E M Miloslavsky1, U Specks2, P A Merkel3, P Seo4, R Spiera5, C A Langford6, G S Hoffman6, C G M Kallenberg7, E W St Clair8, N K Tchao9, L Ding10, D Iklé11, M Villareal11, N Lim12, P Brunetta13, F C Fervenza2, P A Monach14, J H Stone1. 1. Massachusetts General Hospital, Boston. 2. Mayo Clinic, Rochester, Minnesota. 3. University of Pennsylvania, Philadelphia. 4. Johns Hopkins University, Baltimore, Maryland. 5. Hospital for Special Surgery, New York, New York. 6. Cleveland Clinic Foundation, Cleveland, Ohio. 7. University of Groningen and University Medical Center, Groningen, The Netherlands. 8. Duke University Medical Center, Durham, North Carolina. 9. Immune Tolerance Network, South San Francisco, California. 10. National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland. 11. Rho, Chapel Hill, North Carolina. 12. Immune Tolerance Network, Bethesda, Maryland. 13. Genentech, South San Francisco, California. 14. Boston University and Boston Medical Center, Boston, Massachusetts.
Abstract
OBJECTIVE:Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated withprednisone according to a prespecified protocol. METHODS:RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.
RCT Entities:
OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.
Authors: J H Stone; G S Hoffman; P A Merkel; Y I Min; M L Uhlfelder; D B Hellmann; U Specks; N B Allen; J C Davis; R F Spiera; L H Calabrese; F M Wigley; N Maiden; R M Valente; J L Niles; K H Fye; J W McCune; E W St Clair; R A Luqmani Journal: Arthritis Rheum Date: 2001-04
Authors: Michael Walsh; Oliver Flossmann; Annelies Berden; Kerstin Westman; Peter Höglund; Coen Stegeman; David Jayne Journal: Arthritis Rheum Date: 2012-02
Authors: E M Miloslavsky; U Specks; P A Merkel; P Seo; R Spiera; C A Langford; G S Hoffman; C G M Kallenberg; E W St Clair; N K Tchao; L Viviano; L Ding; D Iklé; M Villarreal; B Jepson; P Brunetta; N B Allen; F C Fervenza; D Geetha; K Keogh; E Y Kissin; P A Monach; T Peikert; C Stegeman; S R Ytterberg; J H Stone Journal: Arthritis Rheumatol Date: 2014-11 Impact factor: 10.995
Authors: JulieAnne G McGregor; Susan L Hogan; Yichun Hu; Caroline E Jennette; Ronald J Falk; Patrick H Nachman Journal: Clin J Am Soc Nephrol Date: 2011-12-01 Impact factor: 8.237
Authors: Lorraine Harper; Matthew D Morgan; Michael Walsh; Peter Hoglund; Kerstin Westman; Oliver Flossmann; Vladimir Tesar; Phillipe Vanhille; Kirsten de Groot; Raashid Luqmani; Luis Felipe Flores-Suarez; Richard Watts; Charles Pusey; Annette Bruchfeld; Niels Rasmussen; Daniel Blockmans; Caroline O Savage; David Jayne Journal: Ann Rheum Dis Date: 2011-11-29 Impact factor: 19.103
Authors: Loïc Guillevin; Christian Pagnoux; Alexandre Karras; Chahera Khouatra; Olivier Aumaître; Pascal Cohen; François Maurier; Olivier Decaux; Jacques Ninet; Pierre Gobert; Thomas Quémeneur; Claire Blanchard-Delaunay; Pascal Godmer; Xavier Puéchal; Pierre-Louis Carron; Pierre-Yves Hatron; Nicolas Limal; Mohamed Hamidou; Maize Ducret; Eric Daugas; Thomas Papo; Bernard Bonnotte; Alfred Mahr; Philippe Ravaud; Luc Mouthon Journal: N Engl J Med Date: 2014-11-06 Impact factor: 91.245
Authors: Christian Pagnoux; Alfred Mahr; Mohamed A Hamidou; Jean-Jacques Boffa; Marc Ruivard; Jean-Pierre Ducroix; Xavier Kyndt; François Lifermann; Thomas Papo; Marc Lambert; José Le Noach; Mehdi Khellaf; Dominique Merrien; Xavier Puéchal; Stéphane Vinzio; Pascal Cohen; Luc Mouthon; Jean-François Cordier; Loïc Guillevin Journal: N Engl J Med Date: 2008-12-25 Impact factor: 91.245
Authors: Jason Springer; Benjamin Nutter; Carol A Langford; Gary S Hoffman; Alexandra Villa-Forte Journal: Medicine (Baltimore) Date: 2014-03 Impact factor: 1.889
Authors: Jan Henrik Schirmer; Peer M Aries; Kirsten de Groot; Bernhard Hellmich; Julia U Holle; Christian Kneitz; Ina Kötter; Peter Lamprecht; Ulf Müller-Ladner; Eva Reinhold-Keller; Christof Specker; Michael Zänker; Frank Moosig Journal: Z Rheumatol Date: 2017-11 Impact factor: 1.372
Authors: Lynn A Fussner; Amber M Hummel; Darrell R Schroeder; Francisco Silva; Rodrigo Cartin-Ceba; Melissa R Snyder; Gary S Hoffman; Cees G M Kallenberg; Carol A Langford; Peter A Merkel; Paul A Monach; Philip Seo; Robert F Spiera; E William St Clair; Nadia K Tchao; John H Stone; Ulrich Specks Journal: Arthritis Rheumatol Date: 2016-07 Impact factor: 10.995
Authors: Eli M Miloslavsky; Na Lu; Sebastian Unizony; Hyon K Choi; Peter A Merkel; Philip Seo; Robert Spiera; Carol A Langford; Gary S Hoffman; Cees G M Kallenberg; E William St Clair; Nadia K Tchao; Fernando Fervenza; Paul A Monach; Ulrich Specks; John H Stone Journal: Arthritis Rheumatol Date: 2016-12 Impact factor: 10.995
Authors: Divi Cornec; Brian F Kabat; John R Mills; Melissa Cheu; Amber M Hummel; Darrell R Schroeder; Matthew D Cascino; Paul Brunetta; David L Murray; Melissa R Snyder; Fernando Fervenza; Gary S Hoffman; Cees G M Kallenberg; Carol A Langford; Peter A Merkel; Paul A Monach; Philip Seo; Robert F Spiera; E William St Clair; John H Stone; David R Barnidge; Ulrich Specks Journal: Rheumatology (Oxford) Date: 2018-04-01 Impact factor: 7.580
Authors: Karolina A Zielińska; Laura Van Moortel; Ghislain Opdenakker; Karolien De Bosscher; Philippe E Van den Steen Journal: Front Immunol Date: 2016-12-14 Impact factor: 7.561