Rheumatoid arthritis (RA) is a painful and debilitating condition that, according to the World Health Organisation, impacts around 18 million people worldwide.
Methotrexate is usually the first medication prescribed to RA patients, and the most common, with more than 900,000 people taking it in the US alone. However, methotrexate may not be suitable for everyone, and it may even stop working in some patients. As such, it’s important to be aware of alternative treatments that are available.
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What is methotrexate?
Methotrexate is a ‘disease-modifying antirheumatic drug’ (DMARD) commonly prescribed for rheumatoid arthritis (RA). It acts as an immunosuppressant, which means it slows the body's immune system and reduces inflammation – therefore alleviating pain and long-term damage to the joints.
The drug is typically sold under the brand names Otrexup, Trexall, and Rasuvo, and it is often the initial treatment a medical professional will recommend for RA. However, DMARDs can present serious risks for some people, so they aren't suitable for everyone.
What is methotrexate used for?
As well as treating RA, methotrexate can be taken for other inflammatory conditions such as psoriasis. It is also used in certain cancer patients to slow the growth of cancerous cells.
What are the side effects of methotrexate?
Common side effects include stomach pain or indigestion, a loss of appetite, diarrhea, feeling or being sick, tiredness, headaches, and hair loss.
According to the Arthritis Foundation, people taking methotrexate have a 23% higher rate of experiencing gastrointestinal symptoms, such as nausea and vomiting, and are 15% more likely to get an infection.
It’s also important to be aware that this population has a 42% higher rate of lung problems, including trouble breathing and coughing. A small number may also suffer with inflammation of the lungs with a conduction called pneumonitis, which can be fatal.
How to know if methotrexate is working for rheumatoid arthritis
If your RA symptoms are improving, methotrexate is likely working. However, blood tests and regular checkups with a medical professional can help determine this.
Other tests that gauge the impact of methotrexate can include:
- Imaging tests, including X-rays, MSUS, and magnetic resonance imaging (MRI) to check for worsening joint damage
- Erythrocyte sedimentation rate (ESR) tests to measure inflammation levels
- Multi-biomarker disease activity (MBDA, Vectra DA) tests to determine how aggressive your RA is
- C-reactive protein (CRP) tests to measure inflammation in your body
How to know if methotrexate is not working
Undergoing the above tests can confirm whether or not methotrexate is not working for you. However, you can also keep a lookout for symptoms yourself, such as an increase in stiffness or flares, more intense symptoms that interfere with daily activities, and new symptoms, including pain in other joints. Increased tiredness can also be a telltale sign.
Why might methotrexate stop working for rheumatoid arthritis?
Research about the risk factors of methotrexate in RA patients indicates that around a quarter of patients stop taking it after a year, often due to it not working anymore. This might be due to your body adapting to the drug and developing antibodies that fight it, rendering it partially or fully ineffective.
Another study about treatment failure in rheumatoid arthritis suggests that methotrexate might not be suitable for people who don’t express enough of a particular receptor and are therefore less likely to be helped by the medicine.
What can I do when methotrexate stops working for RA?
If methotrexate doesn’t seem to be working for you, speak to your doctor who will be able to organize the tests previously mentioned to identify how effective it's been so far. Depending on the results, they may suggest altering the dose or switching to a different treatment option. In some instances, they may also recommend methotrexate injections if it isn't effective in tablet or liquid form.
What treatments are available if methotrexate is not working?
Several other treatments for rheumatoid arthritis are available if your methotrexate isn’t effective, usually falling into one of the following categories.
DMARDs
DMARDs (disease-modifying anti-rheumatic drugs) include methotrexate as well as sulfasalazine, hydroxychloroquine, leflunomide, and azathioprine, and they are usually the first type of medication a doctor will recommend. This type of medication helps reduce inflammation and slow the progression of your RA. If you’re not responding to methotrexate, a combination of DMARDs might be prescribed.
Biologics
Biologics are created from live cells and mimic the natural proteins of your immune system. They’re generally prescribed instead of or in addition to DMARDs if they’re not working for you. They may also be safer for people with certain pre-existing health conditions (such as liver problems), or for pregnant women. However, they do pose their own risks, including urinary tract infections, upper respiratory infections, skin infections, and pneumonia.
Corticosteroids
Corticosteroids, also known as glucocorticoids or steroids, are anti-inflammatory and immunosuppressive, and generally prescribed for fast-acting relief during flare-ups, whilst waiting for DMSRDs to take effect. However, although they’re very effective, long-term use poses the risk of side effects, ranging from weight gain and insomnia to infections and osteoporosis.
Pain relievers
Pain relievers are often used to treat the discomfort and inflammation associated with RA. Nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen sodium, and Tylenol (acetaminophen) are available over-the-counter. Alternatively, your healthcare provider may prescribe narcotic pain relievers, which each come with their own risks and benefits.
Combination therapies for rheumatoid arthritis
As every RA medication works differently, they can sometimes be combined to deliver a greater impact if one drug alone isn’t effective.
Double therapy
As already mentioned, methotrexate can sometimes be combined with another DMARD, such as azathioprine, cyclosporine, hydroxychloroquine, leflunomide – or sulfasalazine, which is usually the most effective. Two biologic medications can also be combined.
DMARD plus a biologic
Combining a biologic drug with methotrexate can also be very effective and more impactful than using one of the medications in isolation.
Triple therapy
If combining two drugs doesn’t have the desired impact, your medical practitioner may suggest triple therapy. This usually involves methotrexate, hydroxychloroquine, and sulfasalazine.
DMARD plus an anti-inflammatory drug
DMARDs can take weeks or months to begin working, so your doctor might give you an anti-inflammatory drug, such as an NSAID or steroid, to manage your symptoms in the meantime. The combinations can be altered to your specific needs.
Should I consider surgery if methotrexate is not working?
If none of the above treatments are working or you’re unable to take them, your healthcare professionals might consider surgery. This is usually reserved for more severe cases of RA that have resulted in severe joint pain and damage, and you will be assessed to determine whether this type of procedure is suitable for you.
Alternatives to rheumatoid arthritis medication
Changes to your lifestyle can sometimes alleviate your symptoms or make them easier to manage. They include:
- gentle exercise to improve flexibility, support bone strength, and maintain joint range of motion (consult your healthcare provider beforehand)
- resting during a flare-up to reduce inflammation and further damage
- physical therapy with an arthritis specialist to restore joint function and guide movement
- mind-body therapies that may reduce chronic pain and stress, such as yoga, meditation, tai chi, deep breathing, acupuncture, acupressure, and massage
- a healthy diet high in antioxidants to help combat inflammation
- fish oil or turmeric supplements as they may reduce inflammation
- stopping smoking as it can impact blood circulation and inflammation
Clinical trials for rheumatoid arthritis
Despite RA affecting so many people across the globe, more research is needed to understand this distressing disease and find better treatments that can help more patients. Clinical studies in arthritis assess the impacts of these new interventions.
Why get involved in a clinical trial for RA?
Clinical studies are essential for the research process of new treatments. By participating, you can contribute to life-changing medical advances that have the potential to help millions of people across the globe.
If your current treatment for RA isn’t working, taking part in an arthritis clinical trial could also give you access to innovative new treatments that aren’t yet on the market.
How to get involved in a clinical trial for RA
Before participating in a clinical trial, talk to your healthcare professional who might be aware of current studies, and can help you determine whether you’re a suitable candidate. You can also search online clinical trial databases, or speak to members of local support groups who may know about current research in the field.
Conclusion
Although methotrexate is a common treatment for rheumatoid arthritis and has helped countless patients across the world, it may not work for everyone, and it can stop working after a period of time.
Alternative treatments are available, providing much-needed relief. However, much is still to be discovered about how to treat this debilitating condition, and clinical trials in arthritis are essential for advancing medical discoveries that could transform millions of lives.
FAQs
Why should I take folic acid with methotrexate?
A small dose of folic acid is often prescribed alongside methotrexate to help minimize the side effects. However, large doses stop the drug from working, so it’s important to follow your medical practitioner’s guidance. You should also be careful of eating too many foods that contain folic acid, especially green vegetables such as asparagus, peas, broccoli, and Brussels sprouts, plus brown rice and chickpeas.
Is it ok to take vitamin D supplements with methotrexate?
If you have RA, it’s important that you’re getting enough vitamin D, so you should get your levels checked. It is generally regarded as safe to take vitamin D with methotrexate. However, although no interactions have been found between them, it doesn’t mean they don’t exist, and as such, you should consult your healthcare provider before taking them.