Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2)

Objective To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs). Methods Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group. Results Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2–4) vs 5 (5–5) administrations. Conclusion AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions. Trial registration number NCT01731561; Results.

[1]  D. Schroeder,et al.  Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 , 2016, Arthritis & rheumatology.

[2]  P. Merkel,et al.  EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis , 2016, Annals of the rheumatic diseases.

[3]  M. Ticchioni,et al.  Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis , 2016, Journal of Neuroimmunology.

[4]  Kenneth G. C. Smith,et al.  Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis. , 2015, Rheumatology.

[5]  P. van Paassen,et al.  ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. , 2015, Journal of the American Society of Nephrology : JASN.

[6]  P. Ravaud,et al.  Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. , 2014, The New England journal of medicine.

[7]  O. Decaux,et al.  Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients. , 2014, Rheumatology.

[8]  M. Resche-Rigon,et al.  Are anti-proteinase-3 ANCA a useful marker of granulomatosis with polyangiitis (Wegener's) relapses? Results of a retrospective study on 126 patients. , 2014, Autoimmunity reviews.

[9]  B. Bonnotte,et al.  Rituximab: Recommendations of the French Vasculitis Study Group (FVSG) for induction and maintenance treatments of adult, antineutrophil cytoplasm antibody-associated necrotizing vasculitides. , 2013, Presse medicale.

[10]  P. Merkel,et al.  Efficacy of remission-induction regimens for ANCA-associated vasculitis. , 2013, The New England journal of medicine.

[11]  T. Peikert,et al.  Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. , 2012, Arthritis and rheumatism.

[12]  M. Heller,et al.  Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations , 2011, Annals of the rheumatic diseases.

[13]  P. van Paassen,et al.  Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. , 2010, The New England journal of medicine.

[14]  L. Mouthon,et al.  Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. , 2008, The New England journal of medicine.

[15]  C. Savage,et al.  Relapsed Wegener's granulomatosis after rituximab therapy--B cells are present in new pathological lesions despite persistent 'depletion' of peripheral blood. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[16]  D. Schroeder,et al.  Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis , 2007, Annals of Internal Medicine.

[17]  P. Bacon,et al.  Development of comprehensive disease assessment in systemic vasculitis , 2007 .

[18]  C. Franssen,et al.  Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. , 2003, Kidney international.

[19]  G. Hoffman,et al.  Wegener's granulomatosis: survey of 701 patients in North America. Changes in outcome in the 1990s. , 2002, The Journal of rheumatology.

[20]  P. Limburg,et al.  Prediction of relapses in Wegener's granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. , 2000, Arthritis and rheumatism.

[21]  R. Porter.  Nomenclature of Systemic Vasculitides: Proposal of an International Consensus Conference , 1995 .

[22]  C. Pusey,et al.  ANCA and predicting relapse in systemic vasculitis. , 1995, QJM : monthly journal of the Association of Physicians.

[23]  T. The,et al.  Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre , 1990, The Lancet.

[24]  P. Merkel,et al.  Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis--a meta-analysis. , 2012, Rheumatology.

[25]  R. Panush.  Rituximab versus cyclophosphamide for ANCA-associated vasculitis , 2011 .

[26]  P. Seo.  Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis , 2010 .

[27]  P. Bacon,et al.  Development of comprehensive disease assessment in systemic vasculitis. , 2007, Annals of the rheumatic diseases.