Understanding Methotrexate

How did a cancer drug become a staple treatment for rheumatoid arthritis and other types of inflammatory arthritis?


Methotrexate is one of the mainstays of treatment for inflammatory forms of arthritis, including rheumatoid arthritis (RA) psoriatic arthritis and juvenile idiopathic arthritis, because it not only reduces pain and swelling, but it can actually slow joint damage and disease progression over time. That’s why methotrexate is known as a disease-modifying anti-rheumatic drug (DMARD).

“There are great data to show that it’s extremely effective and safe,” says Prabha Ranganathan, MD, an associate professor of medicine in the division of rheumatology at Washington University School of Medicine. “Most rheumatologists, once they’re convinced that a patient really has rheumatoid arthritis, will use methotrexate as first-line therapy.”

Methotrexate isn’t new – it’s been part of RA treatment for three decades. Researchers first developed this drug in the 1940s as a cancer treatment. Then in 1985, a study published in the New England Journal of Medicine showed that it relieved pain, swelling and other symptoms in people with RA. Three years later, methotrexate won FDA approval for treating RA, and it soon became the treatment of choice for people with this condition and other forms of inflammatory arthritis as well.

Methotrexate Dosing

Most people with RA who use methotrexate – and about 90 percent of patients with this form of arthritis do use the drug at some point – take it by mouth. Typically people will start with a weekly dose of 7.5 to 10 mg, equal to three or four pills. If that doesn’t help with symptoms, the doctor may raise your dosage to 20 to 25 mg per week, or as high a dose as you can tolerate.

When pills alone won’t calm your symptoms, your doctor might give you subcutaneous methotrexate – a shot given under the skin. Taking the drug this way puts more of it into your system without increasing side effects. You can administer methotrexate yourself using an auto-injector.

Pairing With Other Drugs

Methotrexate is effective, but not everyone who takes it gains adequate relief from joint pain, swelling, morning stiffness and other symptoms. “The rest of the patients need something else,” says Yusuf Yazici, MD, an assistant professor of medicine at the New York University School of Medicine’s Hospital for Joint Diseases in New York City.

Fortunately for patients who need more relief, combining methotrexate with other medications will usually do the job, says Dr. Yazici. Most often, methotrexate is combined with other DMARDs, such as leflunomide (Arava), cyclosporine (Neoral), sulfasalazine (Azulfadine) and hydroxychloroquine (Plaquenil).

In people who don’t respond well to a DMARD – alone or in combination – doctors may try combining methotrexate with biologic drugs. These drugs inhibit part of the overactive immune system response that contributes to many types of inflammatory arthritis. The most common biologic combination is with tumor necrosis factor (TNF) inhibitors such as etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade) or certolizumab pegol (Cimzia). These drugs block TNF, a protein that promotes inflammation and damages joints. “TNF inhibitors and methotrexate appear to be synergistic,” says Arthur Kavanaugh, MD, a professor of medicine in the rheumatology division at the University of California at San Diego.

All the biologics seem to work equally well in combination with methotrexate. Research also shows that methotrexate combines effectively with other biologics, such as abatacept (Orencia), rituximab (Rituxan) and tocilizumab (Actemra).

A Long Record of Safety

Methotrexate is widely regarded as one of the safest of all arthritis drugs, though it carries some potential downsides. Gastrointestinal symptoms such as nausea and vomiting are the most frequent side effects linked to the drug. Sometimes the drug will affect liver function tests, especially when it’s taken in higher doses. Your doctor will monitor you for liver effects.

Other possible side effects include hair loss, mouth sores, shortness of breath, headaches, fatigue, drowsiness and dizziness. Taking folic acid daily can help offset these problems. Certain people, notably women who are or may become pregnant, should not take methotrexate. Learn more about methotrexate side effects here.

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