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Targeting the IL-6 cytokine pathway presents exciting opportunities in variety of disease states, experts report

Wednesday, December 12 2007 | Comments
Evidence Grade 0 What's This?
Interleukin-6 (IL-6) is an exciting new therapeutic target with great potential for the treatment of various inflammatory illnesses, according to a panel of experts.

The role of IL-6, which has previously been called B-cell stimulating factor, is long-recognized in the inflammatory cytokine pathway and IL-6 has greater expression in the rheumatoid arthritis synovium than do other major cytokines, such as tumor necrosis factor alpha, according to Dr. Gary Firestein, chief of the division of rheumatology, allergy, and immunology at the University of California, San Diego School of Medicine.

"IL-6 is expressed by almost 20% of cells in the synovium," Dr. Firestein said. "It appears to facilitate the transition from acute to chronic [disease], it enhances mononuclear infiltration into inflamed sites, it provides B-cell help to increase antibody production ... and also perhaps most notably, it's now known to be one of the key cytokines that helps differentiate T-cells into a cell lineage called Th17."

The action of IL-6 appears to be tied to a primitive, broad-based immune response, likely from before the development of more specific immune responses, such as antibodies, according to Dr. Firestein.

"IL-6 levels are increased in a variety of diseases," Dr. Firestein said. "Low levels can be detected in obesity, diabetes, and atherosclerosis; somewhat higher levels have been detected in a variety of neoplastic diseases as well as RA; and the extremely high levels are generally found in infections, especially sepsis, where enormous levels can be detected in the blood."

In addition to these diseases, recent research has revealed a substantial role of IL-6 in systemic inflammation and particularly in cardiovascular disease, according to Dr. Paul Ridker, director of the center for cardiovascular disease prevention at Boston's Brigham and Women's Hospital.

Data from observational cohorts consistently suggest a reduction in cardiovascular mortality among patients taking antiinflammatory agents, including methotrexate and anti-TNF agents, Dr. Ridker noted. This finding, along with findings that levels of C-reactive protein are approximately as predictive of future cardiovascular mortality as hyperlipidemia is, has led many cardiologists to adopt a "dual goal" hypothesis through which both cholesterol and overall inflammation levels are targeted for reduction.

Likewise, IL-6 appears to be an effective target in treating the anemia of chronic diseases (ACD), according to Dr. Daniel Furst of the University of California, Los Angeles. The ACD type of anemia, which is associated with almost any chronic infection, appears to be mediated by the same cytokine pathways that mediate RA, including IL-6.

"IL-6 has a significant effect through hepcidin in the liver, which decreases duodenal iron absorption, reduces iron transport and utilization, and ... also effects the storage of ferritin in macrophages," Dr. Furst said. "It is clearly one of the cytokines that contributes to ACD."

IL-6 also stimulates proliferation of multilineage hematopoietic precursors, in combination with IL-3; it promotes differentiation of megakaryocytes and monocytes; and it encourages bone resorption through effects on RANKL expression, Dr. Furst noted.

Unlike iron deficiency anemia, which is primarily caused by the drugs used to treat RA, the ACD type of anemia is a result of the RA itself, Dr. Furst remarked, and treating the anemia can have a direct effect on the health of patients with RA.

Patients with anemia "have more erosive disease, they tend to be more rheumatoid factor-positive, and they tend to have the classic criteria for RA," Dr. Furst said. "When you treat the anemia ... the swollen joint count is lower, ... the global assessment of disease is lower, ... and it also effects their quality of life."

Targeting of IL-6 to treat illnesses is not an entirely new concept, although successes in targeting it in the clinic are relatively recent.

"One of the reasons anti-IL-6 antibodies really never made it in the clinic is that the preclinical studies with these antibodies suggested that it didn't really interfere with IL-6 signaling," Dr. Firestein said. Newer attempts to target the cytokine employ an IL-6 receptor antibody, which prevents IL-6 from performing its inflammatory action in the cytokine pathway.

Tocilizumab is the most prominent IL-6 receptor antibody that currently has the most clinical data behind it, according to Dr. Arthur Kavanaugh, director of the center for innovative therapy in the division of rheumatology, allergy, and immunology at UCSD.

While tocilizumab has potential in a number of indications, the majority of development research has taken place in the field of rheumatology, where the drug has shown considerable success, Dr. Kavanaugh noted.

Recently reported data from an open-label extension to an early randomized trial of tocilizumab have indicated long-term value with the drug (approximately 5 years of exposure in most patients), as well as high levels of response, Dr. Kavanaugh said.

Data from the randomized CHARISMA trial, which evaluated tocilizumab with and without concomitant methotrexate for 16 weeks, indicated that patients who received monotherapy tocilizumab 4 mg/kg or 8 mg/kg had significantly greater responses according to American College of Rheumatism criteria than did those who received methotrexate monotherapy, Dr. Kavanaugh noted. Moreover, data from the patients who received the combination of tocilizumab plus methotrexate experienced additive benefits that extended to a separate group of patients who received tocilizumab 2 mg/kg.

Additionally, data from the OPTION trial indicated significant improvements in signs and symptoms of disease among patients who received tocilizumab plus methotrexate relative to those who received methotrexate alone, along with significantly greater rates of Disease Activity Score-defined remission, according to Dr. Kavanaugh. This study also demonstrated significant improvements in quality of life, as measured by the Short Form-36 health survey and the Health Assessment Questionnaire, among tocilizumab-treated patients.

However, significant questions about IL-6 receptor inhibition still remain, including whether certain subsets of patients are more likely to respond to therapy and regarding the finer points of the therapeutic mechanisms of action, Dr. Kavanaugh said.

"The more we learn [about IL-6 receptor inhibition], the better we'll be able to use this and bring it to the clinic for our patients," he concluded.

This information concerns a use that has not been approved by the Food and Drug Administration.

By Hunter Kaller

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