25 Years in Arthritis: New Treatments, New Hope

Jan. 2, 2009— -- When MedPage Today contacted Dr. Joan Von Feldt to talk about the changes she'd witnessed in rheumatoid arthritis (RA) care in the past 25 years, she offered one piece of advice:

"I hope, in your article, you reflect the excitement that rheumatologists have in managing this disease, because it's so much more satisfying," said Von Feldt, a rheumatologist at the University of Pennsylvania.

In 1984, the outlook for newly diagnosed RA patients was grim: a regimen of often toxic drugs that might slow the onset of crippling pain, but not for very long. Younger women were advised to forget about having children because they probably would be too disabled for the rigors of motherhood. The best outcome for many patients was joint fusion or replacement surgery.

"Our orthopedic surgeon came around to our offices two or three times a week to just kind of check in," Von Feldt recalled.

Today, although disease flares and progression can't be prevented entirely, doctors can now tell patients to expect long periods of remission and the availability of many effective, nonsurgical treatment options when their current regimens begin to fail.

Dr. Dennis Boulware, a rheumatologist at the University of Alabama at Birmingham, said he tells new patients that they can live normal lives.

"I would also mention one of my former patients with significant rheumatoid arthritis who ran and completed a marathon after we got her condition under control."

Out With the Gold

For RA patients in the mid-1980s, the gold standard for treatment was, in fact, gold.

"Parenteral gold salts ... are the preferred choice for first-line remission inducing drug therapy," according to a 1985 review article on RA management in the American Journal of Medicine.

Most patients would first receive either steroids or nonsteroidal anti-inflammatory drugs (NSAIDs), but since these do not slow destruction of the joints, physicians would eventually prescribe gold or other agents believed to modify the disease process.

At that time, recalled Dr. Nortin Hadler of the University of North Carolina at Chapel Hill, "gold salts were in favor ... drugs like sulfasalazine and methotrexate [were] just gaining ground."

Another option was the malaria drug hydroxychloroquine, also believed to inhibit the autoimmune process that drove the joint degradation.

Antimalarials were considered "effete," Hadler told MedPage Today in an e-mail, although hydroxychloroquine remains in common use for patients with mild and stable symptoms.

It wasn't long after that review was published that methotrexate replaced gold as the go-to drug for inducing symptom remission. It received FDA approval in 1988.

Boulware said he was already recommending it to patients in 1984. "I was fortunate to have completed a fellowship at the University of Washington in 1983 where methotrexate was used early as a remission-inducing agent (the term used at the time)," he said in an e-mail.

Gold was not a pleasant drug to take. Injectable versions induced mouth sores, skin rashes, and itching, while diarrhea was common with oral formulations.

It remains available but is seldom prescribed. "Gold is best used by a jeweler or a banker," said Dr. Eric Matteson of the Mayo Clinic, when asked if he ever considers it.

He called it "a poison," and added that the same could be said of penicillamine, another drug that was in vogue in the 1970s and early 1980s.

Hadler said these disease-modifying anti-rheumatic drugs (DMARDs), as they are now called, "came and went with fleeting zeal because none of [them] were dramatically or consistently effective."

That changed with methotrexate, which was found to induce remissions or at least stabilize disease in most patients with good tolerability at weekly doses of 10 to 20 mg.

Of course, it too has side effects -- its label includes a dozen "black box" warnings, although these are mainly concerns at the higher doses used in cancer therapy -- and about a third of patients still show disease progression, Hadler said.

In With the Biologics

The breakthrough for those patients came in 1998, when two biologic drugs targeting the cytokine known as tumor necrosis factor (TNF) were launched in the United States.

These were infliximab (Remicade), a monoclonal antibody against TNF, and etanercept (Enbrel), a soluble version of a TNF receptor protein, both of which sop up and inactivate TNF in circulation.

They emerged from basic science research beginning in the mid-1980s that identified TNF as a major player -- perhaps the major player -- in chronic inflammatory diseases.

Twenty-five years ago, RA was well understood to be an autoimmune disease. A 1984 report of a National Institutes of Health-sponsored conference on the condition, published in Annals of Internal Medicine, described in great detail the role of T lymphocytes.

It also reviewed findings on abnormal behavior of B cells, which have since become another target for biologic drugs in arthritis.

But the 15-page report contained not a single mention of TNF and only few references to cytokines of any kind.

In fact, it wasn't until the following year that TNF -- which, as its name implied, was first noticed for its tumor-killing ability -- was found to promote inflammatory activity or otherwise regulate immune function.

Thus, the trip from bench to bedside for these powerful new RA treatments took just 13 years.

In line with recommendations from the American College of Rheumatology, physicians surveyed by MedPage Today and ABC News unanimously agreed that anti-TNF biologics were the treatment of choice for patients with persistent disease despite methotrexate therapy.

"The TNF blockers ... have revolutionized rheumatology practice, since their effectiveness is better than any of our prior drugs, with better safety," wrote Dr. Theodore Fields of Weill Cornell Medical College in New York City, in an e-mail.

As part of the poll, respondents were asked what they would have told certain hypothetical patients to expect in 1984, and how that had changed in 2009.

In 1984, for a newly diagnosed patient, a woman in her early 40s, "I'd tell her we could offer her aspirin at high doses (dosed based on GI side effects or until their ears ring), oral gold, gold shots each week, but they all have major side effects, and we have no idea how they work," said Dr. P.J. Utz of Stanford University in Palo Alto, Calif, in an e-mail.

"What I wouldn't tell her is that steroids are really bad, she could end up in a wheelchair from her RA, and as her joints wear out we are getting better and better at joint replacements, but they are imperfect," Utz added.

Now, he said, "we have methotrexate, sulfasalazine, Arava (leflunomide), and at least eight new biologics that target four different pathways -- all approved already by the FDA. We have dozens more therapies in clinical trials. We also have methods being developed to predict response to drugs."

A patient eligible for biologics in 2009 would get an upbeat prognosis from Utz.

"I'd tell her that we would start her on an injectable or infusable biologic that blocks TNF, and that she had an [approximately] 70 percent likelihood of having a response," Utz said.

"If this failed, we'd try a different TNF inhibitor and perhaps even a third one and still could capture a response. If that failed, then we could go on to inhibitors of T-cell costimulation, or B-cell inhibitors, or IL-6 inhibitors, or IL-1 inhibitors. I'd tell her many even cooler drugs were being developed, many of which are oral."

Dr. Beth Jonas, another University of North Carolina rheumatologist, echoed the point that the outlook is still bright for patients who fail biologic treatments.

"Each patient is unique, and it is almost impossible to know up front which drug is best for each individual patient. There is a lot of 'trial and error' at this stage to find the most effective therapy," she said.

Diagnosis and Monitoring Refined

Rheumatologists also agreed that tools for evaluating RA patients had improved markedly, if not so dramatically as treatments have.

Diagnosis and monitoring had been mainly a clinical art in the 1980s. Now, said Matteson, "We've become more comfortable with more formal assessments of disease activity."

He mentioned the 28-item Disease Activity Scale, better known as the DAS-28, as a key tool for the modern rheumatologist.

"Quantitation of patient status" is now routine in rheumatology practice, Matteson said.

Von Feldt pointed out that the role of rheumatologists has itself grown dramatically. She estimated that, a quarter century ago, perhaps 10 to 20 percent of RA patients were managed by specialists.

The figure is now likely above 90 percent, she said.

Another innovation has been the introduction of ultrasound and magnetic resonance imaging to supplement X-rays for monitoring joint erosion.

Matteson said these new technologies help in detecting erosions that don't show up on X-rays.

But several of the rheumatologists contacted for this article indicated that their clinical evaluations would not have changed much. They indicated that X-rays and lab tests for such markers as rheumatoid factor, C-reactive protein, and erythrocyte sedimentation rate, along with clinical assessments, were the mainstays in 1984 and remain so today.

Von Feldt said about diagnosis and evaluation of RA, "It's still a clinical skill."

The Mounting Cost

Life is still not a bowl of cherries for RA patients. Eventual disease progression remains the rule for patients, even though, compared with earlier generations, they will be much older when joint surgery becomes their best option.

Cost of treatment, for one thing, has become a much larger issue.

The retail cost of biologic drugs starts at more than $1,000 per month, and that's for a single agent. The approval of the B-cell-targeting agent rituximab (Rituxan) for RA, which is typically added to a TNF blocker, means costs can mount even faster.

Matteson said he has a discussion of the economics of treatment with all his patients, asking about their financial means and insurance status.

He said the major drug companies offer patient assistance programs for those who could not otherwise afford biologic treatments, but getting patients approved for them is a logistical burden for them and for the clinic staff.

But Matteson believes the extra cost is worth it, not just for reduced symptoms, but also in patient-centered outcomes such as ability to work and staying out of the hospital.

Still, Van Feldt said, the cost of biologic drugs is a problem. "Even the very well-heeled cannot afford $1,000 a month for the rest of their lives."

She said the so-called "doughnut hole" in Medicare drug coverage, which leaves some beneficiaries responsible for the full cost of prescriptions, means that some patients have to delay or stop treatment at least temporarily, risking loss of disease control that may be hard to get back.

And the cost issue may get worse, thanks to a growing movement to treat patients with biologics as soon as RA is confirmed.

Some recent studies -- sponsored by the makers of biologic drugs -- have found that starting TNF inhibitors and perhaps rituximab at the same time that methotrexate is begun leads to higher rates of complete remission.

The hope, still unproved, is that these fast, complete remissions can then be maintained with less intensive drug regimens later on.

"Hit them early, hit them hard," as one researcher put it in 2006.

But Hadler said the jury is still out on whether early, aggressive, and expensive treatment for all patients is worthwhile.

"I represent the conservative school arguing that for perhaps a third [of patients] the disease is monophasic and a spontaneous remission is likely, and for another third the course is persistent but mild," he said.

"It's only a third for whom the disease is aggressive, and I reserve more aggressive therapies once the patient has declared himself as in this third."

Regardless of how this debate plays out, clinicians agree that the outlook for patients today is far, far better than it was in 1984.

"RA back then was a terrible disease," said Utz.

"I keep a picture on my desk of ... a 30-year-old woman who died of amyloidosis on her 30th birthday, all from juvenile RA that could have been effectively treated if she had been born now."