Multiple Sclerosis Hub

Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.

A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).

HUNG KUO CHUN/Thinkstock

“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.

“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.

“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.

EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.

Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.

On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.

The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.

A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).

The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm³ vs. 879.2 mm³; P less than .0001).

More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.

Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.

Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).

“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.

Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).

Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).

SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.

Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.

A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).

HUNG KUO CHUN/Thinkstock

“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.

“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.

“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.

EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.

Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.

On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.

The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.

A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).

The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm³ vs. 879.2 mm³; P less than .0001).

More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.

Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.

Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).

“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.

Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).

Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).

SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.

Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.

A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).

HUNG KUO CHUN/Thinkstock

“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.

“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.

“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.

EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.

Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.

On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.

The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.

A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).

The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm³ vs. 879.2 mm³; P less than .0001).

More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.

Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.

Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).

“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.

Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).

Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).

SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.

Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

solitude72/iStockphoto

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094

Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

solitude72/iStockphoto

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094

Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

solitude72/iStockphoto

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094

Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.

Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.

However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.

Patients taking daclizumab should contact their health care providers. More information can be found in the press release.

—Christopher Palmer

Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.

Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.

However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.

Patients taking daclizumab should contact their health care providers. More information can be found in the press release.

—Christopher Palmer

Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that hadn’t worked well enough.

Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality.

However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.

Patients taking daclizumab should contact their health care providers. More information can be found in the press release.

—Christopher Palmer

SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”

Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).

“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.

In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).

“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering the prospects for different proposed mechanisms

Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”

Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”

Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.

“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”

As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.

The bigger picture

The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said.  A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.

“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A ‘tantalizing prospect’

“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”

More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”

A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”

Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).

“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.

In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).

“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering the prospects for different proposed mechanisms

Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”

Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”

Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.

“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”

As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.

The bigger picture

The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said.  A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.

“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A ‘tantalizing prospect’

“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”

More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”

A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”

Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).

“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.

In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).

“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering the prospects for different proposed mechanisms

Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”

Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”

Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.

“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”

As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.

The bigger picture

The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said.  A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.

“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A ‘tantalizing prospect’

“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”

More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”

A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

SAN DIEGO—Vitamin D levels may be associated with brain imaging measures in patients with progressive multiple sclerosis (MS), according to an analysis presented at the ACTRIMS 2018 Forum. The association appears to be similar in primary progressive MS and secondary progressive MS and may reflect vitamin D’s protective effect on myelin in gray matter.

Research has identified vitamin D deficiency as a risk factor for MS. Low levels of the vitamin are associated with increased risk of brain lesions, relapses, and early progression of disability. Much of the literature focuses on relapsing-remitting MS. Less is known about the part that vitamin D plays in progressive MS, particularly with respect to clinical and imaging findings.

An Analysis of Phase II Data

Justin Abbatemarco, MD, a neurologist at Cleveland Clinic, and colleagues studied results from the phase II clinical trial of ibudilast to examine the association between vitamin D levels and clinical and MRI features in progressive MS. In the trial, investigators measured participants’ serum 25 OH vitamin D levels. At baseline, they collected demographic information such as age, gender, race, disease duration, duration of progression, prior treatment history, Expanded Disability Status Scale score, MS Functional Composite, and neurocognitive testing. Baseline MRI information included brain parenchymal fraction, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR).

Dr. Abbatemarco and colleagues used Spearman correlation to evaluate the associations between total vitamin D and vitamin D3 levels and clinical or imaging characteristics. They created a linear regression model to predict clinical and imaging outcome variables.

Vitamin D Was Associated With Whole Brain MTR

The analysis included 267 patients (47.2% male) with a mean age of 55.6. In all, 137 participants had primary progressive MS, and 130 participants had secondary progressive MS. Mean disease duration was 16.4 years. The population’s mean vitamin D3 level was 40.7 ng/mL, and mean total vitamin D level was 43.8 ng/mL. Mean brain parenchymal fraction was 0.8, mean T2 lesion volume was 10.3 mL, and mean whole brain MTR was 0.1.

The investigators did not observe a significant difference in mean vitamin D levels between patients with secondary progressive MS (44.7 ng/mL) and those with primary progressive MS (42.9 ng/mL). They did find positive associations between vitamin D3 and whole brain MTR, normal appearing brain tissue MTR, and normal appearing gray matter MTR. Dr. Abbatemarco’s group found no significant associations between vitamin D levels and brain parenchymal fraction, T1 or T2 lesion volume, or DTI metrics. The associations between vitamin D3 and MRI features were similar in patients with primary progressive MS and those with secondary progressive MS.

In a multivariate analysis that controlled for age, gender, disease duration, the time that vitamin D level was obtained, and latitude of study site, associations between vitamin D3 level and whole brain MTR remained significant. Every 10-ng/mL increase in vitamin D3 was associated with a 2.1% unit increase in whole brain MTR. The investigators found no association between vitamin D3 and brain parenchymal fraction, T2 lesion volume, T1 lesion volume, and clinical scores.

Dr. Abbatemarco and colleagues plan to test the effect of longitudinal changes on clinical and MRI measures once data become available.

—Erik Greb

Suggested Reading

Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220-1224.

SAN DIEGO—Vitamin D levels may be associated with brain imaging measures in patients with progressive multiple sclerosis (MS), according to an analysis presented at the ACTRIMS 2018 Forum. The association appears to be similar in primary progressive MS and secondary progressive MS and may reflect vitamin D’s protective effect on myelin in gray matter.

Research has identified vitamin D deficiency as a risk factor for MS. Low levels of the vitamin are associated with increased risk of brain lesions, relapses, and early progression of disability. Much of the literature focuses on relapsing-remitting MS. Less is known about the part that vitamin D plays in progressive MS, particularly with respect to clinical and imaging findings.

An Analysis of Phase II Data

Justin Abbatemarco, MD, a neurologist at Cleveland Clinic, and colleagues studied results from the phase II clinical trial of ibudilast to examine the association between vitamin D levels and clinical and MRI features in progressive MS. In the trial, investigators measured participants’ serum 25 OH vitamin D levels. At baseline, they collected demographic information such as age, gender, race, disease duration, duration of progression, prior treatment history, Expanded Disability Status Scale score, MS Functional Composite, and neurocognitive testing. Baseline MRI information included brain parenchymal fraction, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR).

Dr. Abbatemarco and colleagues used Spearman correlation to evaluate the associations between total vitamin D and vitamin D3 levels and clinical or imaging characteristics. They created a linear regression model to predict clinical and imaging outcome variables.

Vitamin D Was Associated With Whole Brain MTR

The analysis included 267 patients (47.2% male) with a mean age of 55.6. In all, 137 participants had primary progressive MS, and 130 participants had secondary progressive MS. Mean disease duration was 16.4 years. The population’s mean vitamin D3 level was 40.7 ng/mL, and mean total vitamin D level was 43.8 ng/mL. Mean brain parenchymal fraction was 0.8, mean T2 lesion volume was 10.3 mL, and mean whole brain MTR was 0.1.

The investigators did not observe a significant difference in mean vitamin D levels between patients with secondary progressive MS (44.7 ng/mL) and those with primary progressive MS (42.9 ng/mL). They did find positive associations between vitamin D3 and whole brain MTR, normal appearing brain tissue MTR, and normal appearing gray matter MTR. Dr. Abbatemarco’s group found no significant associations between vitamin D levels and brain parenchymal fraction, T1 or T2 lesion volume, or DTI metrics. The associations between vitamin D3 and MRI features were similar in patients with primary progressive MS and those with secondary progressive MS.

In a multivariate analysis that controlled for age, gender, disease duration, the time that vitamin D level was obtained, and latitude of study site, associations between vitamin D3 level and whole brain MTR remained significant. Every 10-ng/mL increase in vitamin D3 was associated with a 2.1% unit increase in whole brain MTR. The investigators found no association between vitamin D3 and brain parenchymal fraction, T2 lesion volume, T1 lesion volume, and clinical scores.

Dr. Abbatemarco and colleagues plan to test the effect of longitudinal changes on clinical and MRI measures once data become available.

—Erik Greb

Suggested Reading

Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220-1224.

SAN DIEGO—Vitamin D levels may be associated with brain imaging measures in patients with progressive multiple sclerosis (MS), according to an analysis presented at the ACTRIMS 2018 Forum. The association appears to be similar in primary progressive MS and secondary progressive MS and may reflect vitamin D’s protective effect on myelin in gray matter.

Research has identified vitamin D deficiency as a risk factor for MS. Low levels of the vitamin are associated with increased risk of brain lesions, relapses, and early progression of disability. Much of the literature focuses on relapsing-remitting MS. Less is known about the part that vitamin D plays in progressive MS, particularly with respect to clinical and imaging findings.

An Analysis of Phase II Data

Justin Abbatemarco, MD, a neurologist at Cleveland Clinic, and colleagues studied results from the phase II clinical trial of ibudilast to examine the association between vitamin D levels and clinical and MRI features in progressive MS. In the trial, investigators measured participants’ serum 25 OH vitamin D levels. At baseline, they collected demographic information such as age, gender, race, disease duration, duration of progression, prior treatment history, Expanded Disability Status Scale score, MS Functional Composite, and neurocognitive testing. Baseline MRI information included brain parenchymal fraction, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR).

Dr. Abbatemarco and colleagues used Spearman correlation to evaluate the associations between total vitamin D and vitamin D3 levels and clinical or imaging characteristics. They created a linear regression model to predict clinical and imaging outcome variables.

Vitamin D Was Associated With Whole Brain MTR

The analysis included 267 patients (47.2% male) with a mean age of 55.6. In all, 137 participants had primary progressive MS, and 130 participants had secondary progressive MS. Mean disease duration was 16.4 years. The population’s mean vitamin D3 level was 40.7 ng/mL, and mean total vitamin D level was 43.8 ng/mL. Mean brain parenchymal fraction was 0.8, mean T2 lesion volume was 10.3 mL, and mean whole brain MTR was 0.1.

The investigators did not observe a significant difference in mean vitamin D levels between patients with secondary progressive MS (44.7 ng/mL) and those with primary progressive MS (42.9 ng/mL). They did find positive associations between vitamin D3 and whole brain MTR, normal appearing brain tissue MTR, and normal appearing gray matter MTR. Dr. Abbatemarco’s group found no significant associations between vitamin D levels and brain parenchymal fraction, T1 or T2 lesion volume, or DTI metrics. The associations between vitamin D3 and MRI features were similar in patients with primary progressive MS and those with secondary progressive MS.

In a multivariate analysis that controlled for age, gender, disease duration, the time that vitamin D level was obtained, and latitude of study site, associations between vitamin D3 level and whole brain MTR remained significant. Every 10-ng/mL increase in vitamin D3 was associated with a 2.1% unit increase in whole brain MTR. The investigators found no association between vitamin D3 and brain parenchymal fraction, T2 lesion volume, T1 lesion volume, and clinical scores.

Dr. Abbatemarco and colleagues plan to test the effect of longitudinal changes on clinical and MRI measures once data become available.

—Erik Greb

Suggested Reading

Smolders J, Menheere P, Kessels A, et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14(9):1220-1224.

SAN DIEGO – Early results of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase 2 trial of patients with relapsing-remitting multiple sclerosis demonstrated evidence of remyelination at week 24 among high-dose users, but it did not meet its primary endpoint of active lesions seen on MRI.

In an interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis, study author Robert Glanzman, MD, said that GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination via TLR4.

Doug Brunk/Frontline Medical News

[email protected]

SOURCE: Glanzman R et al. Abstract P034.

SAN DIEGO – Early results of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase 2 trial of patients with relapsing-remitting multiple sclerosis demonstrated evidence of remyelination at week 24 among high-dose users, but it did not meet its primary endpoint of active lesions seen on MRI.

In an interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis, study author Robert Glanzman, MD, said that GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination via TLR4.

Doug Brunk/Frontline Medical News

[email protected]

SOURCE: Glanzman R et al. Abstract P034.

SAN DIEGO – Early results of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase 2 trial of patients with relapsing-remitting multiple sclerosis demonstrated evidence of remyelination at week 24 among high-dose users, but it did not meet its primary endpoint of active lesions seen on MRI.

In an interview at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis, study author Robert Glanzman, MD, said that GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination via TLR4.

Doug Brunk/Frontline Medical News

[email protected]

SOURCE: Glanzman R et al. Abstract P034.

SAN DIEGO—Newer oral and IV disease-modifying therapies (DMTs) for multiple sclerosis (MS) increasingly are used in children, according to data presented at the ACTRIMS 2018 Forum. These DMTs often are second-line therapies, but some patients receive them as first-line treatment.

“Newer DMTs … are being started more often over time at clinics participating in the US Network of Pediatric MS Centers,” said Kristen M. Krysko, MD, Clinical Fellow at the University of California, San Francisco School of Medicine, and colleagues.

Treatment Challenges

About 5% of patients with MS develop symptoms before age 18. “Treatment of pediatric MS is challenging, given high relapse rates and the lack of safety and efficacy data for DMTs in children,” Dr. Krysko and colleagues said. “Conventionally, first-line treatments for pediatric MS include interferon beta and glatiramer acetate, but these agents may be poorly tolerated, since they are given by injection, and may not adequately control the disease. Those with breakthrough events require escalation to more potent agents, which are increasingly used off-label in pediatric MS despite limited data about safety or efficacy in children.”

To characterize the use and safety of newer DMTs in children with MS and clinically isolated syndrome (CIS), Dr. Krysko and colleagues conducted a retrospective cohort study of prospectively collected data at 12 clinics participating in the US Network of Pediatric MS Centers as of August 2017.

The researchers examined patterns of newer DMT use and newer DMT side effects. They classified DMTs as injectable (ie, glatiramer acetate and beta-interferons), oral (ie, dimethyl fumarate, fingolimod, and teriflunomide), or IV (ie, natalizumab, rituximab, alemtuzumab, and ocrelizumab). The researchers considered dimethyl fumarate, fingolimod, teriflunomide, natalizumab, rituximab, ocrelizumab, alemtuzumab, and daclizumab to be newer therapies.

The cohort included more than 1,000 patients with MS or CIS. In all, 618 patients had received a DMT before age 18 (587 patients with a diagnosis of MS at last follow-up and 31 patients with a diagnosis of CIS at last follow-up). About 66% were female, and patients’ mean age at MS onset was approximately 13.

The Use of Oral and IV DMTs

From 2008 to 2017, use of newer oral and IV DMTs increased overall and as first-line therapy in patients younger than 12 and in patients 12 or older. Of the 618 patients who received a DMT before age 18, 259 (42%) received a newer DMT, and 104 (17%) received a newer DMT as a first-line therapy.

Newer DMTs used in patients before age 18 included natalizumab in 101 patients, dimethyl fumarate in 100 patients, rituximab in 57 patients, fingolimod in 37 patients, daclizumab in five patients, and teriflunomide in three patients. Newer DMTs used as first-line therapy in patients before age 18 included dimethyl fumarate in 36 patients, natalizumab in 30 patients, rituximab in 22 patients, fingolimod in 14 patients, and teriflunomide in two patients.

Patients were exposed to dimethyl fumarate for 149 person-years, natalizumab for 140 person-years, rituximab for 75 person-years, fingolimod for 55 person-years, daclizumab for 10 person-years, and teriflunomide for one person-year.

Randomized controlled trials of the efficacy of DMTs in children with MS are ongoing. Future studies may explore predictors of newer DMT use in children with MS, the researchers said.

—Jake Remaly

SAN DIEGO—Newer oral and IV disease-modifying therapies (DMTs) for multiple sclerosis (MS) increasingly are used in children, according to data presented at the ACTRIMS 2018 Forum. These DMTs often are second-line therapies, but some patients receive them as first-line treatment.

“Newer DMTs … are being started more often over time at clinics participating in the US Network of Pediatric MS Centers,” said Kristen M. Krysko, MD, Clinical Fellow at the University of California, San Francisco School of Medicine, and colleagues.

Treatment Challenges

About 5% of patients with MS develop symptoms before age 18. “Treatment of pediatric MS is challenging, given high relapse rates and the lack of safety and efficacy data for DMTs in children,” Dr. Krysko and colleagues said. “Conventionally, first-line treatments for pediatric MS include interferon beta and glatiramer acetate, but these agents may be poorly tolerated, since they are given by injection, and may not adequately control the disease. Those with breakthrough events require escalation to more potent agents, which are increasingly used off-label in pediatric MS despite limited data about safety or efficacy in children.”

To characterize the use and safety of newer DMTs in children with MS and clinically isolated syndrome (CIS), Dr. Krysko and colleagues conducted a retrospective cohort study of prospectively collected data at 12 clinics participating in the US Network of Pediatric MS Centers as of August 2017.

The researchers examined patterns of newer DMT use and newer DMT side effects. They classified DMTs as injectable (ie, glatiramer acetate and beta-interferons), oral (ie, dimethyl fumarate, fingolimod, and teriflunomide), or IV (ie, natalizumab, rituximab, alemtuzumab, and ocrelizumab). The researchers considered dimethyl fumarate, fingolimod, teriflunomide, natalizumab, rituximab, ocrelizumab, alemtuzumab, and daclizumab to be newer therapies.

The cohort included more than 1,000 patients with MS or CIS. In all, 618 patients had received a DMT before age 18 (587 patients with a diagnosis of MS at last follow-up and 31 patients with a diagnosis of CIS at last follow-up). About 66% were female, and patients’ mean age at MS onset was approximately 13.

The Use of Oral and IV DMTs

From 2008 to 2017, use of newer oral and IV DMTs increased overall and as first-line therapy in patients younger than 12 and in patients 12 or older. Of the 618 patients who received a DMT before age 18, 259 (42%) received a newer DMT, and 104 (17%) received a newer DMT as a first-line therapy.

Newer DMTs used in patients before age 18 included natalizumab in 101 patients, dimethyl fumarate in 100 patients, rituximab in 57 patients, fingolimod in 37 patients, daclizumab in five patients, and teriflunomide in three patients. Newer DMTs used as first-line therapy in patients before age 18 included dimethyl fumarate in 36 patients, natalizumab in 30 patients, rituximab in 22 patients, fingolimod in 14 patients, and teriflunomide in two patients.

Patients were exposed to dimethyl fumarate for 149 person-years, natalizumab for 140 person-years, rituximab for 75 person-years, fingolimod for 55 person-years, daclizumab for 10 person-years, and teriflunomide for one person-year.

Randomized controlled trials of the efficacy of DMTs in children with MS are ongoing. Future studies may explore predictors of newer DMT use in children with MS, the researchers said.

—Jake Remaly

SAN DIEGO—Newer oral and IV disease-modifying therapies (DMTs) for multiple sclerosis (MS) increasingly are used in children, according to data presented at the ACTRIMS 2018 Forum. These DMTs often are second-line therapies, but some patients receive them as first-line treatment.

“Newer DMTs … are being started more often over time at clinics participating in the US Network of Pediatric MS Centers,” said Kristen M. Krysko, MD, Clinical Fellow at the University of California, San Francisco School of Medicine, and colleagues.

Treatment Challenges

About 5% of patients with MS develop symptoms before age 18. “Treatment of pediatric MS is challenging, given high relapse rates and the lack of safety and efficacy data for DMTs in children,” Dr. Krysko and colleagues said. “Conventionally, first-line treatments for pediatric MS include interferon beta and glatiramer acetate, but these agents may be poorly tolerated, since they are given by injection, and may not adequately control the disease. Those with breakthrough events require escalation to more potent agents, which are increasingly used off-label in pediatric MS despite limited data about safety or efficacy in children.”

To characterize the use and safety of newer DMTs in children with MS and clinically isolated syndrome (CIS), Dr. Krysko and colleagues conducted a retrospective cohort study of prospectively collected data at 12 clinics participating in the US Network of Pediatric MS Centers as of August 2017.

The researchers examined patterns of newer DMT use and newer DMT side effects. They classified DMTs as injectable (ie, glatiramer acetate and beta-interferons), oral (ie, dimethyl fumarate, fingolimod, and teriflunomide), or IV (ie, natalizumab, rituximab, alemtuzumab, and ocrelizumab). The researchers considered dimethyl fumarate, fingolimod, teriflunomide, natalizumab, rituximab, ocrelizumab, alemtuzumab, and daclizumab to be newer therapies.

The cohort included more than 1,000 patients with MS or CIS. In all, 618 patients had received a DMT before age 18 (587 patients with a diagnosis of MS at last follow-up and 31 patients with a diagnosis of CIS at last follow-up). About 66% were female, and patients’ mean age at MS onset was approximately 13.

The Use of Oral and IV DMTs

From 2008 to 2017, use of newer oral and IV DMTs increased overall and as first-line therapy in patients younger than 12 and in patients 12 or older. Of the 618 patients who received a DMT before age 18, 259 (42%) received a newer DMT, and 104 (17%) received a newer DMT as a first-line therapy.

Newer DMTs used in patients before age 18 included natalizumab in 101 patients, dimethyl fumarate in 100 patients, rituximab in 57 patients, fingolimod in 37 patients, daclizumab in five patients, and teriflunomide in three patients. Newer DMTs used as first-line therapy in patients before age 18 included dimethyl fumarate in 36 patients, natalizumab in 30 patients, rituximab in 22 patients, fingolimod in 14 patients, and teriflunomide in two patients.

Patients were exposed to dimethyl fumarate for 149 person-years, natalizumab for 140 person-years, rituximab for 75 person-years, fingolimod for 55 person-years, daclizumab for 10 person-years, and teriflunomide for one person-year.

Randomized controlled trials of the efficacy of DMTs in children with MS are ongoing. Future studies may explore predictors of newer DMT use in children with MS, the researchers said.

—Jake Remaly

SAN DIEGO—Continuous collection of patient-reported outcomes via a web-based platform may help neurologists identify patients with multiple sclerosis (MS) with active disease who would benefit from additional care coordination, according to a study described at the ACTRIMS 2018 Forum.

MS has a “variable and unpredictable disease course,” said Alexis Ahmad, Director of Clinical Trials for the Georgetown University Department of Neurology in Washington, DC, and colleagues. “Given the chronic and complex nature of MS, patients living with this disease require continuous and specialized care.”

The MS and Neuroimmunology Center at Georgetown University aims to become the first MS center recognized as a Patient-Centered Specialty Practice by the National Committee for Quality Assurance.

To assess whether a web-based platform to capture patient-reported outcomes can help MS practices meet Patient-Centered Specialty Practice standards and achieve MS care goals, the researchers analyzed patient responses in their center’s MS-Advance Study. The MS-Advance Study includes patients from the practice who use a web-based platform to relay patient-reported outcomes in between and at clinic visits.

Patients completed scales and questionnaires at baseline (eg, Modified Fatigue Impact Scale, Patient Health Questionnaire-9, Work Productivity and Activity Improvement Questionnaire, and Treatment Satisfaction Questionnaire for Medication) and journal entries about relapses, mood, energy, nutrition, sleep, and health service or resource utilization. The investigators analyzed responses from patients who completed at least one patient-reported outcome or journal entry between January and August 2017.

Five hundred twenty patients agreed to report outcomes using the online platform; 310 patients completed one or more patient-reported outcome or journal entry. In all, 259 patients reported daily MS symptoms; 212 patients reported three or more daily MS symptoms. The five most common daily symptoms were fatigue, numbness or tingling, leg or foot weakness, poor balance, and muscle tightness or stiffening. In addition, 257 patients reported a relapse in the last year. Using the online journal, six patients reported being “severely limited” in their ability to carry out their usual activities.

“It is challenging for providers and clinicians to incorporate routine review of patient-reported outcomes into their clinic schedules,” the researchers noted. Strategies for reviewing patient-reported outcomes in clinic and eliciting more complete and timely patient reports are warranted, they said.

“Use of an online platform provides an opportunity to learn about patients’ daily experiences. Understanding these experiences can inform care strategies to address total functionality and other clinical outcomes.”

—Jake Remaly

SAN DIEGO—Continuous collection of patient-reported outcomes via a web-based platform may help neurologists identify patients with multiple sclerosis (MS) with active disease who would benefit from additional care coordination, according to a study described at the ACTRIMS 2018 Forum.

MS has a “variable and unpredictable disease course,” said Alexis Ahmad, Director of Clinical Trials for the Georgetown University Department of Neurology in Washington, DC, and colleagues. “Given the chronic and complex nature of MS, patients living with this disease require continuous and specialized care.”

The MS and Neuroimmunology Center at Georgetown University aims to become the first MS center recognized as a Patient-Centered Specialty Practice by the National Committee for Quality Assurance.

To assess whether a web-based platform to capture patient-reported outcomes can help MS practices meet Patient-Centered Specialty Practice standards and achieve MS care goals, the researchers analyzed patient responses in their center’s MS-Advance Study. The MS-Advance Study includes patients from the practice who use a web-based platform to relay patient-reported outcomes in between and at clinic visits.

Patients completed scales and questionnaires at baseline (eg, Modified Fatigue Impact Scale, Patient Health Questionnaire-9, Work Productivity and Activity Improvement Questionnaire, and Treatment Satisfaction Questionnaire for Medication) and journal entries about relapses, mood, energy, nutrition, sleep, and health service or resource utilization. The investigators analyzed responses from patients who completed at least one patient-reported outcome or journal entry between January and August 2017.

Five hundred twenty patients agreed to report outcomes using the online platform; 310 patients completed one or more patient-reported outcome or journal entry. In all, 259 patients reported daily MS symptoms; 212 patients reported three or more daily MS symptoms. The five most common daily symptoms were fatigue, numbness or tingling, leg or foot weakness, poor balance, and muscle tightness or stiffening. In addition, 257 patients reported a relapse in the last year. Using the online journal, six patients reported being “severely limited” in their ability to carry out their usual activities.

“It is challenging for providers and clinicians to incorporate routine review of patient-reported outcomes into their clinic schedules,” the researchers noted. Strategies for reviewing patient-reported outcomes in clinic and eliciting more complete and timely patient reports are warranted, they said.

“Use of an online platform provides an opportunity to learn about patients’ daily experiences. Understanding these experiences can inform care strategies to address total functionality and other clinical outcomes.”

—Jake Remaly

SAN DIEGO—Continuous collection of patient-reported outcomes via a web-based platform may help neurologists identify patients with multiple sclerosis (MS) with active disease who would benefit from additional care coordination, according to a study described at the ACTRIMS 2018 Forum.

MS has a “variable and unpredictable disease course,” said Alexis Ahmad, Director of Clinical Trials for the Georgetown University Department of Neurology in Washington, DC, and colleagues. “Given the chronic and complex nature of MS, patients living with this disease require continuous and specialized care.”

The MS and Neuroimmunology Center at Georgetown University aims to become the first MS center recognized as a Patient-Centered Specialty Practice by the National Committee for Quality Assurance.

To assess whether a web-based platform to capture patient-reported outcomes can help MS practices meet Patient-Centered Specialty Practice standards and achieve MS care goals, the researchers analyzed patient responses in their center’s MS-Advance Study. The MS-Advance Study includes patients from the practice who use a web-based platform to relay patient-reported outcomes in between and at clinic visits.

Patients completed scales and questionnaires at baseline (eg, Modified Fatigue Impact Scale, Patient Health Questionnaire-9, Work Productivity and Activity Improvement Questionnaire, and Treatment Satisfaction Questionnaire for Medication) and journal entries about relapses, mood, energy, nutrition, sleep, and health service or resource utilization. The investigators analyzed responses from patients who completed at least one patient-reported outcome or journal entry between January and August 2017.

Five hundred twenty patients agreed to report outcomes using the online platform; 310 patients completed one or more patient-reported outcome or journal entry. In all, 259 patients reported daily MS symptoms; 212 patients reported three or more daily MS symptoms. The five most common daily symptoms were fatigue, numbness or tingling, leg or foot weakness, poor balance, and muscle tightness or stiffening. In addition, 257 patients reported a relapse in the last year. Using the online journal, six patients reported being “severely limited” in their ability to carry out their usual activities.

“It is challenging for providers and clinicians to incorporate routine review of patient-reported outcomes into their clinic schedules,” the researchers noted. Strategies for reviewing patient-reported outcomes in clinic and eliciting more complete and timely patient reports are warranted, they said.

“Use of an online platform provides an opportunity to learn about patients’ daily experiences. Understanding these experiences can inform care strategies to address total functionality and other clinical outcomes.”

—Jake Remaly

SAN DIEGO—In the five years before multiple sclerosis (MS) symptom onset, patients are more likely to see a physician or be admitted to the hospital for problems related to the nervous system, sensory organs, musculoskeletal system, and genitourinary system, compared with controls, according to research presented at the ACTRIMS 2018 Forum.

In addition, patients with MS are more likely to see psychiatrists and urologists and to fill prescriptions related to the musculoskeletal system or the genitourinary system in the five years before MS onset.

“It is possible to measure and phenotype the MS prodrome five years before the clinical recognition of MS,” said Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues. “Our findings inform the etiologically relevant time window and suggest that an earlier recognition and diagnosis of MS is feasible.”

Phenotypic Characteristics

To investigate the phenotypic characteristics of the MS prodrome, Dr. Kingwell and colleagues examined the medical diagnoses and therapeutic drug classes related to inpatient and outpatient health care encounters five years before the clinical recognition of MS. The researchers performed a population-based matched cohort study using linked health administrative and clinical data in four Canadian provinces between 1989 and 2014.

The investigators compared the reasons for physician and hospital encounters, using ICD-10 chapters or physician specialty, and prescriptions filled, using Anatomical Therapeutic Chemical System, level 1 drug classes. The researchers matched people with MS with as many as five people without any demyelinating disease by sex, year of birth, and postal code.

The study included two cohorts of people with MS. One cohort encompassed patients with a first demyelinating disease–related claim (ie, the administrative cohort), and the other cohort comprised patients with a neurologist-confirmed diagnosis of MS (ie, the clinical cohort). The researchers compared inpatient and outpatient encounters between cases and controls in the five years before the cases’ first demyelinating claim or clinically reported symptom onset.

Fewer Pregnancy-Related Encounters

The administrative cohort included 13,951 cases and 66,940 controls (about 73% women; average age, 43). The clinical cohort included 3,202 cases and 16,006 controls (about 74% women; average age, 36.5). Compared with controls, in the five years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous system (rate ratio [RR] = 1.70–4.75), sensory organs (RR = 1.40–2.28), musculoskeletal system (RR = 1.19–1.70), and genitourinary system (RR = 1.17–1.59). Cases also had more encounters with psychiatrists (RR = 1.48–1.66) and urologists (RR = 1.49–1.80), and a higher proportion of filled prescriptions for hormonal preparations and for drugs related to the musculoskeletal or genitourinary systems (1.1–1.5 times higher). In contrast, cases had fewer pregnancy-related encounters, compared with controls (RR = 0.78–0.88).

“Research into factors that might cause or prevent MS should take the MS prodrome into account,” the researchers said.

—Jake Remaly

Suggested Reading

Wijnands JMA, Kingwell E, Zhu F, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 2017;16(6):445-451.

SAN DIEGO—In the five years before multiple sclerosis (MS) symptom onset, patients are more likely to see a physician or be admitted to the hospital for problems related to the nervous system, sensory organs, musculoskeletal system, and genitourinary system, compared with controls, according to research presented at the ACTRIMS 2018 Forum.

In addition, patients with MS are more likely to see psychiatrists and urologists and to fill prescriptions related to the musculoskeletal system or the genitourinary system in the five years before MS onset.

“It is possible to measure and phenotype the MS prodrome five years before the clinical recognition of MS,” said Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues. “Our findings inform the etiologically relevant time window and suggest that an earlier recognition and diagnosis of MS is feasible.”

Phenotypic Characteristics

To investigate the phenotypic characteristics of the MS prodrome, Dr. Kingwell and colleagues examined the medical diagnoses and therapeutic drug classes related to inpatient and outpatient health care encounters five years before the clinical recognition of MS. The researchers performed a population-based matched cohort study using linked health administrative and clinical data in four Canadian provinces between 1989 and 2014.

The investigators compared the reasons for physician and hospital encounters, using ICD-10 chapters or physician specialty, and prescriptions filled, using Anatomical Therapeutic Chemical System, level 1 drug classes. The researchers matched people with MS with as many as five people without any demyelinating disease by sex, year of birth, and postal code.

The study included two cohorts of people with MS. One cohort encompassed patients with a first demyelinating disease–related claim (ie, the administrative cohort), and the other cohort comprised patients with a neurologist-confirmed diagnosis of MS (ie, the clinical cohort). The researchers compared inpatient and outpatient encounters between cases and controls in the five years before the cases’ first demyelinating claim or clinically reported symptom onset.

Fewer Pregnancy-Related Encounters

The administrative cohort included 13,951 cases and 66,940 controls (about 73% women; average age, 43). The clinical cohort included 3,202 cases and 16,006 controls (about 74% women; average age, 36.5). Compared with controls, in the five years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous system (rate ratio [RR] = 1.70–4.75), sensory organs (RR = 1.40–2.28), musculoskeletal system (RR = 1.19–1.70), and genitourinary system (RR = 1.17–1.59). Cases also had more encounters with psychiatrists (RR = 1.48–1.66) and urologists (RR = 1.49–1.80), and a higher proportion of filled prescriptions for hormonal preparations and for drugs related to the musculoskeletal or genitourinary systems (1.1–1.5 times higher). In contrast, cases had fewer pregnancy-related encounters, compared with controls (RR = 0.78–0.88).

“Research into factors that might cause or prevent MS should take the MS prodrome into account,” the researchers said.

—Jake Remaly

Suggested Reading

Wijnands JMA, Kingwell E, Zhu F, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 2017;16(6):445-451.

SAN DIEGO—In the five years before multiple sclerosis (MS) symptom onset, patients are more likely to see a physician or be admitted to the hospital for problems related to the nervous system, sensory organs, musculoskeletal system, and genitourinary system, compared with controls, according to research presented at the ACTRIMS 2018 Forum.

In addition, patients with MS are more likely to see psychiatrists and urologists and to fill prescriptions related to the musculoskeletal system or the genitourinary system in the five years before MS onset.

“It is possible to measure and phenotype the MS prodrome five years before the clinical recognition of MS,” said Elaine Kingwell, PhD, a research associate in the Division of Neurology at the University of British Columbia in Vancouver, and colleagues. “Our findings inform the etiologically relevant time window and suggest that an earlier recognition and diagnosis of MS is feasible.”

Phenotypic Characteristics

To investigate the phenotypic characteristics of the MS prodrome, Dr. Kingwell and colleagues examined the medical diagnoses and therapeutic drug classes related to inpatient and outpatient health care encounters five years before the clinical recognition of MS. The researchers performed a population-based matched cohort study using linked health administrative and clinical data in four Canadian provinces between 1989 and 2014.

The investigators compared the reasons for physician and hospital encounters, using ICD-10 chapters or physician specialty, and prescriptions filled, using Anatomical Therapeutic Chemical System, level 1 drug classes. The researchers matched people with MS with as many as five people without any demyelinating disease by sex, year of birth, and postal code.

The study included two cohorts of people with MS. One cohort encompassed patients with a first demyelinating disease–related claim (ie, the administrative cohort), and the other cohort comprised patients with a neurologist-confirmed diagnosis of MS (ie, the clinical cohort). The researchers compared inpatient and outpatient encounters between cases and controls in the five years before the cases’ first demyelinating claim or clinically reported symptom onset.

Fewer Pregnancy-Related Encounters

The administrative cohort included 13,951 cases and 66,940 controls (about 73% women; average age, 43). The clinical cohort included 3,202 cases and 16,006 controls (about 74% women; average age, 36.5). Compared with controls, in the five years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous system (rate ratio [RR] = 1.70–4.75), sensory organs (RR = 1.40–2.28), musculoskeletal system (RR = 1.19–1.70), and genitourinary system (RR = 1.17–1.59). Cases also had more encounters with psychiatrists (RR = 1.48–1.66) and urologists (RR = 1.49–1.80), and a higher proportion of filled prescriptions for hormonal preparations and for drugs related to the musculoskeletal or genitourinary systems (1.1–1.5 times higher). In contrast, cases had fewer pregnancy-related encounters, compared with controls (RR = 0.78–0.88).

“Research into factors that might cause or prevent MS should take the MS prodrome into account,” the researchers said.

—Jake Remaly

Suggested Reading

Wijnands JMA, Kingwell E, Zhu F, et al. Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study. Lancet Neurol. 2017;16(6):445-451.

SAN DIEGO – Baseline Expanded Disability Status Scale scores and number of relapses during the first year were the most consistent predictors of disability worsening or relapses over the subsequent 3 years in long-term analysis of three phase 3 fingolimod trials.

Those patients identified at higher risk for worse long-term clinical outcomes could benefit from an early review of multiple sclerosis (MS) treatment regimens to help prevent worsening disability, Pavle Repovic, MD, PhD, said in an interview.

Damian McNamara/Frontline Medical News

“The idea for some time now has been to figure out what will tell whether a patient is responding to a therapy early on or not,” Dr. Repovic said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

To explore long-term clinical predictors of disability progression and relapse risk, Dr. Repovic and his colleagues analyzed three phase 3 trials assessing fingolimod (Gilenya). They evaluated parameters at baseline and during the first year of the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

SOURCE: Repovic P et al. Abstract P210.

SAN DIEGO – Baseline Expanded Disability Status Scale scores and number of relapses during the first year were the most consistent predictors of disability worsening or relapses over the subsequent 3 years in long-term analysis of three phase 3 fingolimod trials.

Those patients identified at higher risk for worse long-term clinical outcomes could benefit from an early review of multiple sclerosis (MS) treatment regimens to help prevent worsening disability, Pavle Repovic, MD, PhD, said in an interview.

Damian McNamara/Frontline Medical News

“The idea for some time now has been to figure out what will tell whether a patient is responding to a therapy early on or not,” Dr. Repovic said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

To explore long-term clinical predictors of disability progression and relapse risk, Dr. Repovic and his colleagues analyzed three phase 3 trials assessing fingolimod (Gilenya). They evaluated parameters at baseline and during the first year of the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

SOURCE: Repovic P et al. Abstract P210.

SAN DIEGO – Baseline Expanded Disability Status Scale scores and number of relapses during the first year were the most consistent predictors of disability worsening or relapses over the subsequent 3 years in long-term analysis of three phase 3 fingolimod trials.

Those patients identified at higher risk for worse long-term clinical outcomes could benefit from an early review of multiple sclerosis (MS) treatment regimens to help prevent worsening disability, Pavle Repovic, MD, PhD, said in an interview.

Damian McNamara/Frontline Medical News

“The idea for some time now has been to figure out what will tell whether a patient is responding to a therapy early on or not,” Dr. Repovic said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

To explore long-term clinical predictors of disability progression and relapse risk, Dr. Repovic and his colleagues analyzed three phase 3 trials assessing fingolimod (Gilenya). They evaluated parameters at baseline and during the first year of the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

SOURCE: Repovic P et al. Abstract P210.