MILWAUKEE – Every night, a slew of TV commercials hammer home the benefits of drugs that treat autoimmune diseases such as psoriasis and rheumatoid arthritis – and tack on a reminder about the risks they carry.

More than most, Tom Leith knows the possible perils.

Over the last 20 years, he has been on three of the drugs for his rheumatoid arthritis: Enbrel, Orencia and Rituxan.

In that time, he has had at least two serious medical problems: A life-threatening case of viral meningitis in 2017 and, a short time later, a suspected cancerous tumor on his lung. Doctors say both could be related to the drugs, but there is no way to know for sure.

The drugs are known as biologic medicines, or biologics. Made from living organisms, such as animal cells, instead of chemicals, they have flooded the market over the last two decades – bringing with them promise and pitfalls.

By tamping down overactive immune systems, the drugs can lead to substantial improvement, even remission. But in doing so, they leave patients more susceptible to sometimes-deadly infections and other serious side effects.

In many cases, the problems emerged only after the U.S. Food and Drug Administration deemed the drugs safe and effective treatments and allowed them on the market.

Tom Leith and his wife, Kathy, look over his medical records. Leith, 64, was diagnosed with rheumatoid arthritis in 1983 and was told he eventually would need a wheelchair. Thanks to a variety of drugs, including biologic medicines, he has continued to walk without the need for a wheelchair.

At least 25 times since 2000, the FDA or drug manufacturers have issued warnings, safety updates or found potential signals of serious risk with the drugs, a Milwaukee Journal Sentinel analysis found.

Of the 21 biologic drugs that have won FDA approval, 13 – 62% – have received the agency’s most stringent warning, known as a “black box.” In the majority of those, the warnings were added when new problems were identified after the drugs were on the market.

That’s more than the percentage of warnings found in a 2017 study of new drugs. That study, published in JAMA, found that of 222 drugs that got on the market between 2001 and 2010, 27% later received a black box warning.

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The individual risks from biologic drugs are rare, but they span a growing range of serious problems, including invasive fungal infections; tuberculosis; the bacterial infections listeria and legionella; sepsis; an often-fatal viral brain infection; cancer; heart failure; and liver failure.

What’s more, in rare cases the drugs may leave some patients who are using them to treat autoimmune diseases susceptible to contracting other autoimmune diseases.

“You have to weigh the risks and what you are looking for in your quality of life,” said Leith, 64, who lives near Lake Geneva, Wisconsin.

Dark side effects: Biologics to treat arthritis have flooded the market. They're also linked to 34,000 deaths

When he was diagnosed with rheumatoid arthritis in 1983, doctors told him he would be in a wheelchair in five years. Thirty-six years later, he still is walking.

“I would not change a thing,” he said.

An earlier Journal Sentinel analysis of FDA data found reports linking biologic drugs to more than 500,000 serious side effects since 2004, including more than 34,000 deaths.

The analysis focused on the 19 drugs still on the market. It was limited to biologic drugs that are used to treat conditions of the skin, joints and gastrointestinal system. That is, conditions caused by faulty immune systems.

While the FDA database has limitations, including a lack of verification of the reports and the possibility that other drugs also could have been used, it is the largest publicly available data set of reactions associated with prescription drugs.

If anything, experts say, it undercounts the total potentially dangerous incidents.

“We are learning a lot that we didn’t know at the time of approval,” said Joseph Ross, an associate professor of medicine at Yale School of Medicine, who has studied drug safety. “It raises the question of should we be regulating them differently.”

Benefit vs. risk

Consider the case of Raptiva.

In 2003, drugmaker Genentech submitted an upbeat report to the FDA about Raptiva, for which it was seeking approval to treat psoriasis.

The company said, based on clinical trials, there were few serious side effects and no evidence of increased infections.

“The benefits experienced by most subjects treated with Raptiva outweigh any potential, infrequent risks,” Genentech said in its report. “Raptiva provides a significant new, safe, and efficacious alternative for patients with moderate to severe plaque psoriasis.”

The FDA gave its approval.

Then bad things started happening.

After reports of patients experiencing problems were submitted to the FDA and additional trials turned up new side effects, warnings for Raptiva were issued for a potentially serious red blood cell disorder; susceptibility to a flesh-eating bacteria; pneumonia; viral meningitis; and invasive fungal infections.

In 2008, the FDA issued a “black box” warning on the drug for its association with life-threatening infections, including a rare, but often fatal, viral brain infection known as progressive multifocal leukoencephalopathy, or PML.

A year later, the FDA and the company announced Raptiva was being pulled from the market because of PML brain infections in four users, including three who died.

The Journal Sentinel analysis of FDA data showed 1,470 reports of serious “adverse events” linked to the drug, including 189 deaths.

Genentech spokeswoman Allison Neves said the decision to withdraw the drug was based on the company’s assessment of the balance between benefit and risk.

“It was decided that the benefit risk profile had significantly changed,” she said. “The decision was made based on our commitment to patient safety."

It was a rare move in the world of biologic drugs.

‘No drug is risk-free’

The FDA says it issues black-box warnings when a serious – or life-threatening – risk is detected, but the drug’s overall risk-benefit profile remains favorable.

Of the 19 biologics that treat conditions of the skin, joints and gastrointestinal system on the market, 12 have black box warnings.

“We know an enormous amount more about these products now,” said Caleb Alexander, a drug safety expert with Johns Hopkins Bloomberg School of Public Health.

Alexander said there is a certain amount of subjectivity that goes into FDA decisions, including how it factors in the magnitude of risk, the level of uncertainty, the need for the drug and the number of people using it.

“The FDA doesn’t like to pick winners and to pick on a single product,” he said. “The FDA has quite a tolerance for risk.”

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When a drug is taken off the market, he said, the decision is often made by the company based on the potential cost of lawsuits versus the lost revenue if it is no longer for sale.

Nathan Arnold, a spokesman for the FDA, noted “new safety issues can arise at any time regardless of how long a drug has been in use or its past record of safety.”

Arnold said there is intense scrutiny of drugs by the agency before they are approved, but acknowledged that “much work still remains to monitor approved drugs over time” and said: “No drug is risk-free, and it is not uncommon for new information to be discovered after a drug is on the market and being used by larger numbers of patients.”

‘The right path for us’

When Leith was diagnosed with rheumatoid arthritis in 1983, at age 29, there were no biologic drugs for the condition on the market.

Rheumatoid arthritis, which causes inflammation, leading to swelling, pain, stiffness and potential damage to the joints, affects more than 1 million Americans.

His initial treatment involved generic drugs, including steroids and opioids, prescribed to control his pain. He was able to continue his work as a park ranger at Big Foot Beach State Park on Lake Geneva. He also worked as a part-time police officer for several departments in the area.

But working became increasingly difficult.

The ranger job required walking several miles a day, cutting up dead trees and sometimes doing repairs with tools.

If he needed to loosen a bolt, he would use a pipe to get extra leverage. As the swelling and pain increased, he upped his use of steroids and pain drugs.

The steroids made him more susceptible to tears and breaks of tendons and bones, including a broken leg in 1993, an Achilles tendon tear in 1995 and a rotator cuff tear in 2004.

“I muddled through it,” he said.

In 1998, the FDA approved Enbrel for treating rheumatoid arthritis.

Leith went on the drug in the early 2000s. Going on it allowed him to be weaned off the opioids.

He said Enbrel, which is given weekly by injection, helped control his symptoms. He was able to walk with less pain and he had less swelling in his joints, but after about three years it stopped working.

His doctor shifted him to a different biologic, Orencia, which was given by infusion on about a monthly basis. That also worked for several years before losing its effectiveness.

Around this time, in 2006, Leith took early retirement and went on disability.

He went on his third biologic, Rituxan, in about 2010.

That helped control his arthritis until 2017 when, two days after an infusion, he was severely stricken with viral meningitis, an infection that inflames tissues that cover the brain and spinal cord.

He ended up in the intensive care unit for a week. Following that, he spent 30 days at home hooked to an IV that delivered antiviral medication.

In early 2018, a small tumor was found on his lung. He said doctors suspect it is cancerous and might be related to his medication. He has recently been diagnosed with nonalcoholic liver cirrhosis and is on the transplant list.

Over the years, he’s also had more than 20 squamous cell skin cancers removed from his hands, arms and scalp. He said doctors believe those too may be related to his use of biologics.

Like Raptiva, the drug Rituxan is made by Genentech. Neves, the company spokeswoman, said the company’s review of safety data shows that cirrhosis has not been identified as a side effect from Rituxan.

She also noted that rheumatoid arthritis patients, in general, are at increased risk for cancers and there is no evidence that those patients who use Rituxan face an additional risk.

She acknowledged that Rituxan users are at increased risk for serious viral and other infections.

After an inquiry was made about Leith’s case by a reporter, she said the information would be given to Genentech’s drug safety team, which will enter it into its safety database of reported adverse events.

“Every side effect they warn you about, I probably had,” Leith said.

Though it is impossible to predict how long an individual with rheumatoid arthritis will live, people with the disease have a life expectancy that can be 10 years shorter than normal.

“It think it was the right path for us,” said Leith’s wife, Kathy. “You don’t get out of here alive. We’ve had some really good times.”

Leith now is on a generic, non-biologic drug, mycophenolate, which also suppresses the immune system. It was developed originally to prevent organ rejection in transplant patients but sometimes is used in people with rheumatoid arthritis.

Leith says his arthritis is under control.

“If I could do it all over again I probably wouldn't change anything given the information available at the time,” he said. “The biologics definitely did increase my quality of life.”

‘I feel like I have a normal life’

Many biologic drugs are approved to treat multiple conditions. And for each condition, there is a range of outcomes.

For inflammatory bowel-related diseases, such as colitis and Crohn’s, remission rates are between 20% to 30% with biologic drugs, said David Rubin, a professor of medicine at the University of Chicago who also works as a consultant for several companies that market biologic drugs.

Between 40% and 60% see significant improvement, said Rubin, chairman-elect of the scientific advisory committee of the Crohn’s & Colitis Foundation. In some company-run clinical trials, rates of remission and significant improvement exceeded those numbers.

Serious side effects occur in about 1% of people under the age of 60 and 5% to 6% in those older than 60, Rubin said.

“People who are on these therapies recognize the benefits,” he said, noting patients should also understand the risks. “It is about education.”

Megan Starshak, 35, was diagnosed in 2002 with colitis, an inflammatory condition of the colon that is caused by a faulty immune system.

It began to dominate her life, causing abdominal pain, fatigue and the need to go to the bathroom up to 12 times a day.

She often was afraid to go out because she didn’t know if a bathroom would be nearby.

“I just sat in my apartment with my dog,” said Starshak, who lives in Wauwatosa, Wisconsin.

For a few years, she tried to manage the condition with non-biologic drugs. In 2008, she got her first infusion of Remicade and within a few days started feeling better. Her disease has been in remission ever since.

“I feel like I have a normal life,” she said.

Starshak said she knows the risks that come with the drug.

“Everything has its pros and cons,” she said. “If I didn’t try it, I would have had a 100% chance of having a miserable life.”

A changing safety profile

In 1998, Enbrel became one of the first biologics on the market when it was approved to treat rheumatoid arthritis.

Enbrel is known as a tumor necrosis factor (or TNF) blocker. For those without autoimmune diseases, TNF is kept in balance naturally. Like the biologics Humira and Remicade, Enbrel works by using proteins made in cells to help control inflammation.

Since 2004, Enbrel has been linked to reports of 135,000 serious adverse events, including 8,000 deaths, according to the Journal Sentinel analysis of FDA’s adverse events reporting system.

Many patients may not read or understand the full label – usually found in a folded piece of paper in the original packaging – but it provides the comprehensive list of what is known about the drug.

Enbrel is an example of a drug’s safety profile that has changed significantly over the years.

The 1998 label says “the possibility exists” for drugs like Enbrel to affect the ability of a person to fight infections and cancers, but that the impact of Enbrel on cancers and infections “is not fully understood.”

Then it offered some reassuring points:

Colds and sinus infections were the most common infections.

In clinical trials of Enbrel, no increase in serious infections was found.

The rates of cancers were similar to what was expected for those who were being studied.

The 2018 label, which – after 21 years on the market – is the culmination of numerous updates, offers a more formidable series of warnings. Chief among them are black-box warnings for:

“Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens.”

“Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Enbrel.”

Looking back, the FDA-approved language on the 1998 label was too weak, said Michael Carome, a physician with the watchdog group Public Citizen.

“It is remarkable how much more there is now about the risks,” he said.

Trish Hawkins, a spokeswoman for Enbrel maker Amgen, said the drug has led to significant and often life-changing improvements for patients:

“While changes to a product’s safety information may occur over time as more real-world and clinical data are collected, analyzed and incorporated, Enbrel’s benefits outweigh its risks.”

‘I am pretty fortunate’

In the early 2000s, warnings about transverse myelitis started appearing on the labels of some biologic drugs that are TNF blockers.

Transverse myelitis is one of several conditions that involve inflammation of nerve cells that can occur in people using biologics. The condition can cause pain, weakness and paralysis in the arms and legs. It often occurs after infections.

It is estimated that 33,000 Americans have some type of disability caused by transverse myelitis, according to the National Multiple Sclerosis Society. MS is a related and often disabling condition of the central nervous system. In rare cases, it too has been associated with use of TNF blockers, according to the information on the drug labels.

More than 400 cases of various forms of myelitis in people taking biologics have been reported to the FDA since 2004, according to the Journal Sentinel analysis.

Jeremy Bennett, 44, of Columbus, Ohio, has spent eight years on biologic drugs and now faces the effects of transverse myelitis.

Bennett had suffered from bad psoriasis since he was a teenager, but none of the traditional drugs worked well. He also developed a related condition, psoriatic arthritis, which flared up with hip pain whenever he walked on concrete.

Then, at age 36, Bennett was put on Enbrel. Within a matter of months, his psoriasis cleared up.

However, in the summer after he went on the drug he started feeling numbness in his fingertips. Tests were done, but no cause could be found. The numbness went away but came back a few months later.

Then, one night he woke up and his entire right arm was numb.

“I tried shaking it out, but it wasn’t going away,” he said.

A battery of tests and scans were done, including an MRI.

“The doctor calls and says, ‘We’ve got something here,’ ” Bennett recalled.

He was diagnosed with transverse myelitis. By then, the condition had gotten extremely painful and had spread to his neck. For a time, the numbness spread to his right leg, which forced him to walk with a cane.

Bennett said his doctors surmised that Enbrel may have played a role in the condition and he was immediately taken off the drug. It is not known whether Enbrel caused the transverse myelitis or was some sort of catalyst.

Regardless, he never went back on Enbrel, which caused his psoriasis to return.

He now is using the biologic Cosentyx, which works differently than Enbrel. He said he knows there are risks with Cosentyx – “I was scared at first” – but unlike Enbrel, it does not carry a black-box warning.

Bennett said Cosentyx is about 90% as effective as Enbrel in controlling his psoriasis and a related form of arthritis.

Bennett, who now works for the Transverse Myelitis Association, said he has some permanent nerve pain in his arm, but he is able to use it.

“I am pretty fortunate compared to some people I know,” he said. “I know people who are paralyzed.”

Follow John Fauber on Twitter: @Fauber_MJS

About this project

This story — and others in this series — was produced with the support of the National Institute for Health Care Management Foundation. Officials from the organization played no role in the reporting, editing or presentation of the project.

This article originally appeared on Milwaukee Journal Sentinel: Arthritis, psoriasis drugs: Biologics deemed safe get FDA warning