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 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.

Osteoarthritis Drug Works No Better Than Placebo

By Pat Anson, Editor

Hydroxychloroquine (Plaquenil) is a medication commonly used to treat rheumatoid arthritis, lupus and other autoimmune diseases. It’s also being prescribed off-label to treat inflammation and pain caused by hand osteoarthritis, a joint condition that affects nearly a third of patients over the age of 70.

But in a new study published in the Annals of Internal Medicine, British researchers reported that hydroxychloroquine is no more effective than a placebo in relieving moderate to severe pain caused by hand osteoarthritis.

Researchers at the Leeds Institute of Rheumatic and Musculoskeletal Medicine and the Leeds Biomedical Research Centre randomly assigned 248 patients with radiographic hand osteoarthritis to either hydroxychloroquine (200 to 400 mg) or placebo for a year.

Most of the patients had symptoms of hand osteoarthritis for about 5 years, and their average pain level was 7 out of 10.

After 3, 6 and 12 months, there were no significant differences in treatment outcomes between the hydroxychloroquine and placebo groups.

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“We found that HCQ (hydroxychloroquine) was not a more effective analgesic than placebo when added to usual care in persons with moderate to severe hand osteoarthritis,” researchers reported. “Background analgesic use did not differ between groups, and baseline inflammation and structural damage did not affect response to HCQ. The study therefore presents no evidence that HCQ should be considered within the management plan of patients with hand osteoarthritis.”

Two doctors who reviewed the study say more research is needed to find drugs that can treat the inflammation caused by hand osteoarthritis, a condition for which there are no effective therapies.

“The negative findings in this carefully done trial beg the question of what went awry. Did HCQ fail to reduce inflammation, or did reduced inflammation not translate to pain relief?” wrote Elena Losina, PhD, and Jefferey Katz, MD in an editorial.

“Although HCQ is safe, it is also a weak anti-inflammatory agent seldom used in contemporary practice as a solo disease-modifying therapy for rheumatoid arthritis and other inflammatory conditions. Further therapeutic studies of the effects of anti-inflammatory therapy on nodal hand osteoarthritis will need to use more potent agents or compounds developed to more specifically target the inflammatory pathways documented in this condition.”

Why Does Menopause Worsen Rheumatoid Arthritis?

By Pat Anson, Editor

A large new study is confirming what many women with rheumatoid arthritis (RA) already know – menopause and hormonal changes can significantly worsen their pain and other symptoms. But it's not clear why that happens.

Researchers at the University of Nebraska Medical Center enrolled over 8,000 women with RA – both young and old -- in their observational study. They found that post-menopausal women with RA had a significant increase in the level and rate of functional physical decline. Menopause was also associated with a worsening progression of the disease.

RA is a chronic and disabling autoimmune disease in which the body’s own defenses attack joint tissues, causing pain, inflammation and joint erosion. Women experience RA at a rate three times greater than men, have more severe symptoms and increased disability.

Previous studies have shown that women with RA experience changes in their disease during reproductive and hormonal changes. During pregnancy, women are less likely to develop RA, yet the disease is more likely to progress and flare during the post-partum period. Similarly, women who experience early menopause are more likely to develop RA compared to those who experience normal or late menopause.

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Hormone levels of estrogen increase during pregnancy and decline during menopause – but the association with RA is not fully understood.

"Further study is needed as to why women with rheumatoid arthritis are suffering a greater decline in function after menopause," said the study's lead author, Elizabeth Mollard, PhD, an assistant professor in the College of Nursing at the University of Nebraska Medical Center.

"Not only is this decline causing suffering for women, it is costly to both individuals and the healthcare system as a whole. Research is specifically needed on the mechanism connecting these variables with the eventual goal of identifying interventions that can maintain or improve function in postmenopausal women with rheumatoid arthritis."

The study is published in the journal Rheumatology.

RA affects about 1.3 million Americans and about one percent of the global population. Until the late 1990s, one in three RA patients were permanently disabled within five years of disease onset.

Although there are still no cures for RA, in recent years there has been significant improvement in treatment, with disease control now possible for many patients who receive biologic drugs. Those treatments are expensive, with some biologic therapies costing $25,000 a year.

Legal Battles Brew Over High Cost of Arthritis Drugs

By Julie Appleby, Kaiser Health News

Early last winter, Pfizer launched its new rheumatoid arthritis treatment, Inflectra, pricing it 15 percent below the $4,000-a-dose wholesale price of Remicade, the drug for which it is a close copy.

Pfizer figured its lower price would attract cost-conscious insurers.

A year later, though, its drug has barely scratched the market and Pfizer has filed an antitrust suit against its rivals, alleging they are thwarting lower-priced competition through “exclusionary contracts” and rebates.

The outcome of the case — filed in September in U.S. District Court against Johnson & Johnson, the maker of Remicade, and Janssen Biotech — could affect the future of biosimilars, a new class of drugs. Some policy experts say these near-copies of biologics are key to slowing spending on complex and expensive specialty medications like those used to treat rheumatoid arthritis.

At the heart of the case are rebates, which are discounts off the wholesale price of drugs.

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Manufacturers offer them to help keep their products on insurers’ lists of covered drugs. The money mainly goes back to insurers and pharmacy benefit managers, who say the rebates help reduce health care spending.

But Pfizer alleges that those rebates are being used to thwart biosimilars’ entry into the marketplace.

“This is the first antitrust case we’ve seen like this around biosimilars,” said Michael Carrier, a Rutgers Law School professor “Pfizer is claiming that one form of anti-competitive behavior involves withholding rebates from insurers.”

Biosimilars are costly to produce, so they are not likely to trigger the same sharp pricing drop triggered by generics. Still, their manufacturers say they could bring consumers some relief to rival biologics’ high price tags.

Pfizer’s Inflectra is one of the first biosimilars to hit the market since Congress passed legislation in 2010 to pave the way.

According to Pfizer, weeks after Inflectra gained Food and Drug Admininstration approval, J&J moved to stake out its biologic turf.

J&J began requiring insurers and PBMs to sign “exclusionary contracts … designed to block both insurers from reimbursing and hospitals and clinics from purchasing Inflectra or other biosimilars of Remicade despite their lower pricing,” alleges the case filed in federal district court in Philadelphia.

If insurers don’t agree to the J&J contracts, the loss of rebates could “for some insurers, run into the tens of millions of dollars annually,” the Pfizer case alleges.

Even with its lower price, Pfizer faced an uphill battle to win market share.

Remicade is the fifth-biggest-selling drug by revenue in the U.S., reaping more than $4.8 billion in 2016 for makers J&J and Janssen, the suit said. Often, patients are reluctant to switch once they are established on an RA drug that is working for them.

Still, Pfizer thought it would pick up newly diagnosed patients and gain ground that way. But its lawsuit says the drug accounted for only about 4 percent of total sales, with Remicade getting the rest, by early September.

“We stand by our contracts,” said J&J and Janssen Biotech in a written statement. The firms also defend rebates as “competition that is doing what competition is meant to do: driving deeper discounts that will lead to overall lower costs.”

Yet the price of Remicade has not fallen, the Pfizer case says.

Since approval of Inflectra, J&J has raised the list price of Remicade by close to 9 percent, the lawsuit alleges. As of September, Remicade’s average sales price –after discounts and rebates — is more than 10 percent higher than Inflectra.

“This case is a big deal, because it has the potential to bring to light some of the anti-competitive contracting practices at work to keep … prices extremely high,” said Jaime King, a professor at University of California-Hastings College of the Law.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Rising Cost of Arthritis Drugs Defies Economics

By Julie Appleby, Kaiser Health News

Renda Bower knows well the cost of drugs to treat rheumatoid arthritis – her husband, son and daughter all have the painful, disabling autoimmune disease. And the family’s finances revolve around paying for them.

Even with insurance, Bower’s family last year faced $600 a month in copayments for the drug, plus additional payments on another $16,000 in medical bills racked up in 2016 when a former insurer refused to cover all the doses her 9-year-old daughter needed.

Bowers, of Warsaw, Ind., said her family tries to keep up with prices by cutting back on her children’s sports and extracurriculars and skipping family vacations. She also works as a part-time teacher.

But financially, it’s hard. “The cost should not be this high,” she said.

Wholesale prices for Humira and Enbrel, the two most commonly used treatments for rheumatoid arthritis, known as RA, increased more than 70 percent in the past three years.

Since the first RA drug came to market a decade ago, nearly a dozen have been added. If basic economics prevailed, RA treatments and patients would have benefited from competition.

But, because of industry price-setting practices, legal challenges and marketing tactics, they haven’t. The first RA drug cost $10,000 a year. It now lists for more than $40,000 — even as alternatives have entered the U.S. market.

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“Competition generally doesn’t work to lower prices in branded specialty drugs,” said Peter Bach, director of Memorial Sloan Kettering’s Center for Health Policy and Outcomes.

Humira is the world’s No. 1 prescription drug by revenue. AbbVie manufactures and markets the drug and is on track to reach revenue from the product of $17 billion this year.

Other RA treatments are also among the top 10 drugs by revenue sold in the U.S. Enbrel, made by Amgen, ranks as No. 3. Remicade, by Janssen Biotech, is fifth. Some RA medications are approved for other conditions, including psoriatic arthritis, Crohn’s disease and psoriasis.

About 1.5 million Americans have rheumatoid arthritis. The Bowers found some relief this year but not because prices dropped. Rather, Renda’s husband left his job at an engineering firm to work as a machinist at a medical device company that has an insurance plan with lower copayments. Her daughter was accepted into a clinical trial at Cincinnati Children’s Hospital. The trial covers the drug’s cost but not the associated expense of weekly travel, among other things.

Middlemen Benefit As Wholesale Price Rises

The complicated pharmaceutical supply chain in the United States means middlemen — such as pharmacy benefit managers (PBM) and, in some cases, hospitals and doctors’ offices — can gain financially by choosing more expensive drugs. That’s because PBMs usually get a rebate from the drugmakers on top of whatever profit they get from selling or administering the drug.

Those rebates often are based on a percentage of the list, or wholesale, price. So, the middlemen who get the rebates take in more money when drugmakers raise those sticker prices.

But who pockets the rebates? PBM firms, which oversee drug benefits for millions of Americans, say they share all or part of them with the insurers or employers who hire them. In some cases, the rebates go directly to specialty pharmacies, medical clinics or physicians dispensing the treatments.

The rebates rarely end up directly in patients’ pockets.

Those rebates affect the market in another way: They can make it harder for some companies to offer new treatments or they can thwart less costly rival products.

“We could give [our new drug] away for free and … it would still be more economically advantageous” for insurers and PBMs to send patients to Humira first, said Andreas Kuznik, a senior director at Regeneron Pharmaceuticals, at a conference examining the cost and value of RA treatments.

Thomas Amoroso, medical director for medical policy at Tufts Health Plan, said at the same March conference that he has found drug industry sales representatives to be persistent in tracking how their drugs are positioned on plan formularies.

If insurers decide to add a new, lower-cost drug as the preferred alternative, “our Humira rep would be knocking on our door next week and saying, ‘Hey, that rebate we gave you? We’re taking it back,’” Amoroso said.

The roundtable at which they spoke was part of an assessment of RA drug pricing convened by the Institute for Clinical and Economic Review, a nonprofit that evaluates the value of medical tests and treatments for insurers and other clients.

PBMs won’t disclose the rebates they provide to clients, but studies provide a clue. It’s a huge amount of money.

The Berkeley Research Group, a consulting firm that advises major employers, said that rebates and other discounts paid to insurers, PBMs and the U.S. government for brand-name drugs grew from $67 billion in 2013 to $106 billion in 2015.

Most RA drugs are a complex type of medication, called biologics, which are made in living organisms. Nearly identical copies of biologics are called biosimilars. They hold the promise of lower prices, just as generic drugs did for less complex medications.

While several biosimilar RA treatments have won Food and Drug Administration approval, including replicas of Humira, Enbrel and Remicade, most are tied up in court battles over patents. And those biosimilars that have made it to market are now the subject of new areas of legal challenge.

In mid-September, Pfizer filed what will be a closely watched antitrust lawsuit against Johnson & Johnson. The case alleges that J&J is using exclusionary contracts and the threat of withdrawing rebates to protect Remicade from Pfizer’s lower-priced biosimilar, Inflectra, which hit the market last winter.

J&J defends its contracts, saying they are “driving deeper discounts that will lead to overall lower costs.”

Arguments For And Against Rebates

Rebates are under increasing scrutiny, amid growing alarm about soaring prescription drug prices in the United States. But the Pharmaceutical Care Management Association, the PBM industry’s trade lobby, said that complaints that rebates help fuel higher prices are unfounded.

These rebates, the lobby says, help save the health system millions of dollars by shifting dollars back to insurers or other clients, who can then use them to lower future premium increases. This year, it commissioned a study that found no correlation between rebates and the rising list prices of the top 200 brand-name drugs, suggesting higher rebates didn’t necessarily drive higher prices.

“The rebate system exists because [insurers, employers and other clients] want discounts,” said Steve Miller, chief medical officer for Express Scripts, one of the nation’s three largest PBMs.

Express Scripts offers clients an option to give patients the discount directly, but most choose not to, he said.

“While individual patients would get the benefit, everyone else’s premiums would go up [because the rebate savings would not flow back to the insurer],” Miller said. “Changing where the rebate goes doesn’t lower the price of the drug.”

But rebates play a role in what some patients pay at the pharmacy counter.

It stems from a simple calculation: whether a patient’s insurance copayment is based on a percentage of the drug’s wholesale price or the drug’s price after rebates are given to the middlemen.

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Heidi Barrett , a mother of five from Everett, Wash., faces a 10 percent copay whenever she or one of her four children who have RA, all of whom have been on medication for years, go for their monthly infusion of Remicade.

Although Barrett is shielded from much of the cost because she has good employer-based insurance through her husband’s job, the question of whether her monthly copayments are based on the wholesale price or the after-rebate price rankles her.

“I have asked that question of the insurance company. I’ve asked that of our union,” said Barrett, 47, a paralegal who isn’t working because she spends so much time on her children’s treatments. “I never got any answers back.”

Based on data analyzed by Bach’s group at Sloan Kettering to determine the cost of 100 milligrams of Remicade, it appears she is paying based on the pre-rebate price.

Here’s how that works: Barrett’s 18-year-old son recently received a 600 mg dose that required a copay of $655. That is close to 10 percent of Remicade’s average U.S. wholesale price for that dose of $6,450, the Bach analysis showed.

Barrett is not benefiting from the rebate that middlemen receive.

Rebates and discounts, however, drive down the price for pharmacy benefit managers, hospitals or doctors.

According to the analysis, the average net cost of a 600 mg dose is $4,140, once all discounts are calculated. If Barrett could use that base price as her copay, she would save more than $240. For her entire family — all her children and Barrett take similar doses — that equals a savings of $1,000 a month.

With her current insurance, Barrett quickly meets a yearly $12,900 deductible. She considers herself lucky that her insurer then picks up the drug’s full cost. But the experience has changed her motherly advice to her children, who are 10, 18, 19 and 25, about what to hope for in life.

“I tell them, you can be anything you want when you go grow up. But you need to go to a company with good health insurance, even before you look at the salary or whether you’ll be happy there, your first priority is health insurance,” Barrett said. “It’s an insane world we live in.”

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Stem Cell Vaccine Could Reverse Arthritis

By Pat Anson, Editor

A team of researchers has successfully used gene-editing technology to “rewire” mouse stem cells to fight inflammation – a finding that could pave the way for a new class of biologic drug that replaces cartilage and protect joints from damage caused by arthritis.

The stem cells, known as “smart” cells (stem cells modified for autonomous regenerative therapy), were developed at Washington University School of Medicine and Shriners Hospitals for Children in St. Louis, in collaboration with investigators at Duke University and Cytex Therapeutics in North Carolina.

The research findings are published in the journal Stem Cell Reports.

"Our goal is to package the rewired stem cells as a vaccine for arthritis, which would deliver an anti-inflammatory drug to an arthritic joint but only when it is needed," said senior author Farshid Guilak, PhD, a professor of orthopedic surgery at Washington University School of Medicine.

Guilak and his colleagues grew mouse stem cells in a test tube and then used a gene-editing tool called CRISPR to remove a gene that plays a key role in inflammation. That gene was replaced with a gene that releases a biologic drug that combats inflammation.

Within a few days, the modified stem cells grew into cartilage cells and produced cartilage tissue. Further experiments showed that the engineered cartilage was protected from inflammation.

"We hijacked an inflammatory pathway to create cells that produced a protective drug," explained Jonathan Brunger, PhD, the paper's first author and a postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco.

IMAGE CREDIT: ELLA MARUSHCHENKO

IMAGE CREDIT: ELLA MARUSHCHENKO

Many current biologic drugs used to treat arthritis – such as Enbrel, Humira and Remicade -- attack an inflammation-promoting molecule called TNF-alpha. But the problem with these drugs is that they interfere with the immune system throughout the body and can make patients susceptible to side effects such as infections.

"We want to use our gene-editing technology as a way to deliver targeted therapy in response to localized inflammation in a joint, as opposed to current drug therapies that can interfere with the inflammatory response through the entire body," said Guilak. “If this strategy proves to be successful, the engineered cells only would block inflammation when inflammatory signals are released, such as during an arthritic flare in that joint."

Researchers have begun testing the engineered stem cells in mouse models of rheumatoid arthritis and other inflammatory diseases. If the work can be replicated in living laboratory animals and then developed into a clinical therapy, the cartilage grown from stem cells would respond to inflammation by releasing a drug that protects them from further damage.

"When these cells see TNF-alpha, they rapidly activate a therapy that reduces inflammation," Guilak explained. "We believe this strategy also may work for other systems that depend on a feedback loop. In diabetes, for example, it's possible we could make stem cells that would sense glucose and turn on insulin in response.

"The ability to build living tissues from 'smart' stem cells that precisely respond to their environment opens up exciting possibilities for investigation in regenerative medicine."

Farshid Guilak and co-author Vincent Willard have a financial interest in Cytex Therapeutics, a startup founded by some of the investigators. They may license the technology and realize financial gain if it is eventually is approved for clinical use.

Guilak and his colleagues at Cytex have also used stem cells to grow new cartilage that could someday be implanted into arthritic hips, delaying or eliminating the need for hip replacement surgery.

Stem cells are found throughout the body and are increasingly being used to develop new treatments to repair damaged tissue and reduce inflammation. The Food and Drug Administration considers most stem cell treatments experimental because their safety and efficacy haven’t been proven through clinical studies.