B cell elimination in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus.     

Childhood- and adult-onset lupus: an update of similarities and differences

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune rheumatic disease. Although its highest prevalence is among women of childbearing age, the disease is not confined within this population. A total of 15–20% of cases of SLE are diagnosed in children younger than 16 years (childhood-onset lupus). Although there have been few studies directly comparing childhood- to adult-onset lupus, there is substantial evidence to suggest that pediatric lupus patients display some differences in their disease profile compared with adult-onset populations. Overall, an increased male-to-female ratio, a higher prevalence of nephritis and CNS involvement necessitating a more sustained need for steroids and immnosuppressive drugs, and a higher prevalence of progression to end-stage renal disease are distinguishing features of childhood-onset lupus. In contrast, a higher prevalence of pulmonary involvement, arthritis and discoid lupus are reported in adult-onset SLE patients. Furthermore, childhood-onset lupus patients may experience a serious negative impact on their psychosocial and physical development, issues that pose extra challenges to healthcare providers. Growth delay, osteoporosis, the psychological effect of steroid-induced alterations of the physical image, and often poor treatment compliance are the issues that need to be addressed in pediatric lupus populations. In this review, we compare the epidemiological, clinical and laboratory features, and treatment options of childhood- and adult-onset lupus, and comment on the applicability of the instruments that measure activity, severity and cumulative disease damage in childhood-onset disease. In addition, we highlight special issues of concern for pediatric lupus patients, discussing the significance in the transition from pediatric to adult rheumatology care.     

Prevalence and reversibility of pulmonary dysfunction in refractory systemic lupus: improvement correlates with disease remission following hematopoietic stem cell transplantation

AIM: To report the prevalence and reversibility of pulmonary function test (PFT) abnormalities among systemic lupus erythematosus (SLE) patients, refractory to therapy, undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty-four SLE patients received 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin followed by HSCT. PFTs were performed prior to, at 6 months, and yearly following HSCT. RESULTS: The prevalence of significant PFT abnormalities was high (97%). Low FEV(1) and FVC occurred in 26 of 34 patients (76%). A significant abnormality in diffusion capacity of the lung for carbon monoxide (Dlco) occurred in 26 of 32 individuals able to complete Dlco testing (81%). Dlco 18 months after HSCT. Five of 28 patients had a normal entry FVC; for each, the FVC remains normal. Of the 23 patients with an abnormal baseline FVC, 18 have improved, 15 completely and 3 partially. Eight of these 18 patients also have improved Dlco. The two patients with a diagnosis of SLS and one patient with SLE-related pulmonary hypertension improved in both parameters. Only 5 of 23 patients with an abnormal FVC did not improve. Each of these five patients retained active lupus in spite of HSCT. CONCLUSION: The prevalence of lung impairment among SLE patients requiring long-term immune suppression is high. Following HSCT, pulmonary impairments can improve, which is sustained if disease control is sustained.     

59例狼疮肾炎病理评分与临床评分相关性探讨

目的 分析肾活检病理及相关实验室检测结果,探讨狼疮肾炎(LN)病理评分与临床评分的相关性,试图依据临床评分系统预测和评估其肾脏病理活动性.同时比较2种临床评分系统.方法 回顾性分析了59例肾活检患者的病例资料,根据国际肾脏病协会/肾脏病理学会(ISN/RPS)2003 LN分型标准进行病理分型,并分别进行活动性指数(AI)、慢件指数(CI)和肾小管间质病变(TIL)评分,同时应用英国狼疮评估组2004(BILAG2004)和系统性红斑狼疮疾病活动指数2000(SLEDA12000)2种临床评分系统判断其临床疾病活动度,并与病理评分进行相关性分析.结果 ①59例患者中,病理类型以弥漫性(Ⅳ型)最多,占44%.②LN患者Ⅱ、Ⅲ型及Ⅳ型的SLEDAI2000评分及BILAG2004评分均与其AI呈正相关(0BILAG2004评分与其AI旱正相关(0BILAG2004评分较SLEDAI2000评分与AI具有更好的相关性.④SLEDAI2000评分与Ⅲ型LN患者AI相关性最好,其次为Ⅱ型;BILAG2004评分与Ⅲ型LN患者AI相关性最好,其次为Ⅳ型.结论 BILAG2004和SLEDAI2000评分系统均可以评估LN患者的疾病病理活动性.BILAG2004评分系统对LN患者病理活动性的评估优于SLEDAI2000评分系统,尤其对重型LN患者.BILAG2004评分系统可以更好地指导临床治疗方案的制定.     

Urinary podocalyxin and nephrin levels as biomarkers in lupus nephritis patients: Relation to renal involvement and disease activity

Aim of the workTo evaluate the impact of systemic lupus erythematosus (SLE) on urinary levels of podocalyxin and nephrin and to determine their relationship to renal biopsy and disease activity in lupus nephritis (LN) patients.Patients and methodsThe study included 50 LN patients with their renal biopsy classified according to the international society of nephrology. Disease activity was determined using the British Isles Lupus Assessment Group (BILAG). All patients underwent clinical and laboratory evaluation. Urine samples were collected for the assessment of urinary podocalyxin (UPx) and nephrin (UN) by ELISA and for the estimation of protein (UP) and creatinine (Cr) concentrations. The UPx:Cr, UN:Cr and UP:Cr ratios were calculated.ResultsUrinary levels of podocalyxin (593.8 ± 282.2 ng/ml), nephrin (304.1 ± 236.8 ng/ml) and protein (2.36 ± 0.56 g/l) were significantly higher, while urinary creatinine levels (101.4 ± 28.7 mg/l) lower in LN patients compared to control (38.1 ± 9 ng/ml, 19.2 ± 4.1 ng/ml, 0.34 ± 0.13 g/l and 155.4 ± 26.7 mg/l; p = 0.0008, p = 0.0003, p = 0.00002 and 0.0009, respectively). Consequently, UNCr, UPxCr and UPCr ratios were significantly higher in patients compared to control. There was a significant correlation of the estimated ratios with the LN class and with the BILAG scores being most significant with UPx:Cr ratio. ROC curve and regression analyses defined UPx:Cr ratio as the specific significant predictor of pathological LN grade.ConclusionSLE deleteriously affects fine glomerular structure as reflected by increased urinary levels of podocyte-related proteins; podocalyxin and nephrin. Urinary podocalyxin/creatinine ratio significantly predicts the pathological impact of SLE on the kidney and could be used as a non-invasive marker for such effect and its progression.     

Quantitative clinical assessment of disease activity in systemic lupus erythematosus: progress report and research agenda

Summary No single test allows an adequate measure of disease activity in multisystem diseases such as systemic lupus erythematosus (SLE). In order to evaluate the spectrum of manifestations of disease activity in SLE, investigators have developed numerous ad hoc scales which have not been tested for their validity or reliability. Three instruments have been extensively studied: the British Isles Lupus Activity Group instrument (BILAG), the SLE Disease Activity Index (SLEDAI), and the Systemic Lupus Activity Measure (SLAM). All three have been demonstrated to have convergent and construct validity when compared to the clinician's judgement. The summation of the number of criteria of the American Rheumatism Association (ARA) SLE criteria has been shown to be an inadequate measure of disease activity. Standardized measures of disease activity for SLE should enhance our ability to compare results from different centers in finer distinctions than dead or alive.     

Epratuzumab for systemic lupus erythematosus

Introduction: Systemic lupus erythematosus is an autoimmune multiorgan disease in which the lack of an appropriate therapy can lead to rapid organ failure and death. Immunosuppressive therapies such as corticosteroids or cyclophosphamide can slow down the disease progression but sometimes other therapies are needed. Among such therapies, epratuzumab, an antiCD22 antibody, can be potentially efficacious in this disease.

Areas covered: Discussion of the results from clinical studies evaluating the efficacy and safety of epratuzumab in patients with moderate or severe systemic lupus erythematosus.

Expert opinion: The study demonstrates that epratuzumab can improve the quality of life and can reduce the disease activity burden, but the premature termination of the studies might have limited the generation of further efficacy data.     

Epratuzumab for the treatment of systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. There are three drugs licensed for the treatment of lupus: corticosteroids, hydroxychloroquine and belimumab. Immunosuppressants such as azathioprine, methotrexate and mycophenolate are also used. Despite these treatments there is still considerable morbidity. New treatments are needed for the management of active lupus. Epratuzumab a humanized IgG1 monoclonal antibody that targets CD22 resulting in selective B cell modulation that has been considered a potential treatment for SLE.

Areas covered: Summary of the relevant pathogenesis and disease activity measurements used in SLE patients, current treatments and unmet needs in SLE, pharmacokinetics and pharmacodynamics of epratuzumab therapy, and a summary of the 7 clinical trials that have investigated the efficacy and safety of epratuzumab in SLE.

Expert commentary: It is not clear why trials have failed to demonstrate efficacy but high placebo response rates from optimisation of standard of care and a sub-optimal dosing regimen may have played a role. Post-hoc analysis suggested that there may be subgroups that did respond, such as anti-SSA positive patients with features of Sjogren’s syndrome. Further research is needed to explore this and other potential sub-groups that might respond.