Correspondence
Mycophenolate or Azathioprine Maintenance in Lupus Nephritis
N Engl J Med 2012; 366:572-573February 9, 2012
- Article
To the Editor:
Dooley et al. (Nov. 17 issue)1 report the efficacy of mycophenolate mofetil versus azathioprine as maintenance therapy for lupus nephritis and declare mycophenolate superior. Yet azathioprine was prescribed according to body weight, despite overwhelming evidence favoring the use of thiopurine methyltransferase (TPMT) testing for pharmacogenetic guidance in administration.2 By omitting previous TPMT assessment, the study was conducted contrary to the recommendations of the Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium,2 and the drug's labeling.3 Monitoring of thiopurine metabolites is frequently performed in practice, including for the treatment of lupus,4 since underdosing is common. However, azathioprine was reduced to 50 mg per day in patients without data concerning therapeutic metabolite levels. A traffic-accident death was even analyzed as an adverse event associated with azathioprine rather than being excluded. We note that the results of this study were keenly advertised 17 months ago by Roche,5 which has been seeking FDA licensing of mycophenolate for lupus, but in these results, the finding of superiority for mycophenolate unfortunately gives the appearance that azathioprine had “one arm tied behind its back.”
Pedro R. Chocair, M.D., Ph.D.
Hospital Alemão Oswaldo Cruz, São Paulo, BrazilJohn A. Duley, Ph.D.
University of Queensland, Brisbane, QLD, AustraliaNo potential conflict of interest relevant to this letter was reported.
5 References1
Dooley MA ,Jayne D ,Ginzler EM , et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011;365:1886-1895
Full Text | Web of Science | Medline2
Relling MV ,Gardner EE ,Sandborn WJ , et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89:387-391
CrossRef | Web of Science | Medline3
Pharmacogenomics Knowledge Base. FDA label — azathioprine, TPMT (http://www.pharmgkb.org/drug/PA448515#tabview=tab0&subtab=32).
4
Askanase AD ,Wallace DJ ,Weisman MH , et al. Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J Rheumatol 2009;36:89-95
Web of Science | Medline5
Investor update: CellCept reaches positive results in phase iii trial in lupus nephritis. Basel, Switzerland: Roche, June 3, 2010 (http://www.roche.com/investors/ir_update/inv-update-2010-06-03a.htm).
To the Editor:
Dooley et al. report that mycophenolate mofetil administered at a fixed target dose of 2 g per day was superior to azathioprine for the maintenance of active class III, IV, or V lupus nephritis that had responded to induction therapy. Several groups, including ours, have underlined the strong interindividual pharmacokinetic variability of immunosuppressive agents among patients with systemic lupus erythematosus (SLE).1 For instance, mycophenolate mofetil is an inactive prodrug that must be converted to its active metabolite, mycophenolic acid (MPA). For a fixed dose of mycophenolate mofetil, variation in the exposure to MPA by a factor of 10 occurs,2 as measured by the area under the plasma concentration–time curve from 0 to 12 hours. The assessment of these measurements is truly a critical issue in trials involving patients with SLE, since such analysis allows investigators to distinguish between intrinsic inefficacy and insufficient drug exposure.3 Therefore, the lack of pharmacokinetic monitoring should be considered an important limitation of the study by Dooley et al. Future trials involving patients with SLE should take into account drug-exposure measurements as important end points.
Laurent Arnaud, M.D., Ph.D.
Noël Zahr, D.Pharm., Ph.D.
Zahir Amoura, M.D.
Groupe Hospitalier Pitié-Salpêtrière, Paris, France
laurent.arnaud@psl. aphp. fr Dr. Arnaud reports receiving honoraria from Amgen and participating in conferences sponsored by GlaxoSmithKline; and Dr. Amoura, receiving honoraria from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Neovacs, Roche, Teva Pharmaceuticals, and UCB Pharma.
No other potential conflict of interest relevant to this letter was reported.
3 References1
Arnaud L ,Zahr N ,Costedoat-Chalumeau N ,Amoura Z . The importance of assessing medication exposure to the definition of refractory disease in systemic lupus erythematosus. Autoimmun Rev 2011;10:674-678
CrossRef | Web of Science | Medline2
Zahr N ,Arnaud L ,Marquet P , et al. Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum 2010;62:2047-2054
Web of Science | Medline3
Arnaud L ,Zahr N ,Amoura Z . Preventing relapses in antineutrophil cytoplasmic antibody-associated vasculitis. JAMA 2011;305:996-996
CrossRef | Web of Science | Medline
Author/Editor Response
With respect to the comments of Chocair and Duley: although azathioprine has not been approved for the treatment of lupus nephritis in the United States, the drug was administered in accordance with the package insert, which recommends dose adjustment according to body weight.1 Contrary to their assertion, TPMT testing was not omitted. Although in our study as in other studies,2 such testing was not mandated by the protocol, it was allowed according to local clinical practice, and patients with known TPMT deficiency were excluded from the study. TPMT testing might confer protection against toxicity but would not directly affect the efficacy of azathioprine. In our study, although some patients withdrew because of neutropenia, such patients were not considered to have had treatment failure according to the protocol. Rather, data for these patients were censored at the time of withdrawal and did not necessarily contribute to the primary end point.
The FDA recommends but does not require TPMT testing for the administration of azathioprine.3 The label clearly states that TPMT testing cannot substitute for monitoring of the complete blood count, which was performed in our study.1 We believe that a convincing case for routine TPMT monitoring does not yet exist in lupus nephritis, and it remains unusual in rheumatologic practice to guide the administration of azathioprine by measuring metabolites. Not all studies, including those involving patients undergoing organ transplantation, have shown a correlation between measured metabolites and outcomes of immunosuppression.4
With respect to our reporting of deaths in the azathioprine group: the outcomes of an intention-to-treat analysis must be reported in full, regardless of whether the investigator believes an adverse event was associated with the drug being evaluated. Death was also an element of the prespecified definition of treatment failure, which is not unusual in a survival analysis.
In response to the comments of Arnaud et al. regarding the lack of pharmacokinetic monitoring in our study: we do not agree that this represents a major limitation. Mycophenolate mofetil was administered in accordance with the label for patients undergoing transplantation, and pharmacokinetic testing is currently being performed on samples obtained during the study. There is some evidence to support routine therapeutic drug monitoring for mycophenolate mofetil in patients undergoing transplantation, but no definitive guidance yet exists, and the benefit remains to be proved in patients with lupus nephritis.
Mary Anne Dooley, M.D., M.P.H.
University of North Carolina, Chapel Hill, NCDavid Jayne, M.D.
Addenbrooke's Hospital, Cambridge, United KingdomNeil Solomons, M.D.
Vifor Pharma, Victoria, BC, Canada
neil.solomons@viforpharma. com Since publication of their article, the authors report no further potential conflict of interest.
4 References1
Imuran (azathioprine). San Diego, CA: Prometheus Laboratories, May 2011 (package insert) (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf).
2
Houssiau FA ,D'Cruz D ,Sangle S , et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;69:2083-2089
CrossRef | Web of Science | Medline3
Pharmacogenomics Knowledge Base. FDA label — azathioprine, TPMT (http://www.pharmgkb.org/drug/PA448515#tabview=tab0&subtab=32).
4
Jun JB ,Cho DY ,Kang C ,Bae SC . Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine. Clin Exp Rheumatol 2005;23:873-876
Web of Science | Medline
