Can Methotrexate Cause Anemia? Explaining the Side Effect

Methotrexate can cause anemia, and it does so through a mechanism directly tied to how the drug works: by interfering with the folate-dependent pathways cells need to make DNA, it slows down the production of red blood cells alongside the rapidly dividing cells it is designed to target. The effect ranges from a subtle dip in hemoglobin that only shows up on routine bloodwork to, in rarer cases, severe bone marrow suppression that drops all blood cell lines at once. What makes this side effect tricky is that many people taking methotrexate already have a disease that causes anemia on its own, so sorting out which part of the problem comes from the drug and which part comes from the disease is not always straightforward.

How Methotrexate Disrupts Red Blood Cell Production

Methotrexate is a folate antagonist, meaning it blocks enzymes that cells need to use folate (a B vitamin) for building new DNA. Without adequate DNA synthesis, cells that divide rapidly are the first to suffer. That includes cancer cells, which is why methotrexate was originally developed for oncology, but it also includes the precursor cells in your bone marrow that mature into red blood cells, white blood cells, and platelets.

Inside cells, methotrexate is converted into compounds called polyglutamates that persist longer and inhibit multiple steps in folate metabolism. One key target is an enzyme involved in purine synthesis, which reduces the building blocks cells need to replicate their DNA. The end result is slowed DNA synthesis and a kind of cellular standstill in the bone marrow.

When the bone marrow cannot keep pace with the body’s demand for new red blood cells, hemoglobin levels fall. In milder cases this produces anemia alone. In more severe toxicity, the marrow’s output of white blood cells and platelets also drops, a condition called pancytopenia. Case reports describe patients developing pancytopenia with hemoglobin levels around 10.8 g/dL alongside low white cell counts and reduced platelets, with blood smear findings consistent with bone marrow suppression rather than other causes of anemia like hemolysis.

How Common Is This Side Effect

Estimates of how frequently methotrexate causes blood count abnormalities depend heavily on the population studied, the dose being used, and how anemia is defined. In one observational study of rheumatoid arthritis patients on long-term low-dose methotrexate, roughly 35% had moderate anemia (hemoglobin between 8 and 10.9 g/dL) and about 5% had severe anemia below 8 g/dL.

Those numbers look alarming, but they deserve some context. Rheumatoid arthritis itself commonly produces anemia through chronic inflammation, so in an observational study of RA patients, the anemia rate reflects both the drug’s effects and the disease’s effects layered on top of each other.

A meta-analysis of randomized controlled trials in rheumatic disease patients put the overall incidence of hematologic abnormalities from low-dose methotrexate at the lower end of the historical range, roughly 3% to 10% when combining anemia, low white counts, and low platelets. The authors noted that these figures were consistent with earlier estimates from the era before folic acid supplementation became routine.

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For children with juvenile idiopathic arthritis on methotrexate, one study found anemia in about 12% of patients, with lower white cell counts and platelet drops each occurring in about 6.5%.

⁵ Other reviews of pediatric methotrexate use have described hematological abnormalities as uncommon, suggesting that most children tolerate the drug without significant blood count problems.⁶

Who Is at Higher Risk

Not everyone on methotrexate faces the same odds of developing anemia. Several factors can tip the balance toward toxicity, sometimes dramatically.

Kidney function matters a great deal because methotrexate is primarily cleared through the kidneys. When the kidneys are sluggish, the drug lingers in the body longer and reaches higher concentrations in the blood. In a study of high-dose methotrexate in cancer patients, those who developed toxicity had significantly higher rates of baseline renal impairment compared to those who did not, and they experienced more severe anemia as a result.

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Age is another contributor. Older adults tend to have reduced kidney function even when their lab values look borderline acceptable, and they are more likely to be taking other medications that compete with methotrexate for elimination. Clinicians have noted that advanced age, poor nutritional status with low blood protein levels, and hidden liver disease can all raise the risk of toxicity, sometimes in the absence of any other obvious red flag.

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Genetics play a role too. A well-studied variant in the MTHFR gene (the C677T polymorphism) compromises the body’s ability to process folate. People who carry this variant may be more susceptible to methotrexate toxicity because the drug’s folate-blocking action hits harder when folate metabolism is already impaired.

⁹ Beyond MTHFR, polymorphisms in genes governing methotrexate transport and metabolism have been studied for their influence on both the drug’s effectiveness and its side effects, though routine genetic testing before starting methotrexate is not yet standard practice.¹⁰

Pre-existing nutritional deficiencies deserve special attention. In one case, a patient with undiagnosed pernicious anemia (a condition where the body cannot absorb vitamin B12) developed severe pancytopenia and mucositis on a low dose of methotrexate that would ordinarily be well-tolerated. The pernicious anemia had already compromised folate-related pathways, so adding a folate antagonist on top pushed the bone marrow past its limit.

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Drug interactions round out the picture. Medications that impair kidney function or compete with methotrexate for elimination through the same transporters can slow the drug’s clearance and increase the risk of toxicity. Even low-dose methotrexate, used for conditions like ectopic pregnancy, has triggered severe hematologic toxicity when paired with drugs that inhibit the kidney transporters responsible for flushing methotrexate out of the body.⁹

Does Folic Acid Supplementation Prevent the Anemia

Because methotrexate works by blocking folate, it seems intuitive that supplementing with folic acid should protect the bone marrow. In practice, folic acid supplementation is standard care for anyone on methotrexate for a rheumatic disease, and there is good evidence that it reduces some side effects like mouth sores, nausea, and liver enzyme elevations. But the evidence for whether it specifically prevents blood count drops is surprisingly thin.

A Cochrane systematic review of folic acid and folinic acid supplementation in methotrexate-treated rheumatoid arthritis patients concluded that it was not possible to draw meaningful conclusions about the effect on hematologic side effects due to small numbers of events and inconsistent reporting across trials.

¹² A separate meta-analysis echoed this gap, noting that while low red blood cell folate levels are associated with higher rates of cytopenias in methotrexate users, three meta-analyses looking for a direct protective effect of folic acid supplementation on blood counts all came up empty, largely because of inadequate sample sizes and inconsistent reporting.⁴

This does not mean folic acid supplementation is useless for protecting blood counts. The absence of evidence is not evidence of absence, and the likely explanation is that methotrexate-related cytopenias are uncommon enough that studies were never powered to detect a difference. The practical takeaway is that you should absolutely take your folic acid as prescribed, since it clearly helps with other methotrexate side effects, but do not assume it makes blood monitoring unnecessary.

Telling Drug-Induced Anemia Apart From Disease-Related Anemia

This is one of the genuinely confusing aspects of methotrexate use in rheumatic diseases. Conditions like rheumatoid arthritis frequently cause anemia of chronic disease, where ongoing inflammation signals the body to sequester iron and dampen red blood cell production. So if you are on methotrexate for RA and your hemoglobin is low, the anemia could be from the drug, from the disease, or from both acting together.

One clue is the size of your red blood cells. Methotrexate-related anemia tends to produce larger-than-normal red blood cells, a finding called macrocytosis, because the folate disruption specifically impairs DNA replication during cell division. Anemia of chronic disease, by contrast, typically produces normal-sized or slightly small red blood cells. A routine blood test reporting a rising mean cell volume while hemoglobin is falling is a flag that methotrexate’s folate-blocking effect, rather than inflammation alone, is likely contributing.¹

A pooled analysis of large clinical trials in RA patients found that patients treated with infliximab (a biologic that suppresses inflammation) plus methotrexate actually saw greater improvements in hemoglobin than patients on methotrexate plus placebo. Among patients who were anemic at the start, those getting infliximab plus methotrexate had an average hemoglobin increase of 0.74 g/dL by week 22, compared to 0.30 g/dL for those on methotrexate with placebo. About 43% of the infliximab group achieved normal hemoglobin levels, versus 28% in the placebo group.

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The implication is revealing: in many RA patients, the anemia is driven more by the underlying inflammation than by methotrexate itself. When a biologic dampens that inflammation effectively, hemoglobin goes up even though methotrexate is still in the picture. This doesn’t mean methotrexate never causes the anemia, but it does mean that low hemoglobin in an RA patient on methotrexate isn’t automatically the drug’s fault.

When Anemia Appears and How Quickly It Can Develop

The timeline varies widely. In a large randomized trial of low-dose methotrexate, pancytopenia (which includes anemia along with drops in white cells and platelets) developed as early as four months after starting the drug and as late as three and a half years into treatment.

¹⁴ This unpredictability is exactly why regular blood monitoring is standard for anyone on methotrexate, regardless of how long they have been taking it or how stable their counts have been.

For people on high-dose methotrexate for cancer treatment, the risk is more concentrated around each infusion cycle. Methotrexate levels in the blood are tracked in real time, and toxicity can emerge rapidly if the drug isn’t cleared on schedule. The situation is different enough from low-dose use for autoimmune diseases that the two contexts are almost separate side-effect profiles. In the oncology setting, patients who received higher methotrexate doses experienced significantly more severe anemia than those given lower doses within the same treatment protocol.

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Managing Severe Cases

Mild anemia on methotrexate usually prompts a dose reduction, a temporary hold on the drug, or both. Your doctor will likely recheck your blood counts in a few weeks to see whether the hemoglobin recovers. If it does, methotrexate can sometimes be restarted at a lower dose with closer monitoring.

More serious bone marrow suppression requires a faster response. Leucovorin, a form of active folate, is the standard rescue agent. It bypasses the enzymatic block that methotrexate creates, giving the bone marrow the folate it needs to resume normal cell production. In high-dose methotrexate protocols used in oncology, leucovorin rescue is built into the treatment plan from the start, administered on a set schedule after each infusion.

When high-dose methotrexate causes kidney injury and the drug isn’t clearing from the body as expected, an enzyme called glucarpidase can be used to break methotrexate down directly in the bloodstream. Glucarpidase is approved for situations where methotrexate levels remain dangerously elevated in the setting of kidney dysfunction, and expert consensus guidelines recommend it when specific blood concentration thresholds are exceeded at defined time points after infusion.

¹⁵ European consensus recommendations emphasize that aggressive hydration and urine alkalinization before and during high-dose methotrexate treatment are critical for preventing delayed drug clearance in the first place, with leucovorin and glucarpidase reserved for when these preventive measures are not enough.¹⁶

What Routine Monitoring Looks Like

If you are on methotrexate, you will get regular blood draws. Most guidelines call for a complete blood count before starting the drug, at frequent intervals during the first few months (often every two to four weeks), and then at longer intervals once your counts have proven stable, typically every one to three months. Kidney and liver function tests are checked on the same schedule.

The specific red flags to discuss with your doctor include new fatigue or shortness of breath that was not there before, easy bruising or unusual bleeding (which could signal low platelets rather than anemia specifically), frequent infections (low white cells), and mouth sores that develop between doses. Mouth sores, while a separate side effect, sometimes appear alongside or even slightly before bone marrow suppression, serving as an early warning sign that folate depletion is becoming clinically significant.

If your blood counts do start to drift, the clinical response is usually proportional. A modest hemoglobin drop might just prompt closer monitoring. A more significant drop, especially with simultaneous declines in white cells or platelets, will likely lead to holding methotrexate until counts recover. The drug is typically reintroduced at a lower dose if the anemia resolves and the underlying condition still requires treatment. In rare cases where severe bone marrow suppression occurs, methotrexate may be permanently discontinued in favor of a different medication.

Macrocytosis Without Anemia

Before your hemoglobin actually falls, you may see an increase in mean cell volume on your blood work, meaning your red blood cells are getting bigger even though there are still enough of them. This macrocytosis is a direct fingerprint of folate disruption: when DNA synthesis lags behind, developing red blood cells keep growing without dividing on schedule, so they end up larger than normal.

Macrocytosis on methotrexate is common and by itself is not necessarily a reason to stop the drug. But it does indicate that the medication is having a measurable effect on your bone marrow’s folate pathways, and it may warrant a closer look at your folate status and more frequent blood count checks. Research has found that patients who develop macrocytosis on methotrexate are more likely to need escalation to biologic therapies, possibly because the macrocytosis signals higher drug accumulation or greater sensitivity to the folate-blocking mechanism.¹ Think of it as a yellow light: not an emergency, but a reason to pay attention and talk to your prescriber about whether any adjustments make sense.

1
Journal of Rheumatic Diseases. An erythrocyte macrocytosis by methotrexate is associated with early initiation of biologic or targeted synthetic agents in patients with rheumatoid arthritis – Section: DISCUSSION
2
PubMed Central. A Rare Case of Acute Methotrexate Toxicity Leading to Bone Marrow Suppression – Section: Abstract
3
PubMed Central. Hepatic and hematological adverse effects of long-term low-dose methotrexate therapy in rheumatoid arthritis: An observational study – Section: Results
4
Rheumatology. Cytopenias among patients with rheumatic diseases using methotrexate: a meta-analysis of randomized controlled clinical trials – Section: Discussion
5
Journal of Clinical Pediatrics. Factors Affecting Adverse Effects Of Methotrexate In Juvenile Idiopathic Arthritis – Section: Results
6
The Journal of Rheumatology. Monitoring Methotrexate Toxicity in Juvenile Idiopathic Arthritis – Section: Abstract
7
Journal of Oncology Pharmacy Practice. High-dose methotrexate in adult oncology patients: A case-control study assessing the risk association between drug interactions and methotrexate toxicity – Section: Results
8
Reumatología Clínica (English Edition). Severe Secondary Bone Marrow Aplasia Due to Methotrexate in a Patient With Late Onset Rheumatoid Arthritis – Section: Full Text
9
PubMed Central. Severe hematologic toxicity after low-dose methotrexate in ectopic pregnancy: role of MTHFR polymorphism and drug interaction – a case report and literature review – Section: Abstract
10
Egyptian Journal of Medical Human Genetics. Relationship between the efficacy and adverse effects of methotrexate and gene polymorphism – Section: Abstract
11
BMC Rheumatology. Potential contributors to low dose methotrexate toxicity in a patient with rheumatoid arthritis and pernicious anemia: case report – Section: Abstract
12
PubMed Central. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis – Section: Abstract
13
Seminars in Arthritis and Rheumatism. Treatment with infliximab plus methotrexate improves anemia in patients with rheumatoid arthritis independent of improvement in other clinical outcome measures-a pooled analysis from three large, multicenter, double-blind, randomized clinical trials – Section: RESULTS
14
ACR Open Rheumatology. Adverse Effects of Low‐Dose Methotrexate in a Randomized Double‐Blind Placebo‐Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial – Section: Results
15
PubMed Central. Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance
16
Journal of Cancer Research and Clinical Oncology. A European consensus recommendation on the management of delayed methotrexate elimination: supportive measures, leucovorin rescue and glucarpidase treatment – Section: Abstract