Medication for the treatment of rheumatoid arthritis

Photo of a man taking his medicine (PantherMedia / nyul)

People with rheumatoid arthritis typically have permanent inflammation in several joints. The joints are painful and swollen, and gradually stiffen. Rheumatoid arthritis usually progresses slowly over many years. The aim of treatment with medication is to relieve the symptoms and prevent the progression of the disease as much as possible.

In rheumatoid arthritis, various kinds of medication are used to relieve the symptoms, reduce the inflammation and to keep the joints working properly for as long as possible. There are two types of therapy: disease-modifying therapy and symptomatic therapy.

  • Disease-modifying therapy: These medications are taken regularly for longer periods of time independent of any acute symptoms. They are known as “disease-modifying anti-rheumatic drugs” or “DMARDs” for short. Disease-modifying drugs inhibit inflammatory responses in the joints of people with rheumatoid arthritis. In this way they can at best stop – or at least delay – the progression of the disease, preventing damage to the joints. Their effect is often only noticeable after one to four months of treatment. DMARDs can be divided up into “conventional” and “biological” disease-modifying drugs.
  • Symptomatic therapy: Medications used in symptomatic therapy are taken to relieve acute pain and inflammation. The main ones are non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (also called paracetamol), and steroids (corticosteroids).

How do the conventional DMARDs work?

Conventional disease-modifying drugs have been used for decades now. These drugs have very different mechanisms of action, and they don't produce the same effect for everyone. If one of the drugs is not effective or is not well tolerated, another one can be tried as an alternative. The medications also have different possible side effects.

All of these factors are important to consider when deciding whether or not to use a certain drug. The main conventional DMARDs are:

  • Azathioprine
  • Ciclosporin A
  • Gold salts
  • (Hydroxy)chloroquine
  • Leflunomide
  • Methotrexate (MTX)
  • Sulfasalazine

Out of all the conventional disease-modifying drugs, methotrexate seems to be the best tolerated over the long term. This is why it's generally considered to be first-line treatment. Methotrexate suppresses the activity of the body's defense cells, which reduces their inflammatory response to rheumatoid arthritis. This drug is also used in the treatment of cancer at much higher doses. Methotrexate can be taken once a week in tablet form or injected as a solution.

Some medications can be used during pregnancy, while others cannot. Because the latter, such as methotrexate or leflunomide medications, can cause harm to an unborn baby, it's important to practice contraception while taking them. Ideally, women who have rheumatoid arthritis and would like to have children should talk to their doctor before they get pregnant. Otherwise, they should do so as soon as they find out that they are pregnant.

Some of the medications can lower men's fertility when taken.

What does research say about conventional DMARDs?

Research has shown that conventional disease-modifying drugs can prevent damage to joints and relieve symptoms. In research on medication for rheumatoid arthritis, a treatment is considered to work if it reduces swelling in the joints and at least three of the following improvements occur:

  • Pain relief
  • Reduced inflammation
  • Improved joint function
  • Better overall rating of general health

An analysis of methotrexate studies that lasted one year found the following:

  • Symptoms were reduced by at least half in 23 out of 100 people who took methotrexate.
  • Symptoms were reduced the same amount in 8 out of 100 people who took a placebo (fake drug) for comparison.

So treatment with methotrexate helped 15 out of 100 people to feel significantly better. Symptoms like morning stiffness also improved in a lot more people who took a conventional disease-modifying drug.

There hasn't yet been any good-quality research looking into whether one particular conventional disease-modifying drug is more effective than any of the others. If one of the drugs from this group doesn't help, it's worth trying out another one.

Side effects

Conventional disease-modifying drugs can have various side effects, depending on the drug in question.

  • Methotrexate: upset stomach, nausea, drowsiness and inflammation of the mucous membranes lining the mouth
  • Sulfasalazine: upset stomach, nausea, vomiting, increased sensitivity to light, skin rash, itching and headaches
  • Leflunomide: diarrhea, hair loss and rash
  • (Hydroxy)chloroquine: upset stomach, nausea, vomiting, vision problems
  • Gold salts: skin rash and itching, inflammation of the stomach lining

Gastrointestinal (stomach and bowel) problems are particularly common at the beginning of treatment for many of these drugs. In studies, methotrexate caused these kinds of problems in 4 out of 100 people. Those who took methotrexate were also more likely to have infections. That happened over the course of one year in 12 out of 100 people in one larger study. About 5 out of 100 people experienced hair loss while taking methotrexate.

Some of these side effects arise from methotrexate interfering with the effect that folic acid has in the body. The risk of side effects from methotrexate can be lowered by also taking low-dose folic acid (5 to 10 mg) once a week.

Methotrexate can also be injected subcutaneously (under the skin) or into muscle tissue. It's important to observe the one-week breaks between doses. Injections are associated with fewer nausea and diarrhea symptoms than tablets, and they also help to make the drug work a little better.

In very rare cases the medications can cause serious side effects such as inflammations, changes in blood cell count, and liver damage. During treatment blood and urine are tested regularly to detect these kinds of serious side effects more quickly. It's important to talk to a doctor if side effects occur.

How do biologics work?

Biologics, sometimes also called biologic DMARDs, are obtained from living cell cultures. They interfere with messenger substances in the body's immune system to influence the rheumatic inflammatory response. Biologics are considered as treatment for rheumatoid arthritis when it hasn't shown enough improvement from conventional disease-modifying drugs. The biologics are typically used in combination with methotrexate. People who don't tolerate methotrexate well can start treatment with a biologic only. All of the biologics approved in Germany so far are given as an injection or an infusion (a drip). It's also possible to inject the drug on your own.

The following biologic disease-modifying drugs have been approved for use in Germany and other countries:

  • Abatacept
  • Adalimumab
  • Anakinra
  • Certolizumab pegol
  • Etanercept
  • Golimumab
  • Infliximab
  • Rituximab
  • Tocilizumab

Biologics can reduce pain, swelling and morning stiffness, and also help against fatigue. But they have various side effects too. They can cause skin rashes, itching or pain where the injection or infusion needle was inserted. Infection is also possible. Because these medications haven't been approved for very long, we don't know as much about their long-term safety as we do about the long-term safety of conventional DMARDs.

Research summaries

What other medications can help relieve the symptoms?

There are a number of symptom-relieving medications that can be used in addition to disease-modifying drugs in the treatment of rheumatoid arthritis. These medications may be used in addition: 

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are medications that reduce inflammation and relieve pain. They can relieve joint pain and reduce swelling. Commonly used NSAIDs for the treatment of rheumatoid arthritis include diclofenac, ibuprofen and naproxen. Celecoxib and etoricoxib are two other relatively common NSAIDs. The different NSAIDs are basically equally effective, but their effectwill vary from person to person.

Preventing stomach ulcers associated with painkillers

NSAIDs can cause stomach ulcers when used over a long period of time. Stomach ulcers are usually felt as a pain in the upper abdomen. The pain is particularly noticeable just after eating, when the stomach produces more acid. Sometimes stomach ulcers don't cause any symptoms, and people only find out that they have one if they have serious complications such as bleeding in the stomach.

Stomach ulcers or bleeding occur in about 1 to 2 out of 100 people who take NSAIDs over a period of one year. This is only an average, though. Younger people who don't have any other risk factors are much less likely to have these side effects. People are at higher risk if they

  • are over 65 years old,
  • already had a stomach ulcer in the past,
  • take a certain antidepressant medication (a selective serotonin re-uptake inhibitor, SSRI),
  • take steroids or
  • take several NSAIDs at the same time, for example if they also take acetylsalicylic acid (the drug in medicines like Aspirin) for the prevention of cardiovascular disease.

The risk of complications affecting the gastrointestinal tract can be lowered considerably by taking NSAIDs together with medicine designed to protect the lining of the stomach, such as proton pump inhibitors like omeprazole or pantoprazole.

Celecoxib and etoricoxib are a lot less likely to cause stomach ulcers than the other NSAIDs that have been approved in Germany. But this is only true for people who are not taking acetylsalicylic acid too.

NSAIDs use in people with cardiovascular disease or kidney failure

With the exception of acetylsalicylic acid, NSAIDs can also increase the risk of cardiovascular diseases such as heart attacks. Naproxen has the lowest risk of all of the NSAIDs, so it is recommended for people who have cardiovascular disease in addition to rheumatoid arthritis.

NSAIDs can sometimes be a problem for people who have kidney disease too. Those who are considering using NSAIDs can talk to their doctor about which medication is most suitable for them.

Acetaminophen (paracetamol)

The painkiller acetaminophen (paracetamol) only has a weak anti-inflammatory effect. It is considered to be a well-tolerated drug and is sometimes a suitable alternative, particularly for people who can't take NSAIDs. But higher doses of acetaminophen can cause liver and kidney damage. So adults shouldn't take more than 4 grams (4,000 mg) per day according to the package insert. This is the amount in, for example, 8 tablets containing 500 milligrams of acetaminophen each. Waiting at least six hours between two doses is also recommended. So two 500 mg tablets of acetaminophen every six hours over one day would be the maximum allowed amount.

Corticosteroids (steroids)

Corticosteroids such as prednisolone (also called prednisone) reduce inflammation. They help relieve pain and joint swelling. They start working fast and have a stronger effect than NSAIDs. But corticosteroids can also have a number of serious side effects when taken over longer periods of time. These include an increased risk of bone fractures and infections. In order to prevent bone fractures, corticosteroids are taken together with things like calcium or vitamin D supplements.

Because of the potential side effects, corticosteroids are used at the lowest possible dose. They are used only for a few weeks or months at a time at higher doses. They can help to cover the stretch of time until the basic therapy of disease-modifying drugs takes effect. They can also be used for the temporary treatment of rheumatoid arthritis flare-ups.

Corticosteroids are also used in combination with DMARDs because they might help increase their anti-inflammatory effect. Research on this combination is not conclusive. It's also not clear for how long and at what dose an additional corticosteroid treatment would be best.

Corticosteroids can be injected directly into individual joints to target the most affected joints. This reduces the risk of side effects that affect the whole body. But local side effects, such as an infection in the joint, are still possible. Unfortunately there aren't enough high-quality studies looking at the advantages and disadvantages of these corticosteroid injections. So it's not possible to say what people with rheumatoid arthritis can expect from them.

How are the medications used?

The most suitable medication for a particular person will depend on various factors, including how doctors think the condition will develop, how far it has progressed, and whether certain medications can't be used, for instance because the person also has other medical conditions.

Generally speaking, treatment is started using methotrexate as a basic therapy. This conventional disease-modifying drug is usually taken one a week at a dose of 15 mg. Because it can take a while for methotrexate to start working, the glucocorticoid prednisolone is often used for more immediate symptom relief. After a few weeks there is a check-up to see whether the treatment is helping, and the dose might be adjusted. The check-up involves physical examinations, blood tests and sometimes x-rays too.

If a later check-up shows that the joints are still very inflamed, methotrexate can be used together with another conventional disease-modifying drug. If things still have not improved enough after a few months, treatment with a combination of methotrexate and a biologic drug may be considered. A different biologic can be tried out if the first one proves to be ineffective. If people have to stop using methotrexate because they don't tolerate it well, they can carry on using a biologic drug on its own.

The aim of long-term treatment with disease-modifying drugs is to prevent joint damage, or delay it for a long time, if possible. Some people stop using their medication after a while, for example because they don't tolerate it well or because it's no longer effective enough. They can then switch to a different medication. And sometimes a disease-modifying drug does not have a noticeable effect, so people stop using it for that reason.

NSAIDs, acetaminophen (paracetamol) and corticosteroids are mainly used to relieve acute symptoms such as pain. They are often only used for a short time, for instance during acute flare-ups. If the disease can be kept in check with disease-modifying drugs, treatment with medication for symptom relief is usually reduced as much as possible.

Using medication

Many people are afraid that long-term use of medication could harm their health. For instance, they might be worried that the medication will build up in their bodies, or they might be scared of becoming dependent on it. But there is no medical reason for concern. The body has ways of getting rid of medication. And it is not possible to become dependent on the medication that is used to treat rheumatoid arthritis.

Some people tolerate the medication better than others. Serious side effects can't always be ruled out, even if they're very unlikely. Many people accept this risk because their treatment is effective and helps them cope better with the disease in everyday life. That was also shown in the research on disease-modifying drugs: People who took them were more likely to continue treatment than those who used a placebo containing no active ingredient.