Features June 2012 Issue

When Your RA Medication No Longer Works

Your drug regimen may need changing to keep up with your rheumatoid arthritis, so see your doctor regularly to assess your treatment status.

If you’re like most people with rheumatoid arthritis (RA), you take a combination of medications to counter your immune system’s attack on your joints. And like those other RA patients, the drug regimen you use to manage your condition today may not be the same a year from now.

The effectiveness of RA medications varies from person to person, and over time the efficacy of a particular drug may decline. This loss of effectiveness occurs in many RA patients, and for a variety of reasons.

“Not all of the drugs work for everybody. Some patients do well initially and then lose efficacy, and the majority of people never attain complete remission,” says rheumatologist Chad Deal, MD, Head of the Center for Osteoporosis and Metabolic Bone Disease at Cleveland Clinic. “It’s not uncommon that the dose of a drug needs to be increased or that the type of medication that is used has to be switched.”

As such, it’s important to meet with your doctor regularly, especially when you have continued pain and stiffness in your joints, in order to assess your status and maintain optimal medical therapy to combat the disease process, minimize joint damage, and, ideally, put your RA in remission.

Waning Effectiveness
RA medications work by countering your inflammatory immune response, which causes joint pain, swelling, and eventually joint damage if not adequately treated. Exactly why the drugs lose effectiveness isn’t fully understood, but the answer may lie in how your body adapts to protect itself. Your cells are capable of controlling their contents, pumping out what they don’t want. As such, when cells are repeatedly exposed to a drug, they can grow more proficient at removing it, reducing its effectiveness.

Oncologists have studied this cellular mechanism’s effects on chemotherapy. Rheumatologists also have taken an interest because RA treatments such as disease-modifying antirheumatic drugs (DMARDs)—leflunomide, methotrexate, and sulfasalazine are examples—sometimes lose their effectiveness over time. So, most RA patients who have active disease are treated more effectively with multiple drugs at once, partly because cells have more difficulty adapting to a drug combination.

Not only may conventional DMARDs decline in their effectiveness, but so may newer, biologic drugs, such as infliximab (Remicade). Infliximab belongs to a class of medications that interfere with tumor necrosis factor (TNF), a chemical messenger (cytokine) that regulates the intensity of your body’s immune response.

A 2006 study published in Annals of the Rheumatic Diseases found that infliximab users required more intense DMARD co-therapy and more significant dosing increases compared to those who took the anti-TNF drugs adalimumab (Humira) and etanercept (Enbrel).

The researchers also reported a reduced therapeutic response to infliximab after the first six months of treatment, suggesting that patients developed resistance to the drug’s effects.

This finding may be due to the development of antibodies against the part of the drug that is “non-human”—infliximab has mouse protein as a component. Consequently, most infliximab patients also take methotrexate to reduce the risk of developing neutralizing antibodies that affect infliximab’s efficacy, Dr. Deal says.

Similarly, a study published in April 2011 in the Journal of the American Medical Association found that 28 percent of adalimumab users developed immune antibodies to the drug over a three-year period, and the presence of these antibodies reduced adalimumab concentrations in the body and the overall effectiveness of the medication.

These declines in drug effectiveness seen in some users of DMARDs and anti-TNF drugs have prompted scientists to develop new TNF inhibitors, such as golimumab (Simponi) and certolizumab (Cimzia), and the medication tocilizumab (Actemra), which blocks the cytokine interleukin-6. Other drugs—abatacept (Orencia) and rituximab (Rituxan)—target other immune cells believed to play a role in RA-related inflammation.

All of these treatments give you and your physician more options for managing your RA. “Almost always, patients with rheumatoid arthritis are on more than one drug,” Dr. Deal says.

Stay on Top of RA
Increased pain, fatigue, and stiffness are common signs that your RA medication isn’t working as well as it should. If your medication isn’t controlling your RA sufficiently, it simply may be because the dose is inadequate.

You also may experience an increase in symptoms because your disease is more active, not that your medications are less effective. All RA patients have periods of increased activity that may require temporary or permanent dose adjustment of their medications.

“Oftentimes, it’s not that the drug itself is losing effectiveness but that the disease is getting worse,” Dr. Deal says.

Therefore, make sure you see your doctor for regular evaluations to determine the best course of treatment, often every few months if the disease is active, Dr. Deal advises.

Your doctor will ask about the nature of your RA, assess your functional status, and may order lab tests to measure inflammatory markers of disease activity and gauge how well your RA is being managed. X-rays of the joints also are important to assess the effectiveness of your medications. If necessary, your doctor may increase the dosage, consider alternatives, or try different combinations to find one that works for you.

“Generally, patients aren’t bashful about telling you if the medications are working or not working,” Dr. Deal says. “You have to have a conversation with your doctor about your response to the medication, along with objective evidence based on measures of disease activity, to help you make a rational decision about whether your therapy should be changed.”