An HSS Response to “Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and Malignancies: A systemic review and meta-analysis of rare harmful effects in randomized controlled trials”

1. Introduction
2. The Study
3. Considerations
4. How should patients and physicians respond to this new study?

Introduction

This article, published in May 2006 in the Journal of the American Medical Association (JAMA), has stimulated a great deal of discussion because it addresses a very important question:

Do certain rheumatoid arthritis medications lead to an increased risk of cancer and infections?

The Study

The investigators involved in this study used a research technique called meta-analysis to estimate the risk of cancer and serious infections in rheumatoid arthritis (RA) patients taking either infliximab (Remicade) or adalimumab (Humira). These medications target tumor necrosis factor alpha (TNF), a protein called a cytokine that naturally aids in controlling infections and tumors. However, in certain conditions, like rheumatoid arthritis, TNF can lead to serious joint inflammation and damage. These drugs are monoclonal antibodies that effectively block the effects of TNF and are two of the most effective medications currently available to control the inflammation and joint damage in RA.

Since both cancers and serious infections are relatively rare in patients with rheumatoid arthritis, it takes very large studies to accurately determine if there really is an increased risk associated with anti-TNF therapy. Most studies of rheumatoid arthritis patients involve approximately 3-4,000 patients and thus are not large enough to give us these answers. Meta-analysis attempts to overcome this limitation by combining the results of many small studies, and then creating a mathematical model to estimate how frequently certain uncommon events might actually occur. While meta-analyses can be quite helpful, it is important to remember that they are statistical estimates derived from existing studies, and that the findings can differ tremendously, depending on which mathematical techniques are chosen and, most importantly, which studies are chosen to be included in the first place.

This meta-analysis combines the results of nine randomized controlled trials that have evaluated the effects of either infliximab or adalimumab in patients with rheumatoid arthritis. The authors examined the numbers of new cancers and serious infections reported during the course of these studies and compared the rates in patients on anti-TNF medication to those taking placebo medication. The authors conclude that people receiving either of these anti-TNF medications had 3.3 times increased risk of malignancy and 2.0 times increased risk of infection, compared with patients taking a placebo.

Considerations

Although we know that people on anti-TNF antibody therapy have an increased risk of infections because of their suppressed immune system, the reported 3.3 times increased risk of cancer was somewhat surprising. However, there are a few very important considerations to take into account when evaluating this information:

• The authors included non-melanomatous skin cancers when they calculated the increased risk of malignancies. While these skin cancers should not be ignored, they are easily treated - if caught early - and are not usually considered to be as serious as lymphoma, lung cancer, or breast cancer. When these skin cancers were not included in the calculations, the increased risk in the patients on infliximab or adalimumab was no longer statistically significant.
  
  
• The authors did not take into account how long each patient was on an anti-TNF antibody therapy or when the studies they analyzed took place. This could affect the mathematical model and even potentially change the results.

• This study included new cancers which were found 3-12 months after starting anti-TNF antibody therapy. It would be very surprising if any medication could cause cancer so quickly. One possibility is that these cancers were already present but undiagnosed, and the anti-TNF medications caused them to grow to the point where they could be detected.
  
  
• How important an increased risk of cancer is to you depends on the underlying rate of the disease. For example, if the risk of cancer is one in 10, a threefold risk would increase the chance of getting cancer to 30%. However, if the risk of cancer is one in a million, a threefold risk would only result in a 0.003% risk of cancer.
  
  
• Previous treatment was not considered.
  
  
• Importantly, this study evaluated only patients with rheumatoid arthritis on infliximab or adalimumab. Therefore, the results should not be applied to patients with other forms of arthritis or to rheumatoid arthritis patients using different medications. A similar study of etanercept (Enbrel), an anti-TNF medication that works in a different manner than the two studied, is presently being conducted and should be published in the near future.

How should patients and physicians respond to this new study?

In order to place this study into perspective, it is important to understand rheumatoid arthritis. It is a severe, systemic, autoimmune disorder that, without optimal treatment, will lead to joint damage that can not be reversed, profound loss of function, and shortened lifespan. The RA inflammation also has a negative, spill-over effect on the rest of the body, and poorly controlled inflammation can lead to the development of premature atherosclerosis, coronary artery disease, osteoporosis, and lymphomas. 

Infliximab and adalimumab have dramatically changed the quality of life for many people with rheumatoid arthritis, and they are extremely effective in stopping rheumatoid arthritis in its tracks. They can prevent the destruction of bones and joints that can occur in rheumatoid arthritis and allow patients to live pain free and productive lives. These known disease characteristics and anti-TNF benefits must be weighed against the potential increase in infection and cancer risk suggested by this article.

Given the new information, it is important for patients with rheumatoid arthritis to discuss medication options with their rheumatologist. Patients will need to decide whether the benefits they receive from these medications outweigh a possible increase in infection and cancer at some point in the future. As new and credible information arises, new and practical guidelines seem appropriate:

• Regarding decreasing infection risk while on anti-TNF medications:
  
  
  • Tuberculosis: Prior to taking any anti-TNF, the patient needs to have a TB skin test because, while uncommon, dormant TB can be activated by these medications. If the TB skin is negative, it is safe to begin the anti-TNF medication. If it is positive and a chest X-ray is normal, you can start the anti-TNF medication, but you also need to take isoniazid 300 mg/day for 9 months along with 50 mg of vitamin B6.
    
    
  • General infections:
    
    
    • Yearly, you need to be vaccinated against influenza. This is usually done in October or November so that you can have immunity against that year’s influenza virus by January or February, when the risk is highest.
      
      
    • Every five years, you need to receive a Pneumovax vaccination to protect you against pneumococcal infections.
      
      
    • You need to immediately report to your internist or
      rheumatologist any fever, chills, night sweats, cough, sore throat, symptoms of a urinary tract infection, abdominal pain or diarrhea, or other infections, including those of the skin. You may need an antibiotic, and you may have to stop the anti-TNF for a few days until the infection clears.
      
      
• Cancer: You and your internist or rheumatologist need to set up a plan for an age-appropriate cancer monitoring, just like you should if you are not taking anti-TNF medications. Depending on your age and gender, you may need a colonoscopy, breast examination and mammography, pelvic examination and Pap smear, prostate examination and prostatic specific antigen, and testicular examination. You should report the development of persistent fevers, weight loss, swollen glands, or any persistent pain to your doctor.

As more information on cancers and infections in patients taking anti-TNF therapies becomes available, we will update this website on a regular basis.

Read more on this topic in an ACR Hotline.