贝利尤单抗用于儿童系统性红斑狼疮的研究进展

系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种累及多器官的自身免疫性疾病，狼疮肾炎（lupus nephritis，LN）是其最常见的肾脏并发症。贝利尤单抗是一种完全人源化的单克隆抗体，可减少B细胞的数量，从而减少自身抗体的形成。贝利尤单抗可改善成人和儿童SLE反应指数、SLE疾病活动度评分，延缓LN的进展，对SLE及LN的治疗具有重要作用。该文综述了国内外贝利尤单抗用于治疗儿童和成人SLE的相关研究报道，并分析了其在儿童患者中的有效性及安全性，以期能对贝利尤单抗临床应用于儿童SLE的治疗提供有效的参考价值。     

Lupus nephritis in children

Systemic lupus erythematosus (SLE) is an autoimmune disease with varied clinical manifestations. Children and adolescents comprise one-fourth of affected patients with SLE and 40–80% of them have renal involvement. Lupus nephritis (LN) may present with mild urinary abnormalities or fulminant acute nephritis and renal failure. Diffuse proliferative glomerulonephritis (WHO class IV) is the predominant histological presentation in children and more common in boys than girls. This probably is one of the main reasons for the high mortality reported in the initial studies. Early diagnosis and aggressive treatment have led to improvement prognosis in these children. Cytotoxic therapy including intravenous cyclophosphamide has a definite role in the management WHO class IV and occasionally class III lupus nephritis. Prolonged steroid and cytotoxic therapy may lead to significant toxicity.     

Apoptosis in renal disease: a brief review of the literature and report of preliminary findings in childhood lupus nephritis.

Apoptosis, a programmed form of cell death, is an important mechanism that maintains cellular homeostasis. The cellular content of tissues is regulated by a balance between cell proliferation and cell loss. Apoptosis is important not only in physiological conditions but in pathological processes as well. Apoptosis has been implicated in the pathogenesis of certain renal diseases. In human models, systemic lupus erythematosus (SLE) and IgA nephropathy have been the main interests. These studies have mainly shown that apoptosis is important in the control of mesangial cell population. We have attempted to define the role of apoptosis in a cohort of childhood lupus nephritis. We have analyzed apoptosis by the terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP-biotin nick end-labeling (TUNEL) method in eight SLE pediatric patients, two of whom had hereditary deficiencies of complement components. Although the sample size was small because of the rarity of hereditary complement deficiencies, we have shown that apoptotic activity was the greatest among these pediatric patients. It has been previously suggested that in lupus, autoimmunity develops as a result of inadequate clearance of apoptotic blebs containing nuclear elements; complement deficiencies are the most important hereditary factors predisposing to the inadequate clearance of apoptotic particles. This is the first time this hypothesis has been evaluated in the tissue samples of hereditary complement deficiency-related proliferative lupus nephritis. On the other hand, apoptosis was not different from the other mesangial proliferative glomerulopathies in the lupus nephritis samples. Further studies are needed to confirm our preliminary findings. Apoptosis has been implicated in other renal diseases as well, such as autosomal polycystic kidney disease, and in experimental models. A short review of the relevant literature is presented highlighting the role of apoptosis in the pathogenesis and prognosis of certain renal diseases.     

Current issues in pediatric lupus nephritis: role of revised histopathological classification

Childhood-onset systemic lupus erythematosus (SLE) has an unpredictable natural history with variable clinical manifestations. The prognosis of SLE is linked closely to renal involvement with lupus nephritis (LN), which is more severe in patients with childhood-onset compared with adult-onset disease. The histopathological classification of LN facilitates treatment decisions, protocols, and clinical research. After the World Health Organization and modified WHO classifications of LN from 1974 to 1995, the International Society of Nephrology and Renal Pathology Society Working Group revised the histopathological classification of LN. The reclassification was published in 2004 after their consensus conference held at Columbia University in New York in May 2002. The aims of the reclassification were to standardize definitions, emphasize clinically relevant lesions, and encourage uniform and reproducible reporting among centers. Although the revised classification is time-consuming, it is important for future international collaboration on multicenter trials of disease-modifying agents. The prognosis of SLE and LN is linked to the histopathology of the renal lesion, but the clinical manifestations of LN, including nephrotic syndrome and hypertension, cannot predict the degree of renal involvement. However, we are many years away from completely understanding the etiopathogenesis of LN and the predictive role of the revised histological classification for direction of patient management.     

狼疮抗凝集物检测在系统性红斑狼疮、原发性血小板减少症中的临床应用

目的通过对系统性红斑性狼疮(SLE)310例和原发性血小板减少症(ITP)249例狼疮抗凝集物(LAC)和抗心磷脂抗体亚型(aCL-IgG、IgM、IgA)的测定,研究其与SLE临床表现的关系及LAC在ITP转归中的意义。方法采用脑磷脂-白陶土法(KCCT)及校正试验检测患儿血浆LAC;采用酶联免疫吸附试验(ELISA)测定息儿血清aCL-IgG,IgM、IgA。结果SLE 组中,66.1%显示体内存在高含量LAC,其中45.9%并狼疮肾炎;46.8?L抗体升高,其中90.2%为IgG和(或)IgM,分别有46.9%和11.7%是狼疮并中枢神经系统及血液系统病变。ITP组105例LAC阳性患儿中36.2%经抗核抗体(ANA)检测确诊为SLE,7.6%在2个月-2.4年后发展为SLE。结论LAC和aCL抗体亚型的水平与SLE临床表现密切相关,LAC在狼疮并肾脏病变中为优势病理性自身抗体;aCL抗体亚型的水平则与狼疮性血栓性血管炎性病变有相关关系。对单纯患有ITP的患儿应进行LAC动态观察,可及早确定疾病的转归。     

Post‐transplant immune complex nephritis in a patient with systemic lupus erythematosus associated with ANCA vasculitis

Nearly 20% of SLE corresponds to the pediatric population, and 75% of them have kidney involvement representing an important etiology of chronic kidney disease. A correlation between SLE and ANCA‐associated vasculitis has been identified as an overlapping syndrome. Kidney allograft recurrence is rare in SLE when disease control is achieved and with nowadays immunosuppression treatment. Histologic transformation is unusual, especially when there are negative serologic markers and no immune complex deposition reported in native kidneys. A 17‐year‐old female with crescentic glomerulonephritis, p‐ANCA‐positive antibodies with pauci‐immune pattern in kidney biopsy develops end‐stage renal disease requiring hemodialysis. Deceased donor kidney transplant was performed receiving triple immunosuppression thereafter. Thirteen months later serum creatinine rises without evidence of infection, urinary obstruction, or clinical and serologic disease relapse. Allograft biopsy reports mesangial proliferation and “full‐house” immunofluorescence. The role of ANCA in SLE physiopathology is controversial, and its relation with lupus nephritis is also discordant. ANCA could represent an important factor in the heterogeneity of systemic lupus erythematosus and lupus nephritis.     

Therapieempfehlung zur Lupusnephritis bei Kindern und Jugendlichen

Among the organ manifestations of systemic lupus erythematosus (SLE), involvement of the kidneys plays a key role in morbidity and mortality. Early diagnosis and appropriate treatment of lupus nephritis (LN) is therefore very important. On the basis of the current literature and the experience gathered by members of the SLE working group of the German Society for Pediatric Nephrology (APN), the following article presents consensus recommendations for treating LN in children and adolescents. Depending on the severity of the initial organ involvement (extent of proteinuria, kidney histology) and the initial response to treatment, prednisolone is supplemented, where appropriate, by mycophenolate mofetil, azathioprine, cyclophosphamide or cyclosporine A. In addition to consistent antihypertensive and nephroprotective treatment, adjuvant therapy should attempt to avoid possible side effects such as gonad toxicity and growth disorder. We believe that future prospective recording of the LN patients treated in line with these consensus recommendations can help treatment guidelines to be drawn up for this disease.     

Systemic lupus erythematosus glomerulonephritis in children

This paper reviews the four types of systemic lupus erythematosus (SLE) glomerulonephritis in children and presents the clinical and renal histologic findings. A therapeutic program based upon the hypothesis that the nephritis of SLE is the result of the glomerular deposition of pathogenic dsDNA-anti-ds/DNA immune complexes is outlined. The effectiveness of therapy in suppressing disease activity is best estimated by serial determinations of serum complement components, particularly C3, and secondarily by monitoring serum levels of antibody to native DNA.     

Nephrotic syndrome in mesangial proliferative lupus nephritis

Renal involvement is a major complication of systemic lupus erythematosus (SLE) and occurs in 30-70% of patients with SLE. Lupus nephritis is classified into six classes (I-VI) by the International Society of Nephrology and Renal Pathology Society (ISN/RPS). Although nephrotic syndrome is commonly associated with diffuse (ISN/RPS class IV) or membranous (ISN/RPS class V) lupus nephritis, several reports have described nephrotic syndrome in adult patients with minimal mesangial lupus nephritis (ISN/RPS class I) or mesangial proliferative lupus nephritis (ISN/RPS class II). However, nephrotic syndrome in mesangial proliferative lupus nephritis has rarely been reported in children. Although the pathogenesis of nephrotic syndrome with mesangial lupus nephritis is incompletely understood, three potential mechanisms have been postulated including lupus nephritis itself, non-steroidal anti inflammatory drug (NSAID)-induced minimal change nephrotic syndrome (MCNS) and coincidental occurrence of MCNS. We describe here a child with mesangial proliferative lupus nephritis who developed MCNS.     

2021—2022年度系统性红斑狼疮研究进展盘点北大核心CSCD

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种累及多器官系统的自身免疫性疾病,临床表现复杂多样,治疗效果和预后异质性大,给SLE的诊断分型及同质性治疗带来了巨大挑战。以合成生物学、基因组学、蛋白质组学为代表的新技术、新领域的出现,有助于SLE发病机制、生物标志物的深入挖掘,推动了SLE的精准诊疗。该综述总结2021—2022年度SLE最新研究数据和成果,对近2年相关的研究进行回顾及总结。     

Lupusnephritis

Renal involvement is common in systemic lupus erythematosus (SLE). It can manifest just as proteinuria and/or haematuria, but various serious courses are possible. Detection of haematuria and/or proteinuria in a patient with SLE is an indication for diagnostic tests targeting kidney function. To confirm a diagnosis of nephritis induced by lupus and assess its severity (WHO classification) it is necessary to examine a kidney biopsy specimen. In lupus nephritis type 1 no special treatment is needed in view of the excellent prognosis as far as renal function is concerned. In WHO types 2 and 3A immediate therapy is also not necessary, but close monitoring is essential. In type 3B, in contrast, intensive immunosuppression and consistent blood pressure stabilisation are of importance. In type 4 a terminal kidney failure can rapidly supervene without adequate immunosuppressive therapy. Type 5 patients benefit from administration of an ACE inhibitor in addition. Type 6 is a residual condition in the form of scarring, and in these cases more intensive immunosuppression is pointless. Up to 20% of paediatric patients with lupus nephritis come to need dialysis, though kidney function can be at least partly restored.     

IgA nephropathy and Henoch-Schönlein purpura nephritis

PURPOSE OF REVIEW: IgA nephropathy and Henoch-Sch?nlein purpura nephritis are common glomerular disorders in pediatrics that can potentially progress to end-stage renal disease in some patients. This review summarizes our current understanding of the pathogenesis of these closely related conditions and discusses the rationale for development of diagnostic tests and prognostic markers. The review also presents the best data for long-term outcome, clinical markers of prognosis, and the results of randomized controlled trials. RECENT FINDINGS: Our understanding of the defective galactosylation of O-linked glycans in the hinge region of human IgA1 and its role in the pathogenesis of IgA nephropathy and Henoch-Sch?nlein purpura nephritis has evolved over the past decade. This review discusses studies that suggest that demonstration of galactose-deficient IgA1 in the serum may become an important diagnostic tool for these conditions. Proteomic techniques for development of biomarkers for diagnosis and prognosis show promise. Although data from randomized controlled trials have failed to support the use of immunosuppressive agents in pediatric IgA nephropathy and Henoch-Sch?nlein purpura nephritis, recent data indicate that angiotensin converting enzyme inhibitor therapy is indicated for reduction of proteinuria. SUMMARY: Childhood IgA nephropathy and Henoch-Sch?nlein purpura nephritis have the potential for serious morbidity, either during childhood or later in adulthood. In the future clinical tests will be used for noninvasive diagnosis and as markers for judging response to treatment, particularly in those individuals at highest risk for eventual progression to end-stage renal disease.     

儿童神经精神性狼疮的发病机制及诊治进展

儿童神经精神性狼疮(neuropsychiatric systemic lupus erythematosus,NPSLE)是系统性红斑狼疮(systemic lupus erythematosus,SLE)的严重并发症,发生率高达95％.目前认为NPSLE发病机制是多种因素作用的结果,包括血脑屏障破坏、血管栓塞、神经内分泌功能紊乱、自身抗体的产生以及炎性介质的参与.临床表现复杂多样,主要表现为头痛、癫痫样发作及精神障碍.国际上尚无统一的诊断标准,必须综合应用免疫血清学、脑脊液检测、神经影像学和神经精神的评估,治疗主要应用免疫抑制剂、生物治疗和对症治疗,早期诊断和规范治疗有助于改善预后.     

儿童狼疮性肾炎的性别和临床免疫学特征

目的探讨儿童狼疮性肾炎的性别、临床和免疫学特征。方法将71例女性，6例男性红斑狼疮患者的临床、血清免疫学指标和肾脏损害进行比较。结果女性红斑狼疮患者关节炎、白细胞减少比男性常见，而男性盘状红斑较常见，且肾损害比女性严重。结论红斑狼疮临床表现、血清免疫学特征及发病率与性别有关，但男性狼疮性肾炎预后可能较差。     

儿童系统性红斑狼疮临床特点与起病年龄相关性研究

目的 探讨儿童期起病系统性红斑狼疮(SLE)临床特征及预后与起病年龄的相关性.方法 回顾性分析2011年1月至2016年10月于重庆医科大学附属儿童医院风湿免疫科住院初诊为SLE患儿159例临床资料及预后,采用Spearman相关性分析评估其与起病年龄相关性.结果 159例SLE患儿平均起病年龄(11.05±2.73)...     

Improvement in lupus nephritis following treatment with a Chinese herbal preparation.

OBJECTIVE: To study the effect of a Chinese herbal decoction (CM), which contained 21 different herbs, on clinical remission in a patient with lupus nephritis and chronic nephrotic syndrome. DESIGN: Case report describing the clinical and laboratory markers of lupus activity in the patient before and after treatment with CM. We also studied the in vitro effect of CM and its hydrophobic extract on spontaneous IgG production by peripheral blood mononuclear cells (PBMCs) from 12 patients with systemic lupus erythematosus (SLE) compared with 9 healthy control subjects. RESULTS: Spontaneous PBMC IgG production was significantly higher in patients with SLE (mean +/- SD, 20.4+/-10.6 x 10(-5) g/L) compared with controls (4.7+/-1.9 x 10(-5) g/L) (P<.001). Addition of CM and its hydrophobic extract to PBMCs from patients with SLE resulted in significant suppression of spontaneous IgG production. CONCLUSIONS: The CM may contain some active pharmacological compound with immunosuppressive properties useful in the treatment of SLE. Further controlled studies are important to evaluate the efficacy of this medicine, potential toxic effects, and the possible immunosuppressive mechanisms of the active component(s).     

The favourable effect of cyclophosphamide pulse therapy in the treatment of massive pulmonary haemorrhage in systemic lupus erythematosus

Pulmonary haemorrhage (PH) is a rare but very serious complication of systemic lupus erythematosus (SLE) and the treatment is still controversial. Some authors showed the effectiveness of methylprednisolone pulse therapy for PH, although its effect was often transient. A 12-year-old Japanese girl with lupus nephritis and recurrent massive PH in SLE was treated with methylprednisolone pulse therapy. The effect on PH was transient and she needed three cycles within a month and side-effects developed. Pulse therapy with cyclophosphamide, synchronized with plasmaphaeresis, was tried. Thereafter she did not experience PH for 7 months, whereas lupus nephritis did not improve. Pulse cyclophosphamide would be effective for life threatening massive PH in SLE patients.     

Immunoadsorbent apheresis eliminates pathogenic IgG in childhood lupus nephritis

BACKGROUND: It is suggested that the highly cation-charged fraction of the IgG and IgG3 subclasses may play a pathogenic role in lupus nephritis. In contrast, immunoadsorbent therapy using a sodium dextransulfate fixed cellulose gel column-low invasive selective immunoadsorbent apheresis therapy (SDSC-IAT) has been applied to lupus nephritis with favorable results. However, elimination using pathogenic IgG by SDSC-IAT has never been investigated. METHOD: Two patients with diffuse proliferative lupus nephritis were treated using SDSC-IAT concomitant with immunosuppressive therapy. The eluates from the SDSC, and the patients' serum obtained before and just after SDSC-IAT were subjected to an IgG charge analysis using isoelectric focusing and immunoblotting, and also to laser nephelometry assay, which is used for measuring IgG subclass concentration. Indirect immunofluorescence staining was performed to detect IgG subclass deposition in the glomerulus. RESULTS: Both of the patients had an immediate decrease in anti-double-strand DNA antibody and in the circulating immune complex with a following clinical improvement. Repeated biopsies demonstrated improvement of glomerular lesions with a marked reduction of IgG and C3 deposition. The IgG of the SDSC eluates consisted of highly cation charged (isoelectric points: 9-10) fractions. In addition, IgG3 was specifically removed from the patients' serum using an SDSC among the IgG subclasses. The subclass of deposited IgG in the glomeruli showed IgG3 predominance. CONCLUSION: SDSC-IAT specifically removed the highly cation charged fractions of IgG and IgG3 from the patients' serum and the elimination of these fractions may have resulted in clinical improvement.     

红斑狼疮肾损害诊治进展

狼疮肾炎的病理分型是临床诊治及预后判断的基础。狼疮肾炎的治疗策略与进展更是建立在不断累积的循证医学证据之上。增生性狼疮肾炎因其相对较差的预后而更受关注,其治疗强调序贯使用诱导与维持治疗。经济条件许可,可考虑把MMF与环磷酰胺一样作为活动性狼疮肾炎诱导治疗的一线选择用药,而其他新型免疫制剂的疗效尚缺乏足够证据。维持治疗目前推荐硫唑嘌呤或MMF。部分难治性狼疮肾炎可以尝试其他治疗方法,但疗效都不确定。     

Systemic lupus erythematosus with nephritis.

Thirty-six patients with the onset of symptoms of systemic lupus erythematosus before age 20 years (23 aged less than 15 years at onset) were studied during a 15-year period. All had clinical evidence of nephritis. They were followed for a mean of 5 years (range 6 months to 13 years) or until death. Survival was calculated to be 77% at 10 years for those aged less than 15, and 74% for those aged less than 20, from the onset of clinical nephritis. At referral, renal function was already impaired in two-thirds of patients. Renal biopsies showed mild focal or proliferative changes in 19% of patients, membranous lesions in 11%, and diffuse proliferative lesions in 70%. Three (8%) patients died during follow-up, all from sepsis, and 3 (8%) others required chronic haemodialysis for terminal renal failure. The prognosis even of severe lupus nephritis in childhood and adolescence has improved in recent years. Side effects of treatment remain an important cause of death and morbidity.