Most U.S. rheumatologists would agree that the standard of care when it comes to treating rheumatoid arthritis in is: If a rheumatoid arthritis patient isn't helped by methotrexate, then add an anti-tumor necrosis factor (TNF) drug, one of the so-called biologic agents that have proven so effective in the treatment of rheumatoid arthritis.
The effectiveness of the anti-TNF drugs should not be minimized. These agents (among them Enbrel, Humira and Remicade) have truly revolutionized the treatment of rheumatoid arthritis, in terms of clinical response and in terms of halting bone destruction and deformity. However, these drugs also have a downside, which includes:
1. An increased risk of tuberculosis reactivation.
2. A higher incidence of herpes zoster ("shingles"), which is even more of a concern in the older rheumatoid arthritis patient.
3. An increased risk of life-threatening bacterial and fungal infection.
4. The lack of a universal response.
5. Inconvenient dosing.
Fortunately, the rheumatoid arthritis community currently has at its disposal two new non-anti-TNF biologic agents, Orencia and Rituxan. Unfortunately, there are no head-to-head studies comparing the effectiveness of these newer biologics with the anti-TNF agents. Of course, there will be those patients who have never been treated with an anti-TNF agent and respond to Orencia or Rituxan; or there will be those who do not respond to anti-TNF therapy and do well with Orencia or Rituxan; and there will be those patients who do not respond to anti-TNF drugs, Orencia, or Rituxan.
Although they have been used in rheumatoid arthritis for a shorter period of time, thus far Rituxan and Orencia appear to have less risk of reactivating tuberculosis compared to the anti-TNF drugs. However, Rituxan has been associated with progressive multifocal encephalopathy, which has been in the news lately -- and which has not been observed in those patients treated with the anti-TNF drugs.
Considering the cost of the biologic agents, coupled with the side effect potential, it would be nice to be able to predict whether a particular patient will respond to a particular drug. This is not an unimportant issue, as about 30% of rheumatoid arthritis patients fail to respond adequately to anti-TNF therapy. It would save money and avoid the unnecessary risk of potential toxicity if there were a method to identify those patients who will respond to one type of drug versus another. One approach has been to search for a "biomarker", with the ultimate goal being the availability to rheumatologists of a laboratory test which is able to predict which drug will be effective in a particular patient.
A recent article in "Arthritis Research Therapy" examined 19 rheumatoid arthritis patients, extracting RNA from inflammatory cells before and after the administration of Enbrel, and monitoring their clinical response to treatment. The results were interesting and encouraging, as the researchers concluded that it is possible to predict the response of rheumatoid arthritis patients to Enbrel at an early stage of treatment, with a likelihood greater than 89% based on the expression of gene pairs and triplets.
Once it is known that certain gene sets are differentially regulated by anti-TNF therapy, rheumatologists will have the ability to use this genetic marker information to predict how their patients will respond to a particular therapy. But of course this research is preliminary data on a small pool of patients, and the real challenge which must be undertaken is a long-term study which measures how rheumatoid arthritis patients do going forward on a particular therapy, all the while watching the expression of their genes. Only then will we know which patient will profit most from a particular treatment.
The biologic pipeline is filled with an array of potential candidates for the treatment of rheumatoid arthritis. The day of the knee-jerk response of if-methotrexate-doesn't-work-add-anti-TNF therapy is disappearing. These are all expensive drugs, and a several months' trial can be quite costly if it proves to be a clinical failure. Also, the cost to the patient of time wasted on a therapy doomed to failure must be considered, as bony destruction due to unchecked rheumatoid arthritis can be significant after just a few weeks. It is just a matter of time before the research lab gives us a tool to use in the office, allowing for the accurate prediction of treatment failure or success.
Published On: November 24, 2008