Stem cell injections, platelet rich plasma and ivermectin do big business despite dubious or no evidence supporting their use in rheumatology.
However, far from being a recent development, this type of "quackery" has a long history in medicine.
"The most extreme form of quackery dates back to ancient times, when snake oil salesmen sold products that had no benefit, a high price and potential risk of safety," Kenneth Saag, MD, MSc, of the University of Alabama at Birmingham, told Healio.
However, the internet -- and especially social media -- as well as the COVID-19 pandemic seem to have drawn dubious treatments into the mainstream, according to Adam J. Brown, MD, of the department of rheumatology and immunologic disease at the Cleveland Clinic.
"What is different today is that misinformation has a platform," he said in an interview. "News outlets with millions of viewers and social media sites with users around the world are promoting these sham medicines, and people listen to those outlets and believe what they are being told."
Although the result of this constant volley of conflicting claims can be a reduced trust in science overall, the heart -- and allure -- of dubious treatments chiefly pertains to commerce, according to Allan Gibofsky, MD, JD, FACP, FCLM, professor of medicine at Weill Cornell Medicine, and attending rheumatologist and co-director of the Clinic for Inflammatory Arthritis and Biologic Therapy at Hospital for Special Surgery.
"Historically, quackery was defined as the promotion of a treatment or cure for a commercial advantage," he told Healio.
Meanwhile, patients with rheumatic and autoimmune diseases -- who can often face a lifetime of chronic pain with no cure and expensive treatments -- have long been vulnerable to that type of promotion, said Nancy E. Lane, MD, distinguished professor of medicine and rheumatology at the UC Davis Health System.
"When you have diseases and conditions with no cure, as we do in rheumatology, there are always going to be a lot of alternative therapies," she added. "But they will not fundamentally alter the course of the disease. Whether you call them 'quackery' or something else, patients often feel very committed to them."
For this reason, Grace C. Wright, MD, PhD, FACR, president of the Association of Women in Rheumatology, does not blame patients for their attachment to these treatments.
"They experience chronic pain and disability, sometimes for decades at a time," she said. "They are vulnerable. Often, they think their choices are death or pain. It is our responsibility as providers of care to not prey on the vulnerable and give them the correct information."
However, with so many variables involved in the use, approval and timelines of rheumatology treatments, it can sometimes be difficult even for physicians to glean the "correct information."
Defining "quackery" in rheumatology can be a complicated matter, according to Gibofsky.
"Quackery is often in the eye of the beholder," he said. "As Supreme Court Justice Potter Stewart said of pornography, 'I can't define it, but I know it when I see it.'"
The timeline of when a medication is being used factors into the equation, according to Wright.
"Quackery may be quackery sometimes, but not all the time," she said.
Wright cited the case of steroids, which were initially hailed as miracle drugs in rheumatology but have since been shown to yield significant adverse events.
"What seems like salvation today may become a pariah tomorrow," Wright said. "Some drugs will show their worst adverse events in the short term. Others may take 50 years to understand. We have to pay attention to the data to understand the impact of our treatments over the lifespan of a person taking a medication."
Conversely, treatments may go from pariah to salvation.
"Some of the drugs we now use may have seemed like quackery, but ended up as the standard of care," Wright said.
Indeed, rheumatologists make regular use of off-label treatments that are effective in other inflammatory conditions, particularly in diseases that do not have any FDA-approved medications.
"Does using a drug off-label constitute quackery?" Gibofsky said. "By some definition it might be."
Gibofsky offered an example of leeches as a medical intervention.
"At first, it might seem like quackery," he said. "However, leeches are sometimes used by plastic surgeons on traumatically amputated digits to clear away rotting or destroyed flesh, and to get a clean surgical field for reattachment. We have to be a bit humble about stating a procedure is quackery or calling someone a quack."
Gibofsky urged rheumatologists to consider whether recommendations are based on "evidence or eminence" -- particularly those being promoted by individuals who may have a financial interest in their use -- and be guided accordingly.
He additionally counseled providers to remember that certain treatment guidelines -- including those released and backed by the American College of Rheumatology, as well as professional organizations in other specialties -- may include recommendations based more on the degree of expert consensus than the quality of the evidence.
"The gold standard for all therapeutic recommendations should be evidence-based medicine, ie, those studies where the results show, incontrovertibly, that a treatment is effective," he said.
Although rheumatology has long been subject to this type of uncertainty, Saag argued that these conflicts -- and their ramifications -- have increased exponentially in the wake of the COVID-19 pandemic.
"There is a perception that scientists are no longer trustworthy," he said. "We need to reinforce the idea that physicians and researchers are people who have been trained and devoted their lives to sorting through clinical trial data and FDA approvals to separate fact from fiction."
Although Saag acknowledged that science is often based in nuance and rarely enjoys "black-and-white" evidence or determinations, that differs considerably from treatments that enjoy no evidentiary support, often are not safe, and may be very expensive.
"There is more gray area than there is black-and-white, particularly in rheumatology," Saag added. "Patients who are struggling to find black-and-white answers do not recognize how complicated human physiology is in the way a drug or intervention may work. We need to explain to them that we have reviewed the evidence, we have experience treating their conditions, and will offer them the best possible recommendations given the information available at that time. However, we need to steer them as far away as possible from things that have no evidence base, and particularly those that may be dangerous or generate nefarious profits for persons or companies despite having no efficacy."
Reinforcing these messages will be even more critical in the coming years, as expensive and potentially high-risk treatments like stem cell injections become more prevalent among rheumatology patients.
According to Lane, it is essential to differentiate between the two types of stem cells -- hematopoietic and mesenchymal.
"We do not talk as much about mesenchymal stem cells, but they are potentially important to rheumatology as they are involved in the formation of bone and cartilage, and how muscles regenerate," she said. "They are important to connective tissue."
However, isolating these cells and defining their properties is a far cry from observing their activity in the human body.
"For a long time, we were limited to in vitro models and could not really study these cells in their true microenvironment in the body," Lane said.
Despite these limitations, Lane noted "keen interest" from commercial interests to manufacture and sell these stem cell treatments.
"Many therapies were created using an individual's own stem cells, which had been isolated from fat and manipulated in a lab," she said. "They were injected into sore shoulders or knees."
The question, then, is whether there is any science behind this approach.
"Well, actually, there is," Lane said.
In a 2019 review published in Stem Cell Translational Medicine, Lee and colleagues assessed the efficacy and safety of a single intra-articular injection of adipose-derived mesenchymal stem cells in patients with knee osteoarthritis. Twelve patients were included in the prospective, double-blinded, randomized controlled, phase 2b clinical trial. Results showed a significant improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score in the active therapy group, but no such improvement in the placebo group.
"Mesenchymal stem cell injections may have some anti-inflammatory properties and be somewhat analgesic in some patients," Lane said. "Think of it as a very expensive glucocorticoid injection."
This approach has also been used in patients who have undergone total knee replacement to reduce inflammation and expedite growth, according to Lane. However, the data here have been very thin.
"I do not believe the data are very convincing," Lane said.
PubMed is rife with review papers describing the various applications of mesenchymal stem cells, including a 2019 paper published by Berthelot and colleagues in Arthritis Research Therapy. The researchers reviewed bone marrow-derived mesenchymal stem cells and arrived at the conclusion drawn by many other groups.
"Some [bone marrow mesenchymal stem cells] might be more the problem than the solution in inflammatory rheumatisms," they wrote.
There is one clear conclusion to be drawn from these findings, according to Brown.
"For now, stem cells have not yet lived up to the promise," he said.
However, according to Lane, further study may ultimately find a place for mesenchymal stem cells in rheumatology care, once researchers develop methods to augment their differentiation to skeletal stem cells that will, in turn, grow into new bone and cartilage.
"The question, at the moment, is whether independent clinics offering this treatment at a steep cost constitutes quackery," Lane said. "In terms of obtaining some amount of analgesia, you do get some relief with these injections. However, it is not going to change the course or severity of your disease."
On the other hand, Wright said that an important issue with mesenchymal stem cells is their potential for harm.
"We still do not know exactly how these stem cells are going to differentiate when they are injected into a particular microenvironment," Wright said. "There is the potential for the wrong tissue type to emerge. Nobody talks about this.
"The combination of misinformation, consumerism and crafty marketing created this yearning for a therapy that has not yet been proven," she added.
Brown said he often dispels misinformation among his own patients with a simple, but well-worn, piece of advice.
"I tell my patients that if it sounds too good to be true, it probably is too good to be true," he said.
However, such words may have to contend with flashy advertising full of far-ranging promises from clinics and consumerist impulses among patients.
"These stem cell clinics are expensive, so it feels to patients that it is semi-exclusive and therefore valuable," Wright said. "This is why I try to explain it to patients: 'You are going to try this unproven therapy by putting something unknown into your body?' When I say it that way, it helps them understand that they may have been convinced to accept something that they would not normally have accepted."
Oversight, or the lack thereof, is also a concern.
"The problem is that this space is not regulated," Brown said. "People who are trying to sell these products can say whatever they want."
A similar phenomenon has been observed in the rise of clinics offering platelet-rich plasma (PRP).
The messaging behind platelet-rich plasma makes sense to Wright.
"It is easy for people to believe that it is natural," she said. "The doctor will take something from me and go into a lab and do something to it, and then re-inject it into me. This is acceptable because it came from me. I have the power to repair or transform my body."
The idea that "it makes the body work for you" can be seductive for patients, according to Wright.
"Many patients will tell me that they do not want a chemical in their body," she said. "They do not understand the biology of what happens with PRP."
The evidence for PRP in rheumatology is currently underwhelming, according to studies.
In a 2021 paper published in JAMA, Bennell and colleagues conducted a randomized, placebo-controlled, participant-, injector- and assessor-blinded clinical trial in 288 patients to determine the utility of PRP injections in knee osteoarthritis. Pain score served as the primary endpoint.
"Intra-articular injection of PRP, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months," the researchers wrote. "These findings do not support use of PRP for the management of knee OA."
According to Lane, there are "many clinical trials" demonstrating similar findings -- that PRP injections offer essentially no benefit over placebo in knee OA.
"It makes me wonder why we accept this," Wright said. "We are in this consumer-driven phase of medicine that makes people believe in these therapies without evidence."
Some patients may do well, at least for a short time, on PRP therapy. However, any benefits are typically short-lived, according to Brown.
"I have had a lot of patients pay money for it," he said. "They told me that it worked for a few weeks and then stopped, which is true for most placebos. For the most part, the RCTs that I have seen for PRP have not shown overwhelming efficacy."
One area of novel, investigational treatment that appears in contrast to both PRP and mesenchymal stem cells -- in that there are strong data supporting its use -- is vagus nerve stimulation.
It is possible the FDA could approve vagus nerve stimulation for rheumatoid arthritis by the end of 2025, largely based on results of the RESET RA trial, the key findings of which were presented by John R.P. Tesser, MD, at the ACR Convergence 2024.
In that trial, patients underwent implantation of a tablet-sized device created by Setpoint Medical, which stimulated the vagus nerve for 60 seconds daily. Results showed a statistically significant benefit as assessed by ACR20 response at 12 weeks, regardless of prior exposure to previous RA therapy.
"I think this approach is real," Brown said. "The preclinical models show that it works."
According to Wright, the long history of vagus nerve involvement in other conditions may point toward efficacy in the rheumatology space.
"When vagus nerve stimulation first started, it may have seemed like quackery," she said.
But then, "one trial and then another" demonstrated that patients who underwent this therapy showed improvement, Wright said.
"It is a pathway we do not really understand, but there may be something to it," she said. "My sense is that it is not the solution for everybody, but we are learning."
What is critical, according to Wright, is that the trials were done.
"The approach underwent proper investigations in humans," she said.
However, issues have arisen recently with clinics offering methods of vagus nerve stimulation that have not been tested in certain indications, according to Wright.
"It has become embedded in holistic and wellness care," Wright said. "It has become a bit of a mixed bag of real scientific data and quackery."
As the FDA considers its decision on vagus nerve stimulation, other therapies of varying confidence continue to hold sway over rheumatology patients.
Patients with OA have long been susceptible to medications that are ineffective or could even fall under the umbrella of "quackery," according to Saag.
"Osteoarthritis has no beneficial therapies that prevent disease progression, so alternate and complementary therapies are often used," he said.
Glucosamine is "probably safe," with very limited, if any, good evidence that it provides benefits to patients, Saag added.
In a similar vein, Lane noted a recent uptick in the use of hyaluronic acid in knee OA.
"A little oil in the joints seems to help, particularly in older patients," she said.
Ivermectin is a different story, according to Saag.
"No well-designed study has ever proven that ivermectin has efficacy in anything other than treating worms," he said. "But social media promoted this drug that is unsafe and unproven for treating COVID-19 in particular. Many of the people promoting ivermectin are seriously misinformed or are just charlatans."
Brown said he can understand why the use of medications like ivermectin and hydroxychloroquine -- outside of its approved indications -- may be appealing to some individuals.
"There is a conspiracy that Western medicine is keeping dark secrets, that we have had these cheap and effective drugs all along, but we would rather offer more expensive medications," he said.
It is the duty of physicians to communicate to patients that there are no such secrets, according to Saag. However, explaining the hierarchy of evidence -- with randomized, controlled trials at the top and personal anecdotes at the bottom -- can only go so far in mitigating dubious treatments.
"Of course, beyond ivermectin's inefficacy, other things are also incontrovertible, like the efficacy of many of our vaccines, including the COVID-19 vaccine in reducing mortality," Saag said.
Acknowledging the validity of skeptical patients can also help build trust and mitigate the appeal of dubious treatments, he added.
"Most importantly, we need to help our patients get away from the need to find a sound bite or an easy solution," Saag said. "Many of our diseases and conditions are complicated. We need to help our patients understand how to make the best personalized decisions about their treatments. In this way, we can lead them toward evidence-based treatments and away from those that clearly don't work and are often being promoted by people for their own benefit -- that is quackery."
Tesser J. Abstract L10. Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract L10.