Risk vs. benefit

All immunomodulatory therapy carries safety concerns, and attention to patient safety has to be of equal priority to remission maintenance. IV cyclophosphamide has innumerable undesirable side effects such as infertility, risk of malignancy, and life-threatening infections. The ALMS study indicates that there may be as many adverse events with MMF as there are with cyclophosphamide. There are risks of bone marrow suppression, GI disturbances, and generalized constitutional symptoms.

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There have been reports of increased first-trimester spontaneous abortions and fetal malformations of infants born to women on MMF therapy. Recent compilations of these re-ports define a fetopathy syndrome associated with MMF. This syndrome appears to be characterized by malformations of the palate, lips, and outer ear (Expert Opin Drug Saf. 2008;7:219-222). Thus, women of childbearing age must use safe and effective contraceptive methods, or MMF must be stopped and other remission-maintenance strategies employed.

The adverse effects of rituximab were initially limited to infusion-related reactions and marrow suppression. Now two rituximab-related deaths of individuals with progressive multifocal leukoencephalopathy (PML) due to JC polyomavirus have been described. At least one of the individuals developed PML more than 18 months after receiving rituximab and one received multiple courses of other immunosuppressive agents. The JC polyomavirus is a latent virus present in more than 70% of the general population.

While there are sophisticated tests to determine who harbors this virus, there is no practical way to determine who will actually develop PML. With this in mind, the FDA has issued an advisory which recommends that providers who wish to render treatment with rituximab for off-label conditions like severe or resistant lupus disease do so with full disclosure of this rare but potential complication (www.fda.gov/Cder/Drug/advisory/rituximab.htm, accessed September 15, 2008). This advisory should be included in the decision-making for re-treatment in patients who have quiescent disease.

The road ahead

What approaches are next on the horizon? A number of targeted therapies are being tried in lupus and lupus nephritis, and we all are hopeful that one or some of these agents will prove safe and effective tools in our therapeutic armamentarium. Other issues need to be addressed in the treatment of lupus nephritis.

What, for example, are the best ways to monitor disease remission and relapse? Part of the existing dilemma is that there is no consensus on the definition of complete remission in lupus nephritis and there are no definitive laboratory tools to provide assurance that a remission is secured.

Once remission is clinically established, for how long do we provide maintenance therapy? Perhaps the millions of dollars spent on understanding murine lupus models would be better targeted at the basic pathogenesis of human lupus nephritis and on the translation of these insights into targeted pharmacologic agents and clinical laboratory tests that will push our approach to lupus nephritis into a new era.

Dr. Gibson is clinical assistant professor of medicine in the Division of Nephrology and Hypertension at the University of North Carolina in Chapel Hill, where Dr. Falk is chief of the division, D. J. Thurston Professor of Medicine, and director of the UNC Kidney Center.