus (3mgday611) treatment. The median (mean, range) interval of assessment was 2 (2.4, 1–4) weeks. We also measured serum antibodies against RyR, acetylcholine receptor and muscle-specific receptor tyrosine kinase. Bite force increased after tacrolimus treatment accompanying clinical improvement assessed by Myasthenia Gravis Foundation of America classification, but the bite force difference did not reach statistical significance. Wilcoxon matched-pairs signed-ranks test detected a significant ECCT shortening in 12 patients assessed after 1–2weeks of tacrolimus treatment as well as in eight patients assessed after 3–4weeks. In contrast, masseteric CMAP and % decrement showed no significant changes after short-term tacrolimus treatment. Tacrolimus induces ECCT shortening accompanying clinical improvement despite no improvement in % decrement within 2weeks. This early effect of tacrolimus may imply a pharmacological enhancement of RyR function to improve E–C coupling in MG.
PENN AS, SANDERS DB, JARETZKIA, et al.Myasthenia gravis: recommendations for clinical research standards: task force of the medical scientific advisory board of the myasthenia gravis foundation of America[J]. Neurology, 2000, 55(1): 16-23.
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KONISHIT, YOSHIYAMAY, TAKAMRIM, et al.Clinical study of FK506 in patients with myasthenia gravis[J]. Muscle Nerve, 2003, 28(5): 570-574.
To investigate the usefulness of low-dose FK506 for the treatment of (MG), we treated 19 patients with generalized MG in a 16-week open clinical trial of FK506 (3-5 mg/day). At the end of the trial, total MG scores (range: 0-27 points) improved by 3 points or more in 7 of 19 patients (37%), and activities of daily living () scores (range: 0-6 points) also improved by 1 point or more in 8 of 19 patients (42%). Nine of 19 patients (47%) showed improvement in either MG or scores. Significant reduction of anti-receptor titers and production were observed at the end of this study. Minor but commonly observed side effects were an increase in neutrophil count and a decrease in lymphocyte count. No serious adverse events such as renal toxicity or mellitus were observed during the 16-week treatment period. FK506 could safely serve as an adjunct to steroid therapy for MG at low dosage.
KONISHIT, YOSHIYAMAY, TAKAMRIM, et al.Long-term treatment of generalised myasthenia gravis with FK506 (tacrolimus)[J]. J Neurol Neurosurg Psychiatry, 2005, 76(3):448-450.
Efficacy and safety of long term use of FK506 (2-4.5 mg/ day)for a maximum of two years were evaluated in 12 patients with generalised myasthenia gravis (MG) . At the end of the study,eight patients (67%) showed improvement in either MG score or Activities in Daily Living score, and prednisolone dosage could be redu ced in seven patients (58%), with a mean reduction ratio of 37%. Long term use of FK506 for MG can be more effective than short term administration, with no s erious side effects.
MINAMIN, FUJIKIN, DOIS, et al.Five-year follow-up with low-dose tacrolimus in patients with myasthenia gravis[J]. J Neurol Sci, 2011, 300(1/2):59-62.
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction, and prednisolone (PSL) and immunosuppressive drugs are available for treatment. Tacrolimus, a macrolide that suppresses the immune system, is used as a second-line treatment for MG. There have been several reports of the effects of tacrolimus over a few years of follow-up. Here, we report data from 9 patients with steroid-dependent generalized MG treated with low-dose tacrolimus (2–302mg/day) for 502years. Following treatment with tacrolimus, mean MG-activities of daily living score improved from 4.6 at baseline to 3.3 at 502years after initiation of treatment. Mean dose of PSL could also be reduced, from 24.002mg/day at baseline to 10.202mg/day at 502years, although there were no cases of total withdrawal of PSL. By contrast, 5 of the 9 patients experienced exacerbation of symptoms and transient increases in PSL dose during the 5-year period. Tacrolimus is an important option for treatment of MG; however, careful management is needed for long-term treatment with this drug.
YOSHIKAWAH, KIUCHIT, SAIDAY, et al.Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis[J]. J Neurol Neurosurg Psychiatry, 2011, 82(9):970-977.
Abstract OBJECTIVES: To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study. METHODS: Patients being treated with oral prednisolone at doses equivalent to 10-20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study. RESULTS: Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p = 0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted. CONCLUSIONS: This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT00309088 . Name of the trial registry: FK506 Phase 3 STUDY: A STUDY for Steroid Non-Resistant MG Patients.
AZEMJ, FORT JM, CODINAA, et al.Benefits of FK506 (tacrolimus) for residual, cyclosporine- and prednisone-resistant myasthenia gravis: one-year follow-up of an open-label study[J]. Clin Neurol Neurosurg, 2005, 107(3):187-190.
Thirteen patients with , unresponsive to and cyclosporin after thymectomy, received KF506 () for 12 months, at starting doses of 0.1 mg/kg per day b.i.d. and then adjusted to achieve plasma concentrations between 7 and 8 ng/mL. The doses of were progressively reduced and finally discontinued. Anti-and score for disease severity decreased significantly and muscular strength increased by 37%. All patients achieved pharmacological remission, 11 were asymptomatic and two had minimal weakness of eyelid closure. was well tolerated and appears a suitable approach after unsuccessful treatment with conventional immunosuppressants in patients with disabling .
PONSETI JM, AZEMJ, FORT JM, et al.Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis[J]. Neurology, 2005, 64(9):1641-1643.
Seventy-nine patients with cyclosporine-and prednisone-dependent myasthenia gravis (MG) after thymectomy received tacrolimus for a mean of 2.5 卤0.8 years. Prednisone was withdrawn in all but two patients. Anti-acetylcholine antibodies and MG score for disease severity decreased significantly and muscular strength increased by 39%. Complete stable remission was achieved in 5%of patients and pharmacologic remission in 87.3%. All patients resumed fu ll activities of daily living.
PONSETI JM, AZEMJ, FORT JM, et al.Experience with starting tacrolimus postoperatively after transsternal extended thymectomy in patients with myasthenia gravis[J]. Curr Med Res Opin, 2006, 22(5): 885-895.
Thymectomy is a standard treatment of myasthenia gravis (MG). Immunomodulating agents are frequently given during the post-thymectomy latency period until complete remission is fully consolidated, but serious side effects is a relevant clinical problem for patients on long-term immunomodulating treatment.To assess the effectiveness of starting tacrolimus in the immediate postoperative period in MG patients undergoing transsternal extended thymectomy, with complete stable remission (CSR) as the primary outcome of the study.Forty-eight MG patients received tacrolimus, 0.1 mg/kg per day b.i.d. (started 24 h after thymectomy) and prednisone 1.5 mg/kg/day. Histologically, 34 patients had hyperplasia, 20 thymic involution, and 14 thymoma. Of the 48 patients, 40 completed 1 year of tacrolimus therapy, 38 completed 2 years, 27 completed 3 years, 21 completed 4 years, and 9 more than 5 years. Mean dose of tacrolimus was 4.9 mg/day (range 2-8 mg/day) with a mean plasma drug concentration of 7.6 ng/mL (range 7-9 ng/mL). Prednisone could be withdrawn after the first year in 93.7% of patients and at 2 years in 100%.The mean follow-up was 24.4 months, SD 17.3 (range 6-60 months). Improvement of muscular strength and decrease of anti-AChR antibodies were statistically significant (p < 0.001) shortly after operation. CSR was obtained in 33.4% of patients, pharmacological remission in 62.6%; 4% of patients had minimal symptoms. None of the patients with thymoma achieved CSR. The estimated median follow-up to obtain a CSR was 37.9 months (95% confidence interval [CI] 26.4-49.5 months). The overall crude CSR rate was 33.4%, with 47% for non-thymoma patients. The probability to achieve CSR at 3 years was 67% for the non-thymomatous group.Long-term immune-directed treatment with tacrolimus to improve the effectiveness of thymectomy in MG is feasible and was associated with a high rate of CSR in patients without thymoma.
PONSETI JM, GAMEZJ, AZEMJ, et al.Tacrolimus for myasthenia gravis: a clinical study of 212 patients[J]. Ann N Y Acad Sci, 2008, 1132:254-263.
Tacrolimus is a macrolide T cell immunomodulator that is used in myasthenia gravis (MG) patients to affect muscle contraction (ryanodine receptor by modulating intracellular calcium-release channels and increasing muscular strength), glucocorticoid receptors (increasing intracellular concentration of steroids and blocking the steroid export mechanism), and an increase in T cell apoptosis. In this study, we report the results of low-dose tacrolimus (0.165mg/kg/day) treatment in 21265MG patients. There were 110 thymectomized, cyclosporine- and prednisone-dependent patients; 68 thymectomized patients who started tacrolimus early postoperatively (2465h after operation); and 3465patients over 60 years old with nonthymomatous generalized MG or in whom thymectomy was contraindicated. The mean follow-up time was 49.365±6518.165months. Muscular strength showed an increase of 23% after 165month of treatment and 29% at the end of the study. The acetylcholine receptor antibodies decreased significantly from a mean of 33.565nmol/L at base line to 7.865nmol/L at the final visit. In the thymectomy group with combined prednisone and tacrolimus stratified by histology of the thymus, the mean probability to attain complete stable remission at 565years was 80.8% in patients with hyperplasia, 48.1% in thymic involution, and 9.3% in patients with thymoma. In 4.9% of patients, tacrolimus was withdrawn because of major adverse effects. Our results suggest that a low dose of tacrolimus is effective for MG and could be included to the armamentarium for this autoimmune disease. The present results should be interpreted considering the limitations of a retrospective clinical study. Confirmation of these results in randomized studies is desirable.
PONSETI JM, GAMEZJ, AZEMJ, et al.Post-thymectomy combined treatment of prednisone and tacrolimus versus prednisone alone for consolidation of complete stable remission in patients with myasthenia gravis: a non-randomized, non-controlled study[J]. Curr Med Res Opin, 2007, 23(6): 1269-1278.
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YAGIY, SANJON, YOKOTAT, et al.Tacrolimus monotherapy:a promising option for ocular myasthenia gravis[J]. Eur Neurol, 2013, 69(6):344-345.
CRUZ JL, WOLFF ML, VANDERMAN AJ, et al.The emerging role of tacrolimus in myasthenia gravis[J]. Ther Adv Neurol Disord, 2015, 8(2): 92-103.
Abstract OBJECTIVE: To describe and evaluate the available evidence assessing the role of tacrolimus in the management of patients with myasthenia gravis (MG). DATA SOURCES: A literature search of MEDLINE (1946 to September 2014) and EMBASE (1947 to September 2014) was performed using the terms 'tacrolimus' and 'myasthenia gravis'. Citations of retrieved articles were examined for relevance. STUDY SELECTION AND DATA EXTRACTION: The search was limited to prospective clinical trials focused on clinical outcomes in patients with generalized MG. Case reports, retrospective evaluations and non-English articles were excluded. DATA SYNTHESIS: A total of 12 studies met inclusion criteria, of which seven articles evaluated tacrolimus in steroid-dependent patients and two examined the utility of tacrolimus in patients failing corticosteroids and cyclosporine. Other studies evaluated early initiation of tacrolimus after thymectomy, effectiveness of tacrolimus in de novo MG and the effectiveness of tacrolimus post-thymectomy in thymoma patients versus nonthymoma. A total of eight trials showed statistically significant improvements in quantitative MG score (QMGS) and postintervention status criteria - Myasthenia Gravis Foundation of America (PSC-MGFA). Of the trials examining steroid reduction with tacrolimus, two reported high rates of complete withdrawal; however, the most robust trial was unable to detect a difference in mean steroid dose. Long-term effects of tacrolimus (up to 5 years) were assessed in eight trials, which consistently showed positive effects on QMGS or reduction in adjunct therapies. CONCLUSIONS: There is limited yet promising information to suggest a beneficial role for tacrolimus in reducing QMGS and corticosteroid burden in patients with refractory symptoms or new-onset MG. Long-term use appears to be safe in this population.
New challenges and promises in solid organ transplantation pharmacogenetics: the genetic variability of proteins involved in the pharmacodynamics of immunosuppressive drugs
Myasthenia gravis: recommendations for clinical research standards: task force of the medical scientific advisory board of the myasthenia gravis foundation of America
Post-thymectomy combined treatment of prednisone and tacrolimus versus prednisone alone for consolidation of complete stable remission in patients with myasthenia gravis: a non-randomized, non-controlled study
, 李冉, 刘飞
