PT  - JOURNAL ARTICLE
AU  - ANCA D. ASKANASE
AU  - DANIEL J. WALLACE
AU  - MICHAEL H. WEISMAN
AU  - CHUNG-E TSENG
AU  - LANA BERNSTEIN
AU  - H. MICHAEL BELMONT
AU  - ERNEST SEIDMAN
AU  - MARIKO ISHIMORI
AU  - PETER M. IZMIRLY
AU  - JILL P. BUYON
TI  - Use of Pharmacogenetics, Enzymatic Phenotyping, and Metabolite Monitoring to Guide Treatment with Azathioprine in Patients with Systemic Lupus Erythematosus
AID  - 10.3899/jrheum.070968
DP  - 2009 Jan 01
TA  - The Journal of Rheumatology
PG  - 89--95
VI  - 36
IP  - 1
4099  - http://www.jrheum.org/content/36/1/89.short
4100  - http://www.jrheum.org/content/36/1/89.full
SO  - J Rheumatol2009 Jan 01; 36
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.