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SAN FRANCISCO -- Despite a wide array of modern therapies for rheumatoid arthritis, methotrexate remains the best option for initial treatment, a Dallas-based rheumatology consultant said here.

"Use methotrexate first, because it's your best drug," John J. Cush, MD, of the Baylor Research Institute, said at the meeting. "Not what's the safest drug first, not what we think is tailored for this person, since you're destined to use your best drug first."

Methotrexate in the first-line setting has support in both American and European clinical guidelines. "It is also the most cost-effective drug," added Cush.

Beyond methotrexate, the art of medicine prevails far more often than the science in selecting the "next drug." Lauding rheumatologists as "amazingly accurate and amazingly effective at treating a very difficult disease," Cush said that "when it gets down to writing [the prescription for] that first biologic or that second biologic, you're still guessing. And when I say 'you,' I really mean 'me.' It bothers me a great deal that I really don't know what my next choice is."

On several occasions, Cush surveyed rheumatologists about treatment preferences, posting the same question: A patient on methotrexate discontinues a first tumor necrosis factor (TNF) inhibitor for lack of efficacy. What would you recommend next? A decade ago, abut 80% of 445 rheumatologists surveyed said they would go with a second TNF inhibitor. Abatacept (Orencia) and rituximab (Rituxan) came in far behind at second and third.

Six years later, more than 60% of rheumatologists still chose a second TNF inhibitor. Abatacept came in second again and this time tocilizumab (Actemra) came in third. A similar proportion of the rheumatologists said they would not consider switching to a different mechanism of action until at least two TNF inhibitors had failed to achieve adequate disease control.

Last month Cush conducted an informal online survey that attracted responses from 81 rheumatologists. Tocilizumab (31%), a second TNF inhibitor (28%), and tofacitinib (26%) were the top choices for a next drug after failure of an initial TNF inhibitor.

"What a bunch of liars; what are they trying to kid?" said Cush. "There is no market data to reflect that. What this says is what's in your head. You know you should be changing, but you're not."

The drug approval process has contributed substantially to the lack of consensus. Since 1999 the FDA has approved 23 biologic drugs with indications in rheumatology, including 11 for RA.

"A company comes to me with a new drug and I say, 'Back of the bus,'" said Cush. "'I'm not going to consider you for first line or second line. I have no experience with you. I know your data, but it doesn't win. Until you can tell me, show me the test, show me the biomarker, that gives you a 10%, 20%, or 30% advantage over everybody else, get in line.'"

The most recent clinical guidelines recommended four options for patients who do not respond to initial treatment with a disease-modifying anti-rheumatic drug (DMARD):

• A combination of traditional DMARDs
• A TNF inhibitor with or without methotrexate
• A non-TNF inhibitor biologic with or without methotrexate
• Tofacitinib (Xeljanz) plus methotrexate

"In other words, do whatever you want," said Cush. "It's Amsterdam: It's all free, cheap, and legal."

Triple-DMARD therapy has long been recommended as an option for patients who do not respond to methotrexate, but by and large, rheumatologists have ignored the advice, said Cush. In reality, triple-DMARD therapy works as add-on therapy for patients who achieve adequate response to methotrexate, he added. Multiple trials have demonstrated the equivalence of triple-DMARD therapy and methotrexate-TNF inhibitor therapy in the setting of methotrexate response, and the triple-DMARD strategy is also a cost-saving strategy.

Historically, rheumatologists have favored cycling through anti-TNF agents over switching to a drug with a different mechanism of action. Early studies of transitioning patients from one TNF inhibitor to another often reported high response rates with the subsequent anti-TNF agent. However, most of the data came from small, single-center studies, and rheumatologists had no biologic options aside from TNF inhibitors, said Cush.

Results from recent multicenter trials have given the rheumatology community reason to pause for thought. The trials have often shown lower response rates with the strategy of following one TNF inhibitor with another and provided evidence that patients might be better served by switching to a drug with a different mechanism of action.

As an example, investigators in an open-label observational study compared outcomes in 728 patients who switched to rituximab or to a second TNF inhibitor after failure of initial anti-TNF therapy. The results showed in the Disease Activity Score in 28 joints with rituximab, both in the overall analysis and in the subgroup analysis of patients with seropositive disease.

Encouraging rheumatologists to "stack the odds" with intelligent data, Cush cited several barriers to use of agents other than TNF inhibitors.

"The problem is, we don't have enough experience with the drugs we're not using," he said. "Patients have a fear of the unknown. Even patients who are just doing OK, still have moderate disease activity, are fearful of change. Managed care is also a barrier to how we prescribe."

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