Lupus Nephritis: First ACR Guidelines Published

Janis C. Kelly

May 04, 2012

May 4, 2012 — The American College of Rheumatology (ACR) has issued the first-ever guidelines for the screening, treatment, and management of lupus nephritis (LN). The guidelines are published in the June issue of Arthritis Care & Research and were initially presented at ACR 2011.

Lead author Bevra H. Hahn, MD, professor of medicine and chief of the Division of Rheumatology at the David Geffen School of Medicine, University of California, Los Angeles, told Medscape Medical News that the 2012 guidelines are a significant advance because they address total therapy of LN, not just short-term treatment.

At this time, more than half of patients with systemic lupus erythematosus develop LN within 10 years and up to 30% of those cases progress to end-stage renal disease within 15 years of diagnosis. Renal damage remains the most important predictor of mortality for patients with systemic lupus erythematosus.

The ACR panel, which developed the guidelines, recommends renal biopsy for all patients with clinical evidence of active, previously untreated LN. They do not recommend immunosuppressive treatment for patients with class 1 (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) or class 2 (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium) renal damage. However, they do recommend aggressive treatment for patients with class 3 or higher renal pathology.

Have Background and Acute Therapies in Place

"From the clinician's viewpoint, the most important points are: First, be sure background therapies are in place, as well as acute therapies," Dr. Hahn said. "Choice of induction therapies depends in part on the race of the patient, and 2 different choices can be made regarding dosing of cyclophosphamide, dependent on patient race. Mycophenolate and cyclophosphamide plus glucocorticoids are the mainstay of treatments for induction of improvement in [LN] of serious histologic classes (except if patient is pregnant), and azathioprine [AZA] and mycophenolate are both acceptable for maintenance of improvement (except in pregnancy). Rituximab or calcineurin inhibitors should be considered if standard treatments fail."

Dr. Hahn also noted that an algorithm for management of pregnant woman with active [LN] is included in the guidelines.

The task force panel concluded that mycophenolate mofetil (MMF) "has been similar in efficacy in all races studied to date." However, Asians might require lower doses of MMF for similar efficacy compared with non-Asians. Also, black and Hispanic patients appear to respond less well to intravenous cyclophosphamide (CYC) than do white or Asian patients, and therefore would be candidates for MMF/mycophenolic acid.

Ellen Ginzler, MD, chief of rheumatology at the State University of New York Downstate Medical Center in Brooklyn, reviewed the paper for Medscape Medical News. "To a large extent, the new guidelines reflect standard practice in clinics that concentrate on LN," Dr. Ginzler said, "but they also clear up several points, such as recommending pulse steroids in treatment of class 3 and 4 active proliferative disease. This may also raise the issue of whether such patients will need to be treated in a chemotherapy unit, rather than just getting oral therapy. This is unlikely to be a problem for major medical centers, but could be for patients treated in physician's offices."

Aggressive Therapy for Membraneous Nephritis

Dr. Ginzler also noted that the guidelines clarify best treatment for pure membraneous nephritis. "Some have assumed that aggressive treatment is not needed in such cases, since the short- to medium-term prognosis is not so bad, but I agree with the recommendation for relatively aggressive therapy. Renal failure may not come quite as quickly in pure membraneous nephritis, but the long-term prognosis is not great."

Megan E.B. Clowse, MD, MPH, assistant professor of medicine and clinical chief, Division of Rheumatology, Duke University Medical Center, Durham, North Carolina, also reviewed the article for Medscape Medical News. "The guidelines are a reflection of what most lupus centers have been doing for the past several years, but not necessarily what has been done by rheumatologists and nephrologists who do not specialize in lupus," she said. "These guidelines emphasize the clinical equivalence of MMF and CYC, and thus, I hope, encourage the more frequent and aggressive use of MMF for LN. In my view, MMF has many advantages, including ease of use [and] infection risk, but particularly, limited impact on fertility. In addition, studies have shown that MMF is more effective than CYC in African-American woman, and this is highlighted in these guidelines."

Dr. Clowse added, "I think the guidelines for treating pregnant women are fairly on target. I would probably be more encouraging of the prophylactic use of AZA, particularly in women with a history of LN that are clinically quiescent at conception. The guidelines note that women should be off MMF or CYC for at least 6 weeks prior to conception. My usual recommendation is to switch a woman on either of these drugs to AZA for pregnancy. In my experience, some of these women do have a LN flare during pregnancy that might have been prevented by AZA use. AZA to treat active LN during pregnancy, however, is often ineffective."

Dr. Hahn told Medscape Medical News that the panel did not reach a consensus on the use of calcineurin inhibitors: The agents have potential renal toxicity, but have been shown to be effective in membranous lupus during the short term. "There was more enthusiasm than I expected for the efficacy of [the] Euro-Lupus low-dose cyclophosphamide [regimen]," she said.

The role of rituximab in LN also remains somewhat uncertain. "Many experts have experience suggesting that rituximab is effective in some patients with [LN]; the controlled trial findings do not match [the] experience of these experts. Therefore...rituximab is listed as a relatively late intervention, since the other treatments have been confirmed in controlled trials, but some physicians prefer to use rituximab earlier," Dr. Hahn said.

Areas for Improvement

The task force found a number of areas in which routine clinical care for patients with lupus needs to improve. Dr. Hahn said, "This is the reason for the recommended background therapies for all patients, and also the recommendation to perform renal biopsies whenever the therapeutic decisions would be altered by knowing 1) histologic classification and 2) level of activity and of chronicity on the biopsy.

"There needs to be more use of remission-inducing agents at proper doses for proper duration, transition from induction to maintenance therapies without a gap if possible, prevention of adverse effects when possible," she concluded.

Dr. Ginzler commented that the guidelines do not address the questions of how long to treat during maintenance therapy and when begin to taper MMF because there are few data on the topic.

With regard to the increasing incidence of end-stage renal disease associated with LN, Dr. Ginzler suggested that this might partly reflect the fact that patients with lupus are living longer. "In lupus patients there are fibrotic processes plus other reasons such as hypertension that contribute to atherosclerosis. Many patients progress to renal failure not due to active nephritis, but due to the combined effects of irreversible damage accrued over many years," she said.

Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the Data and Safety Monitoring Board for Anthera. Other co-authors have received consultant fees, speaking fees, and/or honoraria from UCB, Amgen, Pfizer, Lilly, Bristol-Myers Squibb, Genentech/Roche, EMD, Serono, Neovacs, Cephalon, MedImmune, Questcor, Argos, Abbott, Ono, Astellas, Baxter, RPS, Takeda, Human Genome Sciences/GlaxoSmithKline, Parexel, and Celgene. Dr. Ginzler and Dr. Clowse have disclosed no relevant financial relationships.

Arthritis Care Res. 2012;64:797-808. Abstract

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