Does Methotrexate Lower Your Immune System?

Methotrexate does alter how your immune system functions, but at the low doses prescribed for conditions like rheumatoid arthritis or psoriasis, it works more as an immune modulator than a blanket suppressor. Most people on low-dose methotrexate do not show signs of overt immunosuppression, though the drug does blunt certain immune responses enough to modestly raise infection risk and weaken your response to vaccines. The real picture is more nuanced than a simple yes or no, and the details matter for practical decisions like when to get vaccinated or what to watch for.

How Methotrexate Actually Works on Your Immune System

Methotrexate was originally developed as a cancer drug at doses far higher than those used for autoimmune conditions. At the low doses used in rheumatology (typically 7.5 to 25 mg once a week), it does not work by wiping out immune cells the way chemotherapy does. Instead, it operates through several gentler mechanisms that collectively dial down overactive inflammation.

One of the most well-studied mechanisms is adenosine release. Methotrexate causes levels of a molecule called adenosine to rise at inflamed sites in the body. Adenosine acts as a natural brake on inflammation, reducing the accumulation of white blood cells where they are causing damage. In laboratory models, blocking adenosine’s receptor completely reversed methotrexate’s anti-inflammatory effect, confirming that this pathway is central to how the drug works at low doses.¹ Methotrexate also interferes with folate metabolism and regulates several inflammatory signaling pathways.²

The distinction matters because true immunosuppressants (like the high-dose chemotherapy versions of methotrexate or drugs like cyclophosphamide) destroy or severely deplete immune cells. Low-dose methotrexate does something subtler: it calms overactive immune activity without gutting your defenses. That said, “calming” the immune system and “lowering” it are not entirely separate things, and the downstream effects on your ability to fight infections and respond to vaccines are real.

What Happens to Your Immune Cells

Even at low doses, methotrexate has measurable effects on several types of immune cells. Research on T cells found that methotrexate substantially inhibits the proliferation of activated T cells without blocking their initial activation. In other words, T cells can still wake up and recognize a threat, but they struggle to multiply in the numbers needed for a robust response.³ This is a key difference from other immune-suppressing drugs: methotrexate doesn’t shut off the alarm, it limits how many responders show up.

B cells, the immune cells responsible for producing antibodies, are also affected. In patients with juvenile idiopathic arthritis, methotrexate was found to reduce a specific subset of young B cells (called transitional B cells) and lower overall antibody levels in the blood. This was described as an unexpected and previously unknown direct effect of low-dose methotrexate on B cells.⁴ Separately, when patients on methotrexate received a pneumococcal vaccine, their memory B cells and plasmablasts (the cells that crank out antibodies after vaccination) failed to expand the way they did in patients not on the drug.⁵

Actual drops in blood cell counts are possible but uncommon. A meta-analysis of randomized trials in patients with rheumatic diseases found that low white blood cell counts occurred in roughly 1% of patients, and low neutrophil counts in under 2%. Most of the neutrophil drops were mild.⁶ In a large placebo-controlled cardiovascular trial, simultaneous drops in two or more blood cell lines occurred in about 4% of participants on low-dose methotrexate, and full pancytopenia (a drop in all major cell types) was rare at around half a percent.⁷ These numbers are low, but they’re the reason your doctor orders regular blood tests while you’re on the drug.

How Much Does Infection Risk Actually Increase?

This is probably the question that worries people most, and the answer is reassuring but not zero. A systematic review and meta-analysis that pooled data from controlled trials found that methotrexate was associated with about a 25% increase in the relative risk of infection in people with rheumatoid arthritis. When the researchers looked across all inflammatory diseases studied (not just RA), there was no statistically significant increase in total infections or serious infections.⁸ To put that in perspective, the overall risk difference is small in absolute terms. Most patients taking methotrexate don’t get more infections than they would otherwise. The infections that do occur tend to be common respiratory and skin infections rather than exotic ones.

Opportunistic infections, the unusual infections that typically appear only when the immune system is severely compromised, are rare but documented. A review identified 25 published cases, with a type of pneumonia caused by Pneumocystis being the most frequent.⁹ In a large registry study, the most common opportunistic infection in patients on methotrexate was shingles (caused by varicella zoster virus reactivation), followed at a distant second by Pneumocystis.¹⁰ Interestingly, these infections can occur even when white blood cell counts are completely normal, suggesting that methotrexate’s immune effects go beyond simple cell depletion.

When the Risk Goes Up

Several factors can push methotrexate’s immune effects from modest to concerning. Two of the biggest are kidney function and concurrent medications.

Methotrexate is cleared from the body primarily through the kidneys. When kidney function is reduced, the drug accumulates to higher-than-intended levels, amplifying both its therapeutic effects and its side effects. A study of older adults with chronic kidney disease found that those starting methotrexate had roughly double the rate of serious adverse events compared to those starting hydroxychloroquine, and the risk climbed progressively as kidney function declined.¹¹ This is why kidney function tests are checked before starting the drug and monitored periodically.

Adding corticosteroids (like prednisone) on top of methotrexate meaningfully increases infection risk. In a cohort of nearly 3,000 RA patients, the incidence of bacterial infections climbed significantly when higher doses of methotrexate were combined with glucocorticoids at 5 mg or more daily.¹² Similarly, combining methotrexate with biologic drugs like TNF inhibitors raises the risk of serious infections compared to either drug alone.¹³ These combination regimens are common in rheumatology because they often control disease better than one drug alone, but they do come with a step up in immune vulnerability that you and your doctor should weigh.

Age also plays a role. In elderly patients with RA, the pattern actually shifted in one study: compared to newer targeted therapies, methotrexate was associated with somewhat higher hospitalized infection rates in younger patients but lower rates in the oldest group.¹⁴ The relationship between age, methotrexate, and infection isn’t straightforward, and it depends heavily on what the alternative treatment would be.

Vaccines and Methotrexate

This is where methotrexate’s immune effects have the clearest practical consequences. The drug blunts your body’s ability to build a strong antibody response to vaccines. In a pneumococcal vaccination study, only about 10% of RA patients on methotrexate achieved positive antibody responses for both tested strains, compared to 40% of RA patients not on any disease-modifying drug.¹⁵ Research on COVID-19 vaccination showed that methotrexate reduced both antibody levels and the generation of virus-specific T cells needed for durable immunity.¹⁶

The good news is that a simple strategy can help. Temporarily pausing methotrexate around the time of vaccination significantly improves immune response. In a randomized trial of influenza vaccination, patients who held methotrexate for two weeks after their shot achieved a satisfactory vaccine response about 76% of the time, compared to roughly 55% in those who continued the drug. Disease activity did not worsen during the brief pause.¹⁷ A similar approach with COVID-19 vaccination showed that patients who paused methotrexate around at least one dose had notably higher neutralizing antibody levels, especially those over 60.¹⁸

Age amplifies the problem. In patients over 70, methotrexate use was associated with a clear drop in maximum antibody response to COVID-19 vaccination (about 54% reached peak response, versus 77% of those not on methotrexate). In patients under 70, the difference was not statistically significant.¹⁹ If you’re older and on methotrexate, discussing a temporary hold around vaccination time with your rheumatologist is especially worthwhile. The hold that matters most appears to be after the vaccine rather than before, with a critical window of about 10 days post-vaccination.

Surgery and the Counterintuitive Evidence

If methotrexate suppresses the immune system, shouldn’t you stop it before surgery to avoid wound infections? This seems logical, but the evidence says the opposite. In a randomized trial of 388 patients undergoing elective orthopedic surgery, those who continued methotrexate had a surgical complication or infection rate of 2%, while those who stopped it saw a rate of 15%.²⁰ Stopping methotrexate allowed the underlying inflammatory disease to flare, and the resulting inflammation likely impeded wound healing more than any mild immune suppression from the drug itself. Current expert consensus recommends continuing methotrexate through surgery, including on the day of the procedure.²¹

This is one of those areas where patients and even some surgeons operate on intuition rather than data. The instinct to stop anything that touches the immune system before an operation is understandable, but the controlled evidence consistently shows that methotrexate continuation is the safer choice for elective procedures.

How Quickly the Immune System Rebounds

One feature of methotrexate that distinguishes it from many other immune-modifying drugs is how quickly its effects reverse. Activated immune cells accumulate the active form of methotrexate (called methotrexate polyglutamates) rapidly, with levels peaking at about 24 hours. After the drug is withdrawn, these metabolites clear from cells almost completely within 48 hours.²² This rapid on-off dynamic is exactly why a short two-week pause around vaccination works so well: the immune system bounces back fast enough to mount a vaccine response, and the brief interruption usually isn’t long enough to trigger a disease flare.

In more dramatic scenarios, such as the rare development of methotrexate-associated lymphoproliferative disorders (abnormal lymph tissue growths that can occur during treatment), stopping methotrexate often leads to regression of the growths without chemotherapy. Lymphocyte recovery begins within two weeks of stopping the drug, and in cases where tumors regressed, this early lymphocyte recovery was a strong predictor of a good outcome.²³

The Role of Folic Acid

Because methotrexate works partly by interfering with folate metabolism, most rheumatologists prescribe folic acid supplements alongside it. Folic acid reduces common side effects like nausea, mouth ulcers, and liver enzyme elevations, and it also appears to protect against bone marrow toxicity, the mechanism by which methotrexate can lower blood cell counts.²⁴ A Cochrane review confirmed that folic acid supplementation does not reduce methotrexate’s effectiveness against the underlying disease.²⁵ Earlier trial data reinforced this: patients given folic acid had significantly lower toxicity scores with no change in how well methotrexate controlled their arthritis.²⁶

If you’re on methotrexate and not taking folic acid, that’s worth raising with your prescriber. It’s one of the simplest ways to reduce side effects and lower the chance of the blood count changes that represent the drug’s most direct form of immune suppression.

Methotrexate Compared to Other Immune-Active Drugs

Patients often hear that methotrexate “suppresses the immune system” and assume it carries risks comparable to drugs like cyclophosphamide or azathioprine. A systematic review informing European treatment guidelines found that both cyclophosphamide and azathioprine carried increased risks of infection and cancer, whereas methotrexate’s risk profile was considerably milder.²⁷ In a head-to-head comparison with hydroxychloroquine (a drug generally considered to have minimal immune effects), patients on methotrexate had a roughly 26% higher risk of contracting COVID-19 in one retrospective cohort, though the study population had a specific autoimmune condition and the comparison has limits.²⁸

The overall position of methotrexate on the immune-suppression spectrum is somewhere in the mild-to-moderate range. It’s less disruptive than true immunosuppressants and biologics, but it’s not immunologically invisible either. For many patients, it sits in a sweet spot where it controls disease effectively without dramatically increasing vulnerability to infection.

Diet, Monitoring, and What Patients Worry About

Because methotrexate is a folate antagonist, dietary folate intake can theoretically influence how the drug behaves. Excessive or very low dietary folic acid may alter methotrexate’s metabolism in ways that could lead to unexpected side effects.²⁹ Animal research has also suggested that a high-fat, high-sugar diet may worsen methotrexate’s intestinal toxicity by changing the gut environment and reducing how the drug is cleared.³⁰ While human data on this front are limited, it’s a reminder that how your body handles the drug isn’t determined by the drug alone.

Routine blood monitoring, typically including a complete blood count and liver enzymes, is a standard part of methotrexate therapy. In practice, most patients get these tests roughly twice in the first three months and then periodically thereafter.³¹ These tests are the safety net that catches the rare but real drops in blood counts before they become dangerous.

Patient surveys reveal that worry about immune suppression is one of the main concerns people have about methotrexate, and that using the internet as a primary source of medical information is associated with more negative beliefs about the drug’s safety.³² Some patients describe real tension between their fears about the drug and their experiences of it actually working, a dissonance that can lead to skipping doses or stopping treatment altogether.³³ The evidence suggests that for most people on standard low doses, the immune effects are manageable and the drug’s benefits for disease control substantially outweigh the modest increase in infection risk. But that calculus shifts with age, kidney function, and what other medications are on board, which is why an honest conversation with your prescriber about your specific risk profile matters more than a blanket answer.