Why placebos work in arthritis research
A placebo is a treatment – a drug or a procedure- which contains no known active or therapeutic ingredient.
The word “placebo” comes from the Latin, meaning “I will please.” And placebo-controlled studies, while not required by the FDA, are considered the “gold standard” for clinical trials investigating new drug compounds.
The first known placebo controlled trial took place in 1907.
The placebo effect occurs because a patient believes a treatment will change his or her condition. Sometimes placebos have therapeutic effects and a patient’s condition will improve.
In medicine this occurs because of three reasons. First, the patient desires the treatment to work. Second, the patient wants to please the investigator. Third, the investigator believes the treatment will work.
And that’s why the best designed studies are placebo controlled and double-blinded (meaning neither the patient nor the physician knows whether the patient is receiving real drug or not).
The placebo effect is strong. In 1955, HK Beecher published a study (Beecher, HK. The powerful placebo. J Am Med Assoc. 1955; 150(17): 1602-1606) and concluded that 32% of patients responded to placebo across 26 studies.
When you think about it, a 32% response to a “sugar pill” is pretty darned impressive. Which is why, it’s critical to look at things two ways. First, to truly assess whether a drug or procedure is really effective, it’s important to subtract placebo effect.
And the other way to look at the situation is to think, “Wow… if only we could harness the placebo effect and use it to help our patients more…”
So, I hope that explains why we use placebo-controlled methods in arthritis research. Personally, I would love to be able to use the placebo effect to help patients improve.
The more I learn about rheumatoid arthritis, the less I know. The basic science in rheumatoid arthritis can often be dreadfully boring and “so-what” in its results.
But…every so often a study comes out that is so elegant, so completely understandable, and so full of promise, I could just scream. I came across this study on the internet and actually I wrote an article about it but I thought I’d post it in its entirety here first. So here goes…
How does rheumatoid arthritis attack the whole body?
One of the mysteries in the understanding of a complicated disease like rheumatoid arthritis is… how does it attack so many joints? What causes it to spread?
Rheumatoid arthritis is a chronic, systemic, autoimmune condition that usually starts in a single joint but then spreads to involve multiple joints. The hallmark of the disease is its symmetrical joint involvement. Also, because internal organs may be affected, it is a disease that carries with it substantial morbidity (complications) as well as mortality (death).
Rheumatoid arthritis is very different from the other common form of arthritis, osteoarthritis, which is basically a wear and tear problem localized to weight-bearing joints. Osteoarthritis does not produce the destructive changes that are characteristic of rheumatoid disease.
Recent research has provided tantalizing evidence as to how rheumatoid arthritis spreads.
Researchers at Justus-Liebig University in Bad Nauheim, Germany recently published the results of their work in Nature Medicine demonstrating the critical role of rheumatoid arthritis synovial fibroblasts (RASFs) in the spread of the disease.
Fibroblasts are a type of cell that is primarily involved in the wound healing process. They are responsible for the laying down of connective tissue. However, when turned on in a particular fashion, they morph from Dr. Jeckyll into Mr Hyde.
These “turned-on” fibroblasts, now known as “rheumatoid arthritis synovial fibroblasts”, are present in abundance in the synovium- the lining of the joint. These RASFs become very destructive and are felt to be one of the major culprits responsible for the damage to cartilage found in rheumatoid arthritis.
To elucidate the mechanism by which RASFs could spread arthritis from joint to joint, lead author Elena Neumann and her colleagues took human cartilage and implanted it under the skin of mice genetically engineered not to reject tissue from a different species. The implantations were done in the flanks. On one flank, the mice received healthy, normal human cartilage; on the other, they received cartilage loaded with human RASFs.
A control group of mice who received normal healthy cartilage in both flanks showed minimal damage, as did mice that received implants of fibroblasts from patients with osteoarthritis.
Another striking discovery occurred when the researchers sacrificed the mice and examined the spleens. The mice which developed rheumatoid arthritis had spleens packed with RASFs. The spleen is the major organ responsible for filtering blood. The fact that RASFs are found in such abundance in the spleens of the rheumatoid arthritis mice provides strong evidence that RASFs travel through the blood stream to do their damage rather than just secrete chemicals that go into the blood stream.
Apparently RASFs can travel via the blood stream and then leave by crawling through the spaces between cells that form the lining of the blood vessels to invade other joints and other organ systems.
When the researchers look at the joints of the sacrificed mice, they didn’t find RASFs. They hypothesized that it takes time for the RASFs to travel to other joints and can only enter cartilage if there is already some minor damage. This would explain why it often takes many months for rheumatoid arthritis to spread.
The scientific findings have therapeutic implications since treatments designed to prevent RASFs from entering the bloodstream, traveling through the blood stream, or leaving the blood stream to attack healthy tissue could potentially prevent the spread of rheumatoid arthritis.
I personally think this is one of the most exciting bits of news in a long time and the authors should be commended for such fine work.
A study from the recent ACR meeting in Philadelphia raised a few eyebrows. This study, described on the Medscape website, is outlined as follows…
The study, entitled the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial, demonstrated that a triple-drug combination of older drugs (methotrexate, sulfasalazine, and hydroxychloroquine) worked just as well as the combination of methotrexate and a TNF-inhibitor in patients with rheumatoid arthritis.
Dr. Larry Moreland, the chief investigator of the group that performed the study commented, “”Most rheumatologists would have predicted that the biologic therapy [anti-tumor necrosis factor agent] would be better. We still need to see the x-ray results, which will be available in 2010, to see if either treatment [approach] is better.”
These findings raise obvious questions about the value of more expensive therapy with new biologic agents for RA patients. Dr. Moreland went on to say that biologic therapy might be better for specific subsets of patients, but exactly which subsets will have preferential benefit is currently unknown.
[NW note: I personally feel this study supports the need to examine synovial biomarkers (signposts in the lining of the joints) in patients with RA. By knowing what markers a patient has, we might be able to better predict what therapy a given patient will respond to. This would cut down on guesswork, using the inappropriate drug, and facilitating an improved therapeutic outcome.]