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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EA few decades ago, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitide\u2014granulomatosis with polyangiitis, polyangiitis, and microscopic polyangiitis\u2014were associated with high rates of mortality. Tremendous strides have since been made in treating these diseases. The use of less toxic immunosuppressant drugs has improved the outcomes of patients, and, in recent years, the development of biologic agents and a better understanding of disease pathogenesis have contributed to the discovery of rituximab as an effective alternative to the immunosuppressive cyclophosphamide to induce remission in ANCA-associated vasculitis.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EVasculitis\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EA few decades ago, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV)\u2014granulomatosis with polyangiitis (GPA), polyangiitis, and microscopic polyangiitis (MPA)\u2014were associated with high rates of mortality. Tremendous strides have since been made in treating these diseases. The use of less toxic immunosuppressant drugs has improved the outcomes of patients, and, in recent years, the development of biologic agents and a better understanding of disease pathogenesis have contributed to the discovery of rituximab as an effective alternative to the immunosuppressive cyclophosphamide to induce remission in ANCA-associated vasculitis. In light of this development, the roles of cyclophosphamide and rituximab in the treatment of AAV, both in remission induction and maintenance of remission, are evolving.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThe History of B Lymphocytes as a Target\u003C\/h2\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EUlrich Specks, MD, Mayo Clinic, Rochester, Minnesota, USA, discussed targeting B lymphocytes in the treatment of AAV. B lymphocytes have been a target in GPA since cyclophosphamide was shown to have a significant effect on suppressing the function of B lymphocytes in patients with the disease [Cupps TR et al. \u003Cem\u003EJ Immunol\u003C\/em\u003E 1982]. Later, the activity and extent of GPA was shown to be directly linked to the frequency of activated peripheral blood B lymphocytes [Popa ER et al. \u003Cem\u003EJ Allergy Clin Immunol\u003C\/em\u003E 1999]. In 1999, a patient with refractory disease was treated successfully with rituximab [Specks U et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2001], and this success was reproduced in a small cohort of patients treated with rituximab on a compassionate-use basis [Keogh KA et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EEarly success with rituximab in uncontrolled trials encouraged a group of investigators to compare the efficacy of rituximab with cyclophosphamide for induction of remission in AAV. Rituximab was approved for the treatment of patients with GPA or MPA on the basis of this study, the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis [RAVE; Stone JH et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010] trial.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe multicenter, randomized, double-blind, double-dummy, controlled, noninferiority trial compared rituximab with cyclophosphamide for the induction of complete remission by 6 months in patients with severe AAV. A total of 197 subjects with active severe GPA or MPA were randomized to receive either intravenous (IV) rituximab (375 mg\/m\u003Csup\u003E2\u003C\/sup\u003E 1x\/week for 4 weeks, plus placebo cyclophosphamide; n=99), or oral cyclophosphamide (placebo rituximab infusions followed by 2 mg\/kg cyclophosphamide QD for 3 to 6 months; n=98). The study excluded subjects who were in the ICU, had alveolar hemorrhage, or had creatinine \u0026gt;4 mg\/dL.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe primary endpoint was complete clinical remission, defined as a Birmingham Vasculitis Activity Score for Wegener\u0027s granulomatosis of 0 and complete tapering of prednisone dose at 6 months.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003ESubjects in the cyclophosphamide arm who reached remission at 3 to 6 months were eligible to be switched to azathioprine (2 mg\/kg QD). Subjects in the rituximab group who achieved remission at 3 to 6 months were switched to placebo-azathioprine. Both treatment groups received 1 to 3 pulses of methylprednisone (1000 mg each) at the start of treatment, followed by prednisone (1 mg\/kg QD). Doses were tapered so that subjects in remission without disease flares had discontinued glucocorticoids by 5 months.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003ESixty-three subjects in the rituximab group (64%) reached the primary endpoint, compared with 52 (53%) in the control group, which met the criterion for noninferiority (p\u0026lt;0.001). There was no significant difference between treatment arms on the primary endpoint by baseline renal status, ANCA type, or disease type (GPA vs MPA), or in those with alveolar hemorrhage at baseline. RAVE demonstrated that rituximab is noninferior to cyclophosphamide for induction of remission in patients with severe AAV. For the subgroup of patients who had a severe disease relapse at baseline of the trial (n=101), rituximab was shown to be superior to cyclophosphamide (p=0.013). While RAVE showed noninferiority for primary outcome measure, a benefit for rituximab was shown for subjects who relapsed. The drop in B cells did not seem to bear any relation to the treatment effect, and the cyclophosphamide group also showed a reduction in B cells.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EA second randomized controlled trial comparing a rituximab-based regimen with a standard cyclophosphamide\/azathioprine-based regimen in the treatment of active generalized AAV [RITUXVAS] was an international trial with an open-label design of 44 patients who were randomized 3:1 to rituximab plus 2 infusions of cyclophosphamide or IV cyclophosphamide for 6 months followed by oral azathioprine [Jones RB et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010]. All subjects had a new diagnosis of ANCA-positive vasculitis at entry and had severe renal disease. On average, they were 10 years older than patients enrolled in RAVE, and 25% had received plasma exchange immediately prior to randomization.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe primary endpoint, sustained remission at 12 months, was achieved by 76% of the rituximab group versus 82% of the cyclophosphamide group in an intention-to-treat analysis. RITUXVAS demonstrated that over 12 months, 1 course of rituximab achieved the same results as 6 months of cyclophosphamide followed by azathioprine.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003ERemission maintenance was again shown to be similar between the 2 strategies in an analysis of 18-month follow-up of RAVE participants. In RAVE, the duration of complete remission was not different between 1 course of rituximab and 18 months of standard therapy (3 to 6 months of cyclophosphamide followed by azathioprine).\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EA Continued Role for Cyclophosphamide\u003C\/h2\u003E\n         \u003Cp id=\u0022p-12\u0022\u003ECyclophosphamide continues to have a role in remission induction in patients with GPA and MPA, as well as for many severe forms of vasculitis, according to Carol A. Langford, MD, MHS, Cleveland Clinic, Cleveland, Ohio, USA.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EDr. Langford stated that 40 years of learning experience with cyclophosphamide have led to refinement in the way it is used and an improvement in outcomes, as well as specific strategies to reduce toxic side effects.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EAfter the initial 15 patients with GPA were treated successfully with cyclophosphamide in 1973 [Fauci AS, Wolff SM. \u003Cem\u003EMedicine\u003C\/em\u003E 1973], with 12 achieving remission for up to 63 months, cyclophosphamide in combination with corticosteroids was used in more patients who were followed over longer periods of time. Experience with the use of cyclophosphamide over the years has shown that GPA has the potential for relapse and is associated with significant toxicity, including a high rate of bladder cancer and a potential risk of serious infections. The risk of bladder cancer with cyclophosphamide is related to total dose and duration of exposure, with a 5% risk at 10 years from the first cyclophosphamide dose to 15% at 16 years [Talar-Williams C et al. \u003Cem\u003EAnn Intern Med\u003C\/em\u003E 1996]. In a 1995 study of 180 GPA patients, a 6% rate of \u003Cem\u003EPneumocystis jiroveci\u003C\/em\u003E (PCP) was observed with cyclophosphamide treatment. One lesson from this study is that PCP prophylaxis should be given to patients with GPA\/MPA receiving an induction regimen, including rituximab.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003ECyclophosphamide use has evolved, and treatment is now considered in 2 phases: induction of remission followed by maintenance. Azathioprine maintenance after 3 to 6 months of cyclophosphamide induction was found to maintain remission without an increase in the relapse rate [Jayne D et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2003], and methotrexate maintenance following cyclophosphamide induction was found similarly effective as azathioprine in maintenance [Pagnoux C et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2008].\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EThe time to remission induction is equivalent between intermittent IV and daily oral cyclophosphamide at a median of 3 months, but a higher rate of relapse has been observed with IV intermittent therapy [de Groot K et al. \u003Cem\u003EAnn Intern Med\u003C\/em\u003E 2009]. However, patients who receive daily therapy receive a higher total dose and have a higher rate of leukopenia, leading to the recommendation that complete blood count should be monitored every 1 to 2 weeks for the duration of daily therapy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EAnother lesson learned is that nonsevere disease can be successfully treated with alternatives to cyclophosphamide, such as methotrexate (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Hoffman GS et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 1992; Sneller MC et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 1995]. In a study of 100 patients with nonsevere disease, methotrexate was not inferior to cyclophosphamide for remission induction [de Groot K et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u00222012 Treatment of GPA and MPA.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1217136490\u0022 data-figure-caption=\u00222012 Treatment of GPA and MPA.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11717\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-18\u0022 class=\u0022first-child\u0022\u003E2012 Treatment of GPA and MPA.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EGC=glucocorticoid; GPA=granulomatosis with polyangiitis; MPA=microscopic polyangiitis.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from CA Langford, MD, MHS.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EEvidence from the literature supports improved outcomes with cyclophosphamide over time. In a German cohort of 445 patients observed over 4 decades, mortality declined over time, owing in part to improved use of cyclophosphamide [Holle JU et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011]. In addition to \u003Cem\u003EPneumocystis\u003C\/em\u003E prophylaxis and cytopenia prevention mentioned previously, the changes in cyclophosphamide use include the following:\u003C\/p\u003E\n         \u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n               \u003Cp id=\u0022p-20\u0022\u003ELimiting the duration of exposure to 3 to 4 months\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n               \u003Cp id=\u0022p-21\u0022\u003EUrothelial protection in the form of once morning dosing and adequate fluids to maintain a dilute urine for daily cyclophosphamide, and the use of mesna in conjunction with intermittent cyclophosphamide\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n               \u003Cp id=\u0022p-22\u0022\u003EUrinalysis to detect nonglomerular hematuria and urine cytology\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\n               \u003Cp id=\u0022p-23\u0022\u003ECystoscopy for nonglomerular hematuria or atypia seen on urine cytology\u003C\/p\u003E\n            \u003C\/li\u003E\u003C\/ul\u003E\n         \u003Cp id=\u0022p-24\u0022\u003EDr. Langford said that, in the end, the data support cyclophosphamide as an equally valid option to rituximab in newly diagnosed patients with severe disease. The current body experience with cyclophosphamide favors its use over rituximab in patients with rapidly progressive glomerulonephritis with creatinine \u0026gt;4.0 mg\/dL, patients with alveolar hemorrhage requiring mechanical ventilation\u2014as these patients were not included in the RAVE trial\u2014when they experience adverse events specific to rituximab, and patients with active disease despite rituximab.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The editors would like to thank the many members of the American College of Rheumatology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1217136490\u0022 data-figure-caption=\u0022The editors would like to thank the many members of the American College of Rheumatology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure2\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure2\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/19\/4\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11718\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n               \u003Cp id=\u0022p-25\u0022 class=\u0022first-child\u0022\u003EThe editors would like to thank the many members of the American College of Rheumatology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/19\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzn50q\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzn50q\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}