Update on autoimmune hepatitis

Autoimmune hepatitis （AIH） is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features, hyperglobulinemia （IgG）, and the presence of circulating autoantibodies, as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years, a couple of new insights into the genetic aspects, clinical course and treatment of AIH have been reported, which will be the focus of this review. In particular, we concentrate on genome-wide microsatellite analysis, a novel mouse model of AIH, the evaluation of a large AIH cohort for overlap syndromes, suggested novel criteria for the diagnosis of AIH, and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.     

霉酚酸酯对小鼠异基因骨髓移植后急性移植物抗宿主病的预防作用

目的：探讨新型免疫抑制剂霉酚酸酯（MMF）对小鼠异基因骨髓移植（allo-BMT)后急性移植物抗宿主病（aGVHD)的预防作用。方法：用主要组织相容性抗原（MHC）完全不合的纯种近交系小鼠[供鼠：雌性C57BL／6J（H－2^b)鼠；受鼠：雄性BALB／c(H-2^d)鼠]建立allo-BMT/aGVHD动物模型，随机分6组，给予MMF、环孢菌素A（CsA) 甲氨喋呤（MTX）或联合不同剂量MMF作为aGVHD预防方案。观察其aGVHD的预防作用。结果：移植小鼠出现典型的aGVHD症状，未用aGVHD预防方案的移植小鼠（第6组）死亡高峰在移植后第5－第7天，死亡率达100％。用不同aGVHD预防方案的1－5组小鼠aGVHD症状明显减轻，平均生存时间（MST）较第6组显著延长（分别延长3．4，8．4，9．0，6．1，8．8d（P＜0．05）。不同aGVHD预防方案的移植小鼠之间，移植后外周血常规变化差异无显著性。经用各预防方案后，移植小鼠cGVHD病理表现减轻，且MMF、CsA、MTX三药联合组的病理分级轻于MMF单药组或CsA MTX标准方案组。结论：MMF单药及与CsA MTX联合均能有效预防小鼠allo-BMT后的aGVHD，减轻其症状和病理损害程度，显著延长平均生存时间。小剂量MMF（≤30mg/kg）与CsA TMX的联用效果优于大剂量MMF（60mg/kg）与CsA MTX的联用效果。适当剂量的MMF（10－60mg/kg）对骨髓植入和造血恢复没有显著影响。     

Can mycophenolate mofetil substitute cyclophosphamide treatment of pediatric lupus nephritis?

Intravenous cyclophosphamide (CYC) has been the standard of care to induce remission of severe and active lupus nephritis for more than 20 years. Potential side effects are significant, and failure to achieve remission is still high. Mycophenolate mofetil (MMF) has emerged as a potential alternative to CYC, with an improved safety profile thus far. Results of two mayor randomized controlled trials in adults indicate no evidence of inferiority in patients treated with MMF, less adverse events, and higher rate of complete remission. Experience in the pediatric population is very limited. Thus far, the efficacy, toxicity, and tolerability record of MMF in adults makes it an acceptable alternative to CYC in the induction phase of treatment. Early treatment is desired. Several questions remain: the optimal dose and length of induction with MMF are unknown, the effect of MMF in severe cases of lupus nephritis with renal failure at presentation is unknown, and the compliance with long-term oral treatment in the adolescent population is certainly unknown. In this review, intravenous (IV) CYC induction in the sickest patients (renal failure at presentation) is considered and/or when compliance with oral treatment cannot be established. Also, MMF induction in reliable patients with mostly preserved renal function is considered. Most likely, MMF will serve as a therapeutic bridge between the previously well-known, broad-spectrum immunosuppressive drugs and the new, targeted biological agents.     

Rituximab therapy for childhood-onset systemic lupus erythematosus

OBJECTIVE: To describe the safety and efficacy of rituximab in the treatment of childhood-onset systemic lupus erythematosus (SLE). STUDY DESIGN: We conducted a French multicenter retrospective study of childhood-onset SLE treated with rituximab. RESULTS: Eleven girls with severe SLE, including 8 girls with class IV or V lupus nephritis, 2 girls with severe autoimmune cytopenia, and 1 girl with antiprothrombin antibody with severe hemorrhage, were treated with rituximab. The mean age at onset of rituximab treatment was 13.9 years. Patients received 2 to 12 intravenous infusions of rituximab (350-450 mg/m2/infusion), with corticosteroids. Six patients also received different standard immunosuppressive agents, including Cyclophosphamide (2 patients). Remission was achieved in 6 of 8 patients with lupus nephritis and in the 2 patients with autoimmune cytopenia. Steroid therapy was tapered in 5 patients who responded to treatment, and low-dose prednisone treatment was maintained in 1 patient. The mean follow-up period was 13.2 months (range, 6-26 months), and remission lasted in all who patients who responded to treatment, except 1 patient who was successfully retreated with a second course of rituximab. Anti-double-stranded DNA antibody levels decreased in 6 of 11 patients, and anticardiolipin antibody levels decreased in 3 of 4 patients. Severe adverse events developed in 5 patients. Effective depletion of peripheral blood B cells was observed in 7 of 8 patients who were examined, and this paralleled the remission. CONCLUSION: Rituximab may be an effective co-therapy; however, further investigations are required because severe adverse events occurred in 45% of the patients in this study.     

Mycophenolic acid-induced replication arrest, differentiation markers and cell death of androgen-independent prostate cancer cells DU145

Inosine 5'-monophosphate dehydrogenase inhibitors including mycophenolic acid (MPA) are effective inducers of terminal differentiation in a variety of distinct human tumor cell types. Here, we report that MPA also induces such a differentiation in the androgen-independent prostate cancer derived cell line DU145. MPA evoked replication arrest and accumulation of the DU145 cells in the S-phase of the cell cycle. The inhibitor also induced the expression of CD55, clusterin, granulophysin, glucose-regulated protein 78, vasoactive intestinal polypeptide and prostate-specific transglutaminase, which are differentiation markers associated with the phenotype of normal prostate cells. We suggest that inosine 5'-monophosphate dehydrogenase inhibitors, which are already used for the treatment of other diseases, may be used as potential differentiation therapy drugs to control prostate cancer.     

C1q nephropathy in a child with a chromosome 13 deletion

C1q nephropathy (C1qNP) is a rare cause of childhood nephrotic syndrome (NS). We describe a child with retinoblastoma, lipomyelomeningocele and a chromosome 13 deletion who presented with massive proteinuria due to C1qNP. Despite steroid resistance, successful treatment of the NS was achieved with mycophenolate mofetil.     

To what extent does the understanding of pharmacokinetics of mycophenolate mofetil influence its prescription

Within a short period, we have witnessed a dramatic increase in the use of mycophenolate mofetil (MMF) in pediatric renal transplantation, with the drug often replacing azathioprine in combination with calcineurin inhibitor therapy. When the drug was introduced, the manufacturer considered therapeutic drug monitoring (TDM) unnecessary. However, TDM studies revealed substantial inter- and intra-individual variability and drug interactions. There is a substantial drug interaction between MMF and cyclosporine, and lower doses are required in combination with tacrolimus (~500-800 mg/m(2) per day) than with cyclosporine (~1,200 mg/m(2) per day). Patients with autoimmune disease require an intermediate dose when receiving no concomitant calcineurin inhibitor (~900 mg/m(2) per day). It has been possible to detect drug interactions and to minimize adverse events only with TDM. This is especially important with increasing use of combination therapies. Pharmacodynamic monitoring (measuring the biological response to a drug) coupled with pharmacokinetics allow optimization of drug dosing, with maximum efficacy and minimal toxicity. More work is required to establish specific target ranges with the various drug combinations--especially for the pediatric population.     

New perspectives in treatment of glomerulonephritis

In chronic glomerulonephritis (GN) the development of the tissue damage and progression to fibrosis is related to the individual immune response which brings about excessive inflammation, failure to activate regression and glomerular repair and excessive fibrogenic activity. Therefore, the present standard treatment of GN has two aims, to fight the acute inflammation and to inhibit the progressive renal fibrosis. New avenues in the anti-inflammatory and immunosuppressive treatment of the active phase of glomerular diseases include the use of drugs proven to be of value in organ transplantation (mycophenolate mofetil, rapamycin or anti-immune adhesion and anti-co-stimulatory molecules). Interest has recently focused on anti-inflammatory cytokines (monoclonal antibodies, peptidic antagonists or anti-sense oligonucleotides against TNF-, anti-PDGF-, anti-TGF- and cytokine receptor antagonists) and anti-inflammatory natural cytokines (such as IL4, IL10, IL13 or low doses of TGF). Other drugs may act by depleting B cells (such as anti-CD20 monoclonal antibody) or on several immune pathways, such as thalidomide or anti-cyclooxygenase 2. Several anti-sclerogenic drugs are already used for treatment of the chronic phase of glomerular diseases, such as antagonists of angiotensin II, statins and antioxidants. Other drugs are still experimental, including endothelin receptor antagonists and neutral endopeptidase or vasopeptidase inhibitors and other drugs operating on extracellular matrix accumulation/degradation mechanisms, e.g., pirfenidone. There are extremely interesting developments concerning activators of endogenous anti-inflammatory mechanisms, such as those regulated by peroxisome proliferator activated receptors. There is a need for successful treatment of chronic GN in childhood. This short review of the most promising new drugs shows there is reason to believe that the next decade will provide exciting new tools for the treatment of these diseases in children.     

Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade

Steroid-resistant nephrotic syndrome of childhood poses a dilemma in attempting to balance toxicity of medications against long-term prognosis. This report presents our preliminary experience with the novel use of combined mycophenolate mofetil (MMF) and angiotensin blockade (AB) in the treatment of nine children and young adults with focal glomerulosclerosis (FSGS). All patients were steroid resistant and had failed conventional treatment regimens. Prior to the initiation of the MMF-AB protocol, the patients were pre-treated with weekly intravenous methylprednisolone (MP) (15 mg/kg per week) for 4–8 weeks. Angiotensin-converting-enzyme inhibitors and/or angiotensin receptor blockers were begun when intravascular volume was restored. MMF was given at a dose of 250–500 mg/m² per day. Proteinuria, as measured by urine protein/creatinine ratios (Up/c), decreased by 43% following MP (P<0.05). After 6 months of MMF-AB protocol, the Up/c was 72% below baseline (P<0.01). This level was maintained for a minimum of 24 months of observation. Similarly, hyperlipidemia, as measured by total cholesterol and triglycerides, improved significantly with treatment (536±163 to 265±70 mg/dl, 447±168 to 230±92 mg/dl, respectively, P<0.01). Our data support the use of MMF and AB for treatment of steroid-resistant FSGS when other conventional treatments have failed and/or induced toxicity.     

Long-standing refractory polymyositis responding to mycophenolate mofetil: a case report and review of the literature

The authors describe a young patient affected by long-standing polymyositis refractory to conventional treatment who showed a rapid and striking response to mycophenolate mofetil treatment.