Blood-brain barrier health may signal early loss of MS treatment response

 

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of blood-brain barrier permeability in patients with relapsing-remitting multiple sclerosis may serve as an early marker of suboptimal treatment response to natalizumab or fingolimod, Danish researchers reported in a prospective, observational study.

The imaging method, when applied at baseline and at 3 months and 6 months after starting treatment with either drug in 35 patients, yielded a predictive threshold for determining if patients at 2 years of treatment would fail to meet criteria used for no evidence of disease activity (NEDA). The method is believed to work for natalizumab (Tysabri) and fingolimod (Gilenya) by measuring their effect on the passage of lymphocytes through the blood-brain barrier (BBB) because even though the two drugs have different mechanisms of action, “their final effect is the same, i.e., a reduction of the absolute number of lymphocytes trafficking across the BBB,” wrote Stig P. Cramer, MD, PhD, of the Rigshospitalet, Copenhagen, and his colleagues. The report was published in Annals of Neurology.

©Jana Blaková/Thinkstock

Patients who lost NEDA at 2 years had a 51% higher increase in a measure of BBB permeability in normal-appearing white matter at 6 months of treatment than did patients who maintained NEDA. This measure of BBB permeability, which sought to be a proxy for lymphocyte influx into the CNS, had a good ability to predict loss of NEDA at 2 years based on an area under the curve value of 0.84 (95% confidence interval, 0.70-0.99; P = .003). A value above 0.136 mL per 100 g/min for this measure yielded an odds ratio of 12.4 for loss of NEDA at 2 years (95% CI, 2-77; P = .007), with a sensitivity of 73% and a specificity of 82%.

The investigators used three disease activity domains to define NEDA status: no new neurologic symptoms or signs that lasted more than 24 hours in the absence of concurrent fever or illness; no sustained Expanded Disability Status Scale score increase of one or more points for 6 or more months; and no new T2 hyperintense lesions and T1 gadolinium-enhancing lesions. They disregarded disease activity occurring within the first 3 months after initiation of natalizumab or fingolimod when assessing NEDA status to allow for development of a full treatment effect.

“In summary, we find that a single DCE-MRI at 6 months after initiation of natalizumab or fingolimod treatment provides information on the state of health of the BBB that enables reliable stratification of treatment response. Thus, DCE-MRI can enable early detection of long-term suboptimal treatment response in [relapsing-remitting multiple sclerosis], and a personalized medicine approach to treatment, limitations being the long scan time (15 minutes). These results and the proposed thresholds require validation in larger studies,” the researchers said.

The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. But the company had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
 

[email protected]

SOURCE: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.

 

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of blood-brain barrier permeability in patients with relapsing-remitting multiple sclerosis may serve as an early marker of suboptimal treatment response to natalizumab or fingolimod, Danish researchers reported in a prospective, observational study.

The imaging method, when applied at baseline and at 3 months and 6 months after starting treatment with either drug in 35 patients, yielded a predictive threshold for determining if patients at 2 years of treatment would fail to meet criteria used for no evidence of disease activity (NEDA). The method is believed to work for natalizumab (Tysabri) and fingolimod (Gilenya) by measuring their effect on the passage of lymphocytes through the blood-brain barrier (BBB) because even though the two drugs have different mechanisms of action, “their final effect is the same, i.e., a reduction of the absolute number of lymphocytes trafficking across the BBB,” wrote Stig P. Cramer, MD, PhD, of the Rigshospitalet, Copenhagen, and his colleagues. The report was published in Annals of Neurology.

©Jana Blaková/Thinkstock

Patients who lost NEDA at 2 years had a 51% higher increase in a measure of BBB permeability in normal-appearing white matter at 6 months of treatment than did patients who maintained NEDA. This measure of BBB permeability, which sought to be a proxy for lymphocyte influx into the CNS, had a good ability to predict loss of NEDA at 2 years based on an area under the curve value of 0.84 (95% confidence interval, 0.70-0.99; P = .003). A value above 0.136 mL per 100 g/min for this measure yielded an odds ratio of 12.4 for loss of NEDA at 2 years (95% CI, 2-77; P = .007), with a sensitivity of 73% and a specificity of 82%.

The investigators used three disease activity domains to define NEDA status: no new neurologic symptoms or signs that lasted more than 24 hours in the absence of concurrent fever or illness; no sustained Expanded Disability Status Scale score increase of one or more points for 6 or more months; and no new T2 hyperintense lesions and T1 gadolinium-enhancing lesions. They disregarded disease activity occurring within the first 3 months after initiation of natalizumab or fingolimod when assessing NEDA status to allow for development of a full treatment effect.

“In summary, we find that a single DCE-MRI at 6 months after initiation of natalizumab or fingolimod treatment provides information on the state of health of the BBB that enables reliable stratification of treatment response. Thus, DCE-MRI can enable early detection of long-term suboptimal treatment response in [relapsing-remitting multiple sclerosis], and a personalized medicine approach to treatment, limitations being the long scan time (15 minutes). These results and the proposed thresholds require validation in larger studies,” the researchers said.

The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. But the company had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
 

[email protected]

SOURCE: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.

 

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of blood-brain barrier permeability in patients with relapsing-remitting multiple sclerosis may serve as an early marker of suboptimal treatment response to natalizumab or fingolimod, Danish researchers reported in a prospective, observational study.

The imaging method, when applied at baseline and at 3 months and 6 months after starting treatment with either drug in 35 patients, yielded a predictive threshold for determining if patients at 2 years of treatment would fail to meet criteria used for no evidence of disease activity (NEDA). The method is believed to work for natalizumab (Tysabri) and fingolimod (Gilenya) by measuring their effect on the passage of lymphocytes through the blood-brain barrier (BBB) because even though the two drugs have different mechanisms of action, “their final effect is the same, i.e., a reduction of the absolute number of lymphocytes trafficking across the BBB,” wrote Stig P. Cramer, MD, PhD, of the Rigshospitalet, Copenhagen, and his colleagues. The report was published in Annals of Neurology.

©Jana Blaková/Thinkstock

Patients who lost NEDA at 2 years had a 51% higher increase in a measure of BBB permeability in normal-appearing white matter at 6 months of treatment than did patients who maintained NEDA. This measure of BBB permeability, which sought to be a proxy for lymphocyte influx into the CNS, had a good ability to predict loss of NEDA at 2 years based on an area under the curve value of 0.84 (95% confidence interval, 0.70-0.99; P = .003). A value above 0.136 mL per 100 g/min for this measure yielded an odds ratio of 12.4 for loss of NEDA at 2 years (95% CI, 2-77; P = .007), with a sensitivity of 73% and a specificity of 82%.

The investigators used three disease activity domains to define NEDA status: no new neurologic symptoms or signs that lasted more than 24 hours in the absence of concurrent fever or illness; no sustained Expanded Disability Status Scale score increase of one or more points for 6 or more months; and no new T2 hyperintense lesions and T1 gadolinium-enhancing lesions. They disregarded disease activity occurring within the first 3 months after initiation of natalizumab or fingolimod when assessing NEDA status to allow for development of a full treatment effect.

“In summary, we find that a single DCE-MRI at 6 months after initiation of natalizumab or fingolimod treatment provides information on the state of health of the BBB that enables reliable stratification of treatment response. Thus, DCE-MRI can enable early detection of long-term suboptimal treatment response in [relapsing-remitting multiple sclerosis], and a personalized medicine approach to treatment, limitations being the long scan time (15 minutes). These results and the proposed thresholds require validation in larger studies,” the researchers said.

The research was supported by grants from the Research Foundation of the Capital Region of Denmark, the Foundation for Health Research, the Danish Council for Independent Research, Rigshospitalets forskningspuljer, the Danish Multiple Sclerosis Society, and Biogen. Several authors reported financial relationships with Biogen, which sells natalizumab. But the company had no influence on study setup, subject inclusion, data analysis, interpretation of results, or publishing decisions, and any intellectual rights belong to the authors alone, they said.
 

[email protected]

SOURCE: Cramer S et al. Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25219.