Lack of Correlation Between MMF Dose and MPA Level in Pediatric and Young Adult Cardiac Transplant Patients: Does the MPA Level Matter?1

To determine the correlation between mycophenolate mofetil (MMF) dose and mycophenolic acid (MPA) level as well as its impact on rejection among young cardiac transplant recipients (OHT), trough concentrations of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were measured following MMF doses of 1200 mg/m2/d (max 3000 mg/d). Corresponding endomyocardial biopsy (EMB) grades and calcineurin inhibitor levels were recorded with simultaneous MPA/MPAG levels. Correlation coefficients were derived between MMF dose and MPA/MPAG levels. Contingency analysis evaluated the relation between MPA level and EMB score. Twenty-six patients (median age 15.4 years) had 120 MPA/MPAG levels measured. Average MMF dose was 1208.8 mg/m2/d with median MPA and MPAG concentrations: 2.1 (therapeutic: 1.0-3.5 microg/mL) and 48 microg/mL (reference range: 35-100 microg/mL), respectively. Only 50% of patients consistently achieved therapeutic levels with standard dosing. No correlation was found between MMF dose and MPA/MPAG levels. In the presence of therapeutic calcineurin inhibition, EMB grade > or = 2 occurred more with MPA concentrations < 2.5 microg/mL (p = 0.01). In young OHT patients, MMF dose does not correlate with MPA/MPAG levels, and standard MMF dosing fails to consistently achieve 'therapeutic' MPA concentrations. An MPA trough level < 2.5 microg/mL was more frequently associated with EMB grade > or = 2. Concentration rather than dose-driven management is a more prudent strategy when using MMF.     

霉酚酸酯与环磷酰胺冲击治疗狼疮性肾炎临床疗效的比较

目的 比较霉酚酸酯（ＭＭＦ）与间断性环磷酚胺静脉冲击疗法（ＣＴＸ）治疗狼疮肾炎（ＬＮ）的近期及远期疗效、不良反应及安全性。方法Ａ组：间断性环磷酞胺冲击疗法治疗３０例ＬＮ患者，平均随访（１８６５±６．１０）（６～２４）月． Ｂ组：ＭＭＦ联合激素治疗ＬＮ患者，平均随访（２１.８９±７. ４８）（６～４８）月．两组患者的病理类型、病情基本相似，但 Ｂ组（ＭＭＦ）绝大部分为皮质激素联合 ＣＴＸ治疗无效者，Ｂ组患者病程明显较Ａ组长。结果ＣＴＸ组、ＭＭＦ组治疗ＬＮ均能降低蛋白尿和血尿，改善肾功能及免疫指标，两组间差异无显著性意义。ＭＭＦ组患者的平均疗程较ＣＴＸ组明显延长，而疗效却基本相同 ．不良反应：ＭＭＦ组无肝功能受累、性腺抑制副反应，感染率为 １３．３％。ＣＴＸ组感染率为 ２３．３％．肝功能受累为 ２３.３％，性腺抑制为 ２８％．结论 ＣＴＸ、ＭＭＦ都能有效的控制狼疮肾炎，改善肾功能，两者无显著性差异．对病程长、激素联合ＣＴＸ无效及病情迁延者，经ＭＭＦ治疗后达到与ＣＴＸ组同样效果，而且副作用少，提示ＭＭＦ具有一定的优越性。     

Low-dose immunosuppression in a rat hind-limb transplantation model

Composite tissue allografts (CTAs) offer an alternative to conventional reconstructive methods. However, the toxicity of the drugs that are required to prevent rejection has prevented its widespread clinical application. The purpose of this study was to determine whether a low-dose, corticosteroid-free combination regimen of tacrolimus and mycophenolate mofetil (MMF) would prevent rejection in a rat hind-limb model, with minimal toxic side effects. Three groups were used in this study. In group I, Wistar Furth (WF) rats received a syngeneic WF hind-limb. In groups II and III, WF rats received an ACI hind-limb. The latter were treated with tacrolimus-MMF. Assessment for rejection, flow cytometry, and mixed lymphocyte reactions was performed. Biopsies were taken regularly and at the time of killing. Combination therapy with low-dose tacrolimus-MMF effectively prolonged CTA survival indefinitely, with minimal side effects. Toxicity associated with immunosuppressive drugs can be avoided in a low-dose combination corticosteroid-free regimen.     

A case of T-cell lymphoproliferative disorder associated with hypereosinophilia with excellent response to mycophenolate mofetil

Hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by a persistent elevation of blood eosinophil count ?1.5 × 10⁹/L and clinical manifestations attributable to eosinophilia or tissue hypereosinophilia. Lymphocytic variant of HES (HES-L) is a known subtype according to World Health Organization classification. It is well documented in the literature that patients with HES-L are predisposed to develop T-cell lymphoma. We report a case of T-cell lymphoproliferation associated with hypereosinophilia, which has been successfully treated with mycophenolate mofetil, with resolution of skin lesions and normalization of eosinophil count and immunoglobulin E level. We believe this is a clinically relevant case since this is a rare disease with little known knowledge on its best treatment modality.     

Treatment of moderate to severe orbitopathy: Current modalities and perspectives

Graves’ orbitopathy (GO) is the primary cause of exophthalmos in adults. It appears in 30 to 50% of patients with Graves’ disease. About 5% are moderate-to-severe cases that might be see-threatening or lead to long term disabling sequelae. Recommendations have been established in 2016 by the European thyroid association (ETA) and the European group on Grave's orbitopathy (EUGOGO), suggesting a wide use of corticosteroids in moderate to severe forms. However, disappointing results have been reported in 20 to 30% of cases. Improved understanding of pathophysiological mechanisms has allowed the use of non-specific immunomodulatory agents, currently under evaluation, and which place in the therapeutic strategy remains to be determined. Very recently, new promising therapeutic advances have emerged with the identification of new therapeutic targets, such as the TSH receptor and IGF-1 receptor complex.     

Relevance of immunomodulatory therapy for interstitial lung disease in systemic sclerosis

Systemic sclerosis is an autoimmune disease that prominently leads to skin and tissue fibrosis. The efficacy of autologous stem cell transplantation not only attests to the autoimmune pathophysiology for systemic sclerosis, but also for interstitial lung disease as its most frequent manifestation of fatal organ involvement. Accordingly, a variety of immunomodulatory therapies were tried on patients with systemic sclerosis-interstitial lung disease. Until very recently, all of these therapeutic approaches constituted off-label treatment for systemic sclerosis, given that neither of these therapies was approved by the United States Food and Drug Administration (FDA) or the European Medicines Agency. For tocilizumab, this has now changed with FDA approval in March 2021. Already 2020, nintedanib, which is an antifibrotic drug that does not target autoimmunity, became the first approved drug for interstitial lung disease in systemic sclerosis. The present review analyzes the evidence for immunomodulatory treatment of systemic sclerosis-associated interstitial lung disease. The review focuses on randomized controlled trials, which provides evidence for the effects of drugs such as cyclophosphamide, mycophenolate, rituximab and tocilizumab.     

Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.     

Mycophenolate mofetil for maintenance of remission in steroid-dependent autoimmune pancreatitis

Systemic corticosteroids represent the standard treatment for autoimmune pancreatitis with IgG4-associated cholangitis. For steroid-dependent disease, azathioprine has been used for maintenance of remission. Mycophenolate mofetil has been used for transplant immunosuppression and more recently for autoimmune hepatitis; however, there are no case reports to date on the use of mycophenolate mofetil in adult patients with autoimmune pancreatitis. A patient with IgG4-mediated autoimmune pancreatitis and IgG4-associated cholangitis refractory to steroids and intolerant of azathioprine was treated with mycophenolate mofetil, which inhibits de novo guanosine synthesis and blockade of both B and T lymphocyte production. Introduction of mycophenolate mofetil and uptitration to 1000 mg by mouth twice daily over a treatment period of 4 mo was associated with improvement in the patient's energy level and blood glucose control and was not associated with any adverse events. The patient was managed without a biliary stent. However, there was a return of symptoms, jaundice, increase in transaminases, and hyperbilirubinemia when the prednisone dose reached 11 mg per day. In the first report of mycophenolate mofetil use in an adult patient with IgG4-associated autoimmune pancreatitis and IgG4-associated cholangitis, the introduction of mycophenolate mofetil was safe and well-tolerated without adverse events, but it did not enable discontinuation of the steroids. Mycophenolate mofetil and other immunomodulatory therapies should continue to be studied for maintenance of remission in the large subset of patients with refractory or recurrent autoimmune pancreatitis.     

吗替麦考酚酯片在男性健康志愿者体内生物等效性研究

目的评价吗替麦考酚酯片剂在20名男性健康志愿者体内的生物等效性。方法受试者随机、双交叉、单剂量口服国产吗替麦考酚酯分散片和进口吗替麦考酚酯片剂1000mg。药物血浆浓度采用HPLC法测定;药动学参数采用DAS软件处理获得。色谱柱为Agilent Zorbax SB C18,流动相为乙腈-水-三乙胺磷酸溶液(35∶45∶30,v/v),紫外检测波长为250nm,4-乙基苯甲酸为内标。结果两种制剂T1/2ke分别为(12.58±5.27)、(10.59±2.64)h,Cmax分别为(31.47±11.16)、(30.65±10.81)mg·L-1,Tmax分别为(0.63±0.35)、(0.61±0.23)h,AUC0-48分别为(60.08±12.47)、(57.06±10.41)mg·L-1h。试验药相对生物利用度为(110±46)%。经双单侧t检验和方差分析,试验药和参比药符合生物等效标准,结论国产与进口吗替麦考酚酯片剂具有生物等效性。     

Recurrent arterial ischemic stroke with good response to mycophenolate mofetil

Background

Arterial ischemic stroke is rare in childhood. Often, the diagnosis is made after considerable delay. A thorough workup to pinpoint the underlying etiology is necessary, as a correct diagnosis is the determining factor in treatment decision. In case of primary angiitis of the central nervous system, treatment with corticosteroids and immunosuppressive agents is indicated.