What Happens When You Stop Taking Methotrexate?

Stopping methotrexate usually leads to the gradual return of the disease it was keeping in check, though how quickly and how severely depends on what condition you’re being treated for, how long you were on it, and whether you taper or quit cold. In rheumatoid arthritis, roughly half of patients experience a flare within six months of stopping. In psoriasis, relapse can begin within weeks. The drug’s side effects, on the other hand, tend to fade once it clears your system. Understanding what to expect on both sides of that equation can help you and your doctor plan the transition safely.

Rheumatoid Arthritis Flares Are Common and Often Fast

Methotrexate is the backbone drug for rheumatoid arthritis, and the disease tends to reassert itself once you take it away. A study of patients with low disease activity who stopped methotrexate found that about 44% flared within six months, with a median time to flare of roughly 99 days.¹ That means for many people, the disease comes back within about three months of their last dose.

Even brief pauses carry some risk. A post-hoc analysis of two randomized trials found that holding methotrexate for four weeks led to flares in about 21% of patients, compared with roughly 6% of those who kept taking it. A two-week hold, though, didn’t significantly raise flare rates.² The reassuring part is that once methotrexate was resumed after a short hold, the flare rate evened out between groups. So a brief interruption for a vaccine or a minor procedure doesn’t usually cause lasting trouble.

An older but striking double-blind study underscores the point for long-term users: all five patients switched to placebo had to drop out of the study within a month because their disease flared so badly.³ The longer you’ve been on methotrexate and the more active your underlying disease, the more likely a flare is and the faster it tends to arrive.

Psoriasis Tends to Rebound Quickly

If you’re taking methotrexate for psoriasis, the picture is somewhat bleaker than in arthritis. A systematic review noted that in a small study of methotrexate-treated psoriasis patients, the median time to losing half of their improvement after stopping was only about four weeks.⁴ That’s fast. And compared with phototherapy approaches, methotrexate generally offers shorter remission periods after discontinuation.⁵

The good news is that tapering rather than abruptly stopping can make a meaningful difference. In a randomized trial comparing two tapering methods to abrupt cessation, nearly 74% of patients who stopped cold experienced a relapse, versus roughly 13-18% in the taper groups.⁶ Those are dramatically different numbers. If you’re stopping methotrexate for psoriasis, a gradual dose reduction is strongly worth discussing with your dermatologist.

Crohn’s Disease and Inflammatory Bowel Disease

Methotrexate is used less often in Crohn’s disease than in arthritis or psoriasis, but for patients who respond to it, stopping raises real relapse concerns. A Cochrane review found that intramuscular methotrexate kept about 65% of Crohn’s patients in remission at 40 weeks, compared with 39% on placebo.⁷ The flip side of that number: once you stop, you lose that protective effect.

A study tracking inflammatory bowel disease patients after they discontinued methotrexate found that only about 42% remained in remission at six months, dropping to roughly 21% at one year and 16% at a year and a half. The authors noted that relapse was frequent and typically happened within the first year.⁸ If you’re coming off methotrexate for Crohn’s, having a backup plan with your gastroenterologist is essential.

Side Effects Usually Fade After Stopping

While flares are the main worry, there’s a silver lining to stopping methotrexate: many of the drug’s unpleasant side effects reverse. The nausea, fatigue, mouth sores, and general malaise that methotrexate is known for tend to improve within days to weeks of your last dose, since the drug has a relatively short half-life of around six to eight hours for the parent compound (though its active metabolites linger somewhat longer in cells).

Liver enzyme elevations are one of the more closely monitored side effects of long-term methotrexate use. A case series of patients with methotrexate-induced liver injury found that liver function tests typically normalized within two to eight weeks of stopping the drug.⁹ That’s encouraging: the liver is remarkably good at bouncing back once the offending agent is removed, at least in cases where the damage hasn’t progressed to fibrosis. For patients who’ve been on methotrexate for many years, more advanced liver changes may not fully reverse, which is one reason doctors monitor liver blood work regularly.

Hair thinning, another common complaint, usually improves gradually over several months. Immune suppression also eases, meaning your white blood cell counts should normalize and your susceptibility to infections should decrease. Most people notice these improvements within weeks, though subjective energy levels can take longer to fully recover.

Vaccines Work Better When Methotrexate Is Paused

One situation where temporarily stopping methotrexate is actually recommended is around vaccination. Methotrexate blunts the immune response to vaccines, so pausing it for a short window can substantially improve how well the vaccine takes. A large trial studying COVID-19 booster vaccines found that patients who suspended methotrexate for two weeks had roughly double the antibody response compared with those who continued it.¹⁰

For seasonal influenza vaccination, a multicenter trial found that about 69-75% of patients achieved a satisfactory vaccine response when methotrexate was held for either one or two weeks, with no significant difference between those durations.¹¹ Since a two-week hold is generally safe from a flare standpoint, as noted earlier, many rheumatologists now routinely advise pausing methotrexate around important vaccinations. The timing matters: the hold typically starts on the day of vaccination, not before.

Surgery and Perioperative Considerations

Whether to stop methotrexate before surgery has been debated for decades, and the answer has actually shifted. Older thinking assumed you should stop any immunosuppressant before an operation. But research has suggested that continuing methotrexate through surgery may actually lead to fewer complications than stopping it. One study of rheumatoid arthritis patients undergoing joint procedures found that the group who discontinued methotrexate had significantly more postoperative infections, including infected prostheses and deep wound infections, while the group that continued it had none.¹²

The likely explanation is that stopping methotrexate triggers a disease flare, which ramps up systemic inflammation and may actually impair wound healing and immune defense more than the modest immunosuppression from the drug itself. Current guidelines from the American College of Rheumatology generally recommend continuing methotrexate through elective surgery for most patients, though this always depends on the specific procedure, your overall health, and your surgeon’s comfort level.

Tapering Versus Abrupt Cessation

If you and your doctor decide it’s time to come off methotrexate, the way you stop matters. The psoriasis tapering data mentioned above showed a dramatic difference, but even in rheumatoid arthritis, gradual dose reduction offers advantages. Data from the DREAM registry found that patients who tapered methotrexate while continuing a biologic had a relapse rate of about 21% at six months, while those who stopped methotrexate entirely had relapse rates of 21-24% by twelve months.¹³ Being on a biologic clearly cushioned the blow, but the taper group’s early stability is worth noting.

An interesting wrinkle is that the route of methotrexate administration affects tapering outcomes. A study comparing subcutaneous and oral methotrexate tapering found that 53% of patients tapering the subcutaneous form flared within a year, versus 27% tapering the oral form.¹⁴ The likely reason is that subcutaneous methotrexate is more bioavailable, so the same dose delivers more drug. When you taper it, the drop in effective drug level is steeper.

When You’re Also on a Biologic

Many rheumatoid arthritis patients take methotrexate alongside a biologic drug like adalimumab or etanercept. Stopping methotrexate in this context carries a specific concern beyond disease flares: your body may start producing antibodies against the biologic. A study of patients on adalimumab found that when methotrexate was tapered and stopped, the rate of anti-drug antibody detection jumped from 18% to 68%.¹⁵ These antibodies can neutralize the biologic, making it less effective or even useless.

This is why rheumatologists are often cautious about removing methotrexate when a biologic is working well. A trial comparing etanercept monotherapy to methotrexate monotherapy in patients who’d achieved remission on the combination found that about 50% of those kept on etanercept alone maintained remission at 48 weeks, while only about 29% of those kept on methotrexate alone did.¹⁶ The combination of both drugs performed best of all. If one has to go, these numbers suggest stopping methotrexate while keeping the biologic is often the more durable choice, but you lose the protective effect methotrexate has on anti-drug antibody formation.

Restarting Methotrexate After a Break

A practical concern for many patients: if I stop and my disease comes back, will methotrexate still work when I go back on it? The evidence is reassuring. A Danish registry study found that within about a year and a half, half of patients who stopped methotrexate had restarted it, and within three years, two-thirds had.¹⁷ The high restart rate reflects both how effective the drug is and how often people find they need it again.

Crucially, restarting methotrexate after a previous course appears to work at least as well as the first time, and possibly better. A study of re-employed methotrexate found a reduced risk of treatment failure compared with the original course, especially in patients whose initial dose had been low.¹⁸ The authors noted that this effect was unique to methotrexate and wasn’t seen when other disease-modifying drugs were restarted. So if you stop methotrexate and need to come back to it, you haven’t burned a bridge.

Children and Juvenile Arthritis

Children with juvenile idiopathic arthritis face similar questions about methotrexate withdrawal, but the specifics differ in important ways. A large randomized trial compared stopping methotrexate at six months of remission versus twelve months and found virtually no difference: about 40% of children in both groups flared within a year of stopping, and the relapse-free intervals were nearly identical.¹⁹ That finding was somewhat surprising, since you might expect a longer period of treatment to be more protective.

What predicted flares had less to do with the methotrexate tapering strategy and more to do with the child’s individual characteristics. A study found that flares occurred in about 55% of cases overall, and the strongest predictors were younger age at symptom onset, antinuclear antibody positivity, and higher inflammatory markers at the start of treatment.²⁰ In other words, the biology of the disease mattered more than whether methotrexate was stopped at a particular time point or in a particular way. For families weighing whether to keep a child on methotrexate, this means the decision depends more on the child’s disease profile than on hitting a specific treatment duration.

Fertility and Pregnancy Planning

Methotrexate is a known teratogen, meaning it can cause birth defects, so stopping it well before conception is mandatory. Guidelines typically recommend a washout period of at least three months, while the drug manufacturer advises six months. But emerging evidence suggests the actual risk window may be shorter than feared. A retrospective cohort study of women who conceived after receiving methotrexate for ectopic pregnancy found that conceiving within one to three months did not appear to increase the risk of major fetal malformations or other unfavorable pregnancy outcomes compared with waiting longer.²¹

That said, the standard recommendation remains three months minimum for good reason: methotrexate depletes folate stores, and restoring adequate folate levels is critical for early fetal development. Most doctors will have you take high-dose folic acid during the washout period. The ectopic pregnancy context is also worth noting because those patients typically receive just one or two doses of methotrexate, which is very different from the chronic weekly dosing used in arthritis or psoriasis. If you’ve been on weekly methotrexate for months or years, the more conservative waiting period is likely prudent even if the emerging data is reassuring.

The Cost of Stopping and Restarting

There’s a less obvious consequence of stopping methotrexate that has nothing to do with joints or skin: it can be expensive. A study of early arthritis patients found that non-adherence to disease-modifying drugs, including methotrexate, was associated with higher total healthcare costs. The connection wasn’t that non-adherent patients made more doctor visits; rather, their disease escalated, and they were switched sooner to more expensive medications like biologics.²² Methotrexate itself costs very little per month. The biologics that often replace it when disease control is lost can cost thousands of dollars monthly, even with insurance. Stopping methotrexate is sometimes necessary, but it’s worth understanding that the financial downstream effects can be substantial.

How Expectations Shape the Experience

An intriguing finding from recent research suggests that what you believe about methotrexate influences how stopping it plays out. A randomized trial tested whether reframing patients’ mindset about the drug could affect outcomes. Among patients who received standard information, about 35% discontinued methotrexate within 12 weeks, mostly due to the perceived burden of side effects. In the group that received a mindset intervention designed to change how they thought about the medication’s effects, only about 8% stopped.²³

This doesn’t mean methotrexate side effects are imaginary. The patients who stopped were experiencing real symptoms. But it suggests that fear and negative expectations amplify the experience of side effects, pushing some patients to discontinue a drug that’s actually controlling their disease. If you’re thinking about stopping because you feel lousy on methotrexate, it’s worth having an honest conversation with your rheumatologist about whether dose adjustments, folic acid supplementation, or even switching from oral to subcutaneous delivery might address the side effects before you lose the disease control. Stopping is always an option, but it should be an informed one rather than a reflexive escape from symptoms that might be manageable.