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.]
A recent article appeared in the October issue of Rheumatology News.
Dr. Jerry Molitor and colleagues at the University of Minnesota School of Medicine conducted a retrospective study looking at patients with a history of periodontitis. They found that among non-smokers, the presence of periodontitis conferred a significant risk for the delopment of rheumatoid arthritis (RA).
They suggested the antibacterial effect of minocycline may explain the previosuly observed improvement of RA in patients treated with this antibiotic.
Additionally, they proposed screening periodonitis patients with a family history of rheumatoid arthritis for antibodies to anti-CCP which are a risk factor for the future development of RA.
Interesting food for thought. So make sure you brush often and floss regularly.
I’ve been busy this past week serving as the official American College of Rheumatology Blogger for Medscape. The meeting was held in my home town, Philadelphia.
Here’s the link:
Would welcome comments
Now that the stem cell/ PRP launch is out of the way, I can breathe a bit.
Let’s go off in a different direction. I’ve talked about conventional medicines and not-so-conventional procedures. Now let me provide an update on some herbal remedies for arthritis…
This interesting study was written about by Anastasia Stephens in the Daily Mail on September 26, 2009. According to research presented at the British Pharmaceutical Conference, ” when taken orally, concentrated extracts from two types of basil – Ocimum americanum and Ocimum tenuiflorum – reduced joint swelling by up to 73 per cent within just 24 hours.
‘We assessed the antiinflammatory capacity of both plants and found they were similar to those seen with diclofenac, an antiinflammatory drug widely used in the treatment of arthritis,’ says Vaibhav Shinde, of Poona College of Pharmacy in India, who conducted the research.
But unlike diclofenac and other drugs of its type, basil has not so far been found to cause side effects such as gastro-intestinal irritation and abdominal burning and pain. These can be significant problems for arthritis sufferers who take daily pain-relieving medication.
The investigators theorized that “eugenol, the oil that gives basil its distinctive aroma,” may be “the active molecule responsible for the anti-inflammatory effect.”
Another herbal remedy, turmeric, was described by Carole Jackson for Bottom Line’s Daily Health News. She interviewed registered herbalist David Winston, RH (AHG), a founding member of the American Herbalists Guild.
According to Winston, turmeric has a wide variety of healing abilities including powerful anti-inflammatory components which safely reduce the pain and swelling of arthritis, carpal tunnel syndrome, bursitis and tendonitis.
A typical dose of turmeric is two to four milliliters (ml) of the tincture three times a day, or two capsules of the powdered herb two to three times daily. Turmeric should be used with caution in individuals prone to bleeding and, because it stimulates bile secretion, it should not be used by people with a bile duct blockage.
Joe and Teresa Graedon of The People’s Pharmacy reported that celery seed was a traditional treatment for rheumatism. Ethnobotanist James Duke, PhD, author of The Green Pharmacy, attests that celery seed extracts have helped him ward off gout attacks.
Many other readers of the People’s Pharmacy website say that sour cherries can also help against gout. One reader reported: “I used tart cherries to cure a gout attack and it worked. The real news is that the pain from osteoarthritis of the hip joint diminished also.”
Remember…the effects of these herbs will be modest at best. But they are worth knowing about.
Wow! Yesterday was our 25th anniversary. Judy is in Boston helping her parents out. One of them had a medical event. Things are under control. At least up there.
Here… it’s a different story.
I can’t believe we started the stem cell/PRP launch just a couple of days ago. We’re past the halfway point and my staff and I are thinking about “pulling the project off the shelves soon. Permanently or temporarily. Can’t say.
My advice… get it while you still can
You’ll be glad you did.
A bit over 24 hours ago, we launched our new informational project and the response has been sensational.
If you or someone you care about has painful osteoarthritis or tendonitis you need to check this out.
It’s about as natural as you can get (your own biologic material) and you can often avoid surgery and its risks.
It’s possible that joint replacement may be come a thing of the past.
There have been many more questions asked since we released the latest information on stem cells and PRP. I have attempted to consolidate some of the questions and hope my answers make sense…
Question: Do Blue Cross and Blue Shield cover doctor visits and stem cell therapy?
Answer: Most likely not. If you have any insurance questions you can call the office and ask to speak with an insurance person at (301) 694-5800.
Question: How many patients had this procedure done last year?
Answer: 23. Of these, 17 were knees, 2 were shoulders, 4 were hips.
Question: How many decided to have a total knee replacement afterward?
Question: What is the average regrowth after 6 months, 12 months, 18 months, 36 months?
Answer: Since we’ve only been doing this procedure for little more than a year, I can say that we have no data for 18 months and 36 months. The parameters we chose to measure include patient visual analogue scale, physician visual analogue scale, WOMAC 9a measure of quality of life), 50-foot walking time. All these measurements are subjective. We also included ultrasound measurement of patellofemoral compartment thickness at 7 points (objective).
We’ve collected data on 10 patients so far at eight months. All 10 patients have had objective improvement in cartilage thickness at the patellofemoral joint. The increase reaches statistical significance at the p<.001 level. One person had a poor result subjectively but had objective increase in cartilage thickness. He may have a total knee replacement (he hasn’t decided yet). One person has had a fair result subjectively. The other eight have had a good to excellent result. I realize these are small numbers. However, the objective findings are encouraging.
I also must mention that we have been very selective in our choice of candidates for this procedure. Only one patient with stage 4 disease (“bone on bone”) underwent this procedure and he actually had an excellent result both subjective and objective. All others were turned away. Patients exceeding a certain body mass index (too heavy) or who had any type of angulation deformity were also rejected. Roughly only 1 out of every 7 patients who called in about this procedure were accepted.
The ideal study of effectiveness of stem cell therapy would involve arthroscopic digital images of cartilage damage pre and post treatment. Unfortunately, such a study would be expensive and I don’t see this type of funding being available to us in the near future.
Question: What other materials are being used?
Answer: Advanced Biosurfaces has a metal/plastic component that can be inserted. It requires an open incision. Other types of pastes consisting of ground up cartilage and growth factors are also being evaluated. Osteochodral grafting, microfracture, and other cartilage transplant techniques are being evaluated. These require a significant invasive approach and the recuperation is about a year or more.
Question: Any infection or rejection?
Answer: No infection or rejection. We would not expect rejection with our technique which uses autologous stem cells… the patient’s own stem cells. Problems may occur with allogeneic stem cells (donor stem cells). Our technique is done in an operatory… strict sterile technique.
Question: Is anyone doing accelerated cell growth outside the body and implantation similar to what is done for racehorses?
Answer: A center in Denver is doing this. I’m not sure what their data is. They claim that growing cells outside the body is better. I’m not sure I agree with them. And I do know the FDA frowns upon removal of human cells and stimulation with factors outside the body. Because of this FDA regulation, I doubt whether any study will be done in the near future comparing their method with ours.
Question: Can you recommend a doctor in Pennsylvania who has this expertise.
Answer: No one I’m aware of.
We’ve had many questions about stem cells in response to some of the videos that have gone out. Here are the responses…
Have you seen any bodybuilders who have problems with the long head of the biceps as a result of a labral tear operation?
Answer: The simple answer is no. The long head of the biceps has its origin at the superior labrum of the glenoid portion of the scapula. This area is difficult to visualize using ultrasound. Since you can’t see it, it’s not a good idea to try and treat it. However, once the biceps tendon is visualized at the top of the humeral head and further down, it’s easily trackable with ultrasound and we can treat the tendon in that location with good results.
Question: Does insurance pay for stem cell procedures?
Answer: The answer is, it depends. Insurance companies vary in whether they’ll pay for any or part of this procedure. They consider stem cell treatment to be investigational. If you are absolutely dependent on an insurance company paying for your procedure, then I recommend you not get the procedure done. For more information, you can contact our office at (301) 694-5800.
Question: Will stem cells restore normal blood flow to the hip if I have avascular necrosis?
Answer: No, it won’t. It may restore cartilage and possibly new bone if there is not too much deformity. When that happens, blood flow may eventually come back if there is collateral flow. No one really knows. However, if there is complete collapse of the femoral head, I would advise surgery.
Question: How do you know the stem cells stay in place?
Answer: When we do a procedure in a joint, the answer is pretty easy. Each joint is a capsule lined with synovial tissue. Once the stem cells are placed inside the joint, it’s hard for them to leave. So shoulders, knees, elbows, wrists, etc. are self-contained. However, there are complicating features. For instance, 25% of patients have a hip joint that communicates with the iliopsoas bursa, located in front of the joint. If the patient is not kept lying on their back for a couple of days after the procedure, the stem cells can fall out into the bursa … where they’ll do little good. In order to ensure stem cells stay in place, we add another ingredient. That is, we use a matrix of fat (the patient’s own fat) along with other materials that cause the stem cells and PRP to congeal and form a sticky gel that stays put.
Question: Do stem cells cause cancer?
Answer: There is concern that embryonic stem cells may cause cancer. In fact, it has been reported to occur in at least two cases I’m aware of. Also, donor stem cells (allogeneic) are a concern since we don’t know the donor’s family history. We use only autologous stem cells- a patient’s own stem cells. There is no cancer risk.