Can Rheumatoid Arthritis Medications Cause Long Term Side Effects?

Rheumatoid arthritis has become one of the most common forms of inflammatory arthritis. There are now dozens of medications to both treat and slow down its progression, but side effects may occur and vary by person. 

In this blog, we speak to Amy Dedeke, M.D., a board-certified rheumatologist with INTEGRIS Health Medical Group Rheumatology, for an overview of these drugs, their side effects and how to decide if the risks outweigh the rewards.

“Most people associate rheumatoid arthritis with inflammation and joint pain in the hands, feet, knees, hips, shoulders and elbows,” says Dedeke, “but RA also impacts cardiovascular function. Cytokines, proteins released during the inflammatory response, can cause plaque buildup in arteries and cause damage to blood vessels over time – plaque can block blood flow and cause heart attacks and strokes.”

What is rheumatoid arthritis?

Rheumatoid arthritis, or RA, occurs when the immune system mistakenly attacks healthy cells (mainly around joints), leading to inflammation, painful swelling and bone erosion.

In healthy people, a type of connective tissue called the synovium protects joints and reduces friction when bones move. For example, the synovium (also called the synovial membrane) in your knee contains a fluid that lubricates the joints, so it moves freely when you bend and straighten the leg.

But in people who have RA, the immune system attacks this membrane and causes inflammation. Over time, the synovium thickens and will cause pain and stiffness. Eventually, cartilage in bones and joints begins to deteriorate. Without cartilage, which acts as a shock absorber, bones begin to erode.

What medications treat RA?

Several types of medications exist to treat rheumatoid arthritis. Each drug serves a specific purpose, whether to relieve pain and inflammation or to slow down the disease progression altogether.

The three classes of drugs include the following:

• Non-steroidal anti-inflammatory agents (NSAIDs)
• Corticosteroids
• Disease modifying anti-rheumatic drugs (DMARDs)

NSAIDs

Prostaglandins, a type of lipid that has hormone-like qualities, produce inflammation as a natural and necessary response to injury and tissue damage. People with rheumatoid arthritis produce excess prostaglandins that lead to prolonged inflammation. 

• NSAIDs, such as ibuprofen and naproxen, help reduce acute inflammation to minimize pain associated with rheumatoid arthritis. More specifically, NSAIDs block cyclooxygenase enzymes needed to make prostaglandins. Without the enzymes, inflammation is reduced.

Steroids

Cortisol, a steroid hormone produced by the adrenal glands, naturally helps suppress inflammation. But for people with rheumatoid arthritis, the excess inflammation produced by the immune system response is too large for cortisol to handle.

• As a result, doctors can use synthetic hormones called corticosteroids to temporarily reduce inflammation and relieve pain.
• Common examples include prednisone, cortisone and methylprednisolone. Steroids are usually administered via an injection into a muscle or joint, but they can also be given orally.

“Although steroids can help treat patients who are newly diagnosed and need relief until other drugs kick in (DMARDs or biologics can take weeks or months to work), they’re also used in cases with limitation using other therapies or difficult to treat arthritis,” says Dedeke.  

DMARDs

While NSAIDs and steroids provide symptomatic relief from pain and inflammation, neither affects the disease itself. This is where DMARDs come in due to their ability to modify the immune system and slow down disease progression.

DMARDs are categorized one of two ways – conventional or targeted:

• Conventional, or traditional, DMARDs broadly suppress the immune system and the body’s inflammatory response.
• Targeted, or biologic, DMARDs use living cells to zero in on certain immune cells. Biologics target specific molecules, cells and pathways.

Conventional DMARDs

Conventional DMARDs suppress the entire immune system by using drugs with small molecules made in a lab. 

Methotrexate can also be given via injection and used with other DMARDs to form double therapy. Sometimes, three DMARDs are used to form a triple therapy.

“Hydroxychloroquine (Plaquenil) is one the most common DMARDs and often an initial line of therapy,” says Dedeke. 

Other common DMARDs include:

• Methotrexate (Rheumatrex, Trexall): This drug works by initiating the release of adenosine, a molecule that blocks other chemicals responsible for inflammation.
• Sulfasalazine (Azulfidine): This drug works by inhibiting prostaglandins responsible for releasing inflammation.
• Leflunomide (Arava): This drug works by inhibiting dihydroorotate dehydrogenase, an enzyme that helps produce energy for cells.
• Azathioprine (Imuran): This drug works by inhibiting purine metabolism, which is needed to produce DNA and RNA.

Targeted DMARDs (Biologics)

Biologics are a type of DMARD that block specific parts of the immune system by using living cells to create large molecules.

• Tumor necrosis factor (TNF) inhibitors: TNF inhibitors block an inflammatory protein called TNF. Common drugs include etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), certolizumab pegol (Cimzia) and golimumab (Simponi).
• Interleukin inhibitors: Interleukins are a type of inflammatory protein that white blood cells produce. Different drugs target different types of interleukins. For example, tocilizumab (Actemra) is an interleukin-6 (IL-6) inhibitor, while anakinra (Kineret) is an interleukin-1 (IL-1) inhibitor.
• B cell inhibitors: B cells, along with T cells, are the two main types of lymphocytes of the immune system. These drugs prevent B cells from releasing excess inflammation. Examples include belimumab (Benlysta) and rituximab (Rituxan).
• T cell inhibitors: T cells coordinate and attack pathogens that cause disease, but they can mistakenly attack joints in people with RA. These drugs help block overactive T cells. Abatacept (Orencia) is the only drug in this category.

Janus kinase inhibitors

• Janus kinase (JAK) inhibitors are a newer class of medication used to treat RA. They are administered in tablet form as they are small molecule therapies.
• JAKs are a family of four enzymes – JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) – that help create inflammation once a cytokine binds to a receptor. JAK inhibitors interrupt this process to reduce inflammation. The molecules in the drug work by blocking the communication inside cells, compared to DMARDs that block the response from outside cells.
• Examples of JAK inhibitors include tofacitinib (Xeljanz), baricitinib (Olumiant) and upadacitinib (Rinvoq).

Why can these medications have side effects?

Because medications for rheumatoid arthritis suppress the immune system, patients may be at a higher risk of developing diseases that thrive off compromised immune systems. That’s because it weakens your ability to fight off pathogens. Beyond that, some medications for RA have also been shown to negatively impact heart health.

Here is an overview of side effects that may occur when taking RA medications:

• NSAIDs: Long-term use of NSAIDs to treat rheumatoid arthritis can impact the cardiovascular system. NSAIDs make blood clots more likely to occur, which can then trigger a heart attack. They also impact blood flow to the kidneys, which in turn causes more fluid retention. Fluid retention leads to high blood pressure, a common risk factor for cardiovascular disease. In the event it’s necessary to take NSAIDs, naproxen is less likely than other drugs to harm the heart.
  
  
• Steroids: The use of steroids has been linked to plaque buildup, high blood pressure and high cholesterol. One study found patients who receive high levels of prednisone had twice the risk of heart disease. Cortisol also helps regulate electrolyte levels, and using steroids can throw off this balance. Irregularities in fluid retention may lead to high blood pressure. Steroids can also lead to weight gain and issues with glucose regulation. In general, the longer you take steroids, the greater the risk is of developing side effects.
  
  
• DMARDs: An increased risk of infection is by far the biggest side effect of taking DMARDs to treat rheumatoid arthritis. Certain types of DMARDs can impact the heart, though.
  
  
• Biologics: Tocilizumab, a type of interleukin inhibitor, can raise cholesterol levels. Other types of biologics, including a type of B cell inhibitor known as rituximab, require blood pressure monitoring and electrocardiograms to keep tabs on heart health. TNF inhibitors tend to have fewer side effects, although they should be used with caution for patients with a history of heart failure. Like DMARDs, biologics weaken the immune system, and people on these drugs are typically tested for tuberculosis and hepatitis since there’s a higher risk of reactivation in immunocompromised people.
  
  
• JAK inhibitors: One type of JAK inhibitor, tofacitinib, carries an increased risk of heart attack and a type of blood clot called a venous thromboembolism (VTE). The FDA has since responded by issuing a warning about tofacitinib. However, a recent study of more than 100,000 people concluded that patients who took JAK inhibitors and biologics to treat RA didn’t experience an increased risk of cardiovascular disease or cancer compared with other DMARDs.

Are RA medications worth the risk?

Chronic exposure to inflammation can lead to heart disease and other serious illnesses. In fact, a study found RA increased the risk of a heart attack by 68 percent and the risk of cardiovascular disease by 48 percent. 

So, while some RA medications may come with moderate to severe side effects, not treating the problem brings a high likelihood of developing cardiovascular disease and other serious diseases. In other words, the rewards typically outweigh the risks, but each individual case is different.

In general, talk to your doctor about RA medications and be informed of the potential side effects. These are the best ways to prepare for any potential complications that may occur. Be sure you follow directions and don’t make any adjustments without prior authorization from your primary care physician or rheumatologist. 

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