Challenging the Status Quo in Understanding MS

DENVER—Stopping CNS inflammation may not be enough to block brain pathology in patients with multiple sclerosis (MS), said Richard A. ­Rudick, MD, at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Dr. Rudick also challenged the long-held notion that MS is mainly a white matter disease. Instead, he said, gray matter pathology is a larger component of MS than is generally appreciated and deserves further study.

Inflammation in MS
Dr. Rudick, Director of the Mellen Center for MS and Vice Chairman of the Neurological Institute at the Cleveland Clinic Foundation, noted that around 1999, researchers were surprised by the level of axonal pathology and brain atrophy present in patients with relatively early MS. “The question is, what is the relationship between tissue injury and inflammatory lesions?” he said. “It’s plausible to suggest that [the inflammatory lesions] are causing this tissue loss. But on the other hand, we were beginning to appreciate the presence of a progressive, destructive pathology early in the course of MS.”

In one interpretation of MS pathology, Dr. Rudick suggested that a dysfunctional immune system causes brain inflammation. This leads to inflammation-mediated CNS injury and later to degenerative brain disease. The effects loop back around on each other, and the degenerative process eventually drives the disimmune process. “In this scenario, if you block inflammatory CNS injury completely, you’ll block CNS degeneration completely,” he said.

However, a second model is also possible. “In this scenario, there is a degenerative CNS process, which then induces some form of immune dysregulation leading to CNS injury,” said Dr. Rudick. “And then again, this is going to continue to loop.” This presents a problem, however, for those who treat patients with MS. “If this scenario is true, blocking inflammation will not completely block CNS degeneration,” he commented.

Can Anti-Inflammatory Drugs Block MS Pathology?
Results from a phase III, placebo-controlled trial of natalizumab in patients with relapsing-remitting MS suggest that this second, more problematic hypothesis needs careful consideration. Although about a 92% reduction in gadolinium-enhancing lesions and a 68% relapse reduction were observed in the first two years of the study, disability progression only improved by 54%. Furthermore, there was only a 41% reduction in brain atrophy in the second year of the study, after fluid shifts had attenuated. This raises the possibility of a continuing degenerative process not requiring ongoing inflammation.

Use of the humanized monoclonal antibody alemtuzumab, however, may be instructive, based on early study results, said Dr. Rudick. The patients included in phase II studies were younger and less disabled than patients in the natalizumab study, and they were treated earlier in the course of relapsing-remitting MS, while the disease was still active. “The whole concept of this study was to try to take this very potent immunomodulatory drug to the very early stage of MS,” related Dr. Rudick. “The idea here is to attempt to interrupt inflammation at a stage where it may have maximal benefit.”

Alemtuzumab nearly eliminated disease relapses in the first two years of treatment and had an 88% risk reduction in time to sustained disability, compared with high-dose interferon beta-1a. Dr. Rudick noted that brain atrophy findings have not yet been reported and that a phase III trial is in the planning stage. In terms of whether CNS inflammation is sufficient and necessary to explain MS pathology, “I think the jury’s out on this one,” he said. “I worry that anti-inflammatory strategies may not be fully effective, regardless of when we [initiate them].”

A Gray Matter Disease?
Cortical lesions may be virtually invisible on MRI, because there is no increase in water content, but according to Dr. Rudick, the effect of demyelination in this area is a very important—and relatively ignored—component of MS. He shared the results of a four-year longitudinal study of patients with MS in various stages to illustrate the disproportionate occurrence of gray matter atrophy. All MS groups had a white matter atrophy rate about three times greater than healthy controls; however, not only was relative gray matter atrophy greater than white matter atrophy, but it began in the relapsing-remitting stage and increased with disease state.

In all patient groups studied, white matter atrophy progressed about three times faster than in healthy controls. Gray matter atrophy accelerated as the disease worsened. Patients who converted during the study period from clinically isolated syndrome to relapsing-remitting MS had a 3.4-times greater rate of gray matter atrophy relative to healthy controls. Patients with stable relapsing-remitting MS had gray matter atrophy rates that were 8.1 times greater than those in healthy controls. Patients who converted to secondary progressive MS had gray matter atrophy rates that were 12.4 times greater than those in healthy controls. Patients with secondary progressive MS for the entire four years of the study had gray matter atrophy rates that were 14 times greater than those in healthy controls.

“So as this disease moves along, there’s accelerating gray matter atrophy,” said Dr. Rudick. “And in all stages of MS, gray matter atrophy is at least as significant quantitatively as white matter atrophy.”

Gray matter pathology is also trickier to detect directly and appears to change throughout the course of the disease, according to Dr. Rudick. One study found that disability significantly correlated with gray matter atrophy as early as the clinically isolated syndrome. “Gray matter pathology probably explains disability more than white matter [atrophy],” noted Dr. Rudick. In his four-year study, gray matter atrophy correlated with MR measures in the relapsing-remitting phase but not in the secondary progressive phase.

“Based on atrophy studies, MS is predominantly a gray matter disease,” concluded Dr. Rudick. “It’s not that [MS is] not a white matter disease; there’s a lot going on in the white matter. But gray matter pathology has been relatively unrecognized and seems to be a dominant feature of the disease based on what we’ve seen.”

Dr. Rudick added that as clinical trials for MS therapies continue, ways to measure gray matter atrophy will only become more important. “There’s no real reason to think that a disease-modifying drug with a particular mechanism of action is going to have the same effect in the white matter and the gray matter,” he said. “We’ve been looking at the whole brain, but we really need to start looking at compartments of the brain in terms of effective interventions.… Gray matter atrophy measures should be included in clinical trials if we’re going to be measuring atrophy, so that we can determine the effects of intervention in these different compartments.

DENVER—Stopping CNS inflammation may not be enough to block brain pathology in patients with multiple sclerosis (MS), said Richard A. ­Rudick, MD, at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Dr. Rudick also challenged the long-held notion that MS is mainly a white matter disease. Instead, he said, gray matter pathology is a larger component of MS than is generally appreciated and deserves further study.

Inflammation in MS
Dr. Rudick, Director of the Mellen Center for MS and Vice Chairman of the Neurological Institute at the Cleveland Clinic Foundation, noted that around 1999, researchers were surprised by the level of axonal pathology and brain atrophy present in patients with relatively early MS. “The question is, what is the relationship between tissue injury and inflammatory lesions?” he said. “It’s plausible to suggest that [the inflammatory lesions] are causing this tissue loss. But on the other hand, we were beginning to appreciate the presence of a progressive, destructive pathology early in the course of MS.”

In one interpretation of MS pathology, Dr. Rudick suggested that a dysfunctional immune system causes brain inflammation. This leads to inflammation-mediated CNS injury and later to degenerative brain disease. The effects loop back around on each other, and the degenerative process eventually drives the disimmune process. “In this scenario, if you block inflammatory CNS injury completely, you’ll block CNS degeneration completely,” he said.

However, a second model is also possible. “In this scenario, there is a degenerative CNS process, which then induces some form of immune dysregulation leading to CNS injury,” said Dr. Rudick. “And then again, this is going to continue to loop.” This presents a problem, however, for those who treat patients with MS. “If this scenario is true, blocking inflammation will not completely block CNS degeneration,” he commented.

Can Anti-Inflammatory Drugs Block MS Pathology?
Results from a phase III, placebo-controlled trial of natalizumab in patients with relapsing-remitting MS suggest that this second, more problematic hypothesis needs careful consideration. Although about a 92% reduction in gadolinium-enhancing lesions and a 68% relapse reduction were observed in the first two years of the study, disability progression only improved by 54%. Furthermore, there was only a 41% reduction in brain atrophy in the second year of the study, after fluid shifts had attenuated. This raises the possibility of a continuing degenerative process not requiring ongoing inflammation.

Use of the humanized monoclonal antibody alemtuzumab, however, may be instructive, based on early study results, said Dr. Rudick. The patients included in phase II studies were younger and less disabled than patients in the natalizumab study, and they were treated earlier in the course of relapsing-remitting MS, while the disease was still active. “The whole concept of this study was to try to take this very potent immunomodulatory drug to the very early stage of MS,” related Dr. Rudick. “The idea here is to attempt to interrupt inflammation at a stage where it may have maximal benefit.”

Alemtuzumab nearly eliminated disease relapses in the first two years of treatment and had an 88% risk reduction in time to sustained disability, compared with high-dose interferon beta-1a. Dr. Rudick noted that brain atrophy findings have not yet been reported and that a phase III trial is in the planning stage. In terms of whether CNS inflammation is sufficient and necessary to explain MS pathology, “I think the jury’s out on this one,” he said. “I worry that anti-inflammatory strategies may not be fully effective, regardless of when we [initiate them].”

A Gray Matter Disease?
Cortical lesions may be virtually invisible on MRI, because there is no increase in water content, but according to Dr. Rudick, the effect of demyelination in this area is a very important—and relatively ignored—component of MS. He shared the results of a four-year longitudinal study of patients with MS in various stages to illustrate the disproportionate occurrence of gray matter atrophy. All MS groups had a white matter atrophy rate about three times greater than healthy controls; however, not only was relative gray matter atrophy greater than white matter atrophy, but it began in the relapsing-remitting stage and increased with disease state.

In all patient groups studied, white matter atrophy progressed about three times faster than in healthy controls. Gray matter atrophy accelerated as the disease worsened. Patients who converted during the study period from clinically isolated syndrome to relapsing-remitting MS had a 3.4-times greater rate of gray matter atrophy relative to healthy controls. Patients with stable relapsing-remitting MS had gray matter atrophy rates that were 8.1 times greater than those in healthy controls. Patients who converted to secondary progressive MS had gray matter atrophy rates that were 12.4 times greater than those in healthy controls. Patients with secondary progressive MS for the entire four years of the study had gray matter atrophy rates that were 14 times greater than those in healthy controls.

“So as this disease moves along, there’s accelerating gray matter atrophy,” said Dr. Rudick. “And in all stages of MS, gray matter atrophy is at least as significant quantitatively as white matter atrophy.”

Gray matter pathology is also trickier to detect directly and appears to change throughout the course of the disease, according to Dr. Rudick. One study found that disability significantly correlated with gray matter atrophy as early as the clinically isolated syndrome. “Gray matter pathology probably explains disability more than white matter [atrophy],” noted Dr. Rudick. In his four-year study, gray matter atrophy correlated with MR measures in the relapsing-remitting phase but not in the secondary progressive phase.

“Based on atrophy studies, MS is predominantly a gray matter disease,” concluded Dr. Rudick. “It’s not that [MS is] not a white matter disease; there’s a lot going on in the white matter. But gray matter pathology has been relatively unrecognized and seems to be a dominant feature of the disease based on what we’ve seen.”

Dr. Rudick added that as clinical trials for MS therapies continue, ways to measure gray matter atrophy will only become more important. “There’s no real reason to think that a disease-modifying drug with a particular mechanism of action is going to have the same effect in the white matter and the gray matter,” he said. “We’ve been looking at the whole brain, but we really need to start looking at compartments of the brain in terms of effective interventions.… Gray matter atrophy measures should be included in clinical trials if we’re going to be measuring atrophy, so that we can determine the effects of intervention in these different compartments.

DENVER—Stopping CNS inflammation may not be enough to block brain pathology in patients with multiple sclerosis (MS), said Richard A. ­Rudick, MD, at the 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers. Dr. Rudick also challenged the long-held notion that MS is mainly a white matter disease. Instead, he said, gray matter pathology is a larger component of MS than is generally appreciated and deserves further study.

Inflammation in MS
Dr. Rudick, Director of the Mellen Center for MS and Vice Chairman of the Neurological Institute at the Cleveland Clinic Foundation, noted that around 1999, researchers were surprised by the level of axonal pathology and brain atrophy present in patients with relatively early MS. “The question is, what is the relationship between tissue injury and inflammatory lesions?” he said. “It’s plausible to suggest that [the inflammatory lesions] are causing this tissue loss. But on the other hand, we were beginning to appreciate the presence of a progressive, destructive pathology early in the course of MS.”

In one interpretation of MS pathology, Dr. Rudick suggested that a dysfunctional immune system causes brain inflammation. This leads to inflammation-mediated CNS injury and later to degenerative brain disease. The effects loop back around on each other, and the degenerative process eventually drives the disimmune process. “In this scenario, if you block inflammatory CNS injury completely, you’ll block CNS degeneration completely,” he said.

However, a second model is also possible. “In this scenario, there is a degenerative CNS process, which then induces some form of immune dysregulation leading to CNS injury,” said Dr. Rudick. “And then again, this is going to continue to loop.” This presents a problem, however, for those who treat patients with MS. “If this scenario is true, blocking inflammation will not completely block CNS degeneration,” he commented.

Can Anti-Inflammatory Drugs Block MS Pathology?
Results from a phase III, placebo-controlled trial of natalizumab in patients with relapsing-remitting MS suggest that this second, more problematic hypothesis needs careful consideration. Although about a 92% reduction in gadolinium-enhancing lesions and a 68% relapse reduction were observed in the first two years of the study, disability progression only improved by 54%. Furthermore, there was only a 41% reduction in brain atrophy in the second year of the study, after fluid shifts had attenuated. This raises the possibility of a continuing degenerative process not requiring ongoing inflammation.

Use of the humanized monoclonal antibody alemtuzumab, however, may be instructive, based on early study results, said Dr. Rudick. The patients included in phase II studies were younger and less disabled than patients in the natalizumab study, and they were treated earlier in the course of relapsing-remitting MS, while the disease was still active. “The whole concept of this study was to try to take this very potent immunomodulatory drug to the very early stage of MS,” related Dr. Rudick. “The idea here is to attempt to interrupt inflammation at a stage where it may have maximal benefit.”

Alemtuzumab nearly eliminated disease relapses in the first two years of treatment and had an 88% risk reduction in time to sustained disability, compared with high-dose interferon beta-1a. Dr. Rudick noted that brain atrophy findings have not yet been reported and that a phase III trial is in the planning stage. In terms of whether CNS inflammation is sufficient and necessary to explain MS pathology, “I think the jury’s out on this one,” he said. “I worry that anti-inflammatory strategies may not be fully effective, regardless of when we [initiate them].”

A Gray Matter Disease?
Cortical lesions may be virtually invisible on MRI, because there is no increase in water content, but according to Dr. Rudick, the effect of demyelination in this area is a very important—and relatively ignored—component of MS. He shared the results of a four-year longitudinal study of patients with MS in various stages to illustrate the disproportionate occurrence of gray matter atrophy. All MS groups had a white matter atrophy rate about three times greater than healthy controls; however, not only was relative gray matter atrophy greater than white matter atrophy, but it began in the relapsing-remitting stage and increased with disease state.

In all patient groups studied, white matter atrophy progressed about three times faster than in healthy controls. Gray matter atrophy accelerated as the disease worsened. Patients who converted during the study period from clinically isolated syndrome to relapsing-remitting MS had a 3.4-times greater rate of gray matter atrophy relative to healthy controls. Patients with stable relapsing-remitting MS had gray matter atrophy rates that were 8.1 times greater than those in healthy controls. Patients who converted to secondary progressive MS had gray matter atrophy rates that were 12.4 times greater than those in healthy controls. Patients with secondary progressive MS for the entire four years of the study had gray matter atrophy rates that were 14 times greater than those in healthy controls.

“So as this disease moves along, there’s accelerating gray matter atrophy,” said Dr. Rudick. “And in all stages of MS, gray matter atrophy is at least as significant quantitatively as white matter atrophy.”

Gray matter pathology is also trickier to detect directly and appears to change throughout the course of the disease, according to Dr. Rudick. One study found that disability significantly correlated with gray matter atrophy as early as the clinically isolated syndrome. “Gray matter pathology probably explains disability more than white matter [atrophy],” noted Dr. Rudick. In his four-year study, gray matter atrophy correlated with MR measures in the relapsing-remitting phase but not in the secondary progressive phase.

“Based on atrophy studies, MS is predominantly a gray matter disease,” concluded Dr. Rudick. “It’s not that [MS is] not a white matter disease; there’s a lot going on in the white matter. But gray matter pathology has been relatively unrecognized and seems to be a dominant feature of the disease based on what we’ve seen.”

Dr. Rudick added that as clinical trials for MS therapies continue, ways to measure gray matter atrophy will only become more important. “There’s no real reason to think that a disease-modifying drug with a particular mechanism of action is going to have the same effect in the white matter and the gray matter,” he said. “We’ve been looking at the whole brain, but we really need to start looking at compartments of the brain in terms of effective interventions.… Gray matter atrophy measures should be included in clinical trials if we’re going to be measuring atrophy, so that we can determine the effects of intervention in these different compartments.