乌鸦传媒

Mycophenolate mofetil (CellCept) was as effective as cyclophosphamide for remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Japanese researchers reported.

In a meta-analysis of four clinical trials, the overall 6-month remission rates did not differ between patients receiving mycophenolate mofetil and those given cyclophosphamide, with a relative risk of 1.09 (95% CI 0.86-1.38, P=0.48), said Takayoshi Morita, MD, of Osaka University in Suita, and colleagues.

However, as they noted in their study online in , a meta-regression analysis found a positive correlation between 6-month remission rates only among patients whose antineutrophil antibodies target myeloperoxidase (MPO) and not for those targeting proteinase 3 (PR3).

The group of ANCA-associated small-to-medium vessel vasculitides includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. These inflammatory syndromes can affect multiple organs, including the lungs, kidneys, ears, nose, and throat, and can result in organ failure and death. The two different serotypes, MPO-ANCA and PR3-ANCA, have increasingly been shown to be important in disease manifestations and response to treatment.

Cyclophosphamide with glucocorticoids have been the mainstay of treatment for ANCA-associated vasculitis for more than 4 decades, and rituximab (Rituxan) has more recently been accepted as an additional conventional therapy. However, cyclophosphamide can be problematic in older patients, women of childbearing age, and patients with renal insufficiency because of potential adverse events. In addition, rituximab has been associated with hypogammaglobulinemia in patients with vasculitis, which could lead to severe and even fatal infections.

Mycophenolate mofetil has been used since the 1990s for immunosuppression following kidney transplantation, and more recently, for lupus nephritis.

Because have also suggested potential benefits for mycophenolate in ANCA-associated vasculitis, Morita's group conducted a systematic review of the literature and meta-analysis to examine whether this immunosuppressive agent might be a less toxic potential alternative to cyclophosphamide.

The four studies in the meta-analysis, two from Europe and two from China, included 300 patients whose ages ranged from 49 to 61, and had follow-up ranging from 6 months to 4 years.

At baseline, scores on the Birmingham Vasculitis Activity Score ranged from 15 to 19. Seropositivity for MPO-ANCA was 11% to 100% across the studies, while seropositivity for PR3-ANCA was 0% to 89%. These differences in serotypes were not surprising, the researchers explained, because of geographic factors, with PR3-ANCA being predominant among Western countries and MPO-ANCA positivity being more common in Asia.

Kidney involvement was seen in 75% to 100% of the patients, and lung involvement in 46% to 61%.

Dosages of mycophenolate ranged from 1 to 2 g/day, and cyclophosphamide was given orally at 2 mg/kg/day or as intravenous pulses in varying regimens such as 0.75 to 1 g/m² body surface area once monthly.

There was considerable heterogeneity among the studies (I² = 60%), the researchers noted.

Similar efficacy results were seen for the two agents. As with 6-month remission rates, the rate of ANCA negativity at 6 months showed no difference between mycophenolate and cyclophosphamide (RR 1.31, 95% CI 0.91-1.90, P=0.15). The relapse rate throughout follow-up also did not differ (RR 1.36, 95% CI 0.80-2.31, P=0.26).

The safety profiles of the two drugs also were similar:

• Mortality rates, RR 1.05 (95% CI 0.40-2.74, P=0.93)

• Infection rates, RR 1.26 (95% CI 0.79-2.01, P=0.33)

• Leukopenia, RR 0.45 (95% CI 0.16-1.32, P=0.15)

• End-stage renal disease, RR 0.66 (95% CI 0.15-2.79, P=0.57)

• Severe infection or death from infection, RR 0.87 (95% CI 0.31-2.50, P=0.80)

The finding of similar rates of infection and leukopenia suggests that patients with ANCA-associated vasculitis should be monitored for infection whether they are treated with mycophenolate or cyclophosphamide, the researchers said. "However, our results do not lead to the conclusion that the side effects of mycophenolate mofetil and cyclophosphamide are equivalent in every respect, because treatment with cyclophosphamide has some major problems such as carcinogenesis."

Cyclophosphamide has been reported to increase the rates of skin and bladder cancers as well as leukemia and lymphoma in a dose-dependent fashion. Additional long-term observation regarding malignancy among patients treated with mycophenolate will be needed, Morita and co-authors said.

They noted that it has previously been observed that patients with PR3-ANCA are at greater risk of relapse than are those with MPO-ANCA. "Therefore, we speculate that the treatment efficacy of mycophenolate mofetil in patients with ANCA-associated vasculitis may depend on their ANCA subtype," the researchers wrote.

They added that the finding of a positive correlation between 6-month remission and seropositivity for MPO-ANCA "suggests that patients with MPO-ANCA-positive ANCA-associated vasculitis are more likely to respond well to mycophenolate mofetil than patients with PR3-ANCA-positive ANCA-associated vasculitis."

None of the studies included patients with life-threatening vasculitis, and the researchers noted that rituximab should be preferred as an alternative to cyclophosphamide in those patients, because rituximab demonstrated noninferiority to cyclophosphamide in .

"Mycophenolate mofetil may be an alternative remission-induction drug for non-life-threatening ANCA-associated vasculitis," particularly for patients with MPO-ANCA seropositivity, Morita and colleagues concluded.

A limitation of the study, they said, was the possibility of publication bias.

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