EULAR狼疮肾炎指南强调早期活检

欧洲抗风湿联盟(EULAR)和欧洲肾脏协会-欧洲透析和移植协会(ERA-EDTA)在《风湿病年鉴》11月刊上(2012;71:1771-82)联合发布了首个狼疮肾炎(LN)诊治指南，建议对出现最初肾脏受累迹象的患者进行肾活检。这不同于美国风湿病学会(ACR)发布的指南，后者将活检时间交由医生判断。

这份指南的其他亮点还包括，建议将麦考酚酸作为免疫抑制治疗的首选药物，明确类固醇药物推荐剂量，依据疾病严重程度制定分层治疗计划，以及某种药物治疗失败后的详细换药治疗建议。

这份欧洲指南旨在为风湿病、肾病和内科医生对成人和儿童LN患者的诊治提供指导，但在多个关键方面与ACR 6月份发布的相关指南(Arthritis Care Res. 2012;64:797-808)存在不同。

EULAR指南明确支持对出现任何肾脏受累迹象的患者进行肾活检，包括尿液检查结果正常的不明原因肾功能不全患者。相反，ACR指南更多地允许医生自行决定是否进行肾活检。EULAR指南主要作者、希腊克里特大学的Dimitrios T. Boumpas博士说：“活检是一种简单的最佳诊治手段，如果你在诊治LN等严重疾病时回避活检，就不是完善的诊治过程。”

Boumpas博士称，EULAR工作组还将麦考酚酸列为大多数Ⅲ~Ⅳ型LN患者免疫抑制初始治疗的首选药物，并推荐低剂量静注环磷酰胺联合类固醇药物用于这类患者。他指出，虽然麦考酚酸没有像环磷酰胺那样的5年临床数据，但工作组在制定指南时权衡了其安全性和有效性数据，明确将其列为首选药物，同时也注意到这些研究的局限性。

ACR指南没有推荐硫唑嘌呤(AZA)用作诱导治疗。EULAR指南承认AZA与高风险肾脏病变活动有关，因此建议该药物用于不存在临床或组织学不良风险因素的特定患者，并建议对AZA治疗患者进行密切随访。Boumpas博士认为，这对于麦考酚酸没上市的国家尤其重要。

EULAR指南还推荐，如果患者用药3~4个月后未见改善或6~12个月后未达到部分应答，或者2年后未达到完全应答时，应转为其他替代药物治疗。该指南主要作者、同样来自克里特大学的George K. Bertsias博士称，这项建议基于来自对照试验和观察性队列研究的证据。研究表明免疫抑制剂，特别是环磷酰胺达到完全肾性应答需要2年时间。另外，在早期时间节点(3~6个月)未见改善与不良预后相关，应考虑强化治疗或换药治疗。但ACR指南的换药时间有所不同。该指南建议根据医生的临床印象，治疗6个月未见应答的患者应换药。

按照EULAR指南，对于麦考酚酸或环磷酰胺治疗无应答患者，应由麦考酚酸改用环磷酰胺或由环磷酰胺改用麦考酚酸。如果换药失败，可给予生物制剂利妥昔单抗作为添加治疗或单药治疗。Boumpas指出，虽然随机对照试验未能证明利妥昔单抗治疗LN优于标准治疗，但来自多项非对照研究或多家组织的最终证据表明，约半数对传统免疫抑制剂耐受的肾炎患者接受利妥昔单抗治疗后有效。鉴于利妥昔单抗对生殖腺无不良反应，这对于年轻女性患者非常重要，因此工作组决定推荐利妥昔单抗作为添加药物。

与ACR指南不同，EULAR指南中包括了类固醇药物具体推荐剂量。建议初始免疫抑制治疗应联合类固醇药物(500~1,000 mg/d甲基强的松龙，3次)，继以口服糖皮质激素(0.5~1.0 mg/kg /d)，然后逐步降至控制病情所需最小剂量。

EULAR指南还包括了对计划怀孕患者的特殊建议。此外，指南还包括了儿童患者的诊断和治疗建议，这些建议基于成人患者的证据以及儿童患者的非随机证据，大部分建议与成人建议相似。

该指南的撰写工作由EULAR 和 ERA-EDTA资助，作者无利益冲突披露。

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By: JENNIE SMITH, Internal Medicine News Digital Network

The European League Against Rheumatism has issued its first guidelines on management of lupus nephritis, and they advise renal biopsy at the first sign of kidney involvement, unlike the guidance issued by the American College of Rheumatology, which leaves timing of that testing up to the clinician’s judgment.

Other bright spots in EULAR’s guidelines, which it issued jointly with the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) are their position that mycophenolic acid should be the first choice for immunosuppressive therapy, the precise recommendations for steroid dosage, stratification of treatment plans according to disease severity, and explicit advice on switching therapies after one drug has failed.

The European guidelines were published in the November issue of Annals of the Rheumatic Diseases (2012;71:1771-82) and are intended for rheumatologists, nephrologists, and internists managing adult and pediatric patients with lupus nephritis. The EULAR guidelines differ in several key ways from those issued by the American College of Rheumatology (ACR) in June (Arthritis Care Res. 2012;64:797-808).

The EULAR guidelines are unequivocal in their support for renal biopsy at any sign of renal involvement, including when unexplained renal insufficiency is accompanied by normal urinary findings. The ACR guidelines, by contrast, allow for more physician latitude in determining whether to biopsy.

"This can be an emotional issue because rheumatologists do not do biopsies and may try to avoid them," said the EULAR guidelines’ lead author, rheumatologist Dr. Dimitrios T. Boumpas, who is professor of medicine and director of internal medicine/rheumatology at the University of Crete in Heraklion, Greece, in an interview. "We felt that someone should make a position statement. Biopsy is simply best care. If you’re dealing with something severe like LN [lupus nephritis] and you avoid biopsy, that’s not good medicine."

Dr. Boumpas said the EULAR task force had also moved to put mycophenolic acid in the first position as an initial immunosuppressant treatment for most cases of class III-IV LN. Low-dose intravenous cyclophosphamide in combination with steroids is also recommended for this patient group.

There are no 5-year data for mycophenolic acid as there are for cyclophosphamide, Dr. Boumpas said. But the task force that developed the guidelines weighed data on safety and efficacy and found mycophenolic acid "as the clear first choice, while at the same time recognizing the limitations of the studies," he noted.

The ACR guidelines do not recommend use of azathioprine (AZA) as induction treatment. The EULAR recommendations acknowledge that AZA has been associated with a higher risk of renal flares, and call for its use in certain patients who have no adverse clinical or histological risk factors. Patients treated with AZA need close follow-up. "This is particularly important for countries without access to MPA [mycophenolic acid]," Dr. Boumpas said.

The EULAR guidelines also recommend switching to an alternative agent when patients fail to improve in 3-4 months or do not achieve partial response after 6-12 months, or a complete response after 2 years.

"This is based on evidence from both controlled trials and observational cohort studies, which highlight the fact that immunosuppressive agents, particularly cyclophosphamide, may take up to 2 years to achieve complete renal response," Dr. George K. Bertsias, also of the University of Crete in Heraklion and the first author of the guidelines, said in an interview. "On the other hand, lack of improvement at early time points (3-6 months) is associated with adverse prognosis and should evoke discussions for treatment intensification or switch."

This is a different timetable from that described in the ACR guidelines, which advocate switching after patients fail to respond after 6 months of treatment based on the treating physician’s clinical impression.

For patients not responding to mycophenolic acid or cyclophosphamide, treatment may be switched from mycophenolic acid to cyclophosphamide or from cyclophosphamide to mycophenolic acid, according to the guidelines.

If switching fails, rituximab, a biological agent, may be given either as an add-on treatment or as monotherapy. Although randomized controlled trials have failed to demonstrate the superiority of rituximab over standard treatment in lupus nephritis, "there is culminating evidence from several uncontrolled studies and several groups worldwide that rituximab works in about half of patients with nephritis refractory to conventional immunosuppressive therapy," Dr. Boumpas said. "Since rituximab does not have adverse effects on the gonads – a significant issue in the care of young women with lupus – the committee decided to recommend it as an additional treatment resource."

The EULAR guidelines, in contrast to the ACR guidelines, contain specific dosing advice on steroids, advocating pulse steroids (500-1,000 mg of methylprednisolone daily for three doses) in combination with initial immunosuppressive therapy, followed by daily oral glucocorticoids (0.5-1.0 mg/kg per day), afterward tapering to the minimal amount necessary to control disease.

The EULAR guidelines also contain specific recommendations for patients planning pregnancy. In addition, they cover diagnosis and management of pediatric lupus nephritis, which largely follow adult recommendations. The pediatric recommendations are based on evidence in adults, and on nonrandomized evidence in children.

Work on the recommendations was funded by EULAR and the ERA-EDTA. The authors declared no conflicts of interest.