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Anti-TNF agents improve signs, symptoms of AS without preventing progression of radiographic damage; many questions remain unanswered, according to panel of experts

Tuesday, June 19 2007 | Comments

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What's This? Mounting evidence confirms that treatment of ankylosing spondylitis using anti-tumor necrosis factor agents reduces signs and symptoms of AS but does not prevent progression of radiographic damage, according to a panel of experts.

Dr. Desiree van der Heijde of Leiden University Medical Center in the Netherlands presented data from a recent study examining the effects of infliximab therapy on radiographic progression in patients with AS who participated in the ASSERT study.

In the study, a total of 201 patients received infliximab 5 mg/kg and their outcomes were compared with those of participants in the OASIS study, who did not receive infliximab and served as a control group.

Patients from the ASSERT study experienced a mean change in modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) of 0.9, compared with a mean change of 1 among the overall OASIS cohort and a mean change of 1.2 among a subset of the OASIS cohort who would have met inclusion criteria for the ASSERT study.

These differences were not statistically significant, Dr. van der Heijde said.

Previous studies of patients with AS who were treated with etanercept and nonsteroidal antiinflammatory drugs also showed similar levels of progression, according to Dr. van der Heijde. "So, it seems to be that that's about what patients show as progression in a 2-year period with AS [regardless of therapy]," she said.

"Using a historical database comparison, infliximab therapy in the ASSERT trial did not demonstrate inhibition of radiographic progression in AS over 2 years, as measured by change is mSASSS score," Dr. van der Heijde concluded.

When these findings are taken in context with response data from the ASSERT study, a clear disconnect between improvements in symptoms and radiographic progression among anti-TNF-treated patients with AS begins to appear, although the ASSERT study provided no information regarding possible mechanisms behind this disconnect.

To explore the possible mechanisms, researchers have turned to the basic pathways that guide the pathogenesis of AS, including those regulated by TNF.

Unlike rheumatoid arthritis, which follows a catabolic disease pattern, characterized by joint destruction with insufficient disease control, AS follows an anabolic disease pattern and is characterized by inhibition of bone resorption, according to Dr. Georg Schett of Germany's University of Erlangen-Nurnberg.

Both diseases are mediated by the production of osteoclasts, which are proinflammatory cytokines that cause the absorption and release of bone, and osteoblasts, which help create bone. In AS, the overactivity of bone formation causes the fusing of the joints of the spine, which is characteristic of the disease.

"TNF is a very bad guy on the osteoblasts," Dr. Schett said, adding that, since TNF inhibits bone formation, blocking TNF is unlikely to prevent the overactive bone formation found in AS.

Instead, preclinical animal models have suggested that other TNF-regulated pathways may be responsible for the signs and symptoms of AS, thereby allowing the observed improvements in signs and symptoms with anti-TNF therapy without the prevention of radiographic damage, according to Dr. Schett.

"I think the reason why TNF blockers work so well in AS is that they block inflammation," Dr. Schett said. "They block the signs and symptoms of disease, and they may not have a major or strong effect on osteophyte formation or spondylophyte formation."

However, AS differs further from RA in that there is no clearly defined relationship between inflammation and radiographic progression, according to Dr. Robert Landewe of the Netherlands' University Hospital Maastricht.

In RA, there is a well-known link between inflammation and structural damage, both of which lead to functional limitation. However, it is unclear how inflammation (including signs and symptoms of the disease) in AS is related to structural damage and functional limitation, according to Dr. Landewe.

"We are almost sure ... that the presumed relationship ... that must exist between inflammation and structural damage in AS is actually not there," said Dr. Landewe.

Although this represents a significant shift in the way rheumatologists approach patients with AS, it should not necessarily change the way they actually treat them, according to Dr. Landewe. "It is beyond any doubt, I would say, that TNF blockers improve signs and symptoms, improve and maintain function, [and] improve and maintain quality of life," he said.

Moreover, data do not support a steady rate of progression in a majority of patients with AS, according to Dr. Landewe, and instead suggest a stair-step pattern of progression characterized by periods of quiescence followed by periods of disease progression.

"I think what is important for the forthcoming years in the AS field is to confirm and fully investigate a course of progression in AS ... to find out more about the initiating events and the events that maintain progression in AS," Dr. Landewe concluded.

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By Hunter Kaller

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