New Blood Test Could Save Arthritis Patients Time, Money and Pain

By Arthur Allen, KFF Health News

Erinn Maury knew Remicade wasn’t the right drug for Patti Schulte, a rheumatoid arthritis patient the physician saw at her Millersville, Maryland, practice. Schulte’s swollen, painful joints hadn’t responded to Enbrel or Humira, two drugs in the same class.

But the insurer insisted, so Schulte went on Remicade. It didn’t work either.

What’s more, Schulte suffered a severe allergic reaction to the infusion therapy, requiring a heavy dose of prednisone, a steroid with grave side effects if used at high doses for too long.

After 18 months, her insurer finally approved Maury’s drug of choice, Orencia. By then, Schulte’s vertebrae, weakened by prednisone, had started cracking. She was only 60.

Schulte’s story of pain, drug-hopping, and insurance meddling is all too common among patients with rheumatoid arthritis, who often cycle agonizingly through half a dozen drugs in search of one that provides a measure of relief. It’s also a story of how doctors are steered by pharmacy benefit managers — the middlemen of the drug market — as well as by insurers.

Once people with inflammatory conditions such as rheumatoid arthritis reach a certain stage, the first prescription offered is typically Humira, the best-selling drug in history, and part of a class known as tumor necrosis factor inhibitors, or TNFis, which fail to significantly help about half of the patients who take it.

“We practice rheumatology without any help,” said Vibeke Strand, a rheumatologist and adjunct clinical professor at Stanford. She bemoaned the lack of tools available to choose the right drug while bristling at corporate intervention in the decision. “We are told by the insurer what to prescribe to the patient. After they fail methotrexate, it’s a TNF inhibitor, almost always Humira. And that’s not OK.”

If there’s a shred of hope in this story, it’s that a blood test, PrismRA, may herald an era of improved care for patients with rheumatoid arthritis and other autoimmune conditions. But first, it must be embraced by insurers.

PrismRA employs a predictive model that combines clinical factors, blood tests, and 19 gene patterns to identify the roughly 60% of patients who are very unlikely to respond to a TNFi drug.

Over the past 25 years, drug companies have introduced five new classes of autoimmune drugs. TNFis were the first to market, starting in the late 1990s.

Some 1.3 million Americans have rheumatoid arthritis, a disease in which a person’s immune system attacks their joints, causing crippling pain and, if improperly treated, disfigurement. The newer drugs, mostly so-called biologics, are also used by some of the 25 million or more Americans with other autoimmune diseases, such as lupus, Crohn’s disease, and psoriasis. Typically costing tens of thousands of dollars annually, the drugs are prescribed after a patient fails to respond to older, cheaper drugs like methotrexate.

Insurers Often Determine Treatment

Until recently, rheumatologists have had few ways to predict which of the new drugs would work best on which patients. Often, “it’s a coin flip whether I prescribe drug A or B,” said Jeffrey Curtis, a rheumatology professor at the University of Alabama-Birmingham.

Yet about 90% of the patients who are given one of these advanced drugs start on a TNFi, although there’s often no reason to think a TNFi will work better than another type.

Under these puzzling circumstances, it’s often the insurer rather than the doctor who chooses the patient’s drug. Insurers lean toward TNFis such as adalimumab, commonly sold as brand-name Humira, in part because they get large rebates from manufacturers for using them. Although the size of such payments is a trade secret, AbbVie is said to be offering rebates to insurers of up to 60% of Humira’s price. That has enabled it to control 98.5% of the U.S. adalimumab market, even though it has eight biosimilar competitors.

PrismRA’s developer, Scipher Medicine, has provided more than 26,000 test results, rarely covered by insurance. But on Oct. 15, the Centers for Medicare & Medicaid began reimbursing for the test, and its use is expected to rise. At least two other companies are developing drug-matching tests for rheumatoid arthritis patients.

Although critics say PrismRA is not always useful, it is likely to be the first in a series of diagnostics anticipated over the next decade that could reduce the time that autoimmune disease patients suffer on the wrong drug.

Academics, small biotechs, and large pharmaceutical companies are investing in methods to distinguish the biological pathways involved in these diseases, and the best way to treat each one. This approach, called precision medicine, has existed for years in cancer medicine, in which it’s routine to test the genetics of patients’ tumors to determine the appropriate drug treatment.

“You wouldn’t give Herceptin to a breast cancer patient without knowing whether her tumor was HER2-positive,” said Costantino Pitzalis, a rheumatology professor at the William Harvey Research Institute in London. He was speaking before a well-attended session at an American College of Rheumatology conference in San Diego in November. “Why do we not use biopsies or seek molecular markers in rheumatoid arthritis?”

It’s not only patients and doctors who have a stake in which drugs work best for a given person.

When Remicade failed and Schulte waited for the insurer to approve Orencia, she insisted on keeping her job as an accountant. But as her prednisone-related spinal problems worsened, Schulte was forced to retire, go on Medicaid, and seek disability, something she had always sworn to avoid.

Now taxpayers, rather than the insurer, are covering Schulte’s medical bills, Maury noted.

Precision medicine hasn’t seemed like a priority for large makers of autoimmune drugs, which presumably have some knowledge of which patients are most likely to benefit from their drugs, since they have tested and sold millions of doses over the years. By offering rebate incentives to insurers, companies like AbbVie, which makes Humira, can guarantee theirs are the drugs of choice with insurers.

“If you were AbbVie,” Curtis said, “why would you ever want to publish data showing who’s not going to do well on your drug, if, in the absence of the test, everyone will start with your drug first?”

What Testing Could Do

Medicare and commercial insurers haven’t yet set a price for PrismRA, but it could save insurers thousands of dollars a year for each patient it helps, according to Krishna Patel, Scipher’s associate director of medical affairs.

“If the test cost $750, I still only need it once, and it costs less than a month of whatever drug is not going to work very well for you,” said Curtis, a co-author of some studies of the test. “The economics of a biomarker that’s anything but worthless is pretty favorable because our biologics and targeted drugs are so expensive.”

Patients are enthusiastic about the test because so many have had to take TNFis that didn’t work. Many insurers require patients to try a second TNFi, and sometimes a third.

Jen Weaver, a patient advocate and mother of three, got little benefit from hydroxychloroquine, sulfasalazine, methotrexate, and Orencia, a non-TNFi biologic therapy, before finding some relief in another, Actemra. But she was taken off that drug when her white blood cells plunged, and the next three drugs she tried — all TNFis — caused allergic reactions, culminating with an outbreak of pus-filled sores. Another drug, Otezla, eventually seemed to help heal the sores, and she’s been stable on it since in combination with methotrexate, Weaver said.

“What is needed is to substantially shorten this trial-and-error period for patients,” said Shilpa Venkatachalam, herself a patient and the director of research operations at the Global Healthy Living Foundation. “There’s a lot of anxiety and frustration, weeks in pain wondering whether a drug is going to work for you and what to do if it doesn’t.” A survey by her group found that 91% of patients worried their medications would stop working. And there is evidence that the longer it takes to resolve arthritis symptoms, the less chance they will ever stop.

How insurers will respond to the availability of tests isn’t clear, partly because the arrival of new biosimilar drugs — essentially generic versions — are making TNFis cheaper for insurance plans. While Humira still dominates, AbbVie has increased rebates to insurers, in effect lowering its cost. Lower prices make the PrismRA test less appealing to insurers, since widespread use of the test could cut TNFi prescriptions by up to a third.

However, rheumatologist John Boone in Louisville, Kentucky, found to his surprise that insurers mostly accepted alternative prescriptions for 41 patients whom the test showed unlikely to respond to TNFis as part of a clinical trial. Boone receives consulting fees from Scipher.

Although the test didn’t guarantee good outcomes, he said, the few patients given TNFis despite the test results almost all did poorly on that regimen.

Scientists from AbbVie, which makes several rheumatology drugs in addition to Humira, presented a study at the San Diego conference examining biomarkers that might show which patients would respond to Rinvoq, a new immune-suppressing drug in a class known as the JAK inhibitors. When asked about its use of precision medicine, AbbVie declined to comment.

Over two decades, Humira has been a blockbuster drug for AbbVie. The company sold more than $3.5 billion worth of Humira in the third quarter of 2023, 36% less than a year ago. Sales of Rinvoq, which AbbVie is marketing as a treatment for patients failed by Humira and its class, jumped 60% to $1.1 billion.

Shannan O’Hara-Levi, a 38-year-old in Monroe, New York, has been on scores of drugs and supplements since being diagnosed with juvenile arthritis at age 3. She’s been nauseated, fatigued, and short of breath and has suffered allergic reactions, but she says the worst part of it was finding a drug that worked and then losing access because of insurance. This happened shortly after she gave birth to a daughter in 2022, and then endured intense joint pain.

“If I could take a blood test that tells me not to waste months or years of my life — absolutely,” she said. “If I could have started my current drug last fall and saved many months of not being able to engage with my baby on the floor — absolutely.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues.

Chemotherapy and Opioid Shortages Impacting Cancer Care

By Pat Anson, PNN Editor

Over two-thirds of cancer centers in the U.S. are reporting shortages of methotrexate and other drugs used in chemotherapy, according to a survey by the National Comprehensive Cancer Network (NCNN).

Methotrexate is a versatile drug that prevents cells from dividing. It was originally developed to treat cancer, but is also widely used to treat autoimmune and neurological conditions such as lupus, rheumatoid arthritis, migraine and multiple sclerosis.

The NCNN surveyed 27 cancer centers across the U.S. in late May, and found that 67% of them were reporting shortages of methotrexate. Most centers are also reporting chronic shortages of carboplatin and cisplatin, chemotherapy agents that are widely used in cancer treatment. The shortages have resulted in treatment delays or forced doctors to modify their treatment plans using other drugs.

"This is an unacceptable situation. We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now," Robert Carlson, MD, CEO of NCCN, said in a statement. "We were relieved by survey results that show patients are still able to get life-saving care, but it comes at a burden to our overtaxed medical facilities." 

Drugs shortages in the U.S. are currently near record levels, primarily due to shipping delays and other disruptions caused by the pandemic. But the shortage in chemotherapy agents largely stems from a halt in production at a plant in India operated by Intas Pharmaceuticals. FDA inspectors found quality-control violations at the plant late last year and the agency recently slapped an import alert on the company. The agency is working with drug makers in China to make up the difference.

The FDA added methotrexate injectable solution to its drug shortage list in March. Supplies are currently limited and the shortage is not expected to end until December 2023. No shortages are currently reported for methotrexate tablets.

Hydrocodone Shortage

In addition to chemotherapy drugs, some drug makers are also reporting shortages of opioid pain medication. The American Society of Health-System Pharmacists (ASHP) recently added hydrocodone-acetaminophen combinations – commonly known under the brand names Vicodin and Norco-- to its own drug shortage database.

Generic drug makers Amneal, Camber, KVK-Tech, Major and Rhodes currently report shortages of 5 mg, 7.5 mg, and 10 mg hydrocodone tablets. None of the companies provided a reason for the shortage or an estimate for when it might end. Many of the same drug makers reported shortages of oxycodone in March.

The limited supply of opioids is also affecting cancer patients. The University of Utah Health system recently informed its drug wholesaler that it was adding 50 new beds to its cancer clinic and would be needing more pain medication to treat the extra patients.

“And the wholesaler said, ‘Well, let's just wait until we start receiving your orders to increase the amounts that you're going to buy,’” said Erin Fox, PharmD, Senior Pharmacy Director at University of Utah Health, which tracks drug shortages for the ASHP. “We're unable to be proactive. We're trying to think ahead. And we don't want to have that situation where we we're getting very close to running out or not having enough. That's basically what our wholesaler says has to happen.”

“We wish that we could fix all these things, but we don't make the medicines and we can't tell someone that they must make medicines. There are some things that are out of our control,” FDA Commissioner Robert Califf, MD, said in a recent interview with Medscape.

The Drug Enforcement Administration, in consultation with the FDA, sets the annual production quotas for opioids and other controlled substances. The DEA reduced this year’s supply of oxycodone and hydrocodone by about 5 percent, after being advised by FDA that demand for Schedule II opioids would decline. Since peaking a decade ago, DEA production quotas have fallen by 65% for oxycodone and 73% for hydrocodone.

Early Use of Methotrexate Slows Rheumatoid Arthritis

By Pat Anson, PNN Editor

Early treatment with methotrexate can significantly reduce joint pain and inflammation in patients showing early signs of rheumatoid arthritis (RA), according to a new study by Dutch researchers.

First used as a chemotherapy treatment because it prevents cancer cells from dividing, methotrexate became a first-line therapy for RA in the 1980’s because it also acts as an immune system inhibitor. RA is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing pain, swelling, inflammation and bone erosion. 

Treatment with methotrexate usually isn’t initiated until RA is diagnosed, but researchers at Leiden University Medical Centre (LUMC) in the Netherlands found that early treatment of patients in the "pre-rheumatic phase" helped slow progression of the disease.

"At present, methotrexate is only prescribed to the patient following a rheumatoid arthritis diagnosis," said lead author Annette van der Helm, PhD, Professor of Rheumatology at LUMC. "But that is too late. By then, the disease is already considered chronic."

Van der Helm and her colleagues enrolled 236 patients who had joint pain and inflammation that could be seen on an MRI. Although RA was suspected, it was not yet confirmed. Half the patients were treated with methotrexate and the other half with a placebo. The effects of the treatments were assessed a year later.

The study findings, published in The Lancet, show that early treatment with methotrexate did not prevent the development of RA, but the diagnosis was delayed. Patients in the methotrexate group also had less pain and morning stiffness than those treated with a placebo. Their physical function was also better and their MRI scans showed less joint inflammation.

"This is an important step towards reducing disease burden for this group of patients," says Van der Helm. "This chronic disease is extremely burdensome to patients and their families. Our study is paving the way toward arthritis prevention."

In 2019, over a million people were prescribed methotrexate in the United States, where it is approved as a treatment for RA, psoriasis and cancer. The drug is also used “off-label” for lupus, migraine, multiple sclerosis, Crohn’s Disease and other autoimmune problems.   

‘Abortion-Inducing Drug’

Ironically, the Dutch study comes at a time when some female patients in the U.S. are losing access to methotrexate because the drug can cause miscarriages and be used to end ectopic pregnancies. After last month’s Supreme Court ruling that overturned Roe vs. Wade, over half the states enacted or implemented abortion limits, including some that specifically list methotrexate as an “abortion-inducing drug.”  

Although the state laws don’t prohibit methotrexate from being used for other purposes, some doctors, pharmacies and insurers have become cautious about prescribing or dispensing the drug. The Arthritis Foundation has heard from several women who’ve had trouble getting methotrexate, including some beyond childbearing age.

“Some of the stories we’ve gotten in are of women who are over the age of 50 — they are past their reproductive years — and they’re still being asked really invasive questions and having roadblocks thrown up,” Dr. Anna Hyde of the Arthritis Foundation told NBC4 in Washington.

Up to 90% of RA patients are prescribed methotrexate at some point. It doesn’t work for everyone and can have side effects, but it’s the only affordable option for many patients, costing about $50 for a month’s supply of generic methotrexate tablets. Other treatments for RA, such as disease modifying biologic drugs, can cost as much as $3,000 a month and are not covered by insurance.  

Women Losing Access to Arthritis Drugs Due to Abortion Bans

By Pat Anson, PNN Editor

It didn’t take long for last month’s Supreme Court decision overturning Roe v. Wade to have a ripple effect on the U.S. healthcare system – including unintended consequences for women of childbearing age who have painful conditions such as lupus, rheumatoid arthritis, migraine and multiple sclerosis (MS).

Methotrexate and other drugs used to treat autoimmune and neurological conditions can also be used to induce abortions because they prevent cells from dividing. Although not commonly used for that purpose, methotrexate is officially listed in Texas as an “abortion-inducing drug” – an abortifacient -- putting practitioners at risk of running afoul of the state’s $10,000 bounty on anyone who helps a woman end a pregnancy after six weeks.

Even in states where abortion is legal, physicians, pharmacists and other healthcare providers have become cautious about prescribing or dispensing methotrexate.

“I received an email from my rheumatologist today that they are stopping all refills of methotrexate because it is considered an abortifacient,” a Virginia woman with lupus posted on Twitter just days after Roe was overturned. “If this is happening in a blue state with no trigger law, think of those in red states where abortion isn’t even legal. And those states that have trigger laws causing extreme and immediate loss of access.”

On the same day Roe was overturned, another poster on Twitter said his wife’s rheumatologist took all his female patients off medications that might cause a miscarriage

“So those patients are going to have to go off the drugs that were helping to control their condition and have worse health outcomes. People are going to die because of this,” he said.

The Lupus Foundation of America and Arthritis Foundation said they were aware of the situation and encouraged affected patients to contact them directly.

In an op/ed published in JAMA Neurology, neurologists at UC San Francisco School of Medicine warn the new abortion limits could have life-changing and life-threatening consequences for women with migraine, MS and epilepsy.

"Even if prescribed for a neurological condition, there are reports from patients across the country stating they are now unable to access methotrexate because it can also be used to induce abortion," wrote lead author Sara LaHue, MD, of the UCSF Department of Neurology. "This could increase risk of morbidity, mortality and irreversible disability accumulation for women with neurologic diseases."

Ironically, some treatments for neurological conditions also increase the likelihood of an unplanned pregnancy because they reduce the effectiveness of hormonal contraceptives. Physicians may become reluctant to prescribe those drugs to women of childbearing age.

Some neurologists may also rule out the use of monoclonal antibodies for women — not because they are used in abortions, but because they may harm a fetus.

"In many settings, women with MS are treated with less effective therapies, because these medications are perceived to be safer in pregnancy," said co-author Riley Bove, MD, of the UCSF Department of Neurology. "Often, neurologists are not familiar with how to time or optimize certain medications, or of their updated safety profile. The reversal of Roe v. Wade may reinforce decisions to stick with the less effective therapies, which may result in irreversible disability for some women with MS."

This week the Health and Human Services Department (HHS) warned retail pharmacies they are at risk of violating federal civil rights law if they deny women access to medications used in abortions. The warning specifically mentions methotrexate when its prescribed to someone with rheumatoid arthritis or some other disabling condition.

“If the pharmacy refuses to fill the individual’s prescription or does not stock methotrexate because of its alternate uses, it may be discriminating on the basis of disability,” HHS said..

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.

"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.

Rheumatoid Arthritis Drug Linked to Overdoses

Pat Anson, Editor

A drug that’s long been used to treat rheumatoid arthritis and other autoimmune diseases has been linked to dozens of deaths in the U.S. and Australia, mainly because patients have taken it daily rather than the recommended weekly dose, according to a new study published in the Medical Journal of Australia.

Methotrexate was originally developed and is still used for chemotherapy because of its ability to stop the growth and spread of tumors. Because it is also effective as an immune system inhibitor, low doses of methotrexate became a front line therapy for rheumatoid arthritis in the 1950’s. It is also used to treat psoriasis, lupus, sarcoidosis, and inflammatory bowel diseases such as Crohn’s.

Researchers say methotrexate is safe when taken once or twice a week, but the drug is so potent that accidental daily dosing can be lethal.

“The unusual dosing schedule of low dose methotrexate is associated with a risk that it will be prescribed, dispensed or administered daily instead of weekly,” said lead author Rose Cairns, PhD, of the NSW Poisons Information Centre in Australia.

“Used appropriately, methotrexate is considered safe and efficacious; accidental daily dosing, however, can potentially be lethal. Higher or more frequent doses can result in gastro-intestinal mucosal ulceration, hepatotoxicity, myelosuppression, sepsis and death.”

In a review of medication errors in Australia from 2004 to 2014, researchers linked methotrexate to 22 deaths, including seven cases in which erroneous daily dosing was documented. One patient took methotrexate for 10 consecutive days. Reasons for the errors included patient misunderstanding and incorrect packaging of the drug by pharmacists.

A similar study of medication errors in the U.S. over a 4 year period identified over 100 methotrexate dosing errors that resulted in 25 deaths. Over a third (37%) of the errors were attributed to the prescriber, 20% to the patient, 19% to pharmacists, and 18% to administration by a health care professional.

The researchers also found a “worrying increase” in the number of medication errors just in the past year.

“It is difficult to explain this increase, but the risk of methotrexate medication error may be increasing as the population ages. Older people may be at increased risk because of a range of problems that includes confusion, memory difficulties, and age-related decline in visual acuity,” said Cairns.

Cairns and her colleagues say more needs to be done by drug makers and health professionals to reduce the risk of methotrexate overdosing, such as clearer labeling, smaller sized packages, and distinctly colored tablets.

"Methotrexate use is likely to continue increasing as Australia's population ages, so that additional measures are needed to prevent these errors," the authors concluded.