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The clinician treating lupus nephritis today is faced with an almost bewildering number of therapeutic choices and protocols. The place of high-dose intravenous pulse cyclophosphamide plus high-dose corticosteroids as the standard of care for lupus nephritis has been challenged by trials using lower doses of cyclophosphamide or regimens devoid of cyclophosphamide. Adding to this confusion, novel biologic agents have exploded onto the lupus treatment scene with much fanfare and the promise of increased specificity with fewer adverse effects than traditional therapies. To address these complexities and to put lupus nephritis therapy into perspective, three separate guidelines for the management of lupus nephritis have been published within the past few months. These guidelines have incorporated the best available evidence from randomized clinical trials, along with expert opinion as needed. Although the guidelines came from the American College of Rheumatology (ACR),1 the Kidney Disease: Improving Global Outcomes (KDIGO) work group,2 and the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA),3 the overall recommendations from each group are fairly similar. The groups were not totally independent as some of the lupus experts worked with more than one of the sponsoring organizations. Nevertheless, it is reassuring that the interpretations of the existing lupus nephritis data were consistent among a large number of nephrologists and rheumatologists.

Only a few statements in the EULAR/ERA–EDTA guidelines need some qualification, and they mainly concern the initial therapy of lupus nephritis. The EULAR/ERA–EDTA guidelines recommend mycophenolate mofetil (MMF) as the immunosuppressive drug of choice for the initial treatment of proliferative lupus nephritis, whereas KDIGO favours cyclophosphamide and the ACR suggests that either MMF or cyclophosphamide is acceptable. The main concern with MMF as initiation therapy is that it has not yet been shown to preserve kidney function as effectively as cyclophosphamide over the long-term, and some data suggest it may not do as well as cyclophosphamide.4 The EULAR/ERA–EDTA guidelines do acknowledge this concern, however, and recommend studying it as part of a future research agenda for lupus nephritis.

The EULAR/ERA–EDTA guidelines recommend that the target dose of MMF for initial therapy of proliferative and membranous lupus nephritis should be 3 g per day. Although this recommendation recapitulates the dosing used in the randomized clinical trial which demonstrated that MMF and intravenous pulse cyclophosphamide are equivalent,5 3 g per day may be too high for many patients, especially those with a small body habitus. In this trial, this dose of MMF was associated with considerable toxic effects, and almost twice as many patients in the MMF arm as in the cyclophosphamide arm left the study owing to adverse events. The best approach for dosing MMF may be to measure blood levels of MMF,6,7 although the usefulness of this method remains to be convincingly demonstrated.

Additional work in the area of lupus nephritis management is needed, which is highlighted in each guideline...

Finally, EULAR/ERA–EDTA suggests low-dose cyclophosphamide as an alternative to MMF for initial therapy of proliferative lupus nephritis. Low-dose cyclophosphamide has been called the Euro-Lupus protocol, and delivers a total of 3 g of cyclophosphamide in six biweekly 500 mg intravenous pulses over 3 months, after which patients are started on maintenance therapy.8 The Euro-Lupus protocol has been studied mainly in white patients with mild-to-moderate lupus nephritis, and its efficacy in other ethnic or racial groups is unknown. Although this caveat is clearly discussed in the text, it is not mentioned in the table of recommendations and might be overlooked by readers who focus on the tables. An ongoing clinical trial that includes patients with diverse ethnic backgrounds is using the Euro-Lupus protocol for its cyclophosphamide dosing.9 When this trial is completed, data will be available on the efficacy of the Euro-Lupus protocol in non-Caucasians, although Euro-Lupus will not have been directly compared with classic intravenous or oral cyclophosphamide regimens.

For many treating physicians, MMF has become the agent of choice for all forms of lupus nephritis, raising the question within the nephrology community as to whether a kidney biopsy is even necessary for the management of lupus nephritis.10 However, treatment without a biopsy should not be considered acceptable. The kidney biopsy in systemic lupus erythematosus yields important information for individualizing therapy, and can provide unexpected information, such as the presence of a thrombotic microangiopathy. As new treatments become available, including the many biologic agents on the horizon, it is likely that the biopsy will have an increasingly critical role in guiding therapeutic choices. Recommendations for kidney biopsy in systemic lupus erythematosus are thus appropriately aggressive in the EULAR/ERA–EDTA guidelines, and include obtaining a kidney biopsy within 1 month of finding clinical signs of kidney involvement in systemic lupus erythematosus, and performing a biopsy for individuals with proteinuria >0.5 g per day, if this finding is reproducible.

The most important contribution of the EULAR/ERA–EDTA guidelines, and indeed all of the recent lupus nephritis guidelines, might not be their recommendations of how to manage lupus nephritis, but rather their insights into what we do not know and what still needs to be studied in the field of lupus nephritis. All three guidelines concisely summarize current thinking in lupus nephritis therapy and management. They also put their recommendations into perspective by rating the level and quality of the evidence that forms the basis of lupus nephritis therapy. No matter which rating system is used, it is immediately clear that few of the recommendations are supported by strong, high-quality data. Additional work in the area of lupus nephritis management is needed, which is highlighted in each guideline through recommendations for future research. These recommendations include determining the duration of maintenance therapy, the treatment of refractory disease, and whether MMF or any of the new therapeutics being tested preserve long-term kidney function as well as cyclophosphamide does. Studies will require uniform definitions of flare, remission, and disease severity, and surrogate end points for unwanted kidney outcomes such as chronic kidney disease or end-stage renal disease.

In summary, the guidelines discussed above are a welcome update of how lupus nephritis is best managed with current agents. It is hoped that these guidelines will encourage further investigation, and that the next lupus nephritis guidelines will be backed by far more high-quality evidence.