What are the potential side effects of stopping methotrexate. How can patients safely discontinue methotrexate treatment. Why might someone need to stop taking methotrexate. What should patients know about methotrexate withdrawal and disease flares.

Understanding Methotrexate: A Crucial Treatment for Inflammatory Conditions

Methotrexate stands as one of the most widely prescribed medications for inflammatory arthritis and other autoimmune conditions. This disease-modifying antirheumatic drug (DMARD) has been a cornerstone of treatment for over 70 years, originally developed as a cancer therapy. Today, it plays a crucial role in managing conditions such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

Approximately 90% of rheumatoid arthritis patients use methotrexate at some point during their treatment journey. Its effectiveness lies in its ability to reduce pain, swelling, and potentially slow joint damage and disease progression over time. Methotrexate works by calming the immune system, helping to alleviate the inflammatory response associated with various autoimmune conditions.

How is methotrexate administered?

Methotrexate is available in two primary forms:

• Oral tablets
• Injectable solution

The dosage and frequency of administration depend on the specific condition being treated and individual patient factors. Healthcare providers carefully tailor the treatment plan to optimize efficacy while minimizing potential side effects.

Methotrexate Side Effects: Balancing Benefits and Risks

While methotrexate is generally considered one of the safer arthritis drugs, it’s not without potential side effects. Adam Kaye, Pharm.D., a clinical professor of pharmacy at the University of the Pacific, emphasizes that “almost any medication you use will come with risks and methotrexate is no exception.”

Short-term side effects of methotrexate

Some of the more common short-term side effects include:

• Folate deficiency
• Gastrointestinal issues (nausea, vomiting)
• Mouth sores
• Headaches
• Fatigue
• “Methotrexate fog” (general feeling of malaise)
• Increased susceptibility to infections

A 2022 study published in the International Journal of Dermatology found that only about half of the participants taking methotrexate were able to tolerate the drug long-term. The primary reasons for discontinuation were adverse effects.

Long-term concerns with methotrexate use

Extended use of methotrexate can potentially lead to more serious complications. Dr. Kaye notes, “Long term, there is a risk of liver toxicity. Liver toxicity related to methotrexate is seen in the cumulative dosing, meaning a few years or more.”

Due to this potential risk, healthcare providers typically advise patients to:

1. Avoid alcohol consumption while taking methotrexate
2. Undergo regular liver function monitoring

Reasons for Discontinuing Methotrexate Treatment

Despite its effectiveness, there are several reasons why a patient might need to stop taking methotrexate:

Loss of efficacy

In some cases, methotrexate may lose its effectiveness over time. When this occurs, healthcare providers may recommend switching to a different class of drugs to manage the underlying condition.

Legal and accessibility issues

Following the overturning of Roe v. Wade, some patients in states with trigger laws have faced challenges accessing methotrexate. This is due to the drug’s potential to induce pregnancy loss, leading some pharmacies to deny prescriptions.

Vaccine considerations

Temporary discontinuation of methotrexate may be necessary to enhance the effectiveness of certain vaccines. This allows the immune system to mount a stronger response to the vaccination.

The Challenge of Methotrexate Withdrawal: Understanding Flares

While methotrexate itself does not cause a withdrawal syndrome in the traditional sense, discontinuing the medication can lead to significant challenges for patients. Dr. Glen Hazlewood, a rheumatologist and assistant professor at the Cumming School of Medicine in Alberta, Canada, explains, “There is no withdrawal syndrome associated with stopping methotrexate itself, as there is with some other medications such as prednisone. Instead, what can happen with discontinuing methotrexate is having disease flare ups in response.”

What is a disease flare?

A disease flare refers to a period of increased disease activity, often characterized by:

• Heightened pain and inflammation
• Increased joint stiffness
• Fatigue
• Reduced mobility

These flares can significantly impact a patient’s quality of life and may lead to long-term joint damage if not properly managed.

Safely Discontinuing Methotrexate: A Gradual Approach

Given the potential for disease flares upon discontinuation, it’s crucial to approach methotrexate withdrawal carefully and under medical supervision. Abruptly stopping the medication is generally not recommended.

Steps for safe methotrexate discontinuation

1. Consult with your healthcare provider
2. Develop a personalized tapering plan
3. Gradually reduce the dosage over time
4. Monitor for signs of disease activity
5. Implement alternative treatments as needed

The specific tapering schedule will vary depending on individual factors such as the initial dose, duration of treatment, and underlying condition severity.

Managing Disease Activity During Methotrexate Withdrawal

As patients taper off methotrexate, it’s essential to have strategies in place to manage potential increases in disease activity. This may involve a combination of approaches:

Alternative medications

Healthcare providers may prescribe other DMARDs or biologics to help control inflammation and prevent flares during the withdrawal process.

Non-pharmacological interventions

• Physical therapy
• Occupational therapy
• Dietary modifications
• Stress management techniques
• Regular exercise (as tolerated)

These complementary approaches can help support overall health and potentially mitigate some symptoms associated with increased disease activity.

The Importance of Close Monitoring During Methotrexate Withdrawal

Throughout the process of discontinuing methotrexate, close communication with healthcare providers is crucial. Regular check-ups and monitoring can help identify any signs of disease flare early, allowing for prompt intervention.

What should patients monitor?

Patients should be aware of and report any changes in:

• Pain levels
• Joint swelling or stiffness
• Fatigue
• Overall functionality
• Any new or worsening symptoms

Healthcare providers may also recommend periodic blood tests to assess inflammation markers and overall health status during the withdrawal process.

Long-term Considerations After Methotrexate Discontinuation

Successfully discontinuing methotrexate doesn’t necessarily mean the end of treatment. Many patients will require ongoing management of their underlying condition, potentially involving other medications or treatment modalities.

Potential outcomes after methotrexate withdrawal

Patients may experience various outcomes after discontinuing methotrexate:

• Sustained remission with minimal disease activity
• Mild to moderate disease flares requiring intervention
• Significant disease reactivation necessitating reintroduction of methotrexate or alternative treatments

The specific outcome will depend on individual factors such as disease severity, duration of treatment, and overall health status.

In conclusion, while methotrexate is a highly effective treatment for many inflammatory conditions, there are situations where discontinuation may be necessary or desired. Understanding the potential challenges of methotrexate withdrawal, including the risk of disease flares, is crucial for patients and healthcare providers alike. By approaching discontinuation carefully and with proper medical supervision, patients can navigate this process safely and maintain optimal health outcomes.

Are There Side Effects to Stopping Methotrexate?

GettyImages/Roman Tyshchenko

If you have rheumatoid arthritis, there’s a good chance you’re either on, or have discussed being on, methotrexate with your doctor. Methotrexate is known as a disease-modifying antirheumatic drug (DMARD) because it can reduce pain and swelling, and it also has the potential to actually slow joint damage and disease progression over time. About 90% of rheumatoid arthritis (RA) patients use methotrexate at some point in their treatment, according to the Arthritis Foundation.

While methotrexate can be life changing (in a good way), it also can also be difficult for a lot of people to tolerate. If you are taking methotrexate and you’re having trouble dealing with some of the gastrointestinal or other side effects it can cause, it’s still not a good idea to quit the treatment cold turkey. Because as it turns out, stopping methotrexate can be just as tricky as taking it. We asked the experts for the bottom line on methotrexate and the safest way to discontinue treatment.

What Is Methotrexate?

Methotrexate is one of the most prescribed medications for inflammatory arthritis. You may know it by the brand names Rheumatrex, Trexall, Otrexup, and Rasuvo. Methotrexate is by no means a new medication—it was developed over 70 years ago to treat cancer. These days, medical specialists lean on methotrexate in much lower doses to reduce inflammation associated with diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. As far as we know, methotrexate works by calming the immune system. Methotrexate is delivered either by a pill or injection. How often you take it and the dose you take will depend on your condition.

Methotrexate Side Effects

Methotrexate is one of the safest arthritis drugs, according to the Arthritis Foundation. However, “almost any medication you use will come with risks and methotrexate is no exception,” says Adam Kaye, Pharm.D., a clinical professor of pharmacy at the University of the Pacific in Stockton, CA. Short term, methotrexate can deplete the body of folate, potentially causing folate deficiency. It can cause GI problems such as nausea and mouth sores have also been reported. Some people on methotrexate have experienced headaches, fatigue and an overall “blah” feeling (a.k.a. methotrexate fog). Methotrexate can also lower your ability to fight infections. In a 2022 study in the International Journal of Dermatology, only about half of participants on methotrexate were able to tolerate the drug. The main reasons for discontinuation were adverse effects.

Taken over a long period of time, methotrexate can lead to a different set of side effects. “Long term, there is a risk of liver toxicity,” Kaye says. “Liver toxicity related to methotrexate is seen in the cumulative dosing, meaning a few years or more.” For this reason, Kaye discourages anyone who is taking methotrexate from drinking alcohol which can add to the liver’s toxic load. He also suggests that you work with your doctor to regularly monitor the health of your liver when taking methotrexate.

Stopping Methotrexate

Beyond the potential side effects, there are other reasons you may need to discontinue your methotrexate treatment. For example, if methotrexate has lost its effectiveness for your condition, it may be time, in coordination with your doctor, to move to a different class of drugs for treatment.

It’s also possible that your methotrexate has become less available in your state due to Roe v. Wade being overturned. Methotrexate is considered a pregnancy category X drug (absolutely contraindicated) because of its mechanism antagonizing folate and/or folic acid that can induce abortions/pregnancy loss. (That’s also why your doctor has likely talked to you about the need to be on at least one form of definitive birth control with methotrexate if you are still menstruating.) Some women in states with trigger laws—abortion bans made lawful immediately after the SCOTUS decision—are having their prescriptions for methotrexate denied by pharmacies. You may also be asked to temporarily discontinue your methotrexate treatment to allow certain vaccines to work more effectively.

Methotrexate Withdrawal and Flares

Glen Hazlewood, M.D., Ph.D., rheumatologist and an assistant professor in the Division of Rheumatology, Department of Medicine in the Cumming School of Medicine in Alberta, Canada, researches the benefits and risks of reducing arthritis medications (a.k.a. drug tapering). “There is no withdrawal syndrome associated with stopping methotrexate itself, as there is with some other medications such as prednisone,” he says. “Instead, what can happen with discontinuing methotrexate is having disease flare ups in response.”

For example, in a recent study published in Clinical Rheumatology, scientists compared people with rheumatoid arthritis (RA) who discontinued their methotrexate for either two or four weeks with a control group who continued their medication. More than 20% of those who stopped methotrexate for four weeks experienced a flare, compared to only 7% who stayed on their medications during the trial period. The authors summarized the results of the study by stating: Methotrexate discontinuation for four weeks increases flare risk and disease activity.

In another study published in Arthritis Care and Research, researchers followed over 2,000 patients who were living with inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis to determine what effect stopping their DMARDs (which included methotrexate use) would have on their disease. The researchers found interruptions in DMARD use were associated with a significant increase in severe flare ups in disease symptoms.

Tapering Methotrexate

So what to do? If you do need to discontinue your methotrexate, your first step should be to talk to your doctor who may be able to help you find a different medication or gradually decrease the dose of your methotrexate (a.k.a. tapering the dose). “In general, tapering the dose of methotrexate is better than just stopping it,” says Dr. Hazlewood. “The methotrexate is likely important for controlling your underlying condition, so there will be a greater risk of having a flare (or more severe flare) if the medication is stopped abruptly. ”

Another benefit of gradually weaning yourself off the drug: As you taper the medication, you might find a new dose that works for your disease without all the side effects. “Some people might need a lower dose of methotrexate, and tapering slowly allows you to find this dose,” says Dr. Hazlewood. “If people are having side effects from methotrexate, then sometimes these can be controlled with just lowering the dose and not stopping it completely.”

Communicate with your doctor to see if tapering has any benefits for you. If not, don’t give up. There are many effective medications available for inflammatory arthritis. Trial and error will eventually connect you with a treatment plan that works.

Notes: This article was originally published July 24, 2010 and most recently updated August 4, 2022.

Introduction: Arthritis Foundation. (2022.) “Understanding Methotrexate.” https://www.arthritis.org/drug-guide/medication-topics/understanding-methotrexate

Methotrexate: American College of Rheumatology. (2022.) “Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo).”
https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Treatments/Methotrexate-Rheumatrex-Trexall

Methotrexate Side Effects: Arthritis Foundation. (2022.) “Methotrexate: Managing Side Effects.”
https://www.arthritis.org/health-wellness/treatment/treatment-plan/disease-management/methotrexate-managing-side-effects

Methotrexate Tolerance: International Journal of Dermatology. (2021.) “Drug Survival and Predictor Factors for Discontinuation of Methotrexate in Psoriasis: A Real-Life Multicenter Study.” https://onlinelibrary.wiley.com/doi/abs/10.1111/ijd.15628

Methotrexate Discontinuation (1.): Clinical Rheumatology. (2020.) “Effect of Short-Term Methotrexate Discontinuation on Rheumatoid Arthritis Disease Activity: Post-hoc Analysis of Two Randomized Trials.” https://link.springer.com/article/10.1007/s10067-019-04857-y

Methotrexate Discontinuation (2. ): Arthritis Care and Research. (2021.) “Medication Interruptions and Subsequent Disease Flares During the COVID-19 Pandemic: A Longitudinal Online Study of Patients With Rheumatic Disease.” https://onlinelibrary.wiley.com/doi/full/10.1002/acr.24837

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Methotrexate Withdrawal and RA Flares

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Medically reviewed by
Diane M. Horowitz, M.D.

Article written by
Maureen McNulty

Many people with rheumatoid arthritis (RA) try methotrexate (Trexall) as a treatment option. This medication is a disease-modifying antirheumatic drug (DMARD) that can slow disease progression, or prevent joints from being damaged further. Methotrexate calms the immune system to prevent inflammation. It is often the first DMARD prescribed to treat RA.

About two-thirds of people who use methotrexate say that it helps keep their RA from getting worse. However, most people who use it also experience side effects such as fatigue, nausea, diarrhea, abdominal pain, mouth sores, hair loss, or shortness of breath. It can also lead to more serious side effects like lymphoma (a type of blood cancer) or liver disease.

Because of the side effects, cost, or other concerns about methotrexate, some people may want to stop taking it. However, your RA could worsen if you stop treatment.

Methotrexate Withdrawal

Some drugs and medications can lead to dependence — when you have been taking some drugs for a long time, your body begins to rely on them in order to function properly. When you stop using them, you go through withdrawal and experience physical or mental symptoms.

Researchers aren’t yet sure whether people can go through withdrawal from stopping methotrexate treatment. Clinical studies haven’t reported any major methotrexate withdrawal symptoms from people stopping this therapy. However, it is clear that stopping methotrexate treatment can increase the risk of RA flare-ups.

RA Flares and Methotrexate

Flare-ups — periods of time in which symptoms worsen — are common when living with RA. Flare-ups can last days, weeks, or months. They often lead to symptoms like joint stiffness, pain, and swelling, as well as fatigue and fevers.

Some clinical trials have found that people with RA can experience disease flares when they stop using methotrexate. One small study compared people taking methotrexate with people taking a placebo (a “fake” treatment that mimics a real medication) for their RA. Within one month, all of the participants taking the placebo experienced a flare-up.

Other studies have analyzed whether taking methotrexate less often could lead to flare-ups. Studies have found that anywhere from 8 percent to 48 percent of people have an RA flare when they go from taking methotrexate once every week to once every two weeks. This treatment plan may work best for people with early-stage RA who have gone into remission. It can also help when people are using methotrexate in combination with other DMARDs that are working to help control the disease.

This research was conducted many years ago, before biologics became a common RA treatment option. More recently, researchers have found that some people may be able to stop using methotrexate when they are also using biologics. Studies have looked at people who had stable RA after taking tofacitinib (Xeljanz) or etanercept (Enbrel) along with methotrexate. Researchers found that when people stopped using methotrexate but continued taking the biologic drug, they did not have a higher risk of a flare-up.

Is It a Good Idea to Taper Off of Methotrexate?

Methotrexate can help many people with RA go into remission. People in remission have dramatically improved RA symptoms. For example, your doctor may consider you to be in remission if you have just a single swollen joint or if your blood tests show that you have low levels of inflammation.

If you are in remission from RA, your doctor may give you the option of stopping methotrexate therapy or reducing your dose. Some guidelines recommend slowly tapering off methotrexate if your RA is well controlled. Before trying to switch to a lower dose, talk to your rheumatologist to see if it’s the right choice for you. Your doctor will consider factors like:

• Whether you experience side effects from using methotrexate
• How long you’ve been in remission
• Whether you’re concerned about experiencing a disease flare-up if you lower your dose

Your rheumatologist may be OK with you stopping methotrexate altogether. They may also suggest changing your dosage or taking the medication less frequently. This may help prevent flare-ups and help you stay in remission.

Treating Flare-Ups

If you experience a flare-up after stopping or reducing methotrexate, your RA may become active again. In this case, your doctor may suggest going back on your previous treatment plan.

In one study, 36 percent of people who took etanercept and methotrexate for at least six months and then stopped using methotrexate needed to go back to their original therapy. Out of this group, 75 percent were able to get back into remission and 92 percent had low disease activity after restarting methotrexate.

There are also other strategies you may be able to use to treat flare-ups. You may want to try:

• Lowering your stress levels
• Getting more sleep
• Relieving pain with hot water bottles, heated blankets, warm baths, or ice packs
• Getting very light exercise, if your doctor says it’s OK
• Distracting yourself with a fun or interesting activity
• Taking over-the-counter or prescription medications to ease flare symptoms, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids

These strategies may not be enough to treat a flare-up that occurs after you stop taking methotrexate. You may feel better if you go back to your original medication. Work with your health care team to weigh the benefits and risks of your treatment options.

Talking To Your Doctor About Methotrexate

Make sure to talk to your doctor before you stop taking methotrexate or try to change your dose. If you don’t like methotrexate because of its side effects or if you want to try a different treatment, your doctor can help you change your treatment plan. They may also be able to suggest other ways to ease methotrexate side effects, such as:

• Taking methotrexate after a meal, when your stomach is full
• Receiving methotrexate therapy on Friday or Saturday, so you have the weekend to recover
• Taking a folic acid (folate) supplement
• Using other medications to treat side effects like nausea

You should keep taking methotrexate even if you’re feeling good, unless you and your doctor discuss otherwise. Having fewer RA symptoms means that your medication is working — if you stop taking it, your condition could worsen.

Connect With Others Who Understand

On myRAteam, the social network for people with RA and their loved ones, members come together to ask questions, give advice, and share their stories with others who understand life with rheumatoid arthritis.

Have you used methotrexate? Have you experienced flare-ups when stopping this medication? Share your experience in the comments below, or start a conversation by posting on your Activities page.

References

1. Rheumatoid Arthritis Treatment — Johns Hopkins Arthritis Center
2. These Are the Methotrexate Side Effects That Make Arthritis Patients Stop Taking It — CreakyJoints
3. Methotrexate (Oral Route) — Mayo Clinic
4. 10 Methotrexate Myths Rheumatologists Want to Clear Up, Once and for All — CreakyJoints
5. Is There a Difference Between Physical Dependence and Addiction? — National Institute on Drug Abuse
6. Key Findings From Studies of Methotrexate Tapering and Withdrawal in Rheumatoid Arthritis — Expert Review of Clinical Pharmacology
7. Arthritis Flare-Ups: What Causes Them and Exactly What To Do When You Have One — CreakyJoints
8. Methotrexate Withdrawal in Patients With Rheumatoid Arthritis Who Achieve Low Disease Activity With Tofacitinib Modified-Release 11 mg Once Daily Plus Methotrexate (ORAL Shift): A Randomised, Phase 3b/4, Non-Inferiority Trial — The Lancet Rheumatology
9. Clinical, Radiologic, and Functional Outcomes Following Methotrexate Withdrawal in Etanercept-Treated Patients With Active Early Rheumatoid Arthritis: A Subanalysis of COMET Year 2 by Week 52 DAS28 Status — The Open Rheumatology Journal
10. Your RA Is in Remission! Now What? — Arthritis Foundation
11. Etanercept or Methotrexate Withdrawal in Rheumatoid Arthritis Patients in Sustained Remission — Arthritis & Rheumatology

Diane M. Horowitz, M.D. is an internal medicine and rheumatology specialist. Review provided by VeriMed Healthcare Network. Learn more about her here.

Maureen McNulty studied molecular genetics and English at Ohio State University. Learn more about her here.

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50 years of methotrexate in rheumatology | Nasonov E.L.

For the treatment of inflammatory rheumatological diseases, a very large number of drugs with different chemical structures and pharmacological properties are used, the common mechanisms of action of which are the ability to suppress the development of inflammation [1]. Among modern antirheumatic drugs, methotrexate (MT) occupies a special place , the first report on the use of which in rheumatological practice appeared about 50 years ago. However, only in recent years, MT has been considered as one of the most powerful and effective anti-inflammatory drugs for the treatment of not only rheumatic, but also many other human immunoinflammatory diseases [1, 2] (Table 1).

Mechanism of action

Recall that MT belongs to the group of antimetabolites, its structure is similar to folic (ptyrolglutamic) acid, from which it differs by the replacement of the amino group with a carboxyl group in the 4th position of the pteridine molecule and the addition of a methyl group in the 10th position of 4-aminobenzoic acid.

Obviously, the therapeutic efficacy and toxic reactions that occur during the treatment of MT are largely determined by the antifolate properties of the drug. In the human body, folic acid is cleaved by the enzyme dehydrofolate reductase (DHF) with the formation of metabolically active products – dihydrofolic and tetrahydrofolic acids, which are involved in the conversion of homocysteine ​​to methionine, the formation of purines and thymidylate, necessary for DNA synthesis. One of the main pharmacological effects of MT is the inactivation of DHF. In addition, in the cell, MT undergoes polyglutamilation with the formation of metabolites, which are very important in the implementation of the biological activity of MT. These metabolites, in contrast to “native” MT, have an inhibitory effect not only on DHF, but on “distal” folate-dependent enzymes, including thymidylate synthetase, 5-aminoimidazole-4-carboxamidoribonucleotide (AICAR) transamylase, etc. It is assumed that complete inhibition of DHF, leading to to a decrease in DNA synthesis, occurs mainly when prescribing ultra-high doses of MT (100-1000 mg / m2) and forms the basis of the antiproliferative effect of the drug, which is important in the treatment of cancer patients. On the contrary, when using low doses of MT, the pharmacological effects of the drug are associated with the action of its glutamine metabolites, which inhibit the activity of AICAR, which leads to excessive accumulation of adenosine. In this regard, it should be recalled that adenosine, a purine nucleoside formed after intracellular ATP cleavage, has the ability to suppress platelet aggregation and simulate immune and inflammatory responses.

In general, these data allow us to consider MT , at least when used in low doses, not as an antiproliferative (immunosuppressive) agent, but as a representative of a new class of non-steroidal anti-inflammatory drugs (NSAIDs), the anti-inflammatory effect of which is associated not with inhibition of prostaglandin synthesis (as in classical NSAIDs), but with stimulation of the release of adenosine in the focus of inflammation (Table 2).

Finally, some of the pharmacological effects of MT may be related to the effect on the synthesis of polyamines, which are essential for cell proliferation and protein synthesis and are involved in cell-mediated immune responses.

The anti-inflammatory effect of MT has been demonstrated in experimental studies in models of adjuvant arthritis, streptococcal wall immunization-induced arthritis, and collagen arthritis. Clinical studies have shown that when using MT, clinical improvement occurs much faster than with other basic drugs , including cytostatic ones, has a clear dose dependence, quickly disappears after drug withdrawal and correlates with a decrease in the concentration of acute phase proteins.

Considering the fundamental role of immunoregulatory defects in the immunopathogenesis of inflammatory rheumatic diseases, data on the effect of the drug on the synthesis of “immunoregulatory” and “anti-inflammatory” cytokines are of particular interest [3].

In general, it seems that during treatment with low doses of MT, there is a switch in the synthesis of cytokines from Th2 (IL-2, g-IF) to Th3-type (IL-10), which explains the pronounced anti-inflammatory and immunomodulatory effects of low doses of the drug , especially evident in so-called Th2-dependent human diseases such as rheumatoid arthritis (RA). Another point of application of MT is the inhibition of the production of proteolytic enzymes (collagenase and stromelysin), which play an important role in joint destruction in RA. Finally, more recently, data have been obtained that in vitro MT stimulates monocyte differentiation and Fas antigen expression, which is associated with increased release of anti-inflammatory cytokines (soluble antagonist of IL-1 and rTNF-75R) and inhibition of IL-1b synthesis. At the same time, increased differentiation of monocytes is associated with an increase in the sensitivity of these cells to TNF-induced apoptosis. In general, these data suggest that one of the probable mechanisms of the anti-inflammatory action of MT is associated with the suppression of the recruitment of immature and “inflammatory” monocytes from the bone marrow to the area of ​​inflammation and a decrease in the lifespan of these cells in inflamed tissues.

Dosing regimen

MT is available in tablets of 2.5, 5 and 10 mg and in injection solutions (1 ml vials and 5 ml vials and ampoules) containing 10 mg of MT per 1 ml.

In rheumatic diseases, MT is prescribed once a week (orally or parenterally) , since more frequent use of the drug is associated with the development of acute and chronic toxic reactions. Due to the possible intolerance of the simultaneous administration of large doses of the drug it is recommended to prescribe it fractionally, with a 12-hour interval, in the morning and evening hours. The initial dose of MT in most cases should not exceed 7.5 mg per 1 week, and in the elderly – 5 mg per 1 week. The effect is assessed after 4–8 weeks, if it is absent with normal tolerance, the dose of MT is gradually increased by 2.5 mg per week, since the clinical efficacy of MT has a clear dose dependence. In this case, the total weekly oral dose should not exceed 25 mg. This is due both to the possibility of developing toxic reactions, and to the deterioration of the absorption of higher doses of the drug in the gastrointestinal tract (GIT).

When increasing the dose of MT, the assessment of toxicity is carried out 6 days after taking the drug. Parenteral administration of MT is used when oral administration is ineffective or when toxic reactions from the gastrointestinal tract develop. It must be borne in mind that the lack of effect in oral administration of MT in some cases is associated not only with the inefficiency of the drug itself, but with low absorption in the gastrointestinal tract, which does not allow reaching the optimal concentration of the drug in the blood.

Cancellation of MT, as a rule, leads to an exacerbation of the disease in the period between the 3rd and 4th week. Although the negative effect of MT therapy on wound healing and the development of postoperative infectious complications has not been proven, it is recommended to stop the drug a week before the proposed surgical intervention and not prescribe it for 2 weeks after surgery. Of particular importance is the interaction of MT and NSAIDs, since this combination is most often used in the treatment of various rheumatic diseases. During treatment with MT, salicylates should be avoided and short-acting NSAIDs should be used. Some authors recommend replacing NSAIDs with low-dose glucocorticoids (GCs) on the day of MT intake.

Side effects and methods of their correction

The main approaches aimed at preventing the development of side effects, reducing the toxicity of MT and monitoring patients are summarized in Table. 3.

Despite the fact that certain side effects are observed in most patients receiving low doses of MT, in general, the ratio of efficacy/toxicity of MT is significantly better than other basic antirheumatic drugs [4]. In fact, the frequency of toxic reactions during treatment with MT approaches that and is even lower than when taking some NSAIDs. It is noteworthy that the advanced age of patients is not the leading factor determining the increase in toxicity (and decrease in efficacy) of treatment with this drug. Severe adverse reactions (pneumonitis, thrombocytopenia, impaired liver function) most often develop in the first year of treatment with MT; no cumulative toxic reactions are observed over subsequent years.

In general adverse reactions developing during treatment with MT (Table 4) can be conditionally divided into 3 main categories:

• Reactions associated with folate deficiency (stomatitis, hematopoiesis suppression) that can be corrected with folic or folinic acid

• “Idiosyncratic” or allergic reactions (pneumonitis), which sometimes stop when treatment is interrupted

• Reactions associated with the accumulation of polyglutaminated metabolites (liver damage).

There is evidence of a significant reduction in the frequency and severity of side effects of MT treatment (with the exception of cytopenia and lung damage) when prescribing folic acid at a dose of 5-50 mg per day. Along with folic acid, calcium folinate can be used, which is a synthetic form of the reduced metabolically active coenzyme folate (5-formyltetrahydrofolic acid), for the subsequent cleavage of which there is no need for dihydrofolate reductase. The drug is specifically designed to overcome the metabolic block that occurs with the introduction of high doses of MT, and is used as an antidote for toxic reactions to MT and prophylactically to reduce the frequency and severity of side effects of treatment with high doses of the drug.

According to a meta-analysis of randomized controlled trials, folic acid , if given immediately or during the first 6 months of MT treatment, is associated with a 70% reduction in the incidence of gastrointestinal side effects. Attention should be paid to the need to prescribe folic acid no earlier than 24 hours after taking MT and at a dose lower than the dose of MT. There is evidence that the appointment of folic acid (5 – 27.5 mg / day) can reduce the level of homocysteine, and therefore reduce the risk of developing cardiovascular disease.

The development of resistance to MT is a serious problem in patients treated with high doses of the drug for malignant neoplasms. The likelihood of developing resistance to low doses of MT is confirmed by the data of clinical studies, which determined the possibility of exacerbation of the disease against the background of stable, previously effective doses of MT and the need for a gradual increase in dose during long-term treatment. It is believed that resistance to MT may be associated with a violation of MT transport into the cell, a weakening of polyglutamination, a violation of drug binding to DHFR, an increase in the destruction of polyglutaminated MT metabolites, or a decrease in the affinity of adenosine receptors.

Use of methotrexate in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory human diseases, the frequency of which in the population reaches 1%. The introduction of low-dose MT therapy into clinical practice is a major advance in the treatment of RA. The efficacy of MT at a dose of 7.5–25 mg per week in RA (including “early”) in comparison with placebo and other antirheumatic drugs (including in patients resistant to other basic antirheumatic drugs) has been confirmed in many controlled studies [1 ,2,4].

A clinical effect of 50% according to the criteria of the American College of Rheumatology or WHO / EULAR was observed in 70% of patients and was combined with a decrease in the need for GCs and NSAIDs. The action of the drug begins very quickly (between the 4th and 8th weeks) and reaches a maximum by the 4th month. However, complete remission develops quite rarely, and when the drug is discontinued, an exacerbation usually occurs. An important advantage of MT is the possibility of taking it for a long time without a decrease in activity and the development of side effects. It has been established that more than half of the patients continue to take the drug even 5-10 years after the appointment. This greatly exceeds the possibility of long-term treatment with other basic antirheumatic drugs. It is noteworthy that the lack of effect is the basis for discontinuation of treatment in less than 10% of patients.

Important parameters reflecting the effectiveness of MT in RA include its effect on the severity of radiographic progression of destruction of the joints of the hands and feet, which, however, is not observed in all patients. According to R. Rau, MT slows down radiographic progression only in those patients who managed to suppress the overall inflammatory activity of the disease.

MT is central to the combination therapy of RA , which allows to reduce the dose of MT, and thus improve treatment tolerance and reduce the risk of side effects. Of particular interest is the study of the possibility of combined therapy with MT and cyclosporine A (CsA), which is one of the most powerful drugs with selective immunopressive activity. In recent studies, it was found that the combined use of MT and CsA leads to an increase in the concentration of MT in the blood plasma by 26% and a decrease in the concentration of the main metabolite of MT (7-OH-MT) by 80%. At the same time, no change in the metabolism of CsA itself is observed. Thus, in the process of combined therapy of MT and CsA, a new, previously unknown, type of synergistic effect of drugs is observed, which, on the one hand, can cause an increase in the anti-inflammatory effect of MT, and on the other hand, a weakening of adverse reactions caused by the accumulation of a toxic metabolite 7– OH-MT. In patients with severe RA who have incomplete clinical improvement on the background of MT monotherapy, combined treatment of MT in combination with CsA allows to achieve a significant improvement in a number of indicators of the articular syndrome . It is noteworthy that the frequency of adverse events in patients receiving combined therapy with MT and CsA and MT monotherapy was approximately the same. More recently, data have been obtained that the clinical improvement achieved during the first 6 months of combined therapy with MT and CsA is maintained in patients for the next 6 months. In patients who received MT monotherapy with insufficient clinical effect during the previous 6 months, it is possible to achieve clinical improvement in the process of combined therapy of MT and CsA. Other A promising combination is the combination of MT with the introduction of monoclonal antibodies to tumor necrosis factor-a (TNF-a). A synergistic effect of MT and antibodies has been revealed, which manifests itself in an increase in the duration of clinical improvement. It is noteworthy that one of the reasons for the synergistic effect may be associated with the ability of MT to reduce the immunogenicity of antibodies. Preliminary results indicate the promise of combination therapy of MT with other “biological” drugs, such as the IL-1 receptor antagonist Etanercept (soluble 55R-TNF-a linked to the Fc domain of human IgG1).

There is evidence of successful treatment of MT in patients with Felty’s syndrome. In the vast majority of patients treated with low doses of MT (7.5 mg/day), there is an increase in the level of granulocytes and a decrease in ESR after an average of 4-6 weeks from the start of therapy. MT treatment can achieve remission or significant clinical improvement in individuals with adult Still’s disease.

In recent years, there have been several reports of the possibility of intensifying the treatment of MT in RA patients with very high disease activity, severe systemic manifestations, refractory to standard doses of MT or other basic antirheumatic drugs. The effectiveness of intravenous administration of high doses of MT in RA is especially convincing in cases of a torpid course of the disease and in rheumatoid vasculitis. Probably, one can expect an increase in the effectiveness of MT pulse therapy when it is synchronized with program plasmapheresis, by analogy with intensive therapy for systemic lupus erythematosus.

MT has established itself as a promising drug for local therapy. There have been reports of successful use of MT in the form of intra-articular injections in patients with GC-resistant synovitis.

Thus, the theoretical substantiation and widespread use of MT in clinical practice for the treatment of chronic inflammatory human diseases (primarily rheumatic diseases) was undoubtedly one of the most striking achievements of medicine at the end of the 20th century and is not much inferior in importance to the introduction of GCs and NSAIDs.

References can be found at http://www.rmj.ru

DISPUTE MOMENTS OF GCS THERAPY clinical observation and opinion of a rheumatologist — InfoMedPharm Dialogue”

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RHEUMATOID ARTHRITIS: DISPUTE MOMENTS OF GCS THERAPY clinical observation and opinion of a rheumatologist

RHEUMATOID ARTHRITIS: DISPUTE MOMENTS OF GCS THERAPY
clinical observation and opinion of a rheumatologist

Usually, as clinical observations, doctors present some rare, atypical cases that could surprise colleagues with an unusual course of the disease or non-standard and successful solution of therapeutic problems. The clinical observation that I will give below, on the contrary, rather belongs to the category of frequent, unfortunately, situations.

Description

Meshkov Aleksey Dmitrievich N.I. Pirogov, Ph.D.

The patient developed rheumatoid arthritis (RA) at the age of 66 years. The disease debuted with episodes of swelling, pain in the small joints of the hands. Laboratory data at the time of onset of the disease are unknown. The patient was treated with non-steroidal anti-inflammatory drugs (NSAIDs), sulfasalazine at a dose of 2 g per day. Apparently, this therapy was insufficient, since the arthritis became permanent, morning stiffness joined. By this time (more than 1 year has passed since the onset of the disease) are the first known clinical and immunological indicators – increased ESR, CRP, high titers of rheumatoid factor and ACCP, which today allows us to confidently confirm the diagnosis of rheumatoid arthritis.

The treatment was prescribed according to current clinical guidelines – methotrexate at a dose of 10 mg per week and methylprednisolone 8 mg per day. But the logic of the therapeutic approach, chosen as a continuation of treatment, is not entirely clear. As expected, the patient improved fairly quickly on the recommended treatment. Twice attempts were made to reduce the dose of glucocorticosteroids (GCS), both times unsuccessfully – with a decrease in the dose, arthritis worsened. It is not known whether this was a consequence of the patient’s poor compliance (there are quite pronounced cognitive impairments) or it was a deliberate medical tactic, but there has never been an attempt to increase the dose of methotrexate.

After 2 years of glucocorticosteroid therapy, the patient suffers a compression fracture of the spine (L5), and therefore she goes to endocrinologists. Therapy with calcium, vitamin D3 preparations begins, denosumab is prescribed. Endocrinologists recommend that the patient consult a rheumatologist.

He gradually increases the dose of methotrexate to 25 mg per week. This allows you to abandon the use of GCS in a year. Despite short-term episodes of deterioration after each reduction in the dose of corticosteroids, the patient did not develop adrenal insufficiency, and the remission of arthritis was maintained. There were no more compression fractures during this time, and in general the prognosis in this case seems to be quite favorable.

Discussion

Treat to target

There is a fairly common opinion among patients that methotrexate and other cytostatics are “chemistry” and that this treatment will “destroy” the immune system or “destroy” internal organs. Sometimes it is very difficult to convince the patient at the reception, it takes time, effort, psychological stability and extensive knowledge. Not always the doctor has all these resources in abundance, and as a result, patients receive minimal (and therefore ineffective) doses of methotrexate or refuse to use it at all. In the future, there is no escalation of therapy and the requirements of the key strategy for the treatment of rheumatoid arthritis – treat to target – are not observed.

Another, no less dangerous situation lies in hormonal preparations (GCS). According to a British retrospective analysis, corticosteroids are prescribed to more than half of outpatients with RA. They are allowed at the start of therapy or an exacerbation of the disease (change of basic drugs), but with the proviso that most current clinical recommendations require their cancellation after 3 months of treatment, less often after 6. In my opinion, the main danger lies here – when prescribing GCS, doctors do not always warn patients about the need to cancel them. Or they warn, but patients do not adequately and attentively perceive this information. Moreover, if it was possible to achieve remission using a combination of hormonal drugs and methotrexate, it is easier, of course, to leave all treatment “as is” – increasing the dose of methotrexate, lowering the dose of hormones is associated with additional actions, the need to control tests, repeat visits to the doctor, which can be burdensome for the patient and sometimes even for the specialist.

On the part of patients, the situation is also ambiguous. As with methotrexate, most “novice” patients have already read on the Internet, learned on the forums about the side effects of GCS, and this, of course, has many advantages. But at the onset of rheumatoid arthritis, the pain can be so severe that NSAIDs do not help, and then a tablet of methylprednisolone or prednisolone, even if “terrible”, but incredibly effective, for the first time bringing significant investment, begins to be considered by the patient as the only true and possible treatment. Feeling good, there are no side effects of treatment during the “honeymoon” of GCS therapy, why in this case should you see a doctor if nothing hurts?

Thus, we see that at the first (and most important) stages of the meeting between a rheumatologist and his patient, difficulties can arise on both sides, which, under unfavorable circumstances, can lead to patients taking corticosteroids for years with rheumatoid arthritis.

In the first months, this can really turn out to be a win-win solution that benefits both the patient and the doctor, which is why corticosteroids are present in modern clinical guidelines. But the main difficulty and trick, as I wrote above, is that in many patients who have started treatment with GCS, such therapy can continue for years. Ultimately, years later, and in some patients with comorbidities, even months, everything will turn out to the detriment of both the patient and the doctors who will have to cope with this already more difficult situation.

Conscious prescription – from short to lifelong use

A very important caveat – in this case we are talking about rheumatoid arthritis, as the most common and “classic” arthritis, and for the most part can be extrapolated to other arthritis. In the treatment of spondyloarthritis, especially with an isolated axial lesion, there is even less room for systemic corticosteroids. And it is fundamentally important to separate systemic diseases in this case, such as systemic lupus erythematosus, vasculitis, and some others, in which, despite the undoubted success in expanding steroid-sparing treatment regimens and a differential approach using the minimum required doses of corticosteroids, it is this group of drugs that remains key and in most cases allows you to save the organ or life of the patient and, as a rule, is prescribed for long-term use, sometimes for life.

In the case of a “conscious” appointment of GCS for systemic diseases, as a rule, both the doctor and the patient know that this is a necessary and only correct step, and discuss in advance all possible side effects and ways to minimize them. Understanding that this treatment will be long, allows you to immediately begin the prevention of complications. In fact, in accordance with modern schemes for the prevention or treatment of osteoporosis, when taking corticosteroids, in addition to vitamin D3 and calcium preparations, almost all patients should immediately be prescribed bisphosphonates. In those situations where the appointment of corticosteroids is planned for a short time, as a rule, less attention is paid to the prevention of complications, and therefore uncontrolled further intake of corticosteroids without medical supervision may be more destructive.

In the case of rheumatoid arthritis, the use of corticosteroids is unfavorable in two ways. The first is the well-known side effects of steroid therapy: osteoporosis with compression fractures, glycemic disturbances, cataracts, increased risk of cardiovascular events and infections. Secondly, the question remains whether the rate of radiological progression is the same when achieving remission only at the expense of basic anti-inflammatory drugs (DMARDs) or a combination of lower doses of DMARDs in combination with GCS. Although it has been shown that the addition of corticosteroids to the basic drugs (DMARDs) in the case of active RA can slow radiographic progression, direct comparisons of outcomes in achieving remission on DMARDs or DMARDs + GCS have not been conducted. Apparently, there will be no significant need for such studies: in addition to GCS, doctors now have a large number of drugs in their arsenal that reliably slow down the radiological progression of rheumatoid arthritis. These are standard synthetic drugs that can be used in combinations, genetically engineered biological drugs and a relatively new group – Janus kinase inhibitors. It is hard to imagine that none of this variety of drugs will not suit the patient.

Of course, there are limitations – it is rarely possible to completely stop corticosteroids in patients who have received them for decades, and sometimes therapy with corticosteroids is the only possible way to help patients with an active chronic infectious process. Also, GCS may be needed in case of systemic manifestations of RA. Of course, every doctor will be able to find cases in his practice when long-term treatment without GCS was impossible. But this is more the exception than the rule.

Own niche

I don’t want to give the impression that I am categorically against the GKS under the RA. These drugs have their own and very important area of ​​​​use, but, like so much in medicine, the ratio of benefits and harms depends on the nuances: dose, route of administration and, most importantly, the duration of therapy. Perhaps compliance also needs to be taken into account – in the case when the patient does not follow the doctor’s recommendations well, injection therapy is probably preferable, since it is impossible for the patient to continue it on his own. It may be necessary to persistently convey to patients that with this disease this is only a temporary measure and after 3 or maximum after 6 months GCS will definitely need to be canceled. On the other hand, the problems of access to specialized care and drugs are absolutely understandable, especially at the stage of transition to “second-line” therapy – genetically engineered and targeted synthetic drugs.

Of course, corticosteroids have a definite and well-deserved place in the treatment of rheumatoid arthritis, but it is important to minimize the time of their use and not consider remission against the background of their use as a good result. And it’s hard for me not to call those cases when it is possible to completely cancel GCS in patients with RA as small victories.

References

1. van Vollenhoven R. Treat-to-target in rheumatoid arthritis — are we there yet? // Nature Reviews Rheumatology. 2019.
2. Russian Association of Rheumatologists. Clinical guidelines “Rheumatoid arthritis.” 2018.
3. Singh J.A. et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis // Arthritis Care Res. (Hoboken). 2016.
4. Smolen J.S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update // Ann. Rheum. Dis. BMJ Publishing Group, 2017. Vol. 76, No. 6. P. 960–977.
5. Black R.J. et al. Half of UK patients with rheumatoid arthritis are prescribed oral glucocorticoid therapy in primary care: A retrospective drug utilization study // Arthritis Res. Ther. BioMed Central Ltd., 2015. Vol. 17, No. 1.
6. Russian Association of Rheumatologists. Federal clinical guidelines for the diagnosis and treatment of ankylosing spondylitis (Bekhterev’s disease). 2013.
7. Fanouriakis A. et al. 2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus // Annals of the Rheumatic Diseases. BMJ Publishing Group, 2019. Vol. 78, No. 6. P. 736–745.
8. González-Gay M. et al. Treatment of giant cell arteritis // Biochemical Pharmacology. 2019.