ICYMI Multiple Sclerosis

Key clinical point: Patients with relapsing-remitting MS gain comparable benefits from cladribine therapy, regardless of age.

Major finding: The annual rate of qualifying relapses was 0.14 for treated patients older than 45 years and 0.15 for treated patients aged 45 or younger.

Study details: A post hoc analysis of data from the CLARITY and CLARITY extension studies, which included 870 patients.

Disclosures: Merck KGaA, which manufactures and markets cladribine, supported the study. Several of the investigators have received speaker honoraria, consulting fees, or other funding from Merck KGaA.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Patients with relapsing-remitting MS gain comparable benefits from cladribine therapy, regardless of age.

Major finding: The annual rate of qualifying relapses was 0.14 for treated patients older than 45 years and 0.15 for treated patients aged 45 or younger.

Study details: A post hoc analysis of data from the CLARITY and CLARITY extension studies, which included 870 patients.

Disclosures: Merck KGaA, which manufactures and markets cladribine, supported the study. Several of the investigators have received speaker honoraria, consulting fees, or other funding from Merck KGaA.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Patients with relapsing-remitting MS gain comparable benefits from cladribine therapy, regardless of age.

Major finding: The annual rate of qualifying relapses was 0.14 for treated patients older than 45 years and 0.15 for treated patients aged 45 or younger.

Study details: A post hoc analysis of data from the CLARITY and CLARITY extension studies, which included 870 patients.

Disclosures: Merck KGaA, which manufactures and markets cladribine, supported the study. Several of the investigators have received speaker honoraria, consulting fees, or other funding from Merck KGaA.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Treatment with evobrutinib reduced the number of enhancing lesions versus placebo in patients with relapsing multiple sclerosis, supporting further development of this Bruton’s tyrosine kinase (BTK) inhibitor.

Major finding: The cumulative number of MRI-assessed T1 Gd+ lesions from weeks 12-24 was significantly reduced versus placebo; lesion rate ratios were 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively.

Study details: Forty-eight-week results of a randomized, phase 2, placebo-controlled study of 267 patients with relapsing multiple sclerosis.

Disclosures: Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.

Citation: Montalban X et al. AAN 2019. Abstract S56.004.

Key clinical point: Treatment with evobrutinib reduced the number of enhancing lesions versus placebo in patients with relapsing multiple sclerosis, supporting further development of this Bruton’s tyrosine kinase (BTK) inhibitor.

Major finding: The cumulative number of MRI-assessed T1 Gd+ lesions from weeks 12-24 was significantly reduced versus placebo; lesion rate ratios were 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively.

Study details: Forty-eight-week results of a randomized, phase 2, placebo-controlled study of 267 patients with relapsing multiple sclerosis.

Disclosures: Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.

Citation: Montalban X et al. AAN 2019. Abstract S56.004.

Key clinical point: Treatment with evobrutinib reduced the number of enhancing lesions versus placebo in patients with relapsing multiple sclerosis, supporting further development of this Bruton’s tyrosine kinase (BTK) inhibitor.

Major finding: The cumulative number of MRI-assessed T1 Gd+ lesions from weeks 12-24 was significantly reduced versus placebo; lesion rate ratios were 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively.

Study details: Forty-eight-week results of a randomized, phase 2, placebo-controlled study of 267 patients with relapsing multiple sclerosis.

Disclosures: Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.

Citation: Montalban X et al. AAN 2019. Abstract S56.004.

Key clinical point: Twice-daily, extended-release arbaclofen effectively reduces MS-related spasticity.

Major finding: Mean change in TNmAS-MAL was −2.90 with arbaclofen and −1.95 with placebo.

Study details: A multicenter, double-blind, parallel-group study of 341 adults with MS and spasticity.

Disclosures: The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.

Citation: Kantor D et al. CMSC 2019, Abstract SXM07.

Key clinical point: Twice-daily, extended-release arbaclofen effectively reduces MS-related spasticity.

Major finding: Mean change in TNmAS-MAL was −2.90 with arbaclofen and −1.95 with placebo.

Study details: A multicenter, double-blind, parallel-group study of 341 adults with MS and spasticity.

Disclosures: The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.

Citation: Kantor D et al. CMSC 2019, Abstract SXM07.

Key clinical point: Twice-daily, extended-release arbaclofen effectively reduces MS-related spasticity.

Major finding: Mean change in TNmAS-MAL was −2.90 with arbaclofen and −1.95 with placebo.

Study details: A multicenter, double-blind, parallel-group study of 341 adults with MS and spasticity.

Disclosures: The study did not have funding support. Dr. Kantor reported having received consulting fees from AbbVie, Actelion, Bayer, Biogen, Celgene, EMD Serono, Genentech/Roche, Mylan, Novartis, Osmotica, and Sanofi Genzyme.

Citation: Kantor D et al. CMSC 2019, Abstract SXM07.

Key clinical point: Management of multiple sclerosis relapse consists of three main steps: timely and careful evaluation; treatment, if necessary; and assessment of treatment response, according to an algorithm developed by MS clinicians.

Major finding: Between 3 and 5 weeks after the initial evaluation, the group recommends clinical reassessment using a tool such as the Assessing Relapse in Multiple Sclerosis (ARMS) Questionnaire.

Study details: A consensus statement developed by a work group of MS clinicians based on a literature review and clinical experience.

Disclosures: The work group did not receive funding. The authors disclosed financial ties with various pharmaceutical companies.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Management of multiple sclerosis relapse consists of three main steps: timely and careful evaluation; treatment, if necessary; and assessment of treatment response, according to an algorithm developed by MS clinicians.

Major finding: Between 3 and 5 weeks after the initial evaluation, the group recommends clinical reassessment using a tool such as the Assessing Relapse in Multiple Sclerosis (ARMS) Questionnaire.

Study details: A consensus statement developed by a work group of MS clinicians based on a literature review and clinical experience.

Disclosures: The work group did not receive funding. The authors disclosed financial ties with various pharmaceutical companies.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Management of multiple sclerosis relapse consists of three main steps: timely and careful evaluation; treatment, if necessary; and assessment of treatment response, according to an algorithm developed by MS clinicians.

Major finding: Between 3 and 5 weeks after the initial evaluation, the group recommends clinical reassessment using a tool such as the Assessing Relapse in Multiple Sclerosis (ARMS) Questionnaire.

Study details: A consensus statement developed by a work group of MS clinicians based on a literature review and clinical experience.

Disclosures: The work group did not receive funding. The authors disclosed financial ties with various pharmaceutical companies.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Initial treatment with high-efficacy DMT is associated with a reduction in depressive symptoms, compared with an initial low-efficacy DMT.

Major finding: Initiation of high-efficacy DMT was associated with a reduction of 0.58 points/year in depression scores, compared with initiation of low-efficacy DMT.

Study details: An interim analysis of data for 1,501 participants in the ongoing MS PATHS study.

Disclosures: The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported disclosures or conflicts of interest.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Initial treatment with high-efficacy DMT is associated with a reduction in depressive symptoms, compared with an initial low-efficacy DMT.

Major finding: Initiation of high-efficacy DMT was associated with a reduction of 0.58 points/year in depression scores, compared with initiation of low-efficacy DMT.

Study details: An interim analysis of data for 1,501 participants in the ongoing MS PATHS study.

Disclosures: The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported disclosures or conflicts of interest.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Initial treatment with high-efficacy DMT is associated with a reduction in depressive symptoms, compared with an initial low-efficacy DMT.

Major finding: Initiation of high-efficacy DMT was associated with a reduction of 0.58 points/year in depression scores, compared with initiation of low-efficacy DMT.

Study details: An interim analysis of data for 1,501 participants in the ongoing MS PATHS study.

Disclosures: The study was not supported by outside funding. Ellen M. Mowry, MD, one of the investigators, reported having performed contracted research for Biogen, Genzyme, and Sun Pharma. Ms Youkyung and another two investigators reported disclosures or conflicts of interest.

Citation: REPORTING FROM CMSC 2019

Obese children and adolescents with multiple sclerosis (MS) had twice as many relapses on first-line treatment as compared with their non-obese counterparts, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.

The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.

“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.

This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.

Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.

This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.

Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90^th percentile, according to the report.

Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.

A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.

Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).

Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.

“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.

Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.

SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997

Obese children and adolescents with multiple sclerosis (MS) had twice as many relapses on first-line treatment as compared with their non-obese counterparts, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.

The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.

“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.

This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.

Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.

This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.

Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90^th percentile, according to the report.

Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.

A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.

Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).

Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.

“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.

Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.

SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997

Obese children and adolescents with multiple sclerosis (MS) had twice as many relapses on first-line treatment as compared with their non-obese counterparts, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.

The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.

“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.

This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.

Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.

This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.

Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90^th percentile, according to the report.

Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.

A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.

Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).

Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.

“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.

Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.

SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997

Mary Alissa Willis, MD, is the Medical Director for the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We spoke with Dr. Willis about mental health issues in persons with MS and what health care facilities can do to better care for these patients.

What is the prevalence of depression in patients with MS?
Depression and anxiety are common in persons with multiple sclerosis (PwMS). In a systematic review, Ruth Ann Marrie, MD, PhD, and colleagues estimated the prevalence of depression in PwMS to be 23.7%. Approximately half of all PwMS experience depression at some point after their diagnosis.^1-3 This makes depression nearly twice as common in MS as in the general population.

What are some reasons patients with MS might begin to experience depression? What are some warning signs to look out for?

Many people assume that PwMS experience depression because of psychosocial stressors, unpredictability of disease progression, or poor coping strategies. Although these factors do contribute to depression, there is increasing evidence that immune dysregulation and structural changes in the brain caused by MS disease activity make some PwMS uniquely vulnerable to depression. Functional MRI studies have shown abnormalities in the prefrontal-subcortical network connectivity, which is involved in mood regulation. In addition, persistent somatic symptoms such as severe pain and fatigue limit daily activities and social participation—generally considered to be protective factors in depression.⁴ Warning signs for depression include loss of interest in activities, weight loss or weight gain, changes in sleep—too much or too little, an increase in fatigue, expressions of hopelessness or guilt, or increasing drug or alcohol use. 

What are some special considerations for patients with MS battling suicidal ideation?

Anthony Feinstein, MBBCh, MPhil, PhD, and colleagues reported that more than 28% of PwMS had suicidal ideation at some point.⁵ This is a huge number of people struggling with thoughts of suicide. Depression is a risk factor for suicide but other risks specific to PwMS include perceived loss of control, loss of job/income/social roles, loss of driving privileges, and marked physical or cognitive difficulties. While we are doing a better job screening for depression with quick screening tools such as the PHQ9, we could do better in suicide risk assessment.

What can health care providers do better to address depression and risk for suicide? What safety/preventative measures can they take?

 The first step in better addressing depression and risk for suicide is to directly ask patients. Pay attention to changes in appearance, behavior, requests for prescription refills, frequency of appointments, and who accompanies patients to appointments. Explore the reasons for these changes. It is important to respond proactively when comments or behavior suggest a patient at risk. Ask specific questions about plan, access to means, previous suicide attempts, and support network. Refer promptly for emergency or mental health services when appropriate. Familiarity with mental health colleagues, local crisis centers, and helplines can be helpful in engaging a team of people to provide assistance to a patient in need.

References

1. Marrie RA, Fisk JD, Tremlett H, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972-1979.

2. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol. 1990;47(1):98-104.

3. Marrie RA, Walld R, Bolton JM, et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data. BMC Res Notes. 2017;10(1):619.

4. Passamonti L. Cerasa A, Liguori M, et al. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain. 2009;132(pt 12):3380-3391.

5. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. Neurology. 2002;59(5):674-678.

Mary Alissa Willis, MD, is the Medical Director for the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We spoke with Dr. Willis about mental health issues in persons with MS and what health care facilities can do to better care for these patients.

What is the prevalence of depression in patients with MS?
Depression and anxiety are common in persons with multiple sclerosis (PwMS). In a systematic review, Ruth Ann Marrie, MD, PhD, and colleagues estimated the prevalence of depression in PwMS to be 23.7%. Approximately half of all PwMS experience depression at some point after their diagnosis.^1-3 This makes depression nearly twice as common in MS as in the general population.

What are some reasons patients with MS might begin to experience depression? What are some warning signs to look out for?

Many people assume that PwMS experience depression because of psychosocial stressors, unpredictability of disease progression, or poor coping strategies. Although these factors do contribute to depression, there is increasing evidence that immune dysregulation and structural changes in the brain caused by MS disease activity make some PwMS uniquely vulnerable to depression. Functional MRI studies have shown abnormalities in the prefrontal-subcortical network connectivity, which is involved in mood regulation. In addition, persistent somatic symptoms such as severe pain and fatigue limit daily activities and social participation—generally considered to be protective factors in depression.⁴ Warning signs for depression include loss of interest in activities, weight loss or weight gain, changes in sleep—too much or too little, an increase in fatigue, expressions of hopelessness or guilt, or increasing drug or alcohol use. 

What are some special considerations for patients with MS battling suicidal ideation?

Anthony Feinstein, MBBCh, MPhil, PhD, and colleagues reported that more than 28% of PwMS had suicidal ideation at some point.⁵ This is a huge number of people struggling with thoughts of suicide. Depression is a risk factor for suicide but other risks specific to PwMS include perceived loss of control, loss of job/income/social roles, loss of driving privileges, and marked physical or cognitive difficulties. While we are doing a better job screening for depression with quick screening tools such as the PHQ9, we could do better in suicide risk assessment.

What can health care providers do better to address depression and risk for suicide? What safety/preventative measures can they take?

 The first step in better addressing depression and risk for suicide is to directly ask patients. Pay attention to changes in appearance, behavior, requests for prescription refills, frequency of appointments, and who accompanies patients to appointments. Explore the reasons for these changes. It is important to respond proactively when comments or behavior suggest a patient at risk. Ask specific questions about plan, access to means, previous suicide attempts, and support network. Refer promptly for emergency or mental health services when appropriate. Familiarity with mental health colleagues, local crisis centers, and helplines can be helpful in engaging a team of people to provide assistance to a patient in need.

References

1. Marrie RA, Fisk JD, Tremlett H, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972-1979.

2. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol. 1990;47(1):98-104.

3. Marrie RA, Walld R, Bolton JM, et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data. BMC Res Notes. 2017;10(1):619.

4. Passamonti L. Cerasa A, Liguori M, et al. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain. 2009;132(pt 12):3380-3391.

5. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. Neurology. 2002;59(5):674-678.

Mary Alissa Willis, MD, is the Medical Director for the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. We spoke with Dr. Willis about mental health issues in persons with MS and what health care facilities can do to better care for these patients.

What is the prevalence of depression in patients with MS?
Depression and anxiety are common in persons with multiple sclerosis (PwMS). In a systematic review, Ruth Ann Marrie, MD, PhD, and colleagues estimated the prevalence of depression in PwMS to be 23.7%. Approximately half of all PwMS experience depression at some point after their diagnosis.^1-3 This makes depression nearly twice as common in MS as in the general population.

What are some reasons patients with MS might begin to experience depression? What are some warning signs to look out for?

Many people assume that PwMS experience depression because of psychosocial stressors, unpredictability of disease progression, or poor coping strategies. Although these factors do contribute to depression, there is increasing evidence that immune dysregulation and structural changes in the brain caused by MS disease activity make some PwMS uniquely vulnerable to depression. Functional MRI studies have shown abnormalities in the prefrontal-subcortical network connectivity, which is involved in mood regulation. In addition, persistent somatic symptoms such as severe pain and fatigue limit daily activities and social participation—generally considered to be protective factors in depression.⁴ Warning signs for depression include loss of interest in activities, weight loss or weight gain, changes in sleep—too much or too little, an increase in fatigue, expressions of hopelessness or guilt, or increasing drug or alcohol use. 

What are some special considerations for patients with MS battling suicidal ideation?

Anthony Feinstein, MBBCh, MPhil, PhD, and colleagues reported that more than 28% of PwMS had suicidal ideation at some point.⁵ This is a huge number of people struggling with thoughts of suicide. Depression is a risk factor for suicide but other risks specific to PwMS include perceived loss of control, loss of job/income/social roles, loss of driving privileges, and marked physical or cognitive difficulties. While we are doing a better job screening for depression with quick screening tools such as the PHQ9, we could do better in suicide risk assessment.

What can health care providers do better to address depression and risk for suicide? What safety/preventative measures can they take?

 The first step in better addressing depression and risk for suicide is to directly ask patients. Pay attention to changes in appearance, behavior, requests for prescription refills, frequency of appointments, and who accompanies patients to appointments. Explore the reasons for these changes. It is important to respond proactively when comments or behavior suggest a patient at risk. Ask specific questions about plan, access to means, previous suicide attempts, and support network. Refer promptly for emergency or mental health services when appropriate. Familiarity with mental health colleagues, local crisis centers, and helplines can be helpful in engaging a team of people to provide assistance to a patient in need.

References

1. Marrie RA, Fisk JD, Tremlett H, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972-1979.

2. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol. 1990;47(1):98-104.

3. Marrie RA, Walld R, Bolton JM, et al; CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease. Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data. BMC Res Notes. 2017;10(1):619.

4. Passamonti L. Cerasa A, Liguori M, et al. Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis. Brain. 2009;132(pt 12):3380-3391.

5. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. Neurology. 2002;59(5):674-678.

SEATTLE – In patients with multiple sclerosis (MS), black holes are associated with worse cognitive function, including processing speed and visuospatial memory, according to an investigation presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Black holes are not associated with physical function, however. Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment, said the authors.

Black holes (also known as T1-hypointense lesions) can be used as a marker of axonal loss and neuronal tissue destruction in patients with MS. Loss of axons and destruction of neuronal tissue contribute to cognitive and physical disability, but the literature contains few data about whether black holes correlate with cognitive and physical outcomes in MS.

Serkan Özakbas, MD, professor of neurology at Dokuz Eylül University in Izmir, Turkey, and colleagues examined 226 patients with MS to investigate this potential correlation. The population’s median Expanded Disability Status Scale score was 1.5. The researchers categorized participants into two groups according whether they had at least one black hole or not. They assessed patients’ cognitive function by administering the Brief International Cognitive Assessment for MS (BICAMS), which comprises the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test–Revised (BVMTR). They evaluated participants’ physical function using the Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), 6-Minute Walk Test (6MWT), Timed Up and Go (TUG), and 12-Item MS Walking Scale (MSWS-12).

In all, 116 (43.6%) participants had at least one black hole, and 150 (56.4%) had no black hole. Dr. Özakbas and colleagues found no significant difference between patients with and without black holes on the T25FW, 9HPT, 6MWT, TUG, MSWS-12, and CVLT-II. Patients without a black hole, however, had significantly higher SDMT (49.0 vs 42.9) and BVMTR (26.3 vs 23.3) scores, compared with those with at least one black hole.

“This study suggests that presence of black holes is related to cognitive function, but not to physical function,” the researchers concluded.

The investigators had no disclosures and conducted their study without financial support.
 

egreb@mdedge.com

SOURCE: Özakbas S et al. CMSC 2019, Abstract IMG02.

SEATTLE – In patients with multiple sclerosis (MS), black holes are associated with worse cognitive function, including processing speed and visuospatial memory, according to an investigation presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Black holes are not associated with physical function, however. Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment, said the authors.

Black holes (also known as T1-hypointense lesions) can be used as a marker of axonal loss and neuronal tissue destruction in patients with MS. Loss of axons and destruction of neuronal tissue contribute to cognitive and physical disability, but the literature contains few data about whether black holes correlate with cognitive and physical outcomes in MS.

Serkan Özakbas, MD, professor of neurology at Dokuz Eylül University in Izmir, Turkey, and colleagues examined 226 patients with MS to investigate this potential correlation. The population’s median Expanded Disability Status Scale score was 1.5. The researchers categorized participants into two groups according whether they had at least one black hole or not. They assessed patients’ cognitive function by administering the Brief International Cognitive Assessment for MS (BICAMS), which comprises the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test–Revised (BVMTR). They evaluated participants’ physical function using the Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), 6-Minute Walk Test (6MWT), Timed Up and Go (TUG), and 12-Item MS Walking Scale (MSWS-12).

In all, 116 (43.6%) participants had at least one black hole, and 150 (56.4%) had no black hole. Dr. Özakbas and colleagues found no significant difference between patients with and without black holes on the T25FW, 9HPT, 6MWT, TUG, MSWS-12, and CVLT-II. Patients without a black hole, however, had significantly higher SDMT (49.0 vs 42.9) and BVMTR (26.3 vs 23.3) scores, compared with those with at least one black hole.

“This study suggests that presence of black holes is related to cognitive function, but not to physical function,” the researchers concluded.

The investigators had no disclosures and conducted their study without financial support.
 

egreb@mdedge.com

SOURCE: Özakbas S et al. CMSC 2019, Abstract IMG02.

SEATTLE – In patients with multiple sclerosis (MS), black holes are associated with worse cognitive function, including processing speed and visuospatial memory, according to an investigation presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Black holes are not associated with physical function, however. Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment, said the authors.

Black holes (also known as T1-hypointense lesions) can be used as a marker of axonal loss and neuronal tissue destruction in patients with MS. Loss of axons and destruction of neuronal tissue contribute to cognitive and physical disability, but the literature contains few data about whether black holes correlate with cognitive and physical outcomes in MS.

Serkan Özakbas, MD, professor of neurology at Dokuz Eylül University in Izmir, Turkey, and colleagues examined 226 patients with MS to investigate this potential correlation. The population’s median Expanded Disability Status Scale score was 1.5. The researchers categorized participants into two groups according whether they had at least one black hole or not. They assessed patients’ cognitive function by administering the Brief International Cognitive Assessment for MS (BICAMS), which comprises the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test–Revised (BVMTR). They evaluated participants’ physical function using the Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), 6-Minute Walk Test (6MWT), Timed Up and Go (TUG), and 12-Item MS Walking Scale (MSWS-12).

In all, 116 (43.6%) participants had at least one black hole, and 150 (56.4%) had no black hole. Dr. Özakbas and colleagues found no significant difference between patients with and without black holes on the T25FW, 9HPT, 6MWT, TUG, MSWS-12, and CVLT-II. Patients without a black hole, however, had significantly higher SDMT (49.0 vs 42.9) and BVMTR (26.3 vs 23.3) scores, compared with those with at least one black hole.

“This study suggests that presence of black holes is related to cognitive function, but not to physical function,” the researchers concluded.

The investigators had no disclosures and conducted their study without financial support.
 

egreb@mdedge.com

SOURCE: Özakbas S et al. CMSC 2019, Abstract IMG02.

SEATTLE – Among patients with multiple sclerosis (MS), functional gastrointestinal (GI) disorders are prevalent and associated with health-related quality of life, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Managing patients’ psychiatric comorbidities could effectively reduce the burden of functional GI disorders, the researchers said.

Knowledge about the prevalence of functional GI disorders in the population of patients with MS is limited. For the most part, previous studies in this population have focused on irritable bowel syndrome (IBS). A 2013 study by Levinthal et al. (Mult Scler Int. 2013. doi: 10.1155/2013/319201) investigated the prevalence of other functional GI disorders in MS, but the literature contains little information about the clinical and demographic characteristics associated with these disorders. In addition, the extent to which comorbid functional GI disorders influence health-related quality of life in MS is also unknown.

Ruth Ann Marrie, MD, PhD, professor of neurology at the University of Manitoba in Winnipeg, and colleagues sought to determine the prevalence of functional bowel disorders, the demographic and clinical characteristics associated with functional bowel disorders, and the effects of these disorders on health-related quality of life in a large, diverse population of persons with MS. In 2014, the investigators used the Rome III questionnaire to survey participants in the North American Research Committee on MS (NARCOMS) registry about functional bowel disorders. Participants also provided information about their sociodemographic characteristics, their disability status (using Patient-Determined Disease Steps), and any comorbid depression or anxiety, their health behaviors, and their health-related quality of life (using the RAND-12).

Dr. Marrie and colleagues used these data to determine the prevalence of IBS, functional bloating, functional constipation, functional diarrhea, and functional dyspepsia. They used multivariable logistic regression models to examine the factors associated with any functional GI disorder, and they used linear regression to analyze the association between functional GI disorders and health-related quality of life using linear regression.

Dr. Marrie and colleagues identified 6,312 eligible respondents. Approximately 77% of the population was female, and the sample’s mean age was 58.3 years. In all, 2,647 respondents (42%) had a functional GI disorder. The most common was IBS, which affected 28.2% of participants. The prevalence of all functional GI disorders increased with increasing disability. Depression and anxiety were associated with increased odds of IBS and functional dyspepsia. After adjustment for sociodemographic and clinical characteristics, functional GI disorders were associated with lower physical and mental health-related quality of life.

The research was not supported by outside funding. Dr. Marrie had no disclosures, but other researchers had financial relationships with pharmaceutical companies, such as Merck, Novartis, Roche, Sanofi-Aventis, and Teva.
 

egreb@mdedge.com

SOURCE: Marrie RA et al. CMSC 2019, Abstract QOL13.

SEATTLE – Among patients with multiple sclerosis (MS), functional gastrointestinal (GI) disorders are prevalent and associated with health-related quality of life, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Managing patients’ psychiatric comorbidities could effectively reduce the burden of functional GI disorders, the researchers said.

Knowledge about the prevalence of functional GI disorders in the population of patients with MS is limited. For the most part, previous studies in this population have focused on irritable bowel syndrome (IBS). A 2013 study by Levinthal et al. (Mult Scler Int. 2013. doi: 10.1155/2013/319201) investigated the prevalence of other functional GI disorders in MS, but the literature contains little information about the clinical and demographic characteristics associated with these disorders. In addition, the extent to which comorbid functional GI disorders influence health-related quality of life in MS is also unknown.

Ruth Ann Marrie, MD, PhD, professor of neurology at the University of Manitoba in Winnipeg, and colleagues sought to determine the prevalence of functional bowel disorders, the demographic and clinical characteristics associated with functional bowel disorders, and the effects of these disorders on health-related quality of life in a large, diverse population of persons with MS. In 2014, the investigators used the Rome III questionnaire to survey participants in the North American Research Committee on MS (NARCOMS) registry about functional bowel disorders. Participants also provided information about their sociodemographic characteristics, their disability status (using Patient-Determined Disease Steps), and any comorbid depression or anxiety, their health behaviors, and their health-related quality of life (using the RAND-12).

Dr. Marrie and colleagues used these data to determine the prevalence of IBS, functional bloating, functional constipation, functional diarrhea, and functional dyspepsia. They used multivariable logistic regression models to examine the factors associated with any functional GI disorder, and they used linear regression to analyze the association between functional GI disorders and health-related quality of life using linear regression.

Dr. Marrie and colleagues identified 6,312 eligible respondents. Approximately 77% of the population was female, and the sample’s mean age was 58.3 years. In all, 2,647 respondents (42%) had a functional GI disorder. The most common was IBS, which affected 28.2% of participants. The prevalence of all functional GI disorders increased with increasing disability. Depression and anxiety were associated with increased odds of IBS and functional dyspepsia. After adjustment for sociodemographic and clinical characteristics, functional GI disorders were associated with lower physical and mental health-related quality of life.

The research was not supported by outside funding. Dr. Marrie had no disclosures, but other researchers had financial relationships with pharmaceutical companies, such as Merck, Novartis, Roche, Sanofi-Aventis, and Teva.
 

egreb@mdedge.com

SOURCE: Marrie RA et al. CMSC 2019, Abstract QOL13.

SEATTLE – Among patients with multiple sclerosis (MS), functional gastrointestinal (GI) disorders are prevalent and associated with health-related quality of life, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Managing patients’ psychiatric comorbidities could effectively reduce the burden of functional GI disorders, the researchers said.

Knowledge about the prevalence of functional GI disorders in the population of patients with MS is limited. For the most part, previous studies in this population have focused on irritable bowel syndrome (IBS). A 2013 study by Levinthal et al. (Mult Scler Int. 2013. doi: 10.1155/2013/319201) investigated the prevalence of other functional GI disorders in MS, but the literature contains little information about the clinical and demographic characteristics associated with these disorders. In addition, the extent to which comorbid functional GI disorders influence health-related quality of life in MS is also unknown.

Ruth Ann Marrie, MD, PhD, professor of neurology at the University of Manitoba in Winnipeg, and colleagues sought to determine the prevalence of functional bowel disorders, the demographic and clinical characteristics associated with functional bowel disorders, and the effects of these disorders on health-related quality of life in a large, diverse population of persons with MS. In 2014, the investigators used the Rome III questionnaire to survey participants in the North American Research Committee on MS (NARCOMS) registry about functional bowel disorders. Participants also provided information about their sociodemographic characteristics, their disability status (using Patient-Determined Disease Steps), and any comorbid depression or anxiety, their health behaviors, and their health-related quality of life (using the RAND-12).

Dr. Marrie and colleagues used these data to determine the prevalence of IBS, functional bloating, functional constipation, functional diarrhea, and functional dyspepsia. They used multivariable logistic regression models to examine the factors associated with any functional GI disorder, and they used linear regression to analyze the association between functional GI disorders and health-related quality of life using linear regression.

Dr. Marrie and colleagues identified 6,312 eligible respondents. Approximately 77% of the population was female, and the sample’s mean age was 58.3 years. In all, 2,647 respondents (42%) had a functional GI disorder. The most common was IBS, which affected 28.2% of participants. The prevalence of all functional GI disorders increased with increasing disability. Depression and anxiety were associated with increased odds of IBS and functional dyspepsia. After adjustment for sociodemographic and clinical characteristics, functional GI disorders were associated with lower physical and mental health-related quality of life.

The research was not supported by outside funding. Dr. Marrie had no disclosures, but other researchers had financial relationships with pharmaceutical companies, such as Merck, Novartis, Roche, Sanofi-Aventis, and Teva.
 

egreb@mdedge.com

SOURCE: Marrie RA et al. CMSC 2019, Abstract QOL13.

SEATTLE – Neutrophil levels may decline in patients with relapsing multiple sclerosis (MS) who have been on fingolimod for 2 or more years, according to an interim analysis of phase 4 study data.

A decrease in neutrophils over 6 months in a cohort of fingolimod treatment–experienced patients “was a surprise, at least to me,” said study investigator Bruce Cree, MD, PhD, professor of neurology at UCSF Weill Institute for Neurosciences, University of California, San Francisco. Why levels of these innate immune cells decreased in patients who had been on the drug for years “remains to be understood,” Dr. Cree said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “This is something that deserves further investigation ... to understand if that neutrophil count will continue to drop down over time or whether it ultimately plateaus.”

The decline in neutrophils in this cohort of patients continuously treated for at least 2 years was “only about 9%,” from an average of 3,698.56 cells per microliter at study baseline to 3,336.13 cells per microliter at 6 months.

Among fingolimod-naive patients who initiated treatment during the study, neutrophils decreased from 4,058.48 cells per microliter at baseline to 3,475.09 cells per microliter at 6 months, about 14%.

In the treatment-experienced patients, other immune cell subsets remained relatively stable over the 6-month period.

“If we are trying to understand the impact of fingolimod ultimately on propensity for development of opportunistic infection, of course we are focused almost exclusively on adaptive immunity,” Dr. Cree said. “But perhaps we are forgetting that innate immunity might be also extremely important for protecting ourselves against infection.”
 

The FLUENT study

Dr. Cree presented interim, 6-month data from the ongoing, open-label FLUENT study, which is a 12-month, prospective, multicenter, nonrandomized study to assess changes in the immune cell profiles of patients with relapsing MS who receive fingolimod. The study includes a cohort of treatment-experienced patients and a cohort of treatment-naive patients.

Fingolimod is a once-daily oral sphingosine 1–phosphate receptor modulator that prevents egress of lymphocytes from lymph nodes. Since its FDA approval in 2010, rare opportunistic infections, including progressive multifocal leukoencephalopathy (PML), have been reported in patients taking fingolimod.

Investigators did not assess changes in innate and adaptive components of the immune system during fingolimod treatment in the pivotal clinical trials, and the relationship between anti-JCV antibody index and immune cell subsets during fingolimod treatment is not known. Immunologic profiling may help gauge patients’ treatment response and risk of infection.

The FLUENT study’s primary outcome is change from baseline to month 6 in peripheral blood cellular components of the innate and adaptive immune system. Secondary endpoints include change in the immune cell subtype profile at months 3 and 12; anti-JCV antibody status at months 3, 6, and 12; change in anti-JCV antibody index at months 3, 6, and 12; and clinical variables. In addition, the investigators plan to examine changes in serum neurofilament light chain (NfL) levels at months 3, 6, and 12.

FLUENT includes a cohort of fingolimod-naive patients and a cohort of patients who have received continuous, commercially available fingolimod 0.5 mg/day for at least 2 years and plan to continue the drug during the 1-year study. The interim analysis included data from 166 fingolimod-naive patients (median age, 41 years; 77.7% female) and 216 fingolimod-experienced patients (median age, 50 years; 73.1% female). About 70% of patients in the fingolimod-naive cohort had had a relapse in the past 2 years, compared with about 22% of patients in the treatment-experienced cohort. Investigators began enrolling patients in September 2017.
 

Immune cell subsets

In the fingolimod-naive cohort, changes in immune cell subsets were expected and characteristic. Overall CD4+ count declined from baseline to month 6, and the decrease was “driven primarily by a decline in CD4+ naive T cells and CD4+ central memory T cells.” CD4+ effector memory cells, CD4+ Th1 cells, CD4+ Th2 cells, and CD4+ Th17 cells were less affected. “The effector cells do not have an expression of CCR7 [C-C chemokine receptor type 7] so they tend not to hone to the lymph nodes anyway,” Dr. Cree said.

CD8+ cells followed a similar pattern. “The overall count goes down, but perhaps not as much as with the CD4+ cells. The central memory and naive cells are affected a little bit more than the effector memory cells,” Dr. Cree said. “Then we see a comparable pattern with B cells. The absolute CD19+ counts go down. They’re driven by a decline in the naive cells. ... with less of a decline in memory cells and almost no decline in regulatory cells.”

Among innate immune cells, monocytes increased slightly, neutrophils declined, as expected, and natural killer cells declined slightly.

“When you turn your attention to ... those patients who have been on fingolimod, you do not see these changes for the lymphocytes,” Dr. Cree said. “Those lymphocytes are already sequestered, and we are really not seeing much of a change over time at all.”
 

A measure of CNS injury

In the treatment-naive cohort, serum neurofilament light chain (NfL) declined, but this measure did not change by much in the treatment-experienced cohort.

Among patients already on fingolimod, the serum NfL reduction “that would be anticipated as a therapeutic benefit from fingolimod is already being realized,” he said.

The serum NfL levels in the treatment-naive cohort at 6 months were similar to those of the treatment-experienced cohort at baseline, which indicates that “the impact of fingolimod in reducing circulating neurofilament – a marker of central nervous system injury – is seen within 6 months of treatment and likely persists as patients continue on fingolimod therapy,” Dr. Cree said.

Baseline anti-JCV antibody index was about the same for the treatment-naive and treatment-experienced cohorts (1.28 vs. 1.39, respectively), and this measure did not meaningfully change over 6 months in either cohort.
 

Adverse events

No new adverse events were identified in this interim analysis. Most common adverse events occurred more frequently in the treatment-naive cohort than in the treatment-experienced cohort, including headache (7.2% vs. 1.9%), upper respiratory tract infection (4.2% vs. 1.9%), pain in extremity (4.2% vs. 1.4%), lymphopenia (4.8% vs. 0.5%), anxiety (3.6% vs. 1.4%), fatigue (3.6% vs. 1.4%), nausea (3.0% vs. 0.9%), dizziness (3.0% vs. 0.5%), hypoesthesia (3.0% vs. 0.5%), and tremor (3.0% vs. 0%). An exception was falls, which occurred in 3.0% of the treatment-naive cohort and 4.6% of the treatment-experienced cohort.

Serious adverse events were about equal between the two groups (4.2% of the treatment-naive group and 5.1% of the treatment-experienced group), and adverse events leading to treatment discontinuation were more common in the fingolimod-naive cohort (10.2% vs. 5.6%).

Novartis funded the study, and four of the authors are Novartis employees. Dr. Cree disclosed consulting fees from Novartis and other pharmaceutical companies. His coauthors disclosed consulting fees, speaking fees, research support, and serving on advisory boards for pharmaceutical companies, including Novartis.

jremaly@mdedge.com

SOURCE: Mao-Draayer Y et al. CMSC 2019. Abstract DXM03.

SEATTLE – Neutrophil levels may decline in patients with relapsing multiple sclerosis (MS) who have been on fingolimod for 2 or more years, according to an interim analysis of phase 4 study data.

A decrease in neutrophils over 6 months in a cohort of fingolimod treatment–experienced patients “was a surprise, at least to me,” said study investigator Bruce Cree, MD, PhD, professor of neurology at UCSF Weill Institute for Neurosciences, University of California, San Francisco. Why levels of these innate immune cells decreased in patients who had been on the drug for years “remains to be understood,” Dr. Cree said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “This is something that deserves further investigation ... to understand if that neutrophil count will continue to drop down over time or whether it ultimately plateaus.”

The decline in neutrophils in this cohort of patients continuously treated for at least 2 years was “only about 9%,” from an average of 3,698.56 cells per microliter at study baseline to 3,336.13 cells per microliter at 6 months.

Among fingolimod-naive patients who initiated treatment during the study, neutrophils decreased from 4,058.48 cells per microliter at baseline to 3,475.09 cells per microliter at 6 months, about 14%.

In the treatment-experienced patients, other immune cell subsets remained relatively stable over the 6-month period.

“If we are trying to understand the impact of fingolimod ultimately on propensity for development of opportunistic infection, of course we are focused almost exclusively on adaptive immunity,” Dr. Cree said. “But perhaps we are forgetting that innate immunity might be also extremely important for protecting ourselves against infection.”
 

The FLUENT study

Dr. Cree presented interim, 6-month data from the ongoing, open-label FLUENT study, which is a 12-month, prospective, multicenter, nonrandomized study to assess changes in the immune cell profiles of patients with relapsing MS who receive fingolimod. The study includes a cohort of treatment-experienced patients and a cohort of treatment-naive patients.

Fingolimod is a once-daily oral sphingosine 1–phosphate receptor modulator that prevents egress of lymphocytes from lymph nodes. Since its FDA approval in 2010, rare opportunistic infections, including progressive multifocal leukoencephalopathy (PML), have been reported in patients taking fingolimod.

Investigators did not assess changes in innate and adaptive components of the immune system during fingolimod treatment in the pivotal clinical trials, and the relationship between anti-JCV antibody index and immune cell subsets during fingolimod treatment is not known. Immunologic profiling may help gauge patients’ treatment response and risk of infection.

The FLUENT study’s primary outcome is change from baseline to month 6 in peripheral blood cellular components of the innate and adaptive immune system. Secondary endpoints include change in the immune cell subtype profile at months 3 and 12; anti-JCV antibody status at months 3, 6, and 12; change in anti-JCV antibody index at months 3, 6, and 12; and clinical variables. In addition, the investigators plan to examine changes in serum neurofilament light chain (NfL) levels at months 3, 6, and 12.

FLUENT includes a cohort of fingolimod-naive patients and a cohort of patients who have received continuous, commercially available fingolimod 0.5 mg/day for at least 2 years and plan to continue the drug during the 1-year study. The interim analysis included data from 166 fingolimod-naive patients (median age, 41 years; 77.7% female) and 216 fingolimod-experienced patients (median age, 50 years; 73.1% female). About 70% of patients in the fingolimod-naive cohort had had a relapse in the past 2 years, compared with about 22% of patients in the treatment-experienced cohort. Investigators began enrolling patients in September 2017.
 

Immune cell subsets

In the fingolimod-naive cohort, changes in immune cell subsets were expected and characteristic. Overall CD4+ count declined from baseline to month 6, and the decrease was “driven primarily by a decline in CD4+ naive T cells and CD4+ central memory T cells.” CD4+ effector memory cells, CD4+ Th1 cells, CD4+ Th2 cells, and CD4+ Th17 cells were less affected. “The effector cells do not have an expression of CCR7 [C-C chemokine receptor type 7] so they tend not to hone to the lymph nodes anyway,” Dr. Cree said.

CD8+ cells followed a similar pattern. “The overall count goes down, but perhaps not as much as with the CD4+ cells. The central memory and naive cells are affected a little bit more than the effector memory cells,” Dr. Cree said. “Then we see a comparable pattern with B cells. The absolute CD19+ counts go down. They’re driven by a decline in the naive cells. ... with less of a decline in memory cells and almost no decline in regulatory cells.”

Among innate immune cells, monocytes increased slightly, neutrophils declined, as expected, and natural killer cells declined slightly.

“When you turn your attention to ... those patients who have been on fingolimod, you do not see these changes for the lymphocytes,” Dr. Cree said. “Those lymphocytes are already sequestered, and we are really not seeing much of a change over time at all.”
 

A measure of CNS injury

In the treatment-naive cohort, serum neurofilament light chain (NfL) declined, but this measure did not change by much in the treatment-experienced cohort.

Among patients already on fingolimod, the serum NfL reduction “that would be anticipated as a therapeutic benefit from fingolimod is already being realized,” he said.

The serum NfL levels in the treatment-naive cohort at 6 months were similar to those of the treatment-experienced cohort at baseline, which indicates that “the impact of fingolimod in reducing circulating neurofilament – a marker of central nervous system injury – is seen within 6 months of treatment and likely persists as patients continue on fingolimod therapy,” Dr. Cree said.

Baseline anti-JCV antibody index was about the same for the treatment-naive and treatment-experienced cohorts (1.28 vs. 1.39, respectively), and this measure did not meaningfully change over 6 months in either cohort.
 

Adverse events

No new adverse events were identified in this interim analysis. Most common adverse events occurred more frequently in the treatment-naive cohort than in the treatment-experienced cohort, including headache (7.2% vs. 1.9%), upper respiratory tract infection (4.2% vs. 1.9%), pain in extremity (4.2% vs. 1.4%), lymphopenia (4.8% vs. 0.5%), anxiety (3.6% vs. 1.4%), fatigue (3.6% vs. 1.4%), nausea (3.0% vs. 0.9%), dizziness (3.0% vs. 0.5%), hypoesthesia (3.0% vs. 0.5%), and tremor (3.0% vs. 0%). An exception was falls, which occurred in 3.0% of the treatment-naive cohort and 4.6% of the treatment-experienced cohort.

Serious adverse events were about equal between the two groups (4.2% of the treatment-naive group and 5.1% of the treatment-experienced group), and adverse events leading to treatment discontinuation were more common in the fingolimod-naive cohort (10.2% vs. 5.6%).

Novartis funded the study, and four of the authors are Novartis employees. Dr. Cree disclosed consulting fees from Novartis and other pharmaceutical companies. His coauthors disclosed consulting fees, speaking fees, research support, and serving on advisory boards for pharmaceutical companies, including Novartis.

jremaly@mdedge.com

SOURCE: Mao-Draayer Y et al. CMSC 2019. Abstract DXM03.

SEATTLE – Neutrophil levels may decline in patients with relapsing multiple sclerosis (MS) who have been on fingolimod for 2 or more years, according to an interim analysis of phase 4 study data.

A decrease in neutrophils over 6 months in a cohort of fingolimod treatment–experienced patients “was a surprise, at least to me,” said study investigator Bruce Cree, MD, PhD, professor of neurology at UCSF Weill Institute for Neurosciences, University of California, San Francisco. Why levels of these innate immune cells decreased in patients who had been on the drug for years “remains to be understood,” Dr. Cree said at the annual meeting of the Consortium of Multiple Sclerosis Centers. “This is something that deserves further investigation ... to understand if that neutrophil count will continue to drop down over time or whether it ultimately plateaus.”

The decline in neutrophils in this cohort of patients continuously treated for at least 2 years was “only about 9%,” from an average of 3,698.56 cells per microliter at study baseline to 3,336.13 cells per microliter at 6 months.

Among fingolimod-naive patients who initiated treatment during the study, neutrophils decreased from 4,058.48 cells per microliter at baseline to 3,475.09 cells per microliter at 6 months, about 14%.

In the treatment-experienced patients, other immune cell subsets remained relatively stable over the 6-month period.

“If we are trying to understand the impact of fingolimod ultimately on propensity for development of opportunistic infection, of course we are focused almost exclusively on adaptive immunity,” Dr. Cree said. “But perhaps we are forgetting that innate immunity might be also extremely important for protecting ourselves against infection.”
 

The FLUENT study

Dr. Cree presented interim, 6-month data from the ongoing, open-label FLUENT study, which is a 12-month, prospective, multicenter, nonrandomized study to assess changes in the immune cell profiles of patients with relapsing MS who receive fingolimod. The study includes a cohort of treatment-experienced patients and a cohort of treatment-naive patients.

Fingolimod is a once-daily oral sphingosine 1–phosphate receptor modulator that prevents egress of lymphocytes from lymph nodes. Since its FDA approval in 2010, rare opportunistic infections, including progressive multifocal leukoencephalopathy (PML), have been reported in patients taking fingolimod.

Investigators did not assess changes in innate and adaptive components of the immune system during fingolimod treatment in the pivotal clinical trials, and the relationship between anti-JCV antibody index and immune cell subsets during fingolimod treatment is not known. Immunologic profiling may help gauge patients’ treatment response and risk of infection.

The FLUENT study’s primary outcome is change from baseline to month 6 in peripheral blood cellular components of the innate and adaptive immune system. Secondary endpoints include change in the immune cell subtype profile at months 3 and 12; anti-JCV antibody status at months 3, 6, and 12; change in anti-JCV antibody index at months 3, 6, and 12; and clinical variables. In addition, the investigators plan to examine changes in serum neurofilament light chain (NfL) levels at months 3, 6, and 12.

FLUENT includes a cohort of fingolimod-naive patients and a cohort of patients who have received continuous, commercially available fingolimod 0.5 mg/day for at least 2 years and plan to continue the drug during the 1-year study. The interim analysis included data from 166 fingolimod-naive patients (median age, 41 years; 77.7% female) and 216 fingolimod-experienced patients (median age, 50 years; 73.1% female). About 70% of patients in the fingolimod-naive cohort had had a relapse in the past 2 years, compared with about 22% of patients in the treatment-experienced cohort. Investigators began enrolling patients in September 2017.
 

Immune cell subsets

In the fingolimod-naive cohort, changes in immune cell subsets were expected and characteristic. Overall CD4+ count declined from baseline to month 6, and the decrease was “driven primarily by a decline in CD4+ naive T cells and CD4+ central memory T cells.” CD4+ effector memory cells, CD4+ Th1 cells, CD4+ Th2 cells, and CD4+ Th17 cells were less affected. “The effector cells do not have an expression of CCR7 [C-C chemokine receptor type 7] so they tend not to hone to the lymph nodes anyway,” Dr. Cree said.

CD8+ cells followed a similar pattern. “The overall count goes down, but perhaps not as much as with the CD4+ cells. The central memory and naive cells are affected a little bit more than the effector memory cells,” Dr. Cree said. “Then we see a comparable pattern with B cells. The absolute CD19+ counts go down. They’re driven by a decline in the naive cells. ... with less of a decline in memory cells and almost no decline in regulatory cells.”

Among innate immune cells, monocytes increased slightly, neutrophils declined, as expected, and natural killer cells declined slightly.

“When you turn your attention to ... those patients who have been on fingolimod, you do not see these changes for the lymphocytes,” Dr. Cree said. “Those lymphocytes are already sequestered, and we are really not seeing much of a change over time at all.”
 

A measure of CNS injury

In the treatment-naive cohort, serum neurofilament light chain (NfL) declined, but this measure did not change by much in the treatment-experienced cohort.

Among patients already on fingolimod, the serum NfL reduction “that would be anticipated as a therapeutic benefit from fingolimod is already being realized,” he said.

The serum NfL levels in the treatment-naive cohort at 6 months were similar to those of the treatment-experienced cohort at baseline, which indicates that “the impact of fingolimod in reducing circulating neurofilament – a marker of central nervous system injury – is seen within 6 months of treatment and likely persists as patients continue on fingolimod therapy,” Dr. Cree said.

Baseline anti-JCV antibody index was about the same for the treatment-naive and treatment-experienced cohorts (1.28 vs. 1.39, respectively), and this measure did not meaningfully change over 6 months in either cohort.
 

Adverse events

No new adverse events were identified in this interim analysis. Most common adverse events occurred more frequently in the treatment-naive cohort than in the treatment-experienced cohort, including headache (7.2% vs. 1.9%), upper respiratory tract infection (4.2% vs. 1.9%), pain in extremity (4.2% vs. 1.4%), lymphopenia (4.8% vs. 0.5%), anxiety (3.6% vs. 1.4%), fatigue (3.6% vs. 1.4%), nausea (3.0% vs. 0.9%), dizziness (3.0% vs. 0.5%), hypoesthesia (3.0% vs. 0.5%), and tremor (3.0% vs. 0%). An exception was falls, which occurred in 3.0% of the treatment-naive cohort and 4.6% of the treatment-experienced cohort.

Serious adverse events were about equal between the two groups (4.2% of the treatment-naive group and 5.1% of the treatment-experienced group), and adverse events leading to treatment discontinuation were more common in the fingolimod-naive cohort (10.2% vs. 5.6%).

Novartis funded the study, and four of the authors are Novartis employees. Dr. Cree disclosed consulting fees from Novartis and other pharmaceutical companies. His coauthors disclosed consulting fees, speaking fees, research support, and serving on advisory boards for pharmaceutical companies, including Novartis.

jremaly@mdedge.com

SOURCE: Mao-Draayer Y et al. CMSC 2019. Abstract DXM03.