Can You Get a Flu Shot While on Methotrexate?

Getting a flu shot while taking methotrexate is not only safe but strongly recommended by rheumatology guidelines. The inactivated influenza vaccine poses no special risk to people on methotrexate, and annual vaccination reduces flu-related hospitalizations and deaths in this population. The more interesting question is whether the shot works as well when methotrexate is on board, and whether a brief pause in the drug around vaccination time could sharpen your immune response.

How Well the Flu Shot Works on Methotrexate

Research on this question is genuinely mixed, and that ambiguity is worth being honest about. Roughly half the studies looking at antibody levels after flu vaccination in methotrexate-treated patients find a reduced response compared to healthy controls, while the other half find no meaningful difference. When researchers pooled all the data and looked at individual flu strains one at a time, they found no clear effect of methotrexate on the immune response. But when they combined the response to all three strains in a single analysis, methotrexate did dampen the antibody response.

The reassuring news is that even in those studies showing a reduced response, most patients on methotrexate still developed antibody levels considered protective. And studies that tracked real-world outcomes rather than just antibody numbers found that flu vaccination in people with inflammatory diseases reduced the rate of flu infections, hospitalizations, and deaths.

¹ So the vaccine clearly does useful work, even if the antibody numbers on paper look a bit lower than they would without methotrexate.

What the Guidelines Actually Recommend

The 2022 American College of Rheumatology (ACR) vaccine guideline offers a specific, practical recommendation: hold methotrexate for two weeks after your flu shot, as long as your disease activity is stable enough to tolerate the break.² This is a conditional recommendation, meaning it applies to most people but acknowledges that some patients and their doctors will reasonably decide the flare risk outweighs the immune benefit. The key word is “after”: you take your flu shot on schedule, then skip your next one or two methotrexate doses.

This recommendation came largely from a landmark randomized trial published in 2018 that tested the idea head-on. The study enrolled patients with rheumatoid arthritis and split them into two groups: one continued methotrexate as usual, the other paused it for two weeks following the seasonal flu shot. The results were substantial. About 76% of patients who paused methotrexate achieved a satisfactory vaccine response, compared to roughly 55% of those who kept taking it. The hold group also showed higher antibody levels against all four flu strains in that season’s vaccine.³

Is One Week Off Enough?

Two weeks without methotrexate sounds manageable to many patients, but for some it is a long stretch. A follow-up trial tested whether skipping methotrexate for just one week after the flu shot could deliver similar benefits. The results were encouraging: about 69% of patients in the one-week group achieved a satisfactory vaccine response, compared to 75% in the two-week group, a difference that was not statistically meaningful. The proportion of patients who mounted a strong antibody response to at least one flu strain was virtually identical between the two groups, around 92% to 93%.⁴

This finding matters practically. If you are worried about flaring during a two-week break, a one-week pause may capture most of the immune benefit with less exposure to disease rebound. That said, the ACR guideline still references two weeks as the standard recommendation, and your rheumatologist may factor in your specific disease status when advising on duration.

The Flare Trade-Off

Pausing methotrexate is not free. The drug keeps inflammation in check, and taking a break can let your underlying disease reassert itself. A large trial called VROOM, which studied methotrexate pauses around COVID-19 booster vaccination rather than flu shots but is directly relevant to the underlying question, tracked disease flares closely. At four weeks, 53% of patients who suspended methotrexate reported at least one disease flare, compared to 33% in the group that continued their medication. At twelve weeks, flares remained more common in the pause group. By twenty-six weeks, however, the two groups had converged, with no meaningful difference in disease activity or control.⁵

Most of those flares were mild enough that patients managed them on their own. The proportion seeking medical help for a flare was similar in both groups throughout the study, hovering around 4% to 6% in the first four weeks and 13% on both sides by twelve weeks.⁵ So while flares are real and genuinely uncomfortable, they tend to be self-limiting and rarely send patients to the clinic.

A related set of trials from India, called MIVAC, looked at a middle-ground strategy for COVID-19 vaccines: holding methotrexate only after the second dose rather than after both doses. That approach produced a similar antibody response to holding it after both doses, without the added flare risk that came with two separate treatment interruptions.⁶ The principle here generalizes to flu vaccination: if you are getting a two-dose vaccine schedule for any reason, you may not need to pause methotrexate every single time.

Whether a High-Dose Flu Vaccine Helps

Another strategy for improving your flu shot response on methotrexate is to get a more potent version of the vaccine itself. High-dose influenza vaccines contain several times more antigen than the standard formulation, and they were originally developed for older adults whose immune systems respond sluggishly to regular flu shots. Researchers tested whether these high-dose vaccines could also benefit people with rheumatoid arthritis.

In a randomized trial comparing high-dose to standard-dose flu vaccines in RA patients, the high-dose group was roughly two to three times more likely to mount a strong antibody response, depending on the flu strain. For the H3N2 strain, the odds of seroconversion were about three times higher with the high-dose vaccine. For other strains, the advantage ranged from about double to triple. Local reactions like sore arms and systemic effects like mild fatigue were comparable between the two vaccine types, and neither formulation worsened RA disease activity.⁷

High-dose flu vaccines are widely available in many countries, particularly for adults 65 and older, but they are sometimes accessible to younger immunosuppressed patients by prescription or through pharmacy discussion. If you are on methotrexate and want to maximize your protection without pausing your medication, asking your doctor about a high-dose option is a reasonable conversation to have.

What Methotrexate Does to Your Immune Response

Methotrexate does not just generally weaken the immune system; it interferes with specific cell populations that are crucial for building vaccine-driven immunity. One study found that patients on methotrexate produced fewer vaccine-specific helper T cells after vaccination compared to patients not taking the drug. These helper T cells are the coordinators of the immune response. They tell B cells to ramp up antibody production, so when their numbers are lower, the downstream antibody response tends to suffer too. The researchers found a direct correlation between the reduced T cell numbers and lower antibody levels, but only in the methotrexate-treated group, suggesting that this T cell bottleneck is a key part of how the drug blunts vaccination.⁸

The B cell side of the equation is also affected. After vaccination, healthy people typically see a burst of memory B cells and plasmablasts, the short-lived antibody factories that produce the initial wave of protection. In a study tracking these cells after pneumococcal vaccination, both healthy controls and patients on no immunosuppressive drugs showed clear expansions of memory B cells and plasmablasts. Patients on methotrexate showed no such expansion. Methotrexate also reduced circulating levels of a particular subset of helper T cells involved in mucosal defense.⁹

This helps explain why pausing methotrexate around vaccination time works. If the drug is out of the system when the immune cells encounter the vaccine, those T cells and B cells can expand and do their jobs more freely during the critical window when immune memory is being formed. Once you resume methotrexate a week or two later, the memory cells are already established.

Flu Shots for Children on Methotrexate

Kids with juvenile idiopathic arthritis and other inflammatory conditions sometimes take methotrexate, and their parents understandably worry about whether flu shots will work. A study of children on methotrexate, some also taking biologic drugs, found that post-vaccination seroprotection rates were comparable to those of healthy children. Seroconversion, the shift from unprotected to protected antibody levels, was somewhat less likely in the immunosuppressed group, but the difference was not statistically significant. No serious adverse events were reported.¹⁰

The bottom-line message for parents mirrors the adult picture: children on methotrexate can and should receive the inactivated flu vaccine. Their protection rates look reassuringly similar to those of children not taking immunosuppressive drugs. The question of whether to pause methotrexate around vaccination in children is less well studied than in adults, so pediatric rheumatologists tend to weigh each child’s disease stability individually.

Live Vaccines and the One Hard Rule

Everything discussed so far applies to inactivated flu vaccines, which are the injected shots made from killed virus or virus fragments. There is one absolute restriction that deserves emphasis: live attenuated influenza vaccines, delivered as a nasal spray, are contraindicated for anyone on methotrexate. Because methotrexate suppresses immune function, a live vaccine could potentially cause the very infection it is meant to prevent. This is not a theoretical concern but a firm clinical rule across every major guideline. If you take methotrexate in any form and for any condition, always get the flu shot as an injection, never as a nasal spray.

This rule extends beyond flu vaccines. Live vaccines for measles, varicella, yellow fever, and certain other diseases are generally off-limits while you are on methotrexate. If you need one of these vaccines, your rheumatologist would typically want you off methotrexate for a defined washout period beforehand. For the seasonal flu shot, this concern simply does not arise as long as you receive the standard injectable version.

When Methotrexate Is Combined With Other Drugs

Many people with inflammatory diseases take methotrexate alongside another immunosuppressive or biologic medication, a combination that raises a natural follow-up question: does stacking drugs make the flu shot even less effective? The evidence suggests that adding a biologic agent, particularly a TNF inhibitor, to methotrexate does not dramatically further reduce flu vaccine responses beyond what methotrexate alone does. Several studies that included patients on combination therapy found vaccine responses in a broadly similar range to those on methotrexate monotherapy. However, certain other classes of immunosuppressives, particularly rituximab, which directly depletes B cells, can profoundly impair the vaccine response in a way that methotrexate alone does not.

If you are on methotrexate plus another drug, the general advice still holds: get the flu shot annually, discuss pausing methotrexate with your doctor, and ask about high-dose formulations if available. The combination of drugs does not change whether you should get vaccinated; it may affect how aggressively you and your doctor pursue strategies to optimize your response. For patients on rituximab in particular, the timing of vaccination relative to the last infusion matters more than the methotrexate question, and that is a separate conversation worth having with your care team.

Practical Timing Tips

If you and your rheumatologist decide to pause methotrexate around your flu shot, the logistics matter. The recommendation is to hold methotrexate after vaccination, not before. You take your flu shot on whatever day works, ideally early in flu season so your immune system has time to build antibodies before peak transmission, and then skip your next scheduled methotrexate dose or doses to cover a one- or two-week window. Some patients find it easiest to get their flu shot the day after their usual methotrexate day, which naturally creates the longest gap before the next dose.

Planning this around a period of relatively low disease activity makes the brief pause more tolerable. If you are in the middle of a flare or have recently adjusted your treatment regimen, your doctor may advise against holding methotrexate and instead recommend getting the standard flu shot without any medication changes. A flu shot on methotrexate still provides meaningful protection, and skipping vaccination entirely because the timing is not perfect is the worst option of all. People on immunosuppressive drugs are at higher risk of flu complications, which is precisely why vaccination matters most for this group.