SNOWMASS, COLO. — Mycophenolate mofetil and rituximab are expected to join the lupus armamentarium, promising to be particularly useful for lupus nephritis, Dr. Susan M. Manzi predicted at a symposium sponsored by the American College of Rheumatology.
“Those are two we are putting our money on,” said Dr. Manzi, codirector of the Lupus Center of Excellence at the University of Pittsburgh.
Advancement in lupus treatment has not kept pace with breakthroughs in rheumatoid arthritis (RA) therapy, in general, Dr. Manzi said. The tumor necrosis factor inhibitors that are so effective in RA do not appear to have much benefit in lupus, although ongoing experiments continue to assess the effectiveness of very short-term use of these biologic agents in lupus.
And because of the failure of some promising novel agents—notably the still-controversial anti-CD40 ligand—physicians have gotten the impression that advances in lupus treatment have been few and far between.
But that would be a misperception, Dr. Manzi said.
A recently published study compared mycophenolate mofetil (CellCept) with an IV cyclophosphamide regimen in a total of 140 patients, Dr. Manzi said.
Full remissions were more common in patients treated with mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor with anti-inflammatory action that is approved for prevention of transplant rejection. Specifically, 22% of the patients on mycophenolate mofetil versus 6% of those on IV cyclophosphamide met the American College of Rheumatology criteria for complete remission (N. Eng. J. Med. 2005;353:2219–28). Patients in both treatment groups showed a significant lessening of their lupus nephritis, and all the patients benefited.
The main advantage seen with mycophenolate mofetil was that it was much better tolerated than IV cyclophosphamide, Dr. Manzi said. Diarrhea was more common in patients on mycophenolate mofetil; all other minor side effects occurred more frequently with cyclophosphamide therapy. Severe infections, such as pneumonia and sepsis, occurred in 1 of 71 patients treated with mycophenolate mofetil, but in 6 of 69 patients treated with cyclophosphamide.
Two patients died during cyclophosphamide therapy, and two others developed irreversible amenorrhea.
One question unanswered by the study was what happens later, Dr. Manzi said. The study drugs were given for 24 weeks, and the patients were assessed at 12 and 24 weeks. It has been suggested that the full beneficial effect of cyclophosphamide occurs after 24 weeks.
However, findings from a previous study that also compared the two agents in lupus nephritis and followed the patients for a full year showed that similar percentages of patients (about 80%) on each agent had achieved full remission of their nephritis at the end of the study. That study was considered somewhat less definitive than the new one, at least in this country, because it used oral cyclophosphamide, a practice not common in the United States.
Based on the new study, Dr. Manzi suggested that appropriate patients for mycophenolate mofetil treatment are going to be those without rapidly progressing glomerulonephritis, who were excluded from the study, for whom there might be a risk of infection during the treatment, and, maybe more importantly, women of childbearing age.
At Dr. Manzi's center, mycophenolate mofetil is already being used as a maintenance treatment after short courses of cyclophosphamide.
Rituximab (Rituxan) has been used to treat lupus nephritis in a handful of open-label trials, in a total of about 100 patients. The results are “impressive,” Dr. Manzi said. The agent's sole indication is for cancer, specifically B-cell non-Hodgkin's lymphoma.
Two different regimens have been used with the B-cell-depleting agent, one in which treatment is given every 4 weeks, as for non-Hodgkin's lymphoma, and another in which rituximab is given the first day, followed by intravenous cyclophosphamide, followed by tapering prednisone. And, overall 80% of patients treated have had partial remission at 4–6 months, with over 50% achieving long-term remission lasting longer than 12 months.
As with the mycophenolate mofetil, the major advantages of rituximab are tolerability and safety, Dr. Manzi said. Bcause of its widespread use in cancer therapy, safety data are plentiful.
“This drug has a lot of potential,” she said. “We certainly are using it off-label now in patients with refractory nephritis—it's just a matter of wrestling with insurance companies to get [the reimbursement] approved.”
The major advantages of the two drugs are tolerability and safety. DR. MANZI