The European League Against Rheumatism (EULAR) has updated its recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, focusing on remission induction, maintenance, and long-term concerns.

These recommendations represent an update of the EULAR 2009 recommendations, and reflect considerable increased knowledge and experience, with almost 1,700 papers on systemic vasculitis having been published during the past 5 years. An additional treatment, rituximab (Rituxan), also has been licensed for used in ANCA-associated vasculitis (AAV), a group of diseases that includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis.

The recommendations, formulated by a task force that represented EULAR and the European Renal Association-European Dialysis and Transplant Association, consist of 15 statements "termed 'recommendations' as opposed to 'guidelines' or 'points to consider' because they offer guidance which needs to be tailored to meet individual requirements," according to Chetan Mukhtyar, MBBS, MD, of Norfolk and Norwich University Hospital in Norwich, England, and colleagues.

"They are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries, and drug regulatory organizations," the task force wrote online in Annals of the Rheumatic Diseases.



"I think these are all very sound recommendations," said Steven R. Ytterberg, MD, a rheumatologist at the Mayo Clinic in Rochester, Minn., who was not involved in the development of the recommendations.

"This clearly reflects the standard of care," he told MedPage Today.

Challenges of the Disease
Mukhtyar and colleagues preceded the specific statements with a comment about the challenge of treating AAV, because of the variability and potential lethality of the disease, the likelihood of relapse, and negative impact of both disease and treatment on quality of life.

The first recommendation advises that patients with AAV be treated at centers with expertise in vasculitis, or at least in close collaboration with such a center, because of the complexity of the diagnosis and the need for multiple specialist interventions. This is particularly important for patients with refractory disease, who may be best managed at centers involved in clinical trials, according to the authors of the recommendations.

A second recommendation strongly supports the use of biopsy in the diagnosis of AAV, although the sensitivity depends on the specific organ involved, with ranges from 12% to 91.5%.

Remission Induction
The recommendations then go on to address the induction of remission in new-onset disease that appears organ- or life-threatening, with a combination of glucocorticoids and either cyclophosphamide or rituximab.

The authors noted that oral cyclophosphamide has been largely supplanted by pulsed intravenous administration because of lower cumulative doses and less toxicity.

Patients receiving cyclophosphamide, according to this recommendation, should routinely be given antiemetics along with the infusion, should be monitored for the development of leukopenia, and should receive prophylaxis against Pneumocystis jirovecii.

The new recommendation for the use of rituximab rests on the outcomes of in two randomized studies in which the therapy was given in doses of 375 mg/m2, once weekly for 4 weeks. In both studies, this B-cell depleting agent was found to be non-inferior to cyclophosphamide.

One scenario in which rituximab might be preferred is for a patient who wants to preserve reproductive potential. For prednisone in these combination regimens, the goal of tapering is to reach a target of 7.5 to 10 mg/day by 3 to 5 months.

The next statement addressed the induction of remission among patients with non-organ-threatening disease, who can be given a combination of glucocorticoids plus either methotrexate or mycophenolate mofetil (CellCept). Examples of patients who could be given one of these treatments include those with nasal and paranasal involvement without erosions or olfactory dysfunction, those with cutaneous involvement only, and for patients with noncavitating pulmonary nodules.

However, methotrexate or mycophenolate should not be used for remission induction in patients with retro-orbital or cardiac involvement or with pulmonary hemorrhage, the authors emphasized.

Relapses and Maintenance
The recommendations then advise that for major relapses considered organ- or life-threatening, patients be treated as for new-onset disease, with glucocorticoids and cyclophosphamide or rituximab. For less severe relapses, an increase in the prednisone dose may be sufficient. For rapidly progressive glomerulonephritis or severe diffuse alveolar hemorrhage, plasma exchange can be considered.

"They are still recommending plasma exchange, although there has been some question about the utility of that," Ytterberg said. The wording is important here, he noted. "For the remission induction of organ-threatening disease, they stated "we recommend treatment," whereas for plasma exchange they state that it "should be considered," which is clearly not as emphatic," he pointed out.

There is a large ongoing trial known as PEXIVAS looking at the utility of plasma exchange in these patients, he noted. The next statements suggest that for maintenance of remission, low-dose glucocorticoids be given with azathioprine, rituximab, methotrexate, or mycophenolate mofetil. Maintenenace therapy should continue for at least 2 years, and if withdrawal of treatment is considered, prednisone should generally be tapered before immunosuppressives.

However, "a meta-analysis of 13 studies ( 8 randomized clinical trials and 5 observational studies with 983 participants) examining the effect of duration of glucocorticoids on relapse rate concluded that continuing glucocoticoids is associated with fewer relapses," Mukhtyar's group wrote.

The recommendation for continuing on low-dose prednisone reflects a cross-Atlantic difference, according to Ytterberg. "The Europeans have tended to keep patients on low-dose prednisone, whereas in many of the American studies patients have been pushed to get to a prednisone dose of zero. This is an area of ongoing investigation. Personally I often keep patients on a low dose of prednisone," Ytterberg said.

Refractory AAV -- patients who are unable to achieve remission with their initial induction therapy -- was also addressed. If the initial treatment was with cyclophosphamide, the patient should be switched to rituximab, and vice versa. "These are common sense recommendations," Ytterberg said. "And if they don't respond to either cyclophosphamide or rituximab, you find someone doing a study."

For apparent refractory disease, consideration also should be given to potential reasons for the lack of response, such as whether the diagnosis was correct, whether the disease activity is actually damage, or if infection or malignancy could explain the findings.

Other Concerns
Additional recommendations include regular assessment of cardiovascular risk and for organ damage, as well as follow-up for hematuria among patients treated with cyclophosphamide and for hypoimmunoglobulinemia among those given rituximab. The task force also advised reliance on regular clinical assessment rather than testing for ANCA for treatment decision-making. "The role of ANCA testing as a means of predicting future relapse is controversial and evolving," the authors wrote.

Guidance for patients is also important. "We recommend that patients with AAV should be given a clear verbal explanation of the nature of their disease, the treatment options, the side effects of treatment, and the short-term and long-term prognoses."

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