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Use of Pharmacogenetics, Enzymatic Phenotyping, and Metabolite Monitoring to Guide Treatment with Azathioprine in Patients with Systemic Lupus Erythematosus

ANCA D. ASKANASE, DANIEL J. WALLACE, MICHAEL H. WEISMAN, CHUNG-E TSENG, LANA BERNSTEIN, H. MICHAEL BELMONT, ERNEST SEIDMAN, MARIKO ISHIMORI, PETER M. IZMIRLY, and JILL P. BUYON

ABSTRACT.

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. (J Rheumatol First Release Dec 1 2008; doi:10.3899/jrheum.070968)

Key Indexing Terms:

SYSTEMIC LUPUS ERYTHEMATOSUS
AZATHIOPRINE
METABOLITE
6-THIOGUANINE
MONITORING
TREATMENT

From the Departments of Medicine and Rheumatology, Hospital for Joint Diseases, New York University School of Medicine, New York, New York, USA; Cedars-Sinai Medical Center UCLA, Los Angeles, California, USA; and Research Institute, McGill University Health Center, Montreal, Quebec, Canada.

Supported in part by an Investigator Initiated Grant from Prometheus Laboratories, San Diego, California. Dr. Seidman is supported by a Canada Research Chair in Immune Mediated Disorders.

A.D. Askanase, MD, MPH; C. Tseng, MD; L. Bernstein, MD; P. Izmirly, MD; H.M. Belmont, MD; J.P. Buyon, MD, Departments of Medicine and Rheumatology, Hospital for Joint Diseases, New York University School of Medicine; D.J. Wallace, MD; M.H. Weisman, MD; M. Ishimori, MD, Cedars-Sinai Medical Center UCLA; E. Seidman, MD, Research Institute, McGill University Health Center.

Address reprint requests to Dr. A.D. Askanase, Department of Medicine, Division of Rheumatology, New York University School of Medicine, 560 First Avenue, TCH-407, New York, NY 10016. E-mail: ardinu@aol.com

Accepted for publication August 5, 2008.