Cyclophosphamide For ANCA-associated Vasculitis Research Articles

Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 in ANCA-Associated Vasculitis

Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses.Methods: Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively.Results: A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, p = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, p = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups.Conclusions: A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent.

A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis.

Glucocorticoids (GCs) are a mainstay of treatment for patients with ANCA-associated vasculitis (AAV) but are associated with significant adverse effects. Effective remission induction in severe AAV using extremely limited GC exposure has not been attempted. We tested an early rapid GC withdrawal induction regimen for patients with severe AAV. Patients with active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune glomerulonephritis were included. Induction treatment consisted of two doses of rituximab, 3 months of low-dose CYC and a short course of oral GC (for between 1 and 2 weeks). Clinical, biochemical and immunological outcomes as well as adverse events were recorded. A total of 49 patients were included, with at least 12 months of follow-up in 46. All patients achieved remission, with decreases observed in creatinine, proteinuria, CRP, ANCA level and BVAS. Three patients requiring dialysis at presentation became dialysis independent. Two patients required the introduction of maintenance GC for treatment of vasculitis. Overall outcomes were comparable to those of two matched cohorts (n = 172) from previous European Vasculitis Society (EUVAS) trials, but with lower total exposure to CYC and GCs (P < 0.001) and reduced rates of severe infections (P = 0.02) compared with the RITUXVAS (rituximab versus cyclophosphamide in AAV) trial. We found no new cases of diabetes in the first year compared with historic rates of 8.2% from the EUVAS trials (P = 0.04). Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.

Con: Should all patients with anti-neutrophil cytoplasmic antibody-associated vasculitis be primarily treated with rituximab?

Rituximab has enriched our armamentarium in the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Two randomised controlled trials have shown that rituximab is non-inferior compared with cyclophosphamide followed by azathioprine for the induction of remission. The newly diagnosed patients in the Rituximab in ANCA-Associated Vasculitis (RAVE) and Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis (RITUXVAS) trials had a numerically higher response rate in the cyclophosphamide/azathioprine arm, and the number of such patients treated with rituximab numbered <90. We are arguing that in newly diagnosed patients, the evidence for rituximab requires further confirmation and the length of experience with a cyclophosphamide-based induction therapy supports it continuing as the preferred first choice for induction. Also, there is an absence of information regarding rituximab as 'sole' remission induction along with steroids in patients with advanced renal presentations or lung haemorrhage. Reported side effects were similar in both trials; however, the number of participants with at least one serious adverse event following rituximab induction treatment was numerically higher in the RAVE trial. In addition, hypogammaglobulinaemia with the need of substitution in some cases and late-onset neutropaenia are complications not seen with cyclophosphamide. Over the longer term it is unclear what relapse prevention strategy should be employed after rituximab, and there was a trend to a higher relapse risk after rituximab in the RITUXVAS trial at 2 years. Further health economic studies are required to understand all the costs associated with rituximab. In the context of concomitant underlying infectious complications, in terms of fertility concerns, especially in young patients, and when malignancy is underlying we would recommend the use of rituximab as first-line therapy.

Rituximab versus cyclophosphamide for ANCA-associated vasculitis

Rituximab versus cyclophosphamide for ANCA-associated vasculitis

Rituximab has similar short-term safety and efficacy to cyclophosphamide in ANCA-associated vasculitis

Therapy: Rituximab has similar short-term safety and efficacy to cyclophosphamide in ANCA-associated vasculitis

Is Rituximab Superior to Cyclophosphamide for ANCA-Associated Vasculitis for Induction of Remission, and with a Better Safety Profile?

Antineutrophil cytoplasmic autoantibody (ANCA)-associated renal vasculitis usually manifests as a rapidly progressive glomerulonephritis, with pauci-immune necrotizing, crescentic glomerulonephritis on biopsy. The current therapeutic approach for remission induction is the same as for other systemic vasculitides: cyclophosphamide with high-dose glucocorticoids, with a reported effectiveness ranging from 70% to 90% but associated with high rates of severe adverse events, including death. This has led to the use of other therapies that may be as effective and perhaps less toxic. Cyclophosphamide plus glucocorticoids has long been established as the gold standard therapy for remission induction in severe ANCA-associated vasculitis. Its use is followed by better outcomes in severe disease, including mortality rates and remission in some cases [1]. However, as in most autoimmune disorders, an important number of patients do not respond adequately to standard therapy, most likely secondary to the complex role of the immune system in triggering disease. During the past few years, several papers have shown positive results for rituximab as treatment for patients with refractory vasculitis, especially Wegener’s granulomatosis (WG). These results seem to confirm that B cells play an important role in disease pathogenesis. With this in mind, Stone et al. compared rituximab with cyclophosphamide in patients with ANCAassociated vasculitis.

Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis

Letters5 January 2010Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated VasculitisLorraine Harper, MD, PhD, Kirsten de Groot, MD, and Caroline O. Savage, MD, PhDLorraine Harper, MD, PhDFrom Klinikum Offenbach GmbH, 63069 Offenbach/Main, Germany; and University of Birmingham, Edgbaston B15 2TT, United Kingdom.Search for more papers by this author, Kirsten de Groot, MDFrom Klinikum Offenbach GmbH, 63069 Offenbach/Main, Germany; and University of Birmingham, Edgbaston B15 2TT, United Kingdom.Search for more papers by this author, and Caroline O. Savage, MD, PhDFrom Klinikum Offenbach GmbH, 63069 Offenbach/Main, Germany; and University of Birmingham, Edgbaston B15 2TT, United Kingdom.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-1-201001050-00022 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We appreciate our colleagues' comments and are glad that our analysis has stimulated further thought among clinicians. We agree with Dr. Padhan that Wegener granulomatosis may be difficult to differentiate from tuberculous infection. However, studies suggest that the presence of both positive cytoplasmic ANCA by immunofluorescence and proteinase 3 enzyme-linked immunosorbent assay has a low prevalence in tuberculosis (1). Even in those rare patients in whom the diagnosis of Wegener granulomatosis is doubted and the balance of evidence favors ANCA-associated vasculitis, we believe that patients should be treated with pulse cyclophosphamide rather than with daily oral cyclophosphamide. The ...Reference1. Teixeira L, Mahr A, Jaureguy F, Noël LH, Nunes H, Lefort A, et al. Low seroprevalence and poor specificity of antineutrophil cytoplasmic antibodies in tuberculosis. Rheumatology (Oxford). 2005;44:247-50. [PMID: 15546964] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Klinikum Offenbach GmbH, 63069 Offenbach/Main, Germany; and University of Birmingham, Edgbaston B15 2TT, United Kingdom.Disclosures: None disclosed. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoPulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody—Associated Vasculitis Kirsten de Groot , Lorraine Harper , David R.W. Jayne , Luis Felipe Flores Suarez , Gina Gregorini , Wolfgang L. Gross , Rashid Luqmani , Charles D. Pusey , Niels Rasmussen , Renato A. Sinico , Vladimir Tesar , Philippe Vanhille , Kerstin Westman , Caroline O.S. Savage , and Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis Prasanta Padhan Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis Lee A. Hebert and Brad H. Rovin Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis Stuart M. Levine Metrics 5 January 2010Volume 152, Issue 1Page: 65KeywordsCyclophosphamideHeart rateProteinuriaRenal analysisRenal failureSafetyToxicityVasculitisWegener granulomatosis ePublished: 5 January 2010 Issue Published: 5 January 2010 CopyrightCopyright © 2010 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...

Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis

Letters5 January 2010Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated VasculitisStuart M. Levine, MDStuart M. Levine, MDFrom Johns Hopkins University, Baltimore, MD 21218.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-1-201001050-00021 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The study by de Groot and colleagues (1) shows that the higher cumulative dosing of traditional (2 mg/kg) daily oral cyclophosphamide regimens offers no advantage over lower-dose regimens delivered by intravenous pulse for the induction of remission in patients with ANCA-associated vasculitis. However, the authors did not evaluate whether lower-dose (1.0 to 1.25 mg/kg) daily oral regimens, with their lower risks for bone marrow and bladder toxicities, would be similarly efficacious in achieving remission. Before intravenous pulse cyclophosphamide for induction of remission in this patient population is broadly recommended, comparison studies with less toxic oral regimens are ...Reference1. de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150:670-80. [PMID: 19451574] LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Johns Hopkins University, Baltimore, MD 21218.Disclosures: None disclosed. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoPulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody—Associated Vasculitis Kirsten de Groot , Lorraine Harper , David R.W. Jayne , Luis Felipe Flores Suarez , Gina Gregorini , Wolfgang L. Gross , Rashid Luqmani , Charles D. Pusey , Niels Rasmussen , Renato A. Sinico , Vladimir Tesar , Philippe Vanhille , Kerstin Westman , Caroline O.S. Savage , and Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis Lorraine Harper , Kirsten de Groot , and Caroline O. Savage Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis Prasanta Padhan Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis Lee A. Hebert and Brad H. Rovin Metrics Cited ByPauci-Immune Necrotizing Glomerulonephritis 5 January 2010Volume 152, Issue 1Page: 65KeywordsBladderBone marrowConflicts of interestCyclophosphamideHeart rateToxicityVasculitis ePublished: 5 January 2010 Issue Published: 5 January 2010 CopyrightCopyright © 2010 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...

Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis

Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis

Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated Vasculitis

Letters5 January 2010Pulse Versus Daily Oral Cyclophosphamide in ANCA-Associated VasculitisLee A. Hebert, MD and Brad H. Rovin, MDLee A. Hebert, MDFrom Ohio State University Medical Center, Columbus, OH 43210.Search for more papers by this author and Brad H. Rovin, MDFrom Ohio State University Medical Center, Columbus, OH 43210.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-1-201001050-00020 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:de Groot and colleagues (1) provide a balanced discussion of the strengths and weaknesses of their randomized trial. Unfortunately, that balance was lost in the abstract's Conclusion section, which, if taken verbatim, clearly favors pulse (intravenous) cyclophosphamide over daily oral cyclophosphamide. The back story, however, is far more complex and provides substantial support for the daily oral regimen.First, recovery of kidney function may have been better with daily oral therapy. The graph showing trends in estimated glomerular filtration rate (eGFR) censored the eGFR values after onset of end-stage renal disease (ESRD). This inflated the eGFR in ...

The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review.

The study aimed at studying efficacy and adverse effects of pulse cyclophosphamide (pCyc) treatment and to compare it to continuous cyclophosphamide (cCyc) for induction of remission in ANCA-associated vasculitides from data in the published literature. A Medline search identified 14 studies, containing more than five patients. From the 11 non-randomized studies, data on outcome following pCyc treatment were extracted. Results were given as fraction of the number of evaluable patients. A meta-analysis was performed on the three prospective, randomized controlled trials to compare outcomes concerning remission, relapses, infection, leucopenia, death and renal failure in patients treated with pCyc as opposed to cCyc. The 11 non-randomized studies comprised 202 patients receiving pCyc. Cyc pulses of 375-1000 mg/sqm/pulse were applied at weekly to monthly intervals with different concomitant prednisolone regimens and variable adjunctive therapy. Complete remission was achieved in 112/191, partial remission in 23/191 evaluable patients. Relapses occurred in 68/135 patients, 40/115 patients were non-responders. Leucopenia, infections, haemorrhagic cystitis, and deaths were rare. The meta-analysis, comprising 143 patients, showed that pCyc compared with cCyc treatment was significantly less likely to fail to induce remission (OR 0.29; 95% CI 0.12-0.73) and had a significantly lower risk of infection (OR 0.45; 95% CI 0.23-0.89) and leucopenia (OR 0.36; 95% CI 0.17-0.78). Relapses occurred slightly, although not statistically significantly, more often under pCyc treatment (OR 1.79; 95% CI 0.85-3.75). There were no differences in end-stage renal failure or deaths between the two regimens. The currently available, rather sparse data show that pCyc is less toxic than cCyc therapy and is an at least equally potent inductor of remission, but possibly at the expense of a higher relapse rate. The existing data do not give sufficient information on outcomes as time to remission and relapse, irreversible damage or quality of life without which a treatment regimen cannot satisfactorily be evaluated today. A large prospective randomized controlled trial is needed to address these issues and their relative importance.