Is it normal for a patient with rheumatoid arthritis (RA) on methotrexate (MTX) to have elevated white blood cell (WBC) and neutrophil counts during disease flares?

Elevated WBC and Neutrophils in RA Flares on Methotrexate

Elevated WBC and neutrophils during RA flares are expected findings related to disease activity itself, not methotrexate therapy, but require careful interpretation to distinguish from infection or drug toxicity.

Understanding the Clinical Context

Disease-Related Leukocytosis

• Adult-onset Still's disease (AOSD), a systemic inflammatory condition that can mimic RA, characteristically presents with marked leukocytosis (often >15,000 cells/L, with 37% of patients exceeding 20,000 cells/L) due to striking neutrophilia from bone marrow granulocyte hyperplasia 1
• Active RA itself causes neutrophil activation with increased reactive oxygen species production and upregulation of surface activation markers (CD177, CD11b, CD32, CD16) 2, 3
• Circulating neutrophils in RA patients show significantly higher activation status compared to healthy controls, even when disease is controlled 3

Methotrexate's Effect on White Blood Cells

• Methotrexate typically causes myelosuppression, not leukocytosis—the expected toxicity is LOW WBC counts (<3,000 cells/L) and LOW neutrophils (<1,000 cells/L), which requires immediate dose reduction or discontinuation 1
• MTX treatment actually reduces neutrophil ROS production by 55% and decreases CD177 expression, indicating reduced neutrophil activation 2
• In patients on stable MTX therapy, only 7.2% develop WBC abnormalities and 6.7% develop neutrophil abnormalities, with most abnormalities being cytopenias, not elevations 4

Critical Differential Diagnosis

When Elevated WBC/Neutrophils Are Concerning

You must actively exclude:

• Infection: Patients on MTX with fever, sore throat, or other infectious symptoms require immediate evaluation, as MTX-induced immunosuppression increases infection risk 1
• Systemic inflammatory conditions: Consider AOSD or other systemic rheumatic diseases if leukocytosis is marked (>15,000 cells/L) with high fevers 1
• Medication effects: Review all concurrent medications, particularly corticosteroids which commonly cause leukocytosis 5

Expected Monitoring Parameters on Methotrexate

• The American College of Rheumatology recommends CBC with differential every 3-4 months for stable patients, with more frequent monitoring (1-2 months) after initiation or dose changes 6
• Action thresholds for LOW counts (toxicity): withhold/decrease MTX for WBC <3,000 cells/L or neutrophils <1,000 cells/L 1
• Avoid testing within 2 days after the weekly MTX dose, as transient abnormalities may occur; wait at least 4 days for accurate interpretation 6

Clinical Algorithm for Elevated WBC/Neutrophils

If WBC/neutrophils are elevated during an RA flare:

1. Assess for infection first: Check for fever, localizing symptoms, and consider inflammatory markers (ESR, CRP) 1
2. Evaluate disease activity: Use DAS-28 or similar measures to confirm active RA flare 3
3. Review medication list: Confirm patient is not on corticosteroids or other medications causing leukocytosis 5
4. Continue MTX if counts are elevated: Leukocytosis is not a contraindication to continuing MTX and likely reflects disease activity, not drug effect 2, 3
5. Optimize RA treatment: Address inadequate disease control rather than stopping MTX for elevated counts 1

Key Pitfalls to Avoid

• Do not stop MTX for elevated WBC/neutrophils alone—this represents disease activity, not drug toxicity 2, 3
• Do not confuse disease-related leukocytosis with drug toxicity—MTX causes cytopenias, not elevations 1
• Ensure folic acid supplementation (1-5 mg daily except on MTX dosing day) to reduce hematologic toxicity 6, 7
• Be vigilant for the opposite problem: severe pancytopenia from MTX toxicity can occur rapidly, particularly in elderly patients, those with renal impairment, or with concurrent NSAID use 8, 9