PHILADELPHIA—At the ACR/ARHP Annual Scientific Meeting in Philadelphia, three researchers continued the ongoing debate about optimal treatment strategies of lupus nephritis. As the debate indicated, lack of solid data on certain populations, concerns about side effects, and insufficient follow-up preclude consensus until more research has been completed.
For induction therapy, the choices are generally highdose IV cyclophosphamide (CY), the so-called National Institutes of Health (NIH) regimen; low-dose IV CY, the socalled Euro-Lupus regimen;1 azathioprine (AZ); or mycophenolate mofetil (MMF). There has also been recent use of the biologic rituximab. All of these immunosuppressive agents are used in combination with glucocorticoids.
For maintenance therapy, also the subject of continuing debate, the choices are often high-dose CY; low-dose CY; AZ and the Euro-Lupus regime; MMF; rituximab/CY combination; or rituximab alone.
Much of the debate centers on the efficacy of CY versus MMF. Although the NIH regime has improved survival and remission rates, not all patients have a favorable response, and toxicities are not uncommon with the high-dose regimen. These toxicities can include ovarian failure, severe infections, and reduced efficacy in black patients. Complicating the decision making at this point is the lack of long-term data for other therapies, as well as trials that do not indicate superiority of one drug over another.
According to Ellen M. Ginzler, MD, MPH, chief of rheumatology at State University of New York-Downstate Medical Center in Brooklyn, there is an “unmet need for new agents.” But until those agents are developed, “if we can show equal efficacy, then we need to consider the tolerability and compliance issues, the racial and ethnic issues, the cost, availability, and reimbursement for these agents,” she said.2
Frederic A. Houssiau, MD, PhD, of the department of rheumatology at Universite Catholique Louvain in Brussels, Belgium, said that further drug development is needed for better maintenance therapy. “We don’t have a good maintenance therapy so far,” he said, adding that what a physician does at the bedside remains most important, including good follow-up; controlling blood pressure, blood sugar, and proteinuria with either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers; and treating dyslipidemia. To illustrate the factors that complicate treatment strategies, the panel considered three high-risk cases.
Case 1: Young Black Woman
The first case was that of a 34-year-old black woman with new-onset class IV lupus nephritis and moderate renal function. She has one child and does not want another. After treatment for six months, she had complete renal remission. The two questions related to her case centered on the best induction therapy and best maintenance therapy.
Mary Ann Dooley, MD, MPH, associate professor of medicine at the University of North Carolina at Chapel Hill, referred to the lack of data for treating black patients with CY. The rate of lupus in blacks is three times that of whites, Dr. Dooley said. About 40% of black patients treated with six months of CY therapy end up on dialysis at the end of five years, she said, adding that Boumpas and others have reported racial disparities with CY therapy.3-4
Although MMF may be an alternate therapy and can be used in patients who have not responded to IV CY, there are concerns, she said. Most importantly, there are no published long-term follow-up data beyond about three years. The Apreva Lupus Management Trial found that response rates did not vary between MMF and IV CY, she said.
Dr. Dooley said that she would begin treatment in this high-risk patient with six monthly doses of IV CY and then switch to either MMF or AZ with another biopsy before continuing treatment.
Dr. Ginzler cited data from a Food and Drug Administration– funded, randomized, open-label trial that compared the two agents as induction therapy. Those data, she said, suggested that MMF is superior to CY for achieving remission and is also better tolerated. Patients received either MMF or monthly IV CY. The primary endpoint was complete remission at six months; the secondary endpoint, partial remission. An intention-to-treat analysis found that significantly more patients had complete remission with MMF; the partial remission rate was also more frequent with MMF.5
“One needs to consider the long-term effects,” Dr. Ginzler said. “It has been suggested that MMF acid has antiproliferative effects that are not related to immunology of the treatment, with a decrease in smooth muscle cell proliferation, decrease in fibroblast cell proliferation. This effect may be important in the prevention of progression of renal disease to end-stage disease and … for decrease in risk of atherosclerosis in lupus patients,” she said.
Her choice for the 34-year-old black woman would be 3 gm/daily of MMF, building up to that over a month and continuing with the 3-gram dose “as long as tolerated.” At three years, she would consider tapering the MMF and eventually discontinuing it.6 That decision would depend on the patient’s immunologic parameters, her blood pressure, level of serum creatinine, and degree of proteinuria, Dr. Ginzler said.
Dr. Houssiau said that the Euro-Lupus regime is generally the better strategy: Begin with low-dose IV CY, and then treat with AZ. “Induction IV therapy is very important to ensure optimal compliance. We know that noncompliance is a major issue in treatment of lupus long term,” Dr. Houssiau said. AZ is his first choice for maintenance therapy because it costs less, can be continued during pregnancy, and has a good toxicity profile. Results of the MAINTAIN trial, which were presented at the ACR meeting, showed that MMF was not superior to AZ for prevention of renal relapses at a median follow-up of 53 months.7
However, for this patient, he said, induction therapy should be MMF because of data showing more complications with CY in non-white patients.
Case 2: Young Asian Woman
The second case was a 26-year-old Asian woman with class IV lupus nephritis diagnosed in 1998. She was initially treated with prednisone for six months and then with AZ for four years. She relapsed and was subsequently treated with prednisone and MMF for three years, followed by another relapse. She had a repeat biopsy showing a mixed class III/V. She hopes to have children in the future.
Dr. Ginzler said that the patient should be reinduced with an increase in her steroids. “I would treat her initially at this point with the Euro-Lupus regime: six infusion low doses of IV CY. At the end of that, I would taper the steroids and return her to MMF if she changes her mind about pregnancy. If she was insistent on pregnancy, I would reluctantly go back to AZ in the dose she could tolerate.”
Dr. Houssiau agreed that the patient should be reinduced. “No drugs work better than glucocorticoids and CY if she clearly still has pregnancy wishes,” he said. But, he said, there are no sufficient data indicating use of the Euro-Lupus regime in Asian patients.
Case 3: Young Hispanic Woman
The final case considered by the panel was that of a 22-yearold Hispanic woman with class IV lupus nephritis. She was treated with 3 gm/daily of MMF for three months and had little improvement. She was then switched to monthly highdose IV CY. After three months, there was no response. She hopes to one day have children.
Dr. Dooley said that the patient is at high risk because of her age, her ethnicity, and because she presented with impaired renal function. First, she said, the physician should be certain that the lack of response is due to lupus nephritis and not to an underlying etiology related to blood pressure, blood sugar, dyslipidemia, or thrombotic thrombocytopenic purpura.
She advised that this patient should finish her six months of therapy with MMF and then transition to AZ or MMF. “Because she is a young woman, she will need longterm immunosuppression,” she said.
Kathy Holliman is a medical journalist based in New Jersey.
References
- Boumpas DT, Austin HA, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet. 1992;340:741-745.
- Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med. 2000;343:1156-1162.
- Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol. 2005;16: 1076-1084.
- Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: Poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997;51: 1188-1195.
- Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219-2228.
- Houssiau FA, D’Cruz DP, Sangle SR, et al. Azathioprine versus mycophenolate mofetil for maintenance immunosuppression of proliferative lupus nephritis: Result of a randomized trial (MAINTAIN). #1150. Presented at the ACR/ARHP Scientific Meeting. Oct. 19, 2009. Philadelphia.
- Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: The Euro-Lupus Nephritis Trial. A randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46:2121-2131.
