Does Azathioprine (Imuran) Increase RDW?
Azathioprine does not typically increase RDW; in fact, lower RDW values are associated with therapeutic azathioprine levels, and a low RDW is an independent predictor of achieving therapeutic drug concentrations.
Evidence from Clinical Studies
The relationship between azathioprine and RDW is counterintuitive but well-documented:
Low RDW predicts therapeutic efficacy: In patients with Crohn's disease treated with azathioprine, multivariate analysis demonstrated that low RDW (P=0.003) was an independent factor for achieving therapeutic 6-thioguanine nucleotide (6-TGN) levels in red blood cells 1.
RDW may increase in specific disease contexts: In systemic lupus erythematosus patients, azathioprine use was significantly associated with higher RDW values after adjustment for confounders, though this likely reflects the underlying disease activity and damage rather than a direct drug effect 2.
What Azathioprine Actually Does to Red Blood Cells
Instead of increasing RDW, azathioprine causes predictable changes in other red cell parameters:
Macrocytosis is the hallmark effect: Azathioprine consistently increases mean corpuscular volume (MCV), with this effect stabilizing after 3-6 months of therapy 3, 4.
MCV increase correlates with therapeutic levels: An MCV increase of at least 6 fL after 6 months of treatment reflects therapeutic 6-TGN levels (approximately 175 pmol/8×10⁸ RBCs) 3.
The mechanism involves uniform cell enlargement: Azathioprine causes macrocytosis in most treated patients, which represents a uniform increase in red cell size rather than increased variation in size (which would raise RDW) 4.
Clinical Monitoring Implications
The key hematologic parameters to monitor with azathioprine are:
Complete blood count with attention to: White blood cell count, neutrophil count, platelet count, and MCV—not RDW 5.
Monitoring frequency: Weekly for the first 4 weeks, then 1-3 monthly thereafter depending on stability 5.
Myelosuppression warning signs: Leucopenia occurs first, followed by thrombocytopenia; dose reduction is recommended if lymphocyte count falls below 0.5 × 10⁹/L, platelet count below 50 × 10⁹/L, or neutrophil count below 1.0 × 10⁹/L 5.
Important Caveats
RDW elevation in SLE patients on azathioprine likely reflects disease activity and cumulative organ damage rather than direct drug toxicity, as RDW correlates with disease activity scores and damage indices in this population 2.
The therapeutic window paradox: Lower baseline RDW actually predicts better achievement of therapeutic drug levels, suggesting that patients with more uniform red cell populations may metabolize azathioprine more effectively 1.