Drugs for Progressive MS Could Target Multiple Disease Mechanisms

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb