BOSTON — The current standard of care for initial treatment of severe Wegener's granulomatosis and microscopic polyangiitis—glucocorticoids plus daily oral or pulse intravenous cyclophosphamide—is far from perfect, according to Dr. Peter A. Merkel of Boston University Medical Center.
“In randomized controlled trials, the remission rate with severe disease associated with this treatment is less than 90%, and sometimes less than 80%, so there are still a substantial number of patients who never reach remission,” Dr. Merkel said at a meeting on rheumatology sponsored by Harvard Medical School. Even when initial treatment induces remission, the risk of relapse and retreatment is high. Moreover, prolonged cyclophosphamide use has been tied to ovarian/testicular failure, bladder carcinoma and hemorrhage, cystitis, infections, and myelodysplasia.
“Because most rheumatologists don't have a high volume of patients with these diseases, most don't have a lot of personal, anecdotal experience with cyclophosphamide treatment, which can lead to problems,” said Dr. Merkel.
“One of the biggest problems I see is undertreatment,” Dr. Merkel noted. “All of the studies and trials use 2 mg/kg per day as the treatment goal, adjusting for renal disease as necessary,” while in practice patients are often receiving less. “It's better to give the right dose up front and adjust down if need be. Many patients require dose reductions. That's fine. It doesn't mean the therapy is wrong.”
Overdosage is also common. “Often, adjustments for renal disease are not being made, and they must be,” said Dr. Merkel. “The goal is not neutropenia, although sustained lymphopenia is associated with prolonged remission.”
Another roadblock to optimal therapy is inadequate lab testing. “There should be labs done on these patients every week initially, certainly no less frequently than every 2 weeks,” said Dr. Merkel. “White count values can drop pretty quickly, which is typically what happens in those patients who end up with neutropenia and sepsis. Often those outcomes could have been prevented with proper monitoring.” Unfortunately, clinicians' tendency to become lax over the course of cyclophosphamide therapy coincides with a patient's most vulnerable period. “This is when steroids are being tapered and the risk of cumulative cyclophosphamide toxicity is greatest.”
With frequent lab testing, “you can anticipate white count drops, and when you see a trend, you can start adjusting, rather than waiting until the count has dropped so low that treatment has to be stopped entirely,” said Dr. Merkel.
Other tips include avoiding twice-daily or evening dosing, “because the cyclophosphamide can accumulate in the bladder overnight.” Encourage hyperhydration to prevent cyclophosphamide-induced cystitis, Dr. Merkel stated.
One of the most prevalent treatment inadequacies “is failing to spend enough time talking to patients about cyclophosphamide,” said Dr. Merkel. “This is a toxic drug and patients need to be educated about it. For example, they need not only to know that they have to drink water, but also why they must drink water and why they should take the drug early in the day. This should be a long conversation, not just an aside.”