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MMF proves viable as alternative option in moderate ANCA-associated vasculitis

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We sometimes encounter patients for whom access to rituximab is a problem, for financial, logistical, or tolerability reasons. Also, some patients are really reluctant about an infusion, and there is still some skittishness about rituximab. I have had some patients who, despite my having strongly reiterated how rare progressive multifocal leukoencephalopathy is, have been unable to get past the fact that that’s in the package insert. It’s helpful to me as a clinician to know that mycophenolate is something we can turn to in these situations. As I discuss the ups and down of different potential strategies with patients, this is something that can be part of the discussion.

Dr. Robert F. Spiera, director of the vasculitis and scleroderma program at the Hospital for Special Surgery, New York

Dr. Robert F. Spiera

This was a really well done study, and they were honest about the limitations. They excluded patients with the most severe disease, so you are still not talking about your patients on dialysis getting mycophenolate. Also, there are questions in terms of it’s not being as effective at sustaining remission, but that’s a bridge you can cross once they are in remission, in terms of how vigilant you are about follow-up. You also can re-induce remission with mycophenolate if you have to.

Robert F. Spiera, MD, is director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York. He had no relevant disclosures, and is on the editorial advisory board of MDedge Rheumatology.



Mycophenolate mofetil was noninferior to pulsed cyclophosphamide for remission induction in ANCA-associated vasculitis, but there were more relapses, in a randomized, unblinded trial of 140 patients with non–life-threatening disease.

“Our results demonstrate that MMF [mycophenolate mofetil] represents an alternative to CYC [cyclophosphamide] for remission induction in AAV [ANCA-associated vasculitis],” said investigators led by Rachel B. Jones, MD, of the department of renal medicine at Addenbrooke’s Hospital, Cambridge, England.

“While treatment with MMF may be associated with a higher risk of relapse compared with pulsed CYC, this increased risk may be acceptable to avoid the potential adverse effects of CYC” – infections, malignancies, and infertility – “particularly when the baseline risk of relapse is low,” as with the elderly or myeloperoxidase (MPO)-ANCA disease, “or if rituximab is unavailable,” Dr. Jones and her colleagues wrote in Annals of the Rheumatic Diseases.

Since enrollment began in 2007, they also noted that “it has become common to use rituximab as an alternative to CYC induction therapy ... However, rituximab is expensive, and its use is restricted in many countries ... Alternative effective low-cost induction therapies” – such as MMF – “may be required in some cases.”

The work, which was done on behalf of the European Vasculitis Study Group, was the largest randomized trial to date of MMF for AAV remission induction, and the first to include children; patients were enrolled at 21 sites in Europe, Australia, and New Zealand.

They were randomly assigned to MMF or pulsed CYC, with 66 adults and 4 children ranging in age from 10 to 16 years in each group. In addition to those with life-threatening disease, patients younger than 6 years old and those on dialysis or with an estimated glomerular filtration rate below 15 mL/min/m2 were excluded. Following remission, subjects were switched to oral azathioprine and a prednisone taper.

The primary outcome was remission by 6 months, defined as the absence of disease activity on two consecutive occasions at least 1 month apart, plus adherence to the taper. Baseline ANCA subtype, disease activity, and organ involvement were similar between the groups.

Overall, 47 patients in the in the MMF group (67%), including 1 child, reached the primary endpoint, versus 43 patients (61%), again including 1 child, in the CYC group (risk difference = 5.7%; 90% confidence interval, –7.5% to 19%), which established noninferiority. The median time to remission was about 90 days in both arms. “Compliance was a contributory factor to the lower remission rate[s] in children,” the authors noted.

More relapses occurred in the MMF group (33% vs. 19% with CYC). Among MPO-ANCA patients, the relapse rate was 15% versus 12% with CYC. In proteinase 3 (PR3)-ANCA patients, almost half in the MMF group relapsed (48% versus 24%).

There were no significant differences in serious infections (26% with MMF versus 17% with CYC; P = .3), malignancies, thromboembolisms, or death (four CYC patients and five MMF patients at 6 months).

Adult patients in the MMF group received MMF 2 g/day, with dose increases to 3 g/day permitted for uncontrolled disease at 4 weeks. Patients younger than 17 years old were dosed according to body surface area. The CYC group received intravenous pulsed CYC 15 mg/kg every 2-3 weeks with reductions for age and renal function. A total of 58 CYC patients (83%) received at least six pulses.

After remission, azathioprine was dosed at 2 mg/kg per day. Oral prednisolone started at 1 mg/kg per day and was reduced to 5 mg/day by 6 months.

Plasma exchange or additional methylprednisolone were allowed at entry; there were no differences in their use between the groups.

The trial was sponsored by Cambridge University Hospitals NHS Foundation Trust. Vifor Pharma provided a research grant to cover the trial and MMF costs. Dr. Jones and the other investigators reported ties to several companies, including GlaxoSmithKline, Genentech/Roche, ChemoCentryx, and Genzyme/Sanofi. Vifor holds an equity stake in ChemoCentryx.

SOURCE: Jones RB et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214245.

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