Skipping Methotrexate When Sick: When Is It Necessary?

Skipping a weekly methotrexate dose during an active infection is a judgment call that depends on the type and severity of the illness, and the answer is more nuanced than a blanket yes or no. For minor colds without fever, many rheumatologists advise continuing as scheduled, because the drug’s immune-dampening effect at low doses is modest and the risk of a disease flare from stopping can be real. For infections that come with significant fever, bacterial involvement, or require antibiotics, holding the dose until you recover is generally the safer move. The tricky part is figuring out which category your illness falls into, and that involves understanding what methotrexate actually does to your body’s defenses.

What Methotrexate Does to Your Immune System

Methotrexate was originally designed as a cancer drug at much higher doses, but the low weekly doses used for rheumatoid arthritis, psoriasis, and other inflammatory conditions work through a different set of mechanisms. Rather than simply killing immune cells, low-dose methotrexate nudges the immune system toward quieter behavior. It increases adenosine release, a molecule that acts as a natural brake on inflammation, and it dials down signaling pathways that drive joint swelling, pain, and tissue damage.¹ It also modifies how T cells behave and suppresses several pro-inflammatory chemical messengers.²

This is worth knowing because it explains why methotrexate is not a sledgehammer to your entire immune system. It does blunt certain immune responses, particularly T cell and antibody responses, which has been clearly demonstrated in studies looking at how patients on methotrexate respond to vaccines.³ But the immune suppression is partial and selective, not total. Your body can still mount a defense against most common pathogens; it just does so with slightly less firepower.

Researchers have pointed out that if methotrexate worked primarily by shutting down immune cell reproduction, it would not make sense for it to work at such low doses taken only once a week.⁴ The drug clears the bloodstream within about a day. So the weekly dose is more like a periodic recalibration of the immune system than a constant suppression of it. This matters for the “skip or don’t skip” question because it means missing one dose does not dramatically change your infection-fighting ability overnight, and continuing one dose does not render you defenseless.

When Holding a Dose Is the Safer Choice

The general principle most rheumatologists follow is that significant active infections warrant holding methotrexate until the infection clears. “Significant” here means infections with notable fever, infections requiring antibiotic or antiviral treatment, and infections that involve organs beyond the upper respiratory tract. Pneumonia, urinary tract infections treated with antibiotics, cellulitis, influenza with high fever, and gastrointestinal infections with vomiting or diarrhea all fall into this category.

The reasoning is straightforward: your immune system is already fighting something, so you do not want to simultaneously dampen its activity. And there is a practical concern beyond immunity. Vomiting and diarrhea cause dehydration, and methotrexate is cleared through the kidneys. When you are dehydrated, the drug lingers in your body longer and at higher concentrations, which raises the risk of side effects like mouth sores, drops in blood counts, and liver irritation. Volume depletion from any cause, including fever-driven fluid loss, can concentrate methotrexate in ways that make a normally safe dose behave more like a higher one.⁵

Herpes zoster (shingles) deserves a specific mention. Patients on methotrexate can develop shingles, and there has been long-standing concern that immunosuppression might lead to the virus spreading beyond the skin. One early study followed patients who developed shingles while on low-dose methotrexate and found no cases of the virus disseminating systemically, even with years of continued therapy afterward.⁶ That said, most doctors still recommend holding methotrexate during an active shingles episode and treating the virus with antivirals. The reassurance is that outcomes tend to be good even if the drug is not stopped immediately.

When You Can Probably Keep Going

A systematic review of the limited evidence on methotrexate and common infections concluded that methotrexate appears to be safe during some ordinary infections in rheumatoid arthritis patients, though the authors were careful to note that the evidence base is thin.⁷ The practical translation: a garden-variety cold, mild sore throat without fever, or seasonal allergies (which people sometimes mistake for illness) do not usually require skipping a dose.

The distinction that matters most is whether your body is fighting a true systemic infection or dealing with a localized, self-limiting nuisance. A runny nose and some sneezing with no fever, no body aches, and no worsening trajectory is generally manageable without interrupting treatment. If you develop a fever above 100.4°F (38°C), if you feel markedly worse than a typical cold, or if you cannot keep fluids down, the calculus shifts toward holding the dose and calling your prescriber.

One practical guideline that many rheumatologists use: if you are well enough that you would go to work (or would have gone pre-pandemic), you are probably well enough to take your methotrexate. If you are sick enough to stay in bed, hold the dose and check in with your doctor. This is not a formal clinical rule, but it captures the spirit of how most practitioners think about it.

How Long Can You Safely Pause

One of the most useful pieces of evidence on this question comes from a study that looked specifically at what happens when methotrexate is stopped for two weeks versus four weeks in people with stable rheumatoid arthritis. Patients who held the drug for two weeks showed no significant increase in disease activity compared to those who continued without interruption. But in the group that stopped for four weeks, disease activity scores rose meaningfully, and roughly one in five experienced a flare, compared to about one in fourteen in the group that kept taking it.⁸

The encouraging finding was that these flares were transient. Once methotrexate was restarted, disease activity returned to baseline. So the risk of a short hold is not permanent damage to your disease control; it is a temporary worsening that reverses once you resume. The clear takeaway is that skipping one or two doses during an illness is unlikely to derail your treatment. But if you find yourself unable to take methotrexate for a month or more, you should expect some disease activity to creep back in and should be in close contact with your rheumatologist about a plan.

The Vaccination Scenario

Illness is not the only reason people pause methotrexate. Vaccination is another common one, and the evidence here is surprisingly strong and specific. Because methotrexate blunts antibody responses, researchers have tested whether briefly pausing the drug around vaccination improves immune protection.

The VROOM trial found that suspending methotrexate for two weeks after a COVID-19 booster dose roughly doubled antibody levels compared to continuing the drug without interruption. The benefit persisted for months, with antibody levels remaining meaningfully higher at both 12 and 26 weeks after the vaccine.⁹ Trials in India using a different vaccine platform reached a similar conclusion: withholding methotrexate after vaccination led to significantly higher antibody levels than continuing it.¹⁰

This has practical implications beyond COVID vaccines. Many rheumatologists now recommend a two-week methotrexate hold after influenza and pneumococcal vaccinations as well. If you are already planning to pause methotrexate because you are sick, timing a vaccination around that pause could be strategic, though this is something to coordinate with your doctor rather than decide independently. The key insight from the flare data is that a two-week hold is well within the safe window for most patients with stable disease.

Antibiotics and Pain Medications That Change the Equation

Sometimes the reason to skip methotrexate when you are sick has less to do with the infection itself and more to do with the medications you are taking to treat it. Several common drugs interact with methotrexate in ways that can amplify its toxicity.

The most dangerous interaction is with trimethoprim-sulfamethoxazole (Bactrim or Septra), an antibiotic commonly prescribed for urinary tract infections and some skin infections. Both methotrexate and trimethoprim-sulfamethoxazole interfere with folate metabolism, and the combination can cause severe drops in blood cell counts that have been fatal in some cases.¹¹ If you are prescribed this antibiotic, your methotrexate should be held for the duration of the course. This is not a gray area; it is a well-documented, potentially life-threatening interaction.

Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen also interact with methotrexate. These are drugs many people reach for when they are sick with body aches or fever. A large pharmacoepidemiologic study found that combining low-dose methotrexate with NSAIDs was associated with a significantly increased risk of serious adverse events.¹² A Cochrane review noted that a specific risk pattern emerged when NSAIDs were taken on the same day of the week as methotrexate, with transient drops in platelet counts observed.¹³ The practical advice: if you need an NSAID while sick, try to take it on days other than your methotrexate day, and consider acetaminophen (Tylenol) as a first-line option for fever and pain instead.

Proton pump inhibitors, certain diuretics, and aminoglycoside antibiotics can also reduce kidney function or compete with methotrexate for excretion, potentially raising drug levels.⁵ While these interactions are more of a concern at higher oncology doses than the typical weekly 10-25 mg rheumatology dose, they still warrant awareness, especially when you are already dehydrated from illness.

Surgery and Methotrexate

Planned surgery is another situation where patients wonder whether to stop methotrexate, and the evidence here is reassuringly clear. A study of patients with rheumatoid arthritis undergoing elective orthopedic surgery found that those who continued methotrexate throughout the perioperative period actually had fewer surgical complications and infections (about 2%) than those who stopped the drug beforehand (about 15%). The group that stopped methotrexate also experienced more disease flares in the six weeks after surgery.¹⁴ Continuing methotrexate did not interfere with wound healing or increase early complication rates.¹⁵

This finding sometimes surprises people. The logic is that uncontrolled inflammation from stopping methotrexate can itself impair healing and increase infection susceptibility. Current guidelines from the American College of Rheumatology generally recommend continuing methotrexate through most elective surgeries. If you are having surgery and your surgeon asks you to stop methotrexate, it is worth asking your rheumatologist to weigh in, because the evidence favors continuation.

Do Not Stop Your Folic Acid

One common source of confusion: if you skip your methotrexate dose, should you also skip the folic acid supplement that typically goes with it? No. Folic acid supplementation is taken to counteract methotrexate’s side effects, not to make the drug work. A randomized trial showed that folic acid reduced methotrexate toxicity scores without affecting the drug’s therapeutic benefit.¹⁶ Continue your folic acid whether or not you take your methotrexate that week. If anything, maintaining folic acid during illness provides a small buffer against any residual methotrexate effects from your previous dose.

Oral Versus Subcutaneous and Why It Matters When Sick

Some patients take methotrexate as a pill, others as a weekly injection under the skin. The route matters when you are sick, particularly with gastrointestinal illness. Vomiting or diarrhea can affect how well an oral dose is absorbed, making it unpredictable. If you are throwing up, an oral dose taken that morning may not have been absorbed at all, or it may have been partially absorbed, leaving you in an uncertain zone. Subcutaneous injection bypasses the gut entirely, so absorption is not affected by gastrointestinal symptoms.

Studies comparing oral and subcutaneous methotrexate have shown that the injectable form generally achieves higher and more consistent drug levels, though the clinical significance varies across conditions.¹⁷ For people who frequently deal with nausea or GI upset, whether from methotrexate itself or from intercurrent illness, the subcutaneous route can remove one variable from the equation. If you are on oral methotrexate and find yourself repeatedly skipping doses because of stomach trouble when sick, it may be worth discussing a switch with your doctor.

The Adherence Trap

There is a psychological dimension to dose-skipping that does not get enough attention. Research on rheumatoid arthritis treatment adherence has identified that fear of side effects and complicated medication decisions are significant barriers to sticking with treatment.¹⁸ The anxiety about whether to take or skip a dose during illness can snowball. Some patients, once they have skipped a dose and felt fine, start skipping more liberally. Others become so worried about making the wrong call that they stop the drug for weeks at a time “just to be safe.”

Both patterns are understandable but counterproductive. The evidence suggests that missing an occasional dose during genuine illness carries minimal risk to your disease control, while chronic underdosing from fear-driven skipping gradually undermines the drug’s effectiveness. Having a clear plan discussed in advance with your rheumatologist removes the in-the-moment decision stress. A simple framework many clinics use: hold for fever over 100.4°F, hold if you cannot keep fluids down, hold if you are on antibiotics (especially trimethoprim-sulfamethoxazole), and resume once you have been fever-free for 24 to 48 hours. Write it down or save it in your phone so you are not trying to remember the rule while feeling miserable.

When High-Dose Methotrexate Changes Everything

Nearly everything discussed so far applies to the low-dose, once-weekly methotrexate used for autoimmune and inflammatory conditions. Patients receiving high-dose methotrexate for cancer, defined as doses of 500 mg per square meter of body surface area or greater, face a completely different risk profile. At those doses, methotrexate can cause bone marrow suppression, kidney damage, and serious infections that require hospital monitoring and rescue medication (leucovorin).¹⁹ If you are on high-dose methotrexate for an oncology indication, the decision to hold or continue during illness is made by your oncology team, not by general guidelines, and the stakes are much higher in both directions.

For the vast majority of people reading this article, those on weekly doses between 7.5 mg and 25 mg for conditions like rheumatoid arthritis, psoriatic arthritis, or psoriasis, the reassurance is that the drug is relatively forgiving of brief interruptions. Your disease may grumble slightly, but it will settle back down once you restart. The greater risk, ironically, often lies in the other direction: in continuing methotrexate during a serious infection when holding it would have been wiser, or in combining it with an interacting medication during illness without realizing the danger.