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Targeted therapies for RA may represent dawn of era of personalized medicine, expert panel reports

Wednesday, October 29 2008 | Comments

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What's This? By Hunter Kaller

Modern targeted therapies for rheumatoid arthritis (RA) provide rheumatologists with an opportunity to tailor treatment strategies to a patient's individual characteristics, and this opportunity for personalized medicine is likely to expand as new agents and diagnostic tests are developed, according to a panel of researchers.

In patients with severe disease and poor prognostic factors, early biologic therapy with an anti-tumor necrosis factor (TNF) agent is appropriate with or without background disease-modifying antirheumatic drugs. However, approximately one-third of patients do not respond to initial anti-TNF therapy--known as primary failure--and other patients may lose their response as time passes--known as secondary failure--according to Dr. Daniel Furst of the University of California, Los Angeles.

After treatment failure, the next course of action is dictated in part by whether the patient experienced primary or secondary treatment failure, Dr. Furst noted.

"For primary failures, you can think about the choice of the next biologic based on the mechanism of action," Dr. Furst said. "One thing you can do in [patients with secondary failure] is raise the dose of [anti-TNF]."

However, Dr. Furst noted that, although study data have indicated that dose escalation is effective in patients treated with infliximab and may be effective in those treated with adalimumab (based on data from patients with psoriatic arthritis), this strategy appears to be ineffective in patients treated with etanercept.

"One can also switch [anti-TNF agents]," Dr. Furst said. "Trying a second one might work, but trying a third decreases the response. One can also see this with abatacept in TNF failures."

When switching to another agent, with or without a change in the mechanism of action (ie, TNF inhibition, B-cell depletion, etc.), rheumatologists must consider the patient's medical history and the potential risk for adverse reactions, according to Dr. Furst.

Anti-TNF agents may increase the risk of infection, may increase the risk of cancer recurrence or other malignancies, and may further raise the already increased risk of tuberculosis (TB) among patients with RA, Dr. Furst noted. In contrast, rituximab has no association with increased risk of malignancies--it is actually used to treat B-cell lymphoma--and appears to be unrelated to TB, while abatacept may reduce the risk of infusion reactions.

These additional side effects that occur even with targeted inhibition are the result of the complex interrelations between immune cells and nonimmune cells, according to Dr. Iain McInnes, professor of experimental medicine and rheumatology at the University of Glasgow.

Using the analogy of the body's immune system as an orchestra, "if you target the conductor, the whole orchestra will stop, so that's not smart ...," Dr. McInnes said. "If you block TNF with an antibody, the only thing you block is TNF and its effects, [but] if you block P38 or JAK [Janus kinase] 1/2/3, you block a whole variety of effects [and] cytokine activities."

By this same line of thinking, inhibition of interleukin-6--such as with the investigational drug tocilizumab--may have a variety of other effects, potentially both desirable and undesirable, because it is produced by a variety of different cells, Dr. Larry Moreland of the University of Pittsburgh added.

However, other potentially attractive therapeutic targets on the horizon include spleen tyrosine kinase, JAK3, CD20, aspects of B-cell function other than simple inhibition, and receptor activator of nuclear factor-kappa B ligand (RANKL), which is the target of the monoclonal antibody denosumab, Dr. Moreland noted.

Additionally, cytokines and their signal pathways, T-cells, and even the joint structure itself, may be effective targets, Dr. McInnes added.

"We may eventually be able to predict who is going to get this disease, and--using these predictive screening biomarkers--immune modify, and, eventually, we might be vaccinating against [RA]," McInnes concluded. "That's science fiction ... but it's plausible science fiction, and we should rejoice in that."

This information concerns uses that have not been approved by the Food and Drug Administration.

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