The Hidden Benefits of Glucosamine

By Pat Anson, PNN Editor

Do you take glucosamine supplements to reduce joint pain and stiffness? You’re not alone if you do. According to a 2007 survey, nearly 20 percent of U.S. adults take glucosamine to prevent or treat pain from osteoarthritis, back pain and other conditions.

The evidence to support the use of glucosamine for joint pain is thin, but a large new study in The BMJ suggests regular use of the supplement can reduce the risk of cardiovascular disease.

Researchers at Tulane University analyzed 7 years of extensive health data for almost half a million adults aged 40 to 69 enrolled in the UK Biobank study. Those who regularly took glucosamine were about 15% less likely to develop heart disease or have a stroke.

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Glucosamine occurs naturally in the fluid around joints and plays an importantly role in building cartilage. Glucosamine is extracted from shellfish and is often combined in supplements with chondroitin, a similar substance that is also found in joints.

People who took glucosamine in the BMJ study were more likely to be women, older, more physically active, have healthier diets and take other supplements.

Over the course of seven years, 2.2% of those who did not use glucosamine had a heart attack or stroke, compared to 2.0% of people who did use glucosamine. People who used glucosamine were also less likely to die from a heart attack or stroke, 0.5% vs. 0.7% of those who didn’t use the supplement.

The difference doesn’t appear to be significant, but when adjusted for risk and other factors, it means that glucosamine users had a 22% lower risk of dying from a heart attack or stroke.

For smokers, the benefits of regular glucosamine use were even greater. They had 37% less risk of having coronary heart disease compared to smokers who didn’t use the supplements.

Researchers didn’t establish the reason why glucosamine lowers the risk of cardiovascular disease (CVD), but they believe the supplements help reduce inflammation – one of the main factors involved in the development of heart disease, as well as chronic pain.

“Several potential mechanisms could explain the observed protective relation between glucosamine use and CVD diseases. In the National Health and Nutrition Examination Survey (NHANES) study, regular use of glucosamine was associated with a statistically significant reduction in C reactive protein concentrations, which is a marker for systemic inflammation,” researchers reported. “Other mechanisms might also be involved, and future investigations are needed to explore the functional roles of glucosamine in cardiovascular health.”

The UK’s National Health Service (NHS) downplayed the study findings, pointing out the cardiovascular benefits of glucosamine are “quite small.”

“If you want to reduce your risk of having a heart attack or stroke, it would be much better to concentrate on living a healthy lifestyle, rather than paying for glucosamine supplements,” the NHS said.

CreakyJoints Under Scrutiny for Ties to Drug Makers 

By Pat Anson, PNN Editor

Patient advocacy groups are coming under scrutiny again for their financial ties to drug companies. The latest is the Global Healthy Living Foundation (GHLF), a non-profit charity that created CreakyJoints, a website and social media platform that raises awareness about arthritis and other chronic illnesses. 

According to Bloomberg News reporter Ben Elgin, the foundation and CreakyJoints have long had a cozy relationship with Pfizer, Amgen, Johnson & Johnson and other corporate donors. Pfizer has donated nearly $1 million to the foundation over the past decade and one of its vice-presidents even serves on GHLF’s board of directors.

In a speech to drug makers in 2010, GHLF president Seth Ginsberg reportedly sought their donations -- while at the same time promising the companies “higher profits” and “sales rep participation in our programs.”

Ginsberg, who was diagnosed with spondyloarthritis as a teenager, co-founded GHLF in 1999 with marketing executive Louis Tharp.

In addition to CreakyJoints, GHLF has two other “grassroots” programs, Fail First Hurts and the 50-State Network, which advocate for healthcare policies that often align with the interests of its donors.  

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According to GHLF’s 2017 tax return, the foundation had over $5 million in annual revenue. Ginsberg was paid a salary of $384,000, while Tharp received $220,000 as Executive Director.  Nearly $300,000 was also paid to a for-profit marketing company established by the two men, although it’s unclear what the payment was for.

Bloomberg reported that GHLF’s tax returns “reflect errors and unexplained entries that have obscured the amounts of money flowing to its cofounders.”

“Are they operating in a way that is extremely transparent? It’s safe to say they’re not,” Brian Mittendorf, a professor of accounting at Ohio State University told Bloomberg. “From looking at their disclosures, you have no idea how closely they’re related to some of the entities it pays.”

At least one GHLF board member and several patient volunteers reportedly left the organization because they were troubled by its relationships with donors.

GHLF did not grant an interview to Bloomberg, but replied to questions in writing.

“The only time we engage in advocacy is when it helps patients. If it doesn’t help patients, we don’t do it,” the foundation said in a statement. “Our mission is to engage in patient-centered research, provide advocacy for access-to-care, and to support people living with chronic disease by providing a supportive environment and accessible education.”

In a related story, Bloomberg reported that several other recently formed non-profits – such as the U.S. Rural Health Network --  appear to be little more than front organizations for the pharmaceutical industry.

“There are a number of groups created by pharma companies that look and act like patient organizations, but they’re 100 percent funded by industry,” said Marc Boutin, chief executive officer of the National Health Council. “They sound and look like patient organizations, but they take positions that industry wants.”

Drug Companies Fined for Co-Pay Programs

Last week two drug companies agreed to pay $125 million in fines to settle allegations that they used charitable foundations as front organizations to bilk Medicare.

Amgen and Japanese drug maker Astellas Pharma paid the foundations to establish co-pay prescription drug programs for Medicare patients. Federal prosecutors say the programs were primarily designed not to help patients, but to illegally pay their co-pays for Astellas and Amgen products.

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Federal anti-kickback laws prohibit pharmaceutical companies from making any kind of payment to induce Medicare patients to purchase their drugs. The prohibition includes co-pays.

“The companies’ payments to the foundations were not ‘donations,’ but rather were kickbacks that undermined the structure of the Medicare program and illegally subsidized the high costs of the companies’ drugs at the expense of American taxpayers,” U.S. Attorney Andrew Lelling said in a statement.

“When pharmaceutical companies use foundations to create funds that are used improperly to subsidize the co-pays of only their own drugs, it violates the law and undercuts a key safeguard against rising drug costs,” said U.S. Assistant Attorney General Jody Hunt.

Last year, Pfizer paid nearly $24 million to settle allegations that it also used a co-pay program to pay Medicare for the company’s prescription drugs.

U.S. Pain Foundation Co-Pay

The U.S. Pain Foundation is under investigation by the U.S. Senate Finance Committee for a similar co-pay program established with Insys Therapeutics, a controversial Arizona drug company. Insys makes Subsys, an expensive and potent fentanyl spray blamed for hundreds of overdose deaths.

U.S. Pain received $2.5 million from Insys to launch the “Gain Against Pain” program, which ostensibly helped Medicare patients pay for drugs prescribed for breakthrough cancer pain. Critics say the program was primarily used to increase prescriptions for Subsys, which can cost $24,000 for just a four-day supply.

Former U.S. Pain CEO Paul Gileno initially defended the co-pay program, saying the money from Insys “does not influence our values,” but later resigned over allegations that he misappropriated $2 million from his own charity.

The Gain Against Pain program was subsequently shutdown in August 2018 and U.S. Pain said it would no longer accept funding from Insys.

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Sen. Ron Wyden (D-OR), the ranking member of the Senate Finance Committee, sent a lengthy letter last December to U.S. Pain interim CEO Nicole Hemmenway asking a series of questions about the Insys co-pay program. According to the senator’s office, Wyden has still not gotten a full response.  

“The U.S. Pain Foundation has yet to provide a substantial amount of the information that Senator Wyden requested in his letter. Staff is in communication with the organization in order to get to the bottom of the organization’s financial relationship with pharmaceutical manufacturers, including Insys, and its compliance with applicable federal laws,” a Wyden spokesperson said in a statement to PNN.

A federal jury in Boston is currently in its third week of deliberations in a criminal case against Insys founder John Kapoor and four former executives of the company, who are accused of bribing doctors to boost sales of Subsys. 

U.S. Pain also remains under investigation by the Connecticut Attorney General’s office for financial irregularities that led to Gileno’s resignation.

New Safety Concerns for Osteoarthritis Drug

By Pat Anson, PNN Editor

Disappointing results from a Phase 3 clinical study are raising new safety concerns about an experimental class of pain-relieving drugs once considered a promising alternative to opioids.

Pfizer and Eli Lilly say 6.3% of osteoarthritis patients taking a 5 mg dose of tanezumab experienced rapidly progressive osteoarthritis in their joints. There was significant improvement in their pain and physical function, but the patients’ overall assessment of their condition was no better than those treated with non-steroidal anti-inflammatory drugs (NSAIDs).

Patients taking a lower 2.5 mg dose of tanezumab did not have any significant improvement in their pain, quality of life or overall condition. And 3.2% experienced rapidly progressive osteoarthritis.

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“We are analyzing these findings in the context of the recent Phase 3 results as we assess potential next steps for tanezumab,” Ken Verburg, Pfizer Global Product Development, said in a statement. “We plan to review the totality of data from our clinical development program for tanezumab with regulatory authorities.”

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases as a result of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from reaching the brain.

Tanezumab was considered so promising a therapy that it was given fast track designation from the FDA in 2017, a process that speeds up the development of new therapies to treat serious conditions.

Ironically, it was the FDA that slowed the development of NGF inhibitors in 2010 because of concerns that tanezumab made osteoarthritis worse in some patients. Most clinical studies of tanezumab did not resume until 2015.

The reappearance of the same safety issue and the marginal pain relief provided by tanezumab could be the last straw for the drug, according to one analyst.

“It is hard for us to imagine how these results could have been much worse. Pfizer indicated that they ‘plan to review the totality of data’ with regulatory authorities, which suggests to us that the co-sponsors will try to find a way to resurrect the program for some subset or sub-population of patients, but recognizes that this result puts the drug’s entire future in doubt,” SVB Leerink research analyst Geoffrey Porges said in a note to clients.

A clinical study of fasinumab, another NGF inhibitor being developed by Teva and  Regeneron Pharmaceuticals, was stopped by the FDA in 2016 after a patient showed signs of severe joint disease. Regeneron and Teva are continuing to study fasinumab in patients with chronic low back pain.

Pfizer and Eli Lilly are also studying tanezumab as a treatment for low back pain, and reported promising results from a Phase 3 trial in February. Rapidly progressive osteoarthritis was also reported in a small number of patients involved in that study.

Elite Hospitals Offering Unproven Stem Cell Treatments

By Liz Szabo, Kaiser Health News

The online video seems to promise everything an arthritis patient could want.

The six-minute segment mimics a morning talk show, using a polished TV host to interview guests around a coffee table. Dr. Adam Pourcho extols the benefits of stem cells and “regenerative medicine” for healing joints without surgery. Pourcho, a sports medicine specialist, says he has used platelet injections to treat his own knee pain, as well as a tendon injury in his elbow. Extending his arm, he says, “It’s completely healed.”

Brendan Hyland, a gym teacher and track coach, describes withstanding intense heel pain for 18 months before seeing Pourcho. Four months after the injections, he says, he was pain-free and has since gone on a 40-mile hike.

“I don’t have any pain that stops me from doing anything I want,” Hyland says.

The video’s cheerleading tone mimics the infomercials used to promote stem cell clinics, several of which have recently gotten into hot water with federal regulators, said Dr. Paul Knoepfler, a professor of cell biology and human anatomy at the University of California-Davis School of Medicine.

But the marketing video wasn’t filmed by a little-known operator. It was sponsored by Swedish Medical Center, the largest nonprofit health provider in the Seattle area.

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Swedish is one of a growing number of respected hospitals and health systems—including the Mayo Clinic, the Cleveland Clinic and the University of Miami—that have entered the lucrative business of stem cells and related therapies. Typical treatments involve injecting patients’ joints with their own fat or bone marrow cells, or with extracts of platelets, the cell fragments known for their role in clotting blood. Many patients seek out regenerative medicine to stave off surgery, even though the evidence supporting these experimental therapies is thin at best, Knoepfler said.

Hospitals say they’re providing options to patients who have exhausted standard treatments. But critics suggest the hospitals are exploiting desperate patients and profiting from trendy but unproven treatments.

The Food and Drug Administration is attempting to shut down clinics that hawk unapproved stem cell therapies, which have been linked to several cases of blindness and at least 12 serious infections. Although doctors usually need preapproval to treat patients with human cells, the FDA has carved out a handful of exceptions, as long as the cells meet certain criteria, said Barbara Binzak Blumenfeld, an attorney who specializes in food and drug law at Buchanan Ingersoll & Rooney in Washington.

Hospitals like Mayo are careful to follow these criteria, to avoid running afoul of the FDA, said Dr. Shane Shapiro, program director for the Regenerative Medicine Therapeutics Suites at Mayo Clinic's campus in Florida.

‘Expensive Placebos’

While hospital-based stem cell treatments may be legal, there’s no strong evidence they work, said Leigh Turner, an associate professor at the University of Minnesota’s Center for Bioethics who has published a series of articles describing the size and dynamics of the stem cell market.

“FDA approval isn’t needed and physicians can claim they aren’t violating federal regulations,” Turner said. “But just because something is legal doesn’t make it ethical.”

For doctors and hospitals, stem cells are easy money, Turner said. Patients typically pay more than $700 a treatment for platelets and up to $5,000 for fat and bone marrow injections. As a bonus, doctors don’t have to wrangle with insurance companies, which view the procedures as experimental and largely don’t cover them.

It’s lucrative. It’s easy to do. All these reputable institutions, they don’t want to miss out on the business. It preys on people’s desperation.
— Dr. James Rickert

“It’s an out-of-pocket, cash-on-the-barrel economy,” Turner said. Across the country, “clinicians at elite medical facilities are lining their pockets by providing expensive placebos.”

Some patient advocates worry that hospitals are more interested in capturing a slice of the stem-cell market than in proving their treatments actually work.

“It’s lucrative. It’s easy to do. All these reputable institutions, they don’t want to miss out on the business,” said Dr. James Rickert, president of the Society for Patient Centered Orthopedics, which advocates for high-quality care. “It preys on people’s desperation.”

In a joint statement, Pourcho and Swedish defended the online video.

“The terminology was kept simple and with analogies that the lay person would understand,” according to the statement. “As with any treatment that we provide, we encourage patients to research and consider all potential treatment options before deciding on what is best for them.”

But Knoepfler said the guests on the video make several “unbelievable” claims.

At one point, Dr. Pourcho says that platelets release growth factors that tell the brain which types of stem cells to send to the site of an injury. According to Pourcho, these instructions make sure that tissues are repaired with the appropriate type of cell, and “so you don’t get, say, eyeball in your hand.”

Knoepfler, who has studied stem cell biology for two decades, said he has never heard of “any possibility of growing eyeball or other random tissues in your hand.” Knoepfler, who wrote about the video in February on his blog, The Niche, said, “There’s no way that the adult brain could send that kind of stem cells anywhere in the body.”

The marketing video debuted in July on KING-TV, a Seattle station, as part of a local lifestyles show called “New Day Northwest.”

Although much of the show is produced by the KING 5 news team, some segments—like Pourcho’s interview—are sponsored by local advertisers, said Jim Rose, president and general manager of KING 5 Media Group.

After being contacted by KHN, Rose asked Swedish to remove the video from YouTube because it wasn’t labeled as sponsored content. Omitting that label could allow the video to be confused with news programming. The video now appears only on the KING-TV website, where Swedish is labeled as the sponsor.

“The goal is to clearly inform viewers of paid content so they can distinguish editorial and news content from paid material,” Rose said. “We value the public’s trust.”

Increasing Scrutiny

Federal authorities have recently begun cracking down on doctors who make unproven claims or sell unapproved stem cell products.

In October, the Federal Trade Commission fined stem cell clinics millions of dollars for deceptive advertising, noting that the companies claimed to be able to treat or cure autism, Parkinson’s disease and other serious diseases.

In a recent interview Scott Gottlieb, the FDA commissioner, said the agency will continue to go after what he called “bad actors.”

With more than 700 stem cell clinics in operation, the FDA is first targeting those posing the biggest threat, such as doctors who inject stem cells directly into the eye or brain.

“There are clearly bad actors who are well over the line and who are creating significant risks for patients,” Gottlieb said.

Products are being promoted that aren’t providing any proven benefits and where patients are paying out-of-pocket.
— Scott Gottlieb, FDA Commissioner

Gottlieb, set to leave office April 5, said he’s also concerned about the financial exploitation of patients in pain.

“There’s economic harm here, where products are being promoted that aren’t providing any proven benefits and where patients are paying out-of-pocket,” Gottlieb said.

Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said there is a broad “spectrum” of stem cell providers, ranging from university scientists leading rigorous clinical trials to doctors who promise stem cells are “for just about anything.” Hospitals operate somewhere in the middle, Marks said.

“The good news is that they’re somewhat closer to the most rigorous academics,” he said.

The Mayo Clinic’s regenerative medicine program, for example, focuses conditions such as arthritis, where injections pose few serious risks, even if that’s not yet the standard of care, Shapiro said.

Rickert said it’s easy to see why hospitals are eager to get in the game.

The market for arthritis treatment is huge and growing. At least 30 million Americans have the most common form of arthritis, with diagnoses expected to soar as the population ages. Platelet-rich plasma (PRP) injections for arthritis generated more than $93 million in revenue in 2015, according to an article last year in The Journal of Knee Surgery.

“We have patients in our offices demanding these treatments,” Shapiro said. “If they don’t get them from us, they will get them somewhere else.”

Doctors at the Mayo Clinic try to provide stem cell treatments and similar therapies responsibly, Shapiro said. In a paper published this year, Shapiro described the hospital’s consultation service, in which doctors explain patients’ options and clear up misconceptions about what stem cells and other injections can do. Doctors can refer patients to treatment or clinical trials.

“Most of the patients do not get a regenerative [stem cell] procedure,” Shapiro said. “They don’t get it because after we have a frank conversation, they decide, ‘Maybe it’s not for me.’”

Lots of Hype, Little Proof

Although some hospitals boast of high success rates for their stem cell procedures, published research doesn’t back up those claims, Rickert said.

The Mayo Clinic website says that 40 to 70 percent of patients “find some level of pain relief.” Atlanta-based Emory Healthcare claims that 75 to 80 percent of patients “have had significant pain relief and improved function.” In the Swedish video, Pourcho claims “we can treat really any tendon or any joint” with PRP.

The strongest evidence for PRP is in pain relief for arthritic knees and tennis elbow, where it appears to be safe and perhaps helpful, said Dr. Nicolas Piuzzi, an orthopedic surgeon at the Cleveland Clinic.

But PRP hasn’t been proven to help every part of the body, he said.

PRP has been linked to serious complications when injected to treat patellar tendinitis, an injury to the tendon connecting the kneecap to the shinbone. In a 2013 paper, researchers described the cases of three patients whose pain got dramatically worse after PRP injections. One patient lost bone and underwent surgery to repair the damage.

“People will say, ‘If you inject PRP, you will return to sports faster,’” said Dr. Freddie Fu, chairman of orthopedic surgery at the University of Pittsburgh Medical Center. “But that hasn’t been proven.”

A 2017 study of PRP found it relieved knee pain slightly better than injections of hyaluronic acid. But that’s nothing to brag about, Rickert said, given that hyaluronic acid therapy doesn’t work, either. While some PRP studies have shown more positive results, Rickert notes that most were so small or poorly designed that their results aren’t reliable.

In its 2013 guidelines for knee arthritis, the American Academy of Orthopaedic Surgeons said it is “unable to recommend for or against” PRP.

“PRP is sort of a ‘buyer beware’ situation,” said Dr. William Li, president and CEO of the Angiogenesis Foundation, whose research focuses on blood vessel formation. “It’s the poor man’s approach to biotechnology.”

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Tests of other stem cell injections also have failed to live up to expectations.

Shapiro published a rigorously designed study last year in Cartilage, a medical journal, that found bone marrow injections were no better at relieving knee pain than saltwater injections. Rickert noted that patients who are in pain often get relief from placebos. The more invasive the procedure, the stronger the placebo effect, he said, perhaps because patients become invested in the idea that an intervention will really help. Even saltwater injections help 70 percent of patients, Fu said.

A 2016 review in the Journal of Bone and Joint Surgery concluded that “the value and effective use of cell therapy in orthopaedics remain unclear.” The following year, a review in the British Journal of Sports Medicine concluded, “We do not recommend stem cell therapy” for knee arthritis.

Shapiro said hospitals and health plans are right to be cautious.

“The insurance companies don’t pay for fat grafting or bone-marrow aspiration, and rightly so,” Shapiro said. “That’s because we don’t have enough evidence.”

Rickert, an orthopedist in Bedford, Indiana, said fat, bone marrow and platelet injections should be offered only through clinical trials, which carefully evaluate experimental treatments. Patients shouldn’t be charged for these services until they’ve been tested and shown to work.

Orthopedists—surgeons who specialize in bones and muscles—have a history of performing unproven procedures, including spinal fusion, surgery for rotator cuff disease and arthroscopy for worn-out knees, Turner said. Recently, studies have shown them to be no more effective than placebos.

Misleading Marketing

Some argue that joint injections shouldn’t be marketed as stem cell treatments at all.

Piuzzi said he prefers to call the injections “orthobiologics,”noting that platelets are not even cells, let alone stem cells. The number of stem cells in fat and bone marrow injections is extremely small, he said.

Patients are attracted to regenerative medicine because they assume it will regrow their lost cartilage, Piuzzi said. There’s no solid evidence that the commercial injections used today spur tissue growth, Piuzzi said. Although doctors hope that platelets will release anti-inflammatory substances, which could theoretically help calm an inflamed joint, they don’t know why some patients who receive platelet injections feel better, but others don’t.

So, it comes as no surprise that many patients have trouble sorting through the hype.

Florida resident Kathy Walsh, 61, said she wasted nearly $10,000 on stem cell and platelet injections at a Miami clinic, hoping to avoid knee replacement surgery.

When Walsh heard about a doctor in Miami claiming to regenerate knee cartilage with stem cells, “it seemed like an answer to a prayer,” said Walsh, of Stuart, Florida. “You’re so much in pain and so frustrated that you cling to every bit of hope you can get, even if it does cost you a lot of money.”

The injections eased her pain for only a few months. Eventually, she had both knees replaced. She has been nearly pain-free ever since. “My only regret,” she said, “is that I wasted so much time and money.”

Kaiser Health News (KHN) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

How Sodas and Smoking Worsen Disability

By Pat Anson, PNN Editor

Most doctors will tell you that smoking and drinking sweetened beverages like soda every day will lead to poor health. They can also worsen your risk of disability if you have rheumatoid arthritis or multiple sclerosis, according to new studies.

Researchers in Germany wanted to know how diet can affect the progression of multiple sclerosis (MS), a chronic disease that attacks the body’s central nervous system, causing numbness, difficulty walking, paralysis, loss of vision, fatigue and pain.  

They surveyed 135 MS patients to see how close their diet was to the Dietary Approaches to Stop Hypertension (DASH) diet – which limits foods that are high in saturated fat and sugar – and recommends whole grains, fruits and vegetables, low-fat dairy products, lean meats, poultry and fish, nuts and legumes.

Researchers did not find a link between what the participants ate and their level of disability, but there was a strong association with what they drank.

"While we did not find a link with overall diet, interestingly, we did find a link with those who drank sodas, flavored juices and sweetened teas and coffees," said study author Elisa Meier-Gerdingh, MD, of St. Josef Hospital in Bochum, Germany.

MS patients who consumed the largest amounts of sugar-sweetened beverages – averaging about 290 additional calories per day -- were five times more likely to have severe disability than people who rarely drank sweetened beverages.

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"While these results need to be confirmed by larger studies that follow people over a long period of time, and the results do not show that soda and sugar-sweetened beverages cause more severe disability, we do know that sodas have no nutritional value and people with MS may want to consider reducing or eliminating them from their diet," said Meier-Gerdingh, who will present her findings at the American Academy of Neurology's annual meeting in Philadelphia in May.

Smoking Worsens Risk of Rheumatoid Arthritis

Previous studies have also found that smoking increases your chances of having MS and several other chronic pain conditions.

A new study by researchers at Brigham and Women's Hospital in Boston demonstrated for the first time that women who stop smoking can reduce their risk of developing the most severe form of rheumatoid arthritis (RA). But it takes time to have a beneficial effect.

"Ours is the first study to show that a behavior change can reduce risk for seropositive RA. Risk isn't just about genes and bad luck--there's a modifiable environmental component to the onset of this disease and a chance for some people to reduce their risk or even prevent RA," said corresponding author Jeffrey Sparks, MD, of the Division of Rheumatology, Immunology and Allergy at the Brigham.

Sparks and colleagues analyzed data from the Nurses' Health Study, which tracked the long-term health of registered nurses from across the U.S.  Brigham researchers identified over 1,500 nurses who developed RA, but they were most interested in those with "seropositive" RA as opposed to "seronegative" RA. Patients with seropositive RA generally have more severe joint deformities and disability.

For seropositive RA, the risk of disability began to go down about five years after women quit smoking and continued to decrease the longer they stayed non-smokers. Participants who quit for good reduced their risk of seropositive RA by 37 percent after 30 years. The team did not find any association between seronegative RA and smoking.

"One of the lessons here is that it takes sustained smoking cessation to reap the full benefit," said Sparks, who published his findings in the journal Arthritis Care & Research.

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"Whereas for other diseases, such as cardiovascular disease, quitting smoking can provide a more immediate effect, here we're seeing benefits decades later for those who quit smoking permanently."

RA is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing pain, inflammation and bone erosion. While the biological mechanisms that link smoking and the development of RA are unclear, Sparks believes that smoking may contribute to the formation of RA-related antibodies that increase inflammation.

In future studies, Brigham researchers want to extend their investigations to include men and to see if smoking cessation can prevent the formation of RA-related antibodies and stop progression of the disease.

New Non-Opioid Drug Effective in Treating Low Back Pain

By Pat Anson, PNN Editor

Pfizer and Eli Lilly have announced positive results from a large Phase 3 study evaluating an experimental non-opioid pain reliever as a treatment for chronic low back pain.

Patients receiving 10 mg injections of tanezumab showed statistically significant improvement in back pain at 16 weeks compared to placebo. A lower dose of tanezumab 5 mg was not as effective. Over 1,800 people with chronic low back pain in North America, Europe and Asia participated in the study.

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases in the body because of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from muscles, skin and organs from reaching the brain.

"This study demonstrates the potential of tanezumab to treat individuals suffering from moderate-to-severe chronic low back pain who have been unable to achieve relief with currently available medicines," said Ken Verburg, Pfizer’s tanezumab development team leader.

“This is one of the longest studies conducted to date in chronic low back pain. We look forward to further analyzing these results, and believe the data from this study will support our planned future global regulatory submissions in chronic low back pain."

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Pizer and Eli Lilly have also reported positive findings in evaluating tanezumab for the treatment of osteoarthritis. The Food and Drug Administration granted “fast track” designation to tanezumab in 2017 to help speed its development.

Tanezumab has a history of safety concerns. Clinical studies were halted in 2010 after Pfizer reported some osteoarthritis patients receiving the drug had worse symptoms and needed joint replacement surgery. Another safety issue arose in 2012 when tanezumab caused adverse changes in the nervous system of animals.  Most clinical studies of tanezumab did not resume until 2015.

In the current study, rapidly progressive osteoarthritis (RPOA) was observed in 1.4 percent of patients receiving tanezumab and 0.1 percent of patients in the other treatment groups. Joint fractures and total joint replacements were experienced in 0.4 percent and 0.7 percent of tanezumab-treated patients, respectively, while none were observed in the other treatment groups.

In addition to back pain, the ongoing Phase 3 program for tanezumab includes studies in osteoarthritis pain and cancer pain due to bone metastases.

One Third of Knee Surgery Patients Still Have Pain

By Liz Szabo, Kaiser Health News

Danette Lake thought surgery would relieve the pain in her knees.

The arthritis pain began as a dull ache in her early 40s, brought on largely by the pressure of unwanted weight. Lake managed to lose 200 pounds through dieting and exercise, but the pain in her knees persisted.

A sexual assault two years ago left Lake with physical and psychological trauma. She damaged her knees while fighting off her attacker, who had broken into her home. Although she managed to escape, her knees never recovered. At times, the sharp pain drove her to the emergency room. Lake’s job, which involved loading luggage onto airplanes, often left her in misery.

When a doctor said that knee replacement would reduce her arthritis pain by 75 percent, Lake was overjoyed.

“I thought the knee replacement was going to be a cure,” said Lake, now 52 and living in rural Iowa. “I got all excited, thinking, ‘Finally, the pain is going to end and I will have some quality of life.’”

But one year after surgery on her right knee, Lake said she’s still suffering.

“I’m in constant pain, 24/7,” said Lake, who is too disabled to work. “There are times when I can’t even sleep.”

Most knee replacements are considered successful, and the procedure is known for being safe and cost-effective. Rates of the surgery doubled from 1999 to 2008, with 3.5 million procedures a year expected by 2030.

But Lake’s ordeal illustrates the surgery’s risks and limitations. Doctors are increasingly concerned that the procedure is overused and that its benefits have been oversold.

DANETTE LAKE (khn photo)

DANETTE LAKE (khn photo)

Research suggests that up to one-third of those who have knees replaced continue to experience chronic pain, while 1 in 5 are dissatisfied with the results. A study published last year in the BMJ found that knee replacement had “minimal effects on quality of life,” especially for patients with less severe arthritis.

One-third of patients who undergo knee replacement may not even be appropriate candidates for the procedure, because their arthritis symptoms aren’t severe enough to merit aggressive intervention, according to a 2014 study in Arthritis & Rheumatology.

“We do too many knee replacements,” said Dr. James Rickert, president of the Society for Patient Centered Orthopedics, which advocates for affordable health care, in an interview. “People will argue about the exact amount. But hardly anyone would argue that we don’t do too many.”

Although Americans are aging and getting heavier, those factors alone don’t explain the explosive growth in knee replacement. The increase may be fueled by a higher rate of injuries among younger patients and doctors’ greater willingness to operate on younger people, such as those in their 50s and early 60s, said Rickert, an orthopedic surgeon in Bedford, Ind. That shift has occurred because new implants can last longer — perhaps 20 years — before wearing out.

Yet even the newest models don’t last forever. Over time, implants can loosen and detach from the bone, causing pain. Plastic components of the artificial knee slowly wear out, creating debris that can cause inflammation. The wear and tear can cause the knee to break. Patients who remain obese after surgery can put extra pressure on implants, further shortening their lifespan.

The younger patients are, the more likely they are to “outlive” their knee implants and require a second surgery. Such “revision” procedures are more difficult to perform for many reasons, including the presence of scar tissue from the original surgery. Bone cement used in the first surgery also can be difficult to extract, and bones can fracture as the older artificial knee is removed, Rickert said.

Revisions are also more likely to cause complications. Among patients younger than 60, about 35 percent of men need a revision surgery, along with 20 percent of women, according to a November article in the Lancet.

Yet hospitals and surgery centers market knee replacements heavily, with ads that show patients running, bicycling, even playing basketball after the procedure, said Dr. Nicholas DiNubile, a Havertown, Pa., orthopedic surgeon specializing in sports medicine. While many people with artificial knees can return to moderate exercise — such as doubles tennis — it’s unrealistic to imagine them playing full-court basketball again, he said.

“Hospitals are all competing with each other,” DiNubile said. Marketing can mislead younger patients into thinking, “‘I’ll get a new joint and go back to doing everything I did before,’” he said. To Rickert, “medical advertising is a big part of the problem. Its purpose is to sell patients on the procedures.”

Rickert said that some patients are offered surgery they don’t need and that money can be a factor.

Knee replacements, which cost $31,000 on average, are “really crucial to the financial health of hospitals and doctors’ practices,” he said. “The doctor earns a lot more if they do the surgery.”

Ignoring Alternatives

Yet surgery isn’t the only way to treat arthritis.

Patients with early disease often benefit from over-the-counter pain relievers, dietary advice, physical therapy and education about their condition, said Daniel Riddle, a physical therapy researcher and professor at Virginia Commonwealth University in Richmond.

Studies show that these approaches can even help people with more severe arthritis.

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In a study published in Osteoarthritis and Cartilage in April, researchers compared surgical and non-surgical treatments in 100 older patients eligible for knee replacement.

Over two years, all of the patients improved, whether they were offered surgery or a combination of non-surgical therapies. Patients randomly assigned to undergo immediate knee replacement did better, improving twice as much as those given combination therapy, as measured on standard medical tests of pain and functioning.

But surgery also carried risks. Surgical patients developed four times as many complications, including infections, blood clots or knee stiffness severe enough to require another medical procedure under anesthesia. In general, 1 in every 100 to 200 patients who undergo a knee replacement die within 90 days of surgery.

Significantly, most of those treated with non-surgical therapies were satisfied with their progress. Although all were eligible to have knee replacement later, two-thirds chose not to do it.

Tia Floyd Williams suffered from painful arthritis for 15 years before having a knee replaced in September 2017. Although the procedure seemed to go smoothly, her pain returned after about four months, spreading to her hips and lower back.

She was told she needed a second, more extensive surgery to put a rod in her lower leg, said Williams, 52, of Nashville.

“At this point, I thought I would be getting a second knee done, not redoing the first one,” Williams said.

Other patients, such as Ellen Stutts, are happy with their results. Stutts, in Durham, N.C., had one knee replaced in 2016 and the other replaced this year. “It’s definitely better than before the surgery,” Stutts said.

Inappropriate Surgeries

Doctors and economists are increasingly concerned about inappropriate joint surgery of all types, not just knees.

Inappropriate treatment doesn’t harm only patients; it harms the health care system by raising costs for everyone, said Dr. John Mafi, an assistant professor of medicine at the David Geffen School of Medicine at UCLA.

The 723,000 knee replacements performed in 2014 cost patients, insurers and taxpayers more than $40 billion. Those costs are projected to surge as the nation ages and grapples with the effects of the obesity epidemic, and an aging population.

To avoid inappropriate joint replacements, some health systems are developing “decision aids,” easy-to-understand written materials and videos about the risks, benefits and limits of surgery to help patients make more informed choices.

In 2009, Group Health introduced decision aids for patients considering joint replacement for hips and knees.

Blue Shield of California implemented a similar “shared decision-making” initiative.

Executives at the health plan have been especially concerned about the big increase in younger patients undergoing knee replacement surgery, said Henry Garlich, director of health care value solutions and enhanced clinical programs.

The percentage of knee replacements performed on people 45 to 64 increased from 30 percent in 2000 to 40 percent in 2015, according to the Agency for Healthcare Research and Quality.

Because the devices can wear out in as little as a few years, a younger person could outlive their knees and require a replacement, Garlich said. But “revision” surgeries are much more complicated procedures, with a higher risk of complications and failure.

“Patients think after they have a knee replacement, they will be competing in the Olympics,” Garlich said.

Danette Lake once planned to undergo knee replacement surgery on her other knee. Today, she’s not sure what to do. She is afraid of being disappointed by a second surgery.

Sometimes, she said, “I think, ‘I might as well just stay in pain.’”

Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.

Why U.S. Biologic Drugs Are So Expensive

By Sarah Jane Tribble, Kaiser Health News

Europeans have found the secret to making some of the world’s costliest medicines much more affordable, as much as 80 percent cheaper than in the U.S.

Governments in Europe have compelled drugmakers to bend on prices and have thrown open the market for so-called biosimilars, which are cheaper copies of biologic drugs made from living organisms. The brand-name products — ranging from Humira for rheumatoid arthritis to Avastin for cancer — are high-priced drugs that account for 40 percent of U.S. pharmaceutical sales.

European patients can choose from dozens of biosimilars, 50 in all, which have stoked competition and driven prices lower. Europe approved the growth hormone Omnitrope as its first biosimilar in 2006, but the U.S. didn’t follow suit until 2015 with cancer-treatment drug Zarxio. 

Now, the U.S. government stops short of negotiating and drugmakers with brand-name biologics have used a variety of strategies — from special contracting deals to overlapping patents known as “patent thickets”— to block copycat versions of their drugs from entering the U.S. or gaining market share.

As a result, only six biosimilars are available for U.S. consumers.

European countries don’t generally allow price increases after a drug launches and, in some cases, the national health authority requires patients to switch to less expensive biosimilars once the copycat product is proven safe and effective, said Michael Kleinrock, research director for IQVIA Institute for Human Data Science.

From $50 to $1,300 a month

If Susie Christoff, a 59-year-old who suffers from debilitating psoriatic arthritis, lived in Italy, the cost of her preferred medicine would be less than quarter of what it is in the U.S., according to data gathered by GlobalData, a research firm.

Christoff tried a series of expensive biologics before discovering a once-a-month injection of Cosentyx, manufactured by Swiss drugmaker Novartis, worked the best.

Without the medicine, Christoff said, her fingers can swell to the size of sausages.

SUSIE CHRISTOFF (KAISER HEALTH NEWS PHOTO)

SUSIE CHRISTOFF (KAISER HEALTH NEWS PHOTO)

“It’s 24/7 constant pain in, like, the ankles and feet,” said Christoff, who lives in Fairfax, Va. “I can’t sleep, [and] I can’t sit still. I cry. I throw pillows. It’s just … awful.”

At first, Christoff’s copay for Cosentyx was just $50 a month. But when a disability led her to switch to a Medicare Advantage plan, her out-of-pocket costs ballooned to nearly $1,300 a month — more than three times her monthly car loan.

Christoff, with the help of her rheumatologist, Dr. Angus Worthing, tried Enbrel, Humira and other drugs before finding Cosentyx, the only drug that provides relief. Christoff’s case is “heartbreaking,” Worthing said.

Novartis declined to respond to questions about Cosentyx’s price. Instead, like other pharmaceutical companies, Novartis says it offers patient assistance programs for those who can’t afford the drug. Christoff said she doesn’t qualify for financial assistance.

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Like other biologics, Cosentyx costs thousands of dollars per month. The annual cost of Christoff’s treatment runs about $65,000 in the U.S. In Italy, where competition and price negotiations play a bigger role, it would run about $15,000, according to GlobalData.

In England, Dr. Christopher Griffiths, a lead researcher at the National Institute for Health Research who treats patients with Cosentyx, said the National Health Service would pay about 10,000 pounds, or less than $13,000.

And those drastic price differences are true even though there is no biosimilar version of Cosentyx yet available in Europe, and might not be for years.

The cost of the drug is taking a toll on Christoff. This past summer, her progressive disease made it difficult to enjoy the annual family vacation with her three grown children and their kids in Virginia Beach, Va.

“I can’t get down on the sand to play with my kids without help. I can’t get up without help,” Christoff recalled. “I’m not ready to stop trying. But I’m also not ready to go through my entire retirement fund to walk.”

Unlike Cosentyx, rival drugs — Humira, Enbrel and Remicade — all face biosimilar competition in Europe. Only Remicade has competition from a lower-cost biosimilar in the U.S., and Humira isn’t expected to have a copycat competitor in the U.S. market until 2023. Humira, made by AbbVie, is the world’s top-selling drug.

In late October, Wall Street analyst Ronny Gal at Sanford C. Bernstein & Co. noted that AbbVie agreed to drop Humira’s price by 80 percent in one Nordic country to combat biosimilar competition. During the company’s quarterly conference call, AbbVie chief executive Richard Gonzalez said the drug’s discount was as low as 10 percent and as high as 80 percent across the continent, with the highest discounts in Nordic countries.

“These are markets where it’s ‘winner takes all’ across the entire… category, so includes Remicade and Enbrel as well,” Gonzalez said in November, adding that Nordic countries represent about 4 to 5 percent of overall revenue in AbbVie’s international business.

Concerned about how much biologics cost the U.S. health system and patients, Food and Drug Administration Commissioner Scott Gottlieb announced an “action plan” this summer that included tapping the Federal Trade Commission for help, saying he was “worried” about the biosimilar market.

“The branded drug industry didn’t build its success by being business naive; they are smart competitors,” Gottlieb told an audience full of advocates, industry insiders and researchers at the Washington, D.C.-based Brookings Institution in July. “But that doesn’t mean we need to embrace all of these business tactics or agree with them and think they are appropriate.”  

Rebate Traps

One of these business tactics involves so-called rebate traps, in which financial deals are cut to make sure patients can get only a biologic, not a biosimilar. International drugmaker Pfizer alleged in a September 2017 lawsuit that exclusionary contracts created by Johnson & Johnson prevented use of its biosimilar by health insurers, hospitals and clinics.

Johnson & Johnson’s wildly successful biologic Remicade, the brand-name version of infliximab, produced $6.3 billion in worldwide in 2017. Pfizer launched its copycat drug, Inflectra, in the U.S. in October 2016, noting in the announcement that it would price the drug at a 15 percent discount to Remicade’s wholesale price.

Still, health systems such as Geisinger Health, based in Pennsylvania, say they have had difficulty switching to the less expensive alternative.

“J&J has done a really good job of entrenching themselves in the market,” said Jason Howay, manager of formulary services at Geisinger.

The health system ultimately decided it wanted to switch all adults to Pfizer’s biosimilar, saying it provided the same quality of treatment. But Johnson & Johnson had “bundled” the prices of other drugs with Remicade. So if Geisinger stopped using Remicade on adult patients, J&J could stop providing discounts on other drugs, such as those used for cardiology, Howay explained. “It weaves a very tangled web.”

A spokeswoman for Janssen, Johnson & Johnson’s main pharmaceutical subsidiary, says the drugmaker does offer “more attractive contract terms” to buyers who use a wider range of J&J medicines. “Our contracting approach has always prioritized access for patients and their providers,” Meredith Sharp says.

Geisinger negotiated with biosimilar maker Pfizer and won still lower prices to make up for lost savings on the other J&J drugs. It’s now transitioning all adult patients to the less expensive biosimilar.

Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.

Gene Therapy Eases Chronic Pain in Dogs

By Lisa Marshall, University of Colorado at Boulder

When Shane the therapy dog was hit by a Jeep, life changed for him and his guardian, Taryn Sargent.

The impact tore through the cartilage of Shane's left shoulder. Arthritis and scar tissue set in. Despite surgery, acupuncture and several medications, he transformed from a vibrant border collie who kept watch over Sargent on long walks to a fragile pet who needed extensive care.

"Sometimes he would just stop walking and I'd have to carry him home," recalls Sargent, who has epilepsy and relies on her walks with Shane to help keep her seizures under control. "It was a struggle to see him in that much pain."

Today, 10-year-old Shane's pain and reliance on medication have been dramatically reduced and he's bounding around like a puppy again, 18 months after receiving a single shot of an experimental gene-therapy invented by CU Boulder neuroscientist Linda Watkins

shane and taryn sargent (casey cass/cu boulder)

shane and taryn sargent (casey cass/cu boulder)

Thus far, the opioid-free, long-lasting immune modulator known as XT-150 has been tested in more than 40 Colorado dogs with impressive results and no adverse effects. With human clinical trials now underway in Australia and California, Watkins is hopeful the treatment could someday play a role in addressing the nation's chronic pain epidemic.

"I'm hoping the impact on pets, their guardians and people with chronic pain could be significant," said Watkins, who has worked more than 30 years to bring her idea to fruition. "It's been a long time coming."

The Role of Glial Cells

Watkins' journey began in the 1980s when, as a new hire in the department of psychology and neuroscience, she began to rock the boat in the field of pain research.

Conventional wisdom held that neurons were the key messengers for pain, so most medications targeted them. But Watkins proposed that then-little-understood cells called "glial cells" might be a culprit in chronic pain. Glial cells are immune cells in the brain and spinal cord that make people ache when they're sick. Most of the time, that function protects us. 

Watkins proposed that in the case of chronic pain, which can sometimes persist long after the initial injury has healed, that ancient survival circuitry somehow gets stuck in overdrive. She was greeted with skepticism.

"The whole field was like 'what on Earth is she talking about?'"

She and her students hunkered down in the lab nonetheless, ultimately discovering that activated glial cells produce specific inflammatory compounds which drive pain. They also learned that, after the initial sickness or injury fades, the cells typically produce a compound called Interleukin 10 (IL-10) to dampen the process they started.

"IL-10 is Mother Nature's anti-inflammatory," she explains. "But in the onslaught of multiple inflammatory compounds in chronic pain, IL-10's dampening cannot keep pace."

Over the years, she and her team experimented with a host of different strategies to boost IL-10. They persisted and, in 2009, Watkins co-founded Xalud Therapeutics. Their flagship technology is an injection, either into the fluid-filled space around the spinal cord or the site of an inflamed joint, that delivers circles of DNA in a sugar/saline solution to cells, instructing them to ramp up IL-10 production.

With financial help from the National Institute of Neurological Disorders and Stroke, the MayDay Fund and CU's Technology Transfer Office – which has provided intellectual property support, assistance with licensing agreements, and help obtaining a $100,000 research grant in 2018 – Watkins is edging closer to bringing her idea to clinical practice.

She has teamed up with veterinary chronic pain specialist Rob Landry, owner of the Colorado Center for Animal Pain Management in Westminster, to launch the IL-10 research study in dogs.

Their results have not been published yet. But thus far, the researchers say, the results look highly promising.

"They're happier, more engaged, more active and they're playing again," said Landry, as he knelt down to scratch Shane's belly after giving him a clean bill of health.

With Shane able to accompany her on her walks again, Sargent has also seen her quality of life improve. Her seizures, which increased in frequency when Shane was injured, have subsided again.

linda watkins with shane (casey cass/cu boulder)

linda watkins with shane (casey cass/cu boulder)

Human Studies Underway

Because the treatment is so localized and prompts the body's own pain-killing response, it lacks the myriad side effects associated with opioids – including constipation and dependency – and it can last for many months after a single injection.

Ultimately, that could make it an attractive option for people with neuropathic pain or arthritis, Watkins says.

This summer, Xalud Therapeutics launched the first human study in Australia, to test the safety, tolerability and efficacy of the compound. Another one-year clinical trial of 32 patients with osteoarthritis of the knee is now underway in Napa, California.

More research is necessary in both pets and people, Watkins stresses. But she's hopeful.

"If all goes well, this could be a game-changer."

New Drug Reduces Rheumatoid Arthritis Pain

By Pat Anson, PNN Editor

Patients with moderate to severe rheumatoid arthritis (RA) may soon have a new treatment option.

Abbvie has announced positive results from a Phase 3 clinical study of its investigational drug upadacitinib and said it would file for FDA approval later this year.

Patients taking daily doses of upadacitinib for 14 weeks showed significant improvements in physical function, quality of life, pain and morning joint stiffness when compared with patients taking methotrexate, a standard first line treatment for RA.

Patients using upadacitinib reported reductions in pain and morning stiffness and better physical function as early as two weeks after starting treatment.

The results were announced at the annual meeting of the American College of Rheumatology (ACR) in Chicago.

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"Upadacitinib as a monotherapy showed significant improvements in rheumatoid arthritis patients' ability to perform daily activities and overall health-related quality of life," said Marek Honczarenko, MD, vice president of global immunology development at AbbVie. "These results show that the improvements in clinical symptoms are accompanied by improvement in outcomes important to patients. These results reinforce upadacitinib's therapeutic potential across diverse rheumatoid arthritis patient populations and its use as a monotherapy treatment option."

Upadacitinib belongs to a class of medication known as JAK inhibitors, which block enzymes that cause inflammation.  The drug is also being investigated as a treatment for psoriatic arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis and atopic dermatitis.

RA is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing swelling, inflammation and bone erosion. Because RA is incurable, treatments focus on suppressing the immune system to reduce inflammation and slow progression of the disease.

Many RA patients do not respond to or cannot tolerate methotrexate, a drug that was first used in chemotherapy because of its ability to stop the growth and spread of tumors. Because it also acts as an immune system inhibitor, low doses of methotrexate became a first line therapy for rheumatoid arthritis in the 1950’s.

Until the late 1990s, one in three RA patients were permanently disabled within five years of disease onset. There has been significant improvement in RA treatment for many patients who receive biologic disease modifying drugs such as Enbrel and Humira. The cost of biologic drugs can be as much as $25,000 a year and many patients can’t afford them or have insurers unwilling to pay for them.