应更加重视生物制剂在狼疮中的作用

阿根廷布宜诺斯艾利斯——目前获准用于治疗系统性红斑狼疮(SLE)的生物制剂主要局限于贝利木单抗，有关阿贝西普或利妥昔单抗对SLE或狼疮性肾炎疗效的令人信服的研究证据还较少。不过在国际系统性红斑狼疮大会上，一些研究者认为，对于这3种生物制剂应抱以乐观态度。

斯德哥尔摩卡罗林斯卡研究所的Ronald F. van Vollenhoven博士对一项拟于6月在欧洲抗风湿病联盟年会上公布的生物制剂狼疮注册研究结果进行了讨论。van Vollenhoven博士及其同事发现，利妥昔单抗是欧洲国家最常超适应证使用的生物制剂，约有1%的狼疮患者使用该药。对于具有较多损害的病情较严重的患者而言，该药是最后的救命稻草。

伦敦帝国学院的肾病学家Elizabeth Lightstone博士讨论了一项即将发表的观察队列研究结果。该研究纳入50例新发或复发狼疮性肾炎患者，探讨了利妥昔单抗作为一线治疗方案联合霉酚酸酯(MMF)的疗效。中位随访时间为163周。12周时，18%的患者获得完全肾脏应答，26周时该比例增至32%，52周时增至50%。值得注意的是，43例接受该方案治疗的患者可在无口服类固醇的情况下治疗成功。Lightstone博士表示，其所在的英国肾病学研究小组即将进行一项随机对照研究，在252例狼疮性肾炎患者对这种基于利妥昔单抗的方案与MMF、类固醇进行比较。

利妥昔单抗在2012 LUNAR狼疮性肾炎研究中以失败告终(Arthritis Rheum. 2012;64:1215-26)。Lightstone博士认为失败的原因是该研究对完全肾脏应答的定义标准过高，并且研究时间过短，仅为1年。该研究其实观察到许多阳性结果。血清学显著复常；在探索性终点中，78周时利妥昔单抗组蛋白尿至少显著降低50%，因此1年后观察结果产生了变化。52周与78周时的免疫抑制需求存在显著差异，并且观察到类固醇使用减少。黑人患者的疗效更佳，虽然该研究的效能不足以证实这方面的显著性，但该结果令人鼓舞。

Lightstone博士还提到了布鲁塞尔天主教鲁汶大学的Frédéric Houssiau博士进行的一项比较利妥昔单抗与标准治疗的随机对照研究，认为该研究可更好地确定利妥昔单抗在狼疮性肾炎中的作用。该研究拟纳入194例患者，计划在2016年结束，研究时间为104周，是LUNAR研究的2倍。该研究将完全应答定义为蛋白/肌酐比值≤0.5(LUNAR研究中为≤0.2)。

van Vollenhoven博士在会上指出，阿贝西普在欧洲临床实践中极少被用于SLE和狼疮性肾炎患者。然而，在一项探讨阿贝西普治疗SLE的阴性研究中(Arthritis Rheum. 2010;62:3077-87)，观察到多发性关节炎患者获益最明显，尽管该结果无统计学显著性，但提示阿贝西普可能适合超适应证用于此类患者。一项事后分析显示，采用定义更佳的疗效标准就可在对照组和安慰剂组之间观察到显著差异(Arthritis Rheum. 2012;64:3660-5)。

目前有若干项阿贝西普研究正在进行中，这些研究表明该药联合环磷酰胺治疗狼疮性肾炎的效果较好。

van Vollenhoven博士表示，虽然贝利木单抗是首个被开发并获准用于治疗SLE的生物制剂，其已被证实可成功治疗SLE，但甚至该药也被忽视。在探讨贝利木单抗治疗SLE的III期研究(n = 867)中，10 mg/kg贝利木单抗相比安慰剂可显著改善标准狼疮疾病活动性评分(Lancet 2011;377:721-31)。但两组的效应量差异仅为10%，效应较弱。造成这一结果的可能至少有两种其他原因，一是贝利木单抗虽然是非常好的药物，但仅对部分患者疗效较好，我们在临床上需要识别这些患者并对其采取这一治疗；二是这些大型研究的统计数据非常多，如果使用的评估工具不是非常好，那么所得出的结果不太显著。

van Vollenhoven博士表示，根据其临床经验，补体、抗DNA抗体水平低且具有活动性疾病的接受类固醇治疗的患者从贝利木单抗治疗中获益的可能性较大。

van Vollenhoven博士和Lightstone博士与罗氏等多家公司存在利益关系。

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By: JENNIE SMITH, Internal Medicine News Digital Network

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.