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Azathioprine was more effective than was mycophenolate mofetil for the prevention of relapse in antineutrophil cytoplasmic antibody–associated vasculitis.
"Although mycophenolate mofetil may be considered in refractory cases, it should not be considered the first-line remission maintenance therapy in AAV," wrote Dr. Thomas F. Hiemstra and colleagues in an article published online Nov. 8 in JAMA (doi:10.1001/jama.2010.1658).
Dr. Hiemstra of the University of Cambridge, England, looked at 156 patients in an open-label, multicenter, randomized controlled trial known as IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).
Patients were aged at least 18 years with a new diagnosis of either Wegener granulomatosis or microscopic polyangiitis, recruited between April, 2002 and January, 2009. All patients had a positive indirect immunofluorescence or enzyme-linked immunosorbent assay test result for antineutrophil cytoplasmic antibodies, or ANCAs.
Initially, all study participants received cyclophosphamide and glucocorticoids for induction of remission. Once remission was established, patients were divided into two groups, to receive either azathioprine or mycophenolate mofetil.
A total of 80 patients in the azathioprine group were given 2 mg/kg per day of azathioprine, up to 200 mg. The dose was titrated to 1.5 mg/kg per day after 12 months of treatment, down to 1 mg/kg per day after 18 months, and discontinued after 42 months.
The remaining 76 patients received mycophenolate mofetil at 2,000 mg/day. The dose was reduced to 1,500 mg/day after 12 months, to 1,000 mg/day after 18 months and withdrawn after 42 months.
The median follow-up for both groups was 39 months. All participants were counted in an intent-to-treat analysis.
Dr. Hiemstra recorded 42 relapses in the mycophenolate mofetil group, out of 76 patients (55%), compared with the azathioprine group, which had 30 relapses out of 80 patients (38%).
That amounted to an unadjusted hazard ratio for relapse of 1.69 among mycophenolate mofetil users (95% confidence interval, 1.06-2.70; P = .03).
"After adjustment for the prespecified factors of age, sex, diagnostic subtype, route of cyclophosphamide administration [during initial treatment], and baseline creatinine level, the HR for relapses associated with mycophenolate mofetil use was 1.80 (95% CI, 1.10-2.93; P = .02)," added the researchers.
There were no significant adverse event rate differences between the groups. According to Dr. Hiemstra, there were 22 severe adverse events in 13 patients in the azathioprine group, and 8 events in 8 patients in the mycophenolate mofetil group.
These included severe infection (8 in the azathioprine group and 3 in the mycophenolate mofetil group); leukopenia (11 episodes in the azathioprine group and 5 in the mycophenolate mofetil group); and malignancies (2 bladder cancers and 3 skin cancers in the azathioprine group, versus 1 skin malignancy among mycophenolate mofetil users).
Intolerance led to discontinuation of therapy among six azathioprine and two mycophenolate mofetil users.
"Although mycophenolate mofetil is frequently regarded as a potent alternative to azathioprine, we found no evidence to support its use as the initial remission maintenance therapy for patients with AAV," they investigators said.
Moreover, "we found no significant advantages to the use of mycophenolate mofetil in terms of safety or tolerability," they added.
Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.
Dr. Gary S. Hoffman of the Cleveland Clinic wrote that while there have been "major contributions" in the field of vasculitis over the last several decades, data on these rare diseases are still lacking.
"The difficulty inherent in the organization of this trial is implied by noting that recruitment of 175 newly diagnosed patients with [antineutrophil cytoplasmic antibody]-positive Wegener's granulomatosis and microscopic polyangiitis required 42 centers from 11 European countries over 7 years," he said.
Indeed, while the current trial "provides important and reliable new knowledge for the clinician," several issues remain unresolved, he added.
For one, "as in other trials involving patients with WG and MPA, severe infections and leukopenia continue to be a major concern," Dr. Hoffman pointed out.
Moreover, the authors only included ANCA-positive patients.
"Approximately 10% of patients with identical clinical phenotypes might be ANCA-negative and also respond to all anti-inflammatory or immunosuppressive therapies shown to be effective for those who are seropositive," he wrote.
Finally, given the side-effect profile, "the risk-benefit formulas of long-term maintenance therapy vs. discontinuation and treatment of relapses require further study."
"Although the therapeutic options have expanded, clinicians face difficult treatment decisions when patients in remission are unable to tolerate or have contraindications to maintenance agents such as methotrexate or azathioprine," he concluded.
Gary S. Hoffman, M.D., holds the Harold C. Schott Chair for Rheumatic and Immunologic Diseases at the Cleveland Clinic, and is director of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. His comments were taken from an editorial accompanying the study (JAMA 2010 Nov. 8 [doi:10.1001/jama.2010.1676]). He reported having no financial disclosures.
Dr. Gary S. Hoffman of the Cleveland Clinic wrote that while there have been "major contributions" in the field of vasculitis over the last several decades, data on these rare diseases are still lacking.
"The difficulty inherent in the organization of this trial is implied by noting that recruitment of 175 newly diagnosed patients with [antineutrophil cytoplasmic antibody]-positive Wegener's granulomatosis and microscopic polyangiitis required 42 centers from 11 European countries over 7 years," he said.
Indeed, while the current trial "provides important and reliable new knowledge for the clinician," several issues remain unresolved, he added.
For one, "as in other trials involving patients with WG and MPA, severe infections and leukopenia continue to be a major concern," Dr. Hoffman pointed out.
Moreover, the authors only included ANCA-positive patients.
"Approximately 10% of patients with identical clinical phenotypes might be ANCA-negative and also respond to all anti-inflammatory or immunosuppressive therapies shown to be effective for those who are seropositive," he wrote.
Finally, given the side-effect profile, "the risk-benefit formulas of long-term maintenance therapy vs. discontinuation and treatment of relapses require further study."
"Although the therapeutic options have expanded, clinicians face difficult treatment decisions when patients in remission are unable to tolerate or have contraindications to maintenance agents such as methotrexate or azathioprine," he concluded.
Gary S. Hoffman, M.D., holds the Harold C. Schott Chair for Rheumatic and Immunologic Diseases at the Cleveland Clinic, and is director of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. His comments were taken from an editorial accompanying the study (JAMA 2010 Nov. 8 [doi:10.1001/jama.2010.1676]). He reported having no financial disclosures.
Dr. Gary S. Hoffman of the Cleveland Clinic wrote that while there have been "major contributions" in the field of vasculitis over the last several decades, data on these rare diseases are still lacking.
"The difficulty inherent in the organization of this trial is implied by noting that recruitment of 175 newly diagnosed patients with [antineutrophil cytoplasmic antibody]-positive Wegener's granulomatosis and microscopic polyangiitis required 42 centers from 11 European countries over 7 years," he said.
Indeed, while the current trial "provides important and reliable new knowledge for the clinician," several issues remain unresolved, he added.
For one, "as in other trials involving patients with WG and MPA, severe infections and leukopenia continue to be a major concern," Dr. Hoffman pointed out.
Moreover, the authors only included ANCA-positive patients.
"Approximately 10% of patients with identical clinical phenotypes might be ANCA-negative and also respond to all anti-inflammatory or immunosuppressive therapies shown to be effective for those who are seropositive," he wrote.
Finally, given the side-effect profile, "the risk-benefit formulas of long-term maintenance therapy vs. discontinuation and treatment of relapses require further study."
"Although the therapeutic options have expanded, clinicians face difficult treatment decisions when patients in remission are unable to tolerate or have contraindications to maintenance agents such as methotrexate or azathioprine," he concluded.
Gary S. Hoffman, M.D., holds the Harold C. Schott Chair for Rheumatic and Immunologic Diseases at the Cleveland Clinic, and is director of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. His comments were taken from an editorial accompanying the study (JAMA 2010 Nov. 8 [doi:10.1001/jama.2010.1676]). He reported having no financial disclosures.
Azathioprine was more effective than was mycophenolate mofetil for the prevention of relapse in antineutrophil cytoplasmic antibody–associated vasculitis.
"Although mycophenolate mofetil may be considered in refractory cases, it should not be considered the first-line remission maintenance therapy in AAV," wrote Dr. Thomas F. Hiemstra and colleagues in an article published online Nov. 8 in JAMA (doi:10.1001/jama.2010.1658).
Dr. Hiemstra of the University of Cambridge, England, looked at 156 patients in an open-label, multicenter, randomized controlled trial known as IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).
Patients were aged at least 18 years with a new diagnosis of either Wegener granulomatosis or microscopic polyangiitis, recruited between April, 2002 and January, 2009. All patients had a positive indirect immunofluorescence or enzyme-linked immunosorbent assay test result for antineutrophil cytoplasmic antibodies, or ANCAs.
Initially, all study participants received cyclophosphamide and glucocorticoids for induction of remission. Once remission was established, patients were divided into two groups, to receive either azathioprine or mycophenolate mofetil.
A total of 80 patients in the azathioprine group were given 2 mg/kg per day of azathioprine, up to 200 mg. The dose was titrated to 1.5 mg/kg per day after 12 months of treatment, down to 1 mg/kg per day after 18 months, and discontinued after 42 months.
The remaining 76 patients received mycophenolate mofetil at 2,000 mg/day. The dose was reduced to 1,500 mg/day after 12 months, to 1,000 mg/day after 18 months and withdrawn after 42 months.
The median follow-up for both groups was 39 months. All participants were counted in an intent-to-treat analysis.
Dr. Hiemstra recorded 42 relapses in the mycophenolate mofetil group, out of 76 patients (55%), compared with the azathioprine group, which had 30 relapses out of 80 patients (38%).
That amounted to an unadjusted hazard ratio for relapse of 1.69 among mycophenolate mofetil users (95% confidence interval, 1.06-2.70; P = .03).
"After adjustment for the prespecified factors of age, sex, diagnostic subtype, route of cyclophosphamide administration [during initial treatment], and baseline creatinine level, the HR for relapses associated with mycophenolate mofetil use was 1.80 (95% CI, 1.10-2.93; P = .02)," added the researchers.
There were no significant adverse event rate differences between the groups. According to Dr. Hiemstra, there were 22 severe adverse events in 13 patients in the azathioprine group, and 8 events in 8 patients in the mycophenolate mofetil group.
These included severe infection (8 in the azathioprine group and 3 in the mycophenolate mofetil group); leukopenia (11 episodes in the azathioprine group and 5 in the mycophenolate mofetil group); and malignancies (2 bladder cancers and 3 skin cancers in the azathioprine group, versus 1 skin malignancy among mycophenolate mofetil users).
Intolerance led to discontinuation of therapy among six azathioprine and two mycophenolate mofetil users.
"Although mycophenolate mofetil is frequently regarded as a potent alternative to azathioprine, we found no evidence to support its use as the initial remission maintenance therapy for patients with AAV," they investigators said.
Moreover, "we found no significant advantages to the use of mycophenolate mofetil in terms of safety or tolerability," they added.
Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.
Azathioprine was more effective than was mycophenolate mofetil for the prevention of relapse in antineutrophil cytoplasmic antibody–associated vasculitis.
"Although mycophenolate mofetil may be considered in refractory cases, it should not be considered the first-line remission maintenance therapy in AAV," wrote Dr. Thomas F. Hiemstra and colleagues in an article published online Nov. 8 in JAMA (doi:10.1001/jama.2010.1658).
Dr. Hiemstra of the University of Cambridge, England, looked at 156 patients in an open-label, multicenter, randomized controlled trial known as IMPROVE (International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides).
Patients were aged at least 18 years with a new diagnosis of either Wegener granulomatosis or microscopic polyangiitis, recruited between April, 2002 and January, 2009. All patients had a positive indirect immunofluorescence or enzyme-linked immunosorbent assay test result for antineutrophil cytoplasmic antibodies, or ANCAs.
Initially, all study participants received cyclophosphamide and glucocorticoids for induction of remission. Once remission was established, patients were divided into two groups, to receive either azathioprine or mycophenolate mofetil.
A total of 80 patients in the azathioprine group were given 2 mg/kg per day of azathioprine, up to 200 mg. The dose was titrated to 1.5 mg/kg per day after 12 months of treatment, down to 1 mg/kg per day after 18 months, and discontinued after 42 months.
The remaining 76 patients received mycophenolate mofetil at 2,000 mg/day. The dose was reduced to 1,500 mg/day after 12 months, to 1,000 mg/day after 18 months and withdrawn after 42 months.
The median follow-up for both groups was 39 months. All participants were counted in an intent-to-treat analysis.
Dr. Hiemstra recorded 42 relapses in the mycophenolate mofetil group, out of 76 patients (55%), compared with the azathioprine group, which had 30 relapses out of 80 patients (38%).
That amounted to an unadjusted hazard ratio for relapse of 1.69 among mycophenolate mofetil users (95% confidence interval, 1.06-2.70; P = .03).
"After adjustment for the prespecified factors of age, sex, diagnostic subtype, route of cyclophosphamide administration [during initial treatment], and baseline creatinine level, the HR for relapses associated with mycophenolate mofetil use was 1.80 (95% CI, 1.10-2.93; P = .02)," added the researchers.
There were no significant adverse event rate differences between the groups. According to Dr. Hiemstra, there were 22 severe adverse events in 13 patients in the azathioprine group, and 8 events in 8 patients in the mycophenolate mofetil group.
These included severe infection (8 in the azathioprine group and 3 in the mycophenolate mofetil group); leukopenia (11 episodes in the azathioprine group and 5 in the mycophenolate mofetil group); and malignancies (2 bladder cancers and 3 skin cancers in the azathioprine group, versus 1 skin malignancy among mycophenolate mofetil users).
Intolerance led to discontinuation of therapy among six azathioprine and two mycophenolate mofetil users.
"Although mycophenolate mofetil is frequently regarded as a potent alternative to azathioprine, we found no evidence to support its use as the initial remission maintenance therapy for patients with AAV," they investigators said.
Moreover, "we found no significant advantages to the use of mycophenolate mofetil in terms of safety or tolerability," they added.
Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.
FROM JAMA
Major Finding: Patients taking mycophenolate mofetil had a 1.80 adjusted hazard ratio for relapse of ANCA-associated vasculitis, compared with azathioprine patients.
Data Source: The International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) trial, an open-label, randomized controlled study.
Disclosures: Dr. Hiemstra reported receiving honoraria from Amgen, and several coinvestigators disclosed financial relationships with other drug makers. The study was partially funded by Hoffmann-La Roche Ltd., which markets mycophenolate mofetil as CellCept.