New Biologic Drugs for Rheumatoid Arthritis: Which Are Safe?

For patients with rheumatoid arthritis, a group of medications known as disease-modifying antirheumatic drugs (DMARDs) not only reduce pain and inflammation but also slow the progression of the disease and prevent joint damage. One of the oldest DMARDs, methotrexate (TREXALL), is still widely prescribed.[1] Methotrexate is much less expensive[2] and generally safer than other DMARDs and often is recommended as the first-choice treatment in patients with moderate to severe rheumatoid arthritis.[3]

Biologic DMARDs are a newer, genetically engineered family of DMARDs. Unlike synthetic DMARDs such as methotrexate, which are taken orally and require more than a month to work, biologic DMARDs are administered by injection and tend to work more rapidly. Biologic DMARDs can improve symptoms in many patients who have failed to respond to methotrexate treatment alone.[4] Despite their clinical benefits, biologic DMARDs carry serious safety concerns, including infections and, in most cases, cancer.

There are several subclasses of biologic DMARDs, each of which target specific proteins that play an important role in joint inflammation and damage. These drugs are known as tumor necrosis factor (TNF) blockers, interleukin (IL) inhibitors, and B-cell or T-cell inhibitors.[5] Nine biologic DMARDs currently available in the U.S. have been approved by the Food and Drug Administration (FDA) for treatment of rheumatoid arthritis (see table).

Three of these drugs — golimumab (SIMPONI), infliximab (REMICADE) and rituximab (RITUXAN) — are approved for treating rheumatoid arthritis only when used in combination with methotrexate. The other six are approved for treating rheumatoid arthritis either alone or in combination with a synthetic DMARD, most often methotrexate.

Biologic Disease-Modifying Anti-Rheumatic Drugs Available in the U.S.

*Limited Use
**Do Not Use
***Do Not Use for Seven Years (until January 2017)

Do Not Use and Limited Use drugs

Public Citizen’s Health Research Group has designated one of these nine biologic DMARDs — certolizumab pegol (CIMZIA) — as Do Not Use because it is associated with unique, serious risks and there is no evidence it is more effective than other biologic DMARDs. Certolizumab pegol was approved by the FDA in 2008. Clinical studies indicated increased risks for complete hair loss, kidney failure and cardiovascular diseases (heart attacks, strokes and abnormal heart rhythms).[6] In fact, the FDA initially delayed approval due to evidence from clinical trials of increased cardiovascular risk.[7]

We also have designated tocilizumab (ACTEMRA) as Do Not Use for Seven Years (until January 2017).

We have designated the other seven biologic DMARDs as Limited Use drugs because there are safer, less expensive first-line treatments available. For example, methotrexate is the first-choice treatment in adults with moderate to severe rheumatoid arthritis.[8],[9]

Key safety warnings

All nine of these biologic DMARDs pose serious risks, some of which are potentially fatal. These risks include:

• Risk of serious bacterial, viral and fungal infections. Because all biologic DMARDs suppress the body’s immune system, they increase risk for serious infections, including tuberculosis and hepatitis B and C. The FDA requires a black-box warning about this infection risk for all TNF blockers.
• Risk of serious allergic reactions. The labels for all biologic DMARDs warn against serious, potentially fatal allergic reactions. Most of these drugs also can cause significant injection site reactions, with swelling, redness, itching and pain.

Many biologic DMARDs carry additional risks, including:

• Cancer risk. Because most of these biologics interfere with the body’s ability to destroy cancer cells, they also increase risk for various types of cancers, particularly lymphomas and nonmelanoma skin cancers. The FDA requires a black-box warning about this cancer risk for all TNF blockers.
• Adverse skin reactions such as Stevens-Johnson syndrome, a rare disorder that causes a severe, blistering rash, often requires hospitalization and is sometimes fatal. These have been seen with use of each of the TNF inhibitors, except golimumab, and with use of rituximab.
• Cardiovascular risks such as risks of congestive heart failure, high blood pressure and persistently high cholesterol and triglycerides.
• Autoimmune disorders including a lupus syndrome, sarcoid granulomatosis (inflammatory lesions that can affect a variety of organs) and vasculitis (inflammation of blood vessels).
• Nerve damage and increased risk for disorders such as multiple sclerosis.
• Liver damage.
• Kidney failure.
• Gastrointestinal perforations (or tears), which can lead to potentially fatal bleeding.

What You Can Do

You should avoid treatment with certolizumab pegol or tocilizumab if you are not currently taking them. If you are taking one of these drugs, you should consult your doctor about switching to an alternative treatment. Do not stop taking any medication without consulting your doctor.

Before starting any biologic DMARD, your doctor should screen you for silent tuberculosis infection.[10] Also, ask your doctor or pharmacist to review with you all potential serious adverse reactions of the drugs.

Because treatment with abatacept (ORENCIA) or rituximab may interfere with the effectiveness of certain vaccines, you should discuss with your doctor whether you should receive any indicated vaccines prior to treatment with these drugs.[11]

Regardless of the treatment chosen by you and your doctor, you should consider engaging in an exercise program and physical therapy designed within the limits of pain. This will help to strengthen muscles and maintain or improve range of motion in the joints.

If you think you are getting any infection or if you have any symptoms of an allergic reaction — including rash, itching, difficulty breathing or swallowing, or dizziness — notify your doctor immediately.

If you are taking a TNF blocker and experience symptoms of heart failure — such as fatigue, difficulty breathing, swelling (especially in the legs and ankles), or rapid or “galloping” heartbeats — immediately notify your doctor. You should not use different types of biologic DMARDs at the same time, due to the risk of serious infections.

References

[1] WorstPills.org. Drug profile for methotrexate. /monographs/view/156.

[2] Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2014;56(1458):127-132.

[3] Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: Integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2008.

[4] Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 2008;148(2):124-134.

[5] Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2014;56(1458):127-132.

[6] DailyMed. CIMZIA- certolizumab pegol injection, solution. Updated October 2015. http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=b4c2c9dc-a0bb-4d64-a667-a67ebe88392d&type=pdf&name=b4c2c9dc-a0bb-4d64-a667-a67ebe88392d. Accessed January 5, 2016.

[7] Rappaport B. Complete response letter to UCB Inc. regarding BL125271 for CIMZIA (certolizumab pegol). January 2, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/bla/2009/125160Orig1s080.pdf. Accessed January 5, 2016.

[8] Donahue KE, Gartlehner G, Jonas DE, et al. Systematic review: Comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 2008;148(2):124-134.

[9] Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: Integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2008.

[10] American College of Physicians. MKSAP 16 Medical Knowledge Self-Assessment Program: Rheumatology. Patrick Alguire (Editor).

[11] Ibid.