Yes, both methotrexate and Plaquenil (hydroxychloroquine) can cause lymphopenia, but methotrexate is the more likely culprit.
Methotrexate and Lymphopenia
Methotrexate is well-documented to cause lymphopenia and has a cell-type specific effect on lymphocytes. The FDA label explicitly lists leukopenia, neutropenia, and lymphopenia as known hematologic adverse reactions 1. More specifically, methotrexate preferentially reduces B-lymphocytes and T-lymphocytes while sparing natural killer cells 2.
The mechanism is dose-dependent suppression of hematopoiesis, which can manifest as:
- Anemia
- Aplastic anemia
- Pancytopenia
- Leukopenia
- Neutropenia
- Thrombocytopenia 1
In controlled clinical trials for rheumatoid arthritis, leukopenia (WBC <3000/mm³) occurred in 2 out of 128 patients, and pancytopenia occurred in 2 patients 1. The FDA label emphasizes that methotrexate should be stopped immediately if there is a significant drop in blood counts 1.
Hydroxychloroquine and Lymphopenia
Hydroxychloroquine can also cause lymphopenia, though this appears less common and less well-characterized than with methotrexate. The FDA label lists "leukopenia" under blood and lymphatic system disorders as a post-approval adverse reaction 3. However, a 2024 retrospective study of 289 patients found that severe laboratory abnormalities (including lymphopenia) while taking hydroxychloroquine were rare, and when they occurred, 70% were likely due to disease progression or other medications rather than hydroxychloroquine itself 4.
Clinical Approach in Your Patient
For a 66-year-old woman with an otherwise normal CBC except for low lymphocytes:
First, determine the degree of lymphopenia:
- Mild: 1000-1500 cells/μL
- Moderate: 500-1000 cells/μL
- Severe: <500 cells/μL
If on methotrexate: This is the more likely cause. Consider:
- Immediate repeat CBC to confirm the finding
- If persistent and significant, hold methotrexate temporarily
- Rule out infection (patients are at risk for opportunistic infections when CD4+ counts drop critically low 5)
- Consider folate supplementation, which may reduce certain toxicities in chronic use 1
- Evaluate renal function, as elderly patients have increased risk of bone marrow suppression 1
If on hydroxychloroquine alone: Less likely to be the primary cause. Investigate:
- Disease activity (underlying rheumatologic condition may cause lymphopenia)
- Other medications
- Other causes of lymphopenia (viral infections, autoimmune conditions, nutritional deficiencies)
If on both medications: Methotrexate is still the more likely culprit, but the combination may have additive effects on bone marrow suppression 6.
Key Monitoring Recommendations
For methotrexate: CBC monitoring is essential and should be performed regularly, especially in elderly patients who have increased risk of bone marrow suppression, thrombocytopenia, and other hematologic toxicity 1
For hydroxychloroquine: CBC and CMP monitoring should be at the prescribing physician's discretion, as severe abnormalities are rare 4
The critical threshold is CD4+ lymphocyte counts—when critically low (similar to HIV infection), patients become predisposed to opportunistic infections regardless of the cause 5. If lymphopenia is severe (<500 cells/μL), consider lymphocyte subset analysis to assess CD4+ counts specifically.