CARRA issues consensus treatment plans for severe pediatric ANCA-associated vasculitis
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The Childhood Arthritis and Rheumatology Research Alliance has developed consensus treatment plans for remission‐induction and remission‐maintenance of severe pediatric antineutrophil cytoplasmic antibody-associated vasculitis.
Published in Arthritis Care & Research, the plans offer alternatives for each set, including rituximab (Rituxan; Genentech, Biogen) or cyclophosphamide for remission induction, and azathioprine/methotrexate or rituximab for remission maintenance.
“International physician surveys, and data from A Registry for Childhood Vasculitis (ARChiVe) reveal a wide variation in treatment practices in ped-[ANCA-associated vasculitis (AAV)] (differences in drugs, combinations, doses, administration routes, and therapy duration) and inconsistent use of evidence-based adult guidelines,” Kimberly A. Morishita, MD, of British Columbia’s Children’s Hospital, at the University of British Columbia, and colleagues wrote.
“If the treatment variation among registry contributors could be limited to two alternatives, data on these individual treatments would accumulate faster, and evaluation of comparative effectiveness and safety of just two treatment alternatives would be feasible,” they added.
To that end, 29 members of Childhood Arthritis and Rheumatology Research Alliance (CARRA), including pediatric rheumatologists and nephrologists, formed a working group to develop consensus treatment plans for severe pediatric ANCA-associated vasculitis. This, in turn, would assist the future study of comparative safety and effectiveness, they wrote. The group conducted a literature review of current evidence-based treatments and guidelines for ANCA-associated vasculitis.
Included guidelines were those from the Canadian Vasculitis group (CanVasc), the British Society of Rheumatologists (BSR), the British Health Professionals for Rheumatology (BHPR), the EULAR/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) and Single Hub and Access point for Pediatric Rheumatology in Europe (SHARE).
The help focus its work, the working group determined its target population would be children aged younger than 18 years with new‐onset granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or renal‐limited ANCA-associated vasculitis, and limited to those with organ‐ or life‐threatening disease. Eosinophilic‐GPA was excluded. In face-to-face meetings, the members then used nominal group techniques to identify treatment strategies for remission‐induction and remission‐maintenance. They also determined specific data that needed to be collected, as well as outcomes to be measured, in future studies.
A random sample of 80 CARRA members voted to accept the developed treatment plans for remission‐induction and remission‐maintenance with 94% and 98% approval rates, respectively.
The working group ultimately developed two consensus treatment plans for each of the remission‐induction and remission‐maintenance phases. For remission-induction, the group stated that cyclophosphamide (CYC) or rituximab (RTX)— combined with glucocorticoids — constituted the primary choices for providers, as both are included in all current guidelines for adult severe ANCA-associated vasculitis.
“There was protracted discussion and deliberation about the need to include combination CYC-RTX as a third CTP alternative for primary induction,” Morishita and colleagues wrote. “The combination is not recommended in any existing or imminent (ie, CanVasc) revised guidelines for induction at outset. Concurrent or prior use of CYC is a known risk factor for prolonged RTX-associated immunoglobulin suppression. Ultimately, we found no consensus to include this combination as a primary remission-induction [consensus treatment plan (CTP)] option, but like SHARE, it was recommended for refractory disease.”
For cyclophosphamide, intravenous (IV) is considered preferable to oral administration, due to lower toxicity, comparable efficacy and measurable adherence.
“The two IV-CYC regimens (pediatric adaptations of the [European Vasculitis Study group (EUVAS)] and NIH adult protocols), considered equivalent for this CTP, should be administered minimally for 3 months until there is sustained disease inactivity, and for a maximum of 6 months,” Morishita and colleagues wrote.
For rituximab remission-induction, four-dose — 375 mg/m2 — or modified two-dose — 750 mg/m2 — regimens were considered equivalent.
Regarding remission maintenance, the working group agreed on azathioprine or methotrexate, or rituximab, as the primary choices. Azathioprine and methotrexate were the most recommended options in the adult guidelines. However, rituximab is now a recommended alternative, according to the working group.
“Long-term (10 years) follow-up showed no difference in relapse rate or survival between AZA and MTX, although AZA was preferred in the presence of renal disease,” Morishita and colleagues wrote. “Among surveyed pediatric rheumatologists, for maintenance therapy, 70% used either AZA (45%) or MTX (25%), less than 15% used [mycophenolate mofetil (MMF)], which seems to be inferior to AZA, and none used leflunomide. MMF was not included as a maintenance therapy option as its inclusion was supported by only 31.8%.”
The working group found “little gain” in comparing the relative efficacy and safety of azathioprine versus methotrexate, they added. They were therefore included collectively in the consensus plan.
Although rituximab use in remission-maintenance is low, ARChiVe data show that its frequency is rising. For this reason, and despite a lack of pediatric experience or studies, the working group decided to include the drug as an alternative to either azathioprine or methotrexate.
“The ultimate goal of this initiative has been to provide a more standardized treatment framework to enable more systematic outcome evaluation of children with AAV,” Morishita and colleagues wrote. “CARRA endorsement aimed to engage more members to participate in a registry-based evaluation of ped-AAV and allow systematic evaluation of limited treatment alternatives.”
“Our study could be rapidly implemented by using the existing ARChiVe registry in PedVas, where there are already willing international contributors,” they added. “Increasing utilization of the registry internationally would facilitate the evaluation of other emerging therapies or strategies such as high versus reduced dose [glucocorticoids (GC)], C5a receptor inhibitor (avacopan) as an alternative to GC, or early combination therapy with [cyclophosphamide] or [rituximab], if these treatments become incorporated in adult practice guidelines.”
Perspective
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In a perfect world, there would be an abundance of randomized clinical trials (RCT) to guide best practices for treating children with autoimmune/autoinflammatory conditions. However, funding for RCTs, relatively small patient population and parent/caregiver reluctance for their children to receive ‘experimental’ treatment are just a few of the obstacles faced by pediatric researchers.
The Childhood Arthritis and Rheumatology Research Alliance (CARRA) has a longstanding commitment to improving the care and treatment of children with rheumatic disease and recognizes the challenges of conducting quality RCTs in pediatrics. CARRA has strategically developed a rigorous process for the creation of consensus treatment plans (CTP) for specific disease processes; the CTP for Severe Pediatric Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (ped-AAV) is CARRA’s latest endeavor.
This CTP covers both the acute and remission phase of ped-AAV, allows practitioners to choose treatment options in both phases (cyclophosphamide or rituximab for acute; DMARD or rituximab for remission), includes provisions for using glucocorticoids and discusses prophylactic treatment for infection.
The information gleaned from this CTP will provide rheumatology practitioners with a more standardized approach to treating ped-AAV, compile data on the short- and long-term effects of medications regimens and pave the way for further research related to ped-AAV. In the imperfect world of pediatric rheumatology research, CARRA’s CTP approach is a win-win.
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