RT Journal Article
SR Electronic
T1 Use of Pharmacogenetics, Enzymatic Phenotyping, and Metabolite Monitoring to Guide Treatment with Azathioprine in Patients with Systemic Lupus Erythematosus
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP 89
OP 95
DO 10.3899/jrheum.070968
VO 36
IS 1
A1 ANCA D. ASKANASE
A1 DANIEL J. WALLACE
A1 MICHAEL H. WEISMAN
A1 CHUNG-E TSENG
A1 LANA BERNSTEIN
A1 H. MICHAEL BELMONT
A1 ERNEST SEIDMAN
A1 MARIKO ISHIMORI
A1 PETER M. IZMIRLY
A1 JILL P. BUYON
YR 2009
UL http://www.jrheum.org/content/36/1/89.abstract
AB Objective. Individualized therapy based on genetic background and monitoring of metabolites can optimize drug safety and efficacy. Such an approach is available for azathioprine (AZA), the thiopurine antimetabolite. AZA exerts therapeutic effects when metabolized to the active thiopurine nucleotide, 6-thioguanine (6-TGN). In inflammatory bowel disease (IBD), 6-TGN levels in the target range of 235–400 pmol/8 ×108 red blood cells (RBC) are associated with a high likelihood of response. Our objective was to evaluate whether drug escalation based on metabolite levels improves efficacy and maintains safety in patients with systemic lupus erythematosus (SLE). Methods. We conducted a 6-month open-label dose-escalation clinical study of patients with active SLE treated with azathioprine dosed by body weight and metabolite levels. The primary endpoint was ≥50% improvement in any one parameter of disease activity, or 50% decrease in glucocorticoid dose. Results. Of 50 patients enrolled in the study, 21 achieved clinical responses, 13 of whom had 6-TGN < 235 pmol/8 ×108 RBC. Ten patients had no clinical response at 6 months, yet achieved either therapeutic IBD 6-TGN levels (> 235, n = 4) or received maximum AZA dose ≥3.5 mg/kg (n = 6). In 19 patients the drug was discontinued prematurely due to side effects or SLE activity. For those patients in whom either liver function test or white blood cell count abnormalities were encountered, metabolites guided attribution to drug or disease activity. Conclusion. Clinical responses in SLE can occur at levels of 6-TGN lower than the target range established for IBD. During followup, measurements of AZA metabolites may provide a rational approach to safety.