Multiple Sclerosis Hub

BARCELONA—Anti-LINGO-1 improved full-field visual evoked potential (FF-VEP) latency of the eye affected by acute optic neuritis relative to placebo, consistent with improved remyelination, according to a study reported at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). This latency recovery was greater in older subjects, subjects given the first dose earlier, and subjects with more severe pretreatment visual impairment.

In a primary efficacy analysis of the RENEW study, Orhan Aktas, MD, of Heinrich-Heine-Universität in Düsseldorf, Germany, and colleagues demonstrated an improvement versus placebo in optic nerve latency (-7.55 ms at week 24; -9.13 ms at week 32) consistent with remyelination in subjects with acute optic neuritis.

Research subjects ages 18 to 50 with a first unilateral acute optic neuritis episode were treated with high-dose steroids, then randomized to 100 mg/kg anti-LINGO-1 IV or placebo once every four weeks (ie, six doses) and followed to week 32. Optic nerve latency was measured using FF-VEP in the affected eye versus the baseline value for the unaffected eye. Between-treatment comparisons were evaluated by ANCOVA in the per-protocol population, defined as subjects who completed the study and did not miss more than one study dose or receive disease-modifying therapy for multiple sclerosis. Further analyses of latency recovery at week 24 (affected eye FF-VEP latency ≤10% worse than baseline of fellow eye) and efficacy stratified by prespecified baseline characteristics using the median as the cutoff were performed.

FF-VEP latency recovery in the affected eye versus baseline of the fellow eye was compared between 33 subjects who received anti-LINGO-1 and 36 treated with placebo. At week 24, 24 subjects had normal or mildly prolonged FF-VEP latency, 15 from the anti-LINGO-1 and nine from the placebo group. Assessment of subjects stratified by prespecified baseline characteristics showed that improvement in FF-VEP latency in the affected eye at week 24 with anti-LINGO-1 was greater in the following patient subgroups: age 33 or older (difference vs placebo, -14.17 ms compared with -0.89 ms in subjects younger than 33); those who received treatment less than 25 days from the onset of acute optic neuritis (-9.01 ms vs -6.68 ms for those receiving treatment more than 25 days after acute optic neuritis onset); and those who had a high-contrast visual acuity score less than 49 (-10.92 ms vs -4.14 ms for a score of 49 or more). None of the subgroup-by-treatment interactions reached statistical significance due to the small sample size.

BARCELONA—Anti-LINGO-1 improved full-field visual evoked potential (FF-VEP) latency of the eye affected by acute optic neuritis relative to placebo, consistent with improved remyelination, according to a study reported at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). This latency recovery was greater in older subjects, subjects given the first dose earlier, and subjects with more severe pretreatment visual impairment.

In a primary efficacy analysis of the RENEW study, Orhan Aktas, MD, of Heinrich-Heine-Universität in Düsseldorf, Germany, and colleagues demonstrated an improvement versus placebo in optic nerve latency (-7.55 ms at week 24; -9.13 ms at week 32) consistent with remyelination in subjects with acute optic neuritis.

Research subjects ages 18 to 50 with a first unilateral acute optic neuritis episode were treated with high-dose steroids, then randomized to 100 mg/kg anti-LINGO-1 IV or placebo once every four weeks (ie, six doses) and followed to week 32. Optic nerve latency was measured using FF-VEP in the affected eye versus the baseline value for the unaffected eye. Between-treatment comparisons were evaluated by ANCOVA in the per-protocol population, defined as subjects who completed the study and did not miss more than one study dose or receive disease-modifying therapy for multiple sclerosis. Further analyses of latency recovery at week 24 (affected eye FF-VEP latency ≤10% worse than baseline of fellow eye) and efficacy stratified by prespecified baseline characteristics using the median as the cutoff were performed.

FF-VEP latency recovery in the affected eye versus baseline of the fellow eye was compared between 33 subjects who received anti-LINGO-1 and 36 treated with placebo. At week 24, 24 subjects had normal or mildly prolonged FF-VEP latency, 15 from the anti-LINGO-1 and nine from the placebo group. Assessment of subjects stratified by prespecified baseline characteristics showed that improvement in FF-VEP latency in the affected eye at week 24 with anti-LINGO-1 was greater in the following patient subgroups: age 33 or older (difference vs placebo, -14.17 ms compared with -0.89 ms in subjects younger than 33); those who received treatment less than 25 days from the onset of acute optic neuritis (-9.01 ms vs -6.68 ms for those receiving treatment more than 25 days after acute optic neuritis onset); and those who had a high-contrast visual acuity score less than 49 (-10.92 ms vs -4.14 ms for a score of 49 or more). None of the subgroup-by-treatment interactions reached statistical significance due to the small sample size.

BARCELONA—Anti-LINGO-1 improved full-field visual evoked potential (FF-VEP) latency of the eye affected by acute optic neuritis relative to placebo, consistent with improved remyelination, according to a study reported at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). This latency recovery was greater in older subjects, subjects given the first dose earlier, and subjects with more severe pretreatment visual impairment.

In a primary efficacy analysis of the RENEW study, Orhan Aktas, MD, of Heinrich-Heine-Universität in Düsseldorf, Germany, and colleagues demonstrated an improvement versus placebo in optic nerve latency (-7.55 ms at week 24; -9.13 ms at week 32) consistent with remyelination in subjects with acute optic neuritis.

Research subjects ages 18 to 50 with a first unilateral acute optic neuritis episode were treated with high-dose steroids, then randomized to 100 mg/kg anti-LINGO-1 IV or placebo once every four weeks (ie, six doses) and followed to week 32. Optic nerve latency was measured using FF-VEP in the affected eye versus the baseline value for the unaffected eye. Between-treatment comparisons were evaluated by ANCOVA in the per-protocol population, defined as subjects who completed the study and did not miss more than one study dose or receive disease-modifying therapy for multiple sclerosis. Further analyses of latency recovery at week 24 (affected eye FF-VEP latency ≤10% worse than baseline of fellow eye) and efficacy stratified by prespecified baseline characteristics using the median as the cutoff were performed.

FF-VEP latency recovery in the affected eye versus baseline of the fellow eye was compared between 33 subjects who received anti-LINGO-1 and 36 treated with placebo. At week 24, 24 subjects had normal or mildly prolonged FF-VEP latency, 15 from the anti-LINGO-1 and nine from the placebo group. Assessment of subjects stratified by prespecified baseline characteristics showed that improvement in FF-VEP latency in the affected eye at week 24 with anti-LINGO-1 was greater in the following patient subgroups: age 33 or older (difference vs placebo, -14.17 ms compared with -0.89 ms in subjects younger than 33); those who received treatment less than 25 days from the onset of acute optic neuritis (-9.01 ms vs -6.68 ms for those receiving treatment more than 25 days after acute optic neuritis onset); and those who had a high-contrast visual acuity score less than 49 (-10.92 ms vs -4.14 ms for a score of 49 or more). None of the subgroup-by-treatment interactions reached statistical significance due to the small sample size.

BARCELONA—Long-term treatment with delayed-release dimethyl fumarate demonstrated strong and sustained effects on relapses and disability progression among patients newly diagnosed with relapsing-remitting multiple sclerosis (MS), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Delayed-release dimethyl fumarate demonstrated efficacy and safety in patients with relapsing-remitting MS in the phase III DEFINE and CONFIRM studies. ENDORSE is an eight-year extension of DEFINE and CONFIRM. In an integrated analysis of the DEFINE, CONFIRM, and ENDORSE trials, Jing Marantz, MD, PhD, and colleagues reported six-year outcomes with delayed-release dimethyl fumarate in newly diagnosed patients with relapsing-remitting MS.

Five-Year Data
In ENDORSE, patients randomized in DEFINE or CONFIRM to delayed-release dimethyl fumarate 240 mg bid or tid continued on the same dosage. Patients randomized to placebo or glatiramer acetate (CONFIRM only) were re-randomized 1:1 to delayed-release dimethyl fumarate bid or tid. Results for the 240 mg bid dose were reported in the integrated analysis, as this represents the approved dosage. The glatiramer acetate arm was excluded from the parent analysis of newly diagnosed patients in DEFINE or CONFIRM.

“Newly diagnosed” was defined as MS diagnosis within one year prior to parent study entry and patients were either treatment-naïve or previously treated with corticosteroids alone. Minimum follow-up (data as of May 14, 2014) was approximately five years; patients who received active treatment bid in previous studies (bid/bid) remaining on study received approximately five years or more of continuous delayed-release dimethyl fumarate treatment; patients receiving placebo bid remaining on study received two years of placebo in DEFINE or CONFIRM, followed by approximately three years of delayed-release dimethyl fumarate in the ENDORSE trial (delayed treatment).

The newly diagnosed population included 144 bid and 85 placebo bid patients. At five years (ENDORSE Year 3), the annualized relapse rate in the newly diagnosed population was 0.137 in the bid patient group and 0.169 in the placebo bid group. Although the annualized relapse rate at five years was lower in the bid patient group compared with those who received delayed treatment (placebo followed by delayed-release dimethyl fumarate bid), those patients who switched to active treatment demonstrated improvements after switching to delayed-release dimethyl fumarate in ENDORSE: annualized relapse rate was 0.244 from years zero to two (DEFINE and CONFIRM), and 0.102 from years three to five (ENDORSE). The Kaplan–Meier estimated proportion of patients with 24-week confirmed disability progression at five years was 8.1% in those who remained on bid dosing and 20.4% in those who switched from placebo to active treatment.

Six-Year Data
New long-term data from the six years of study—two years in DEFINE or CONFIRM followed by four years in the safety extension ENDORSE study—showed that the annualized relapse rate for the 144 newly diagnosed patients who started delayed-release dimethyl fumarate at the beginning of the study remained low (0.14). In those 85 patients who switched from placebo to active treatment, researchers saw that the annualized relapse rate was reduced from 0.26 during the placebo period to 0.1 in years three to six on delayed-release dimethyl fumarate treatment, which represents a 61% reduction. The proportion of patients with a 24-week confirmed disability after six years of treatment was 15.7%, compared with 24.3% in those who switched to active treatment in year three.

The overall risk/benefit profile of delayed-release dimethyl fumarate remained consistent across all patients treated up to six years. “Early initiation of delayed-release dimethyl fumarate therapy does confer a long-term benefit for patients,” the researchers concluded.

BARCELONA—Long-term treatment with delayed-release dimethyl fumarate demonstrated strong and sustained effects on relapses and disability progression among patients newly diagnosed with relapsing-remitting multiple sclerosis (MS), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Delayed-release dimethyl fumarate demonstrated efficacy and safety in patients with relapsing-remitting MS in the phase III DEFINE and CONFIRM studies. ENDORSE is an eight-year extension of DEFINE and CONFIRM. In an integrated analysis of the DEFINE, CONFIRM, and ENDORSE trials, Jing Marantz, MD, PhD, and colleagues reported six-year outcomes with delayed-release dimethyl fumarate in newly diagnosed patients with relapsing-remitting MS.

Five-Year Data
In ENDORSE, patients randomized in DEFINE or CONFIRM to delayed-release dimethyl fumarate 240 mg bid or tid continued on the same dosage. Patients randomized to placebo or glatiramer acetate (CONFIRM only) were re-randomized 1:1 to delayed-release dimethyl fumarate bid or tid. Results for the 240 mg bid dose were reported in the integrated analysis, as this represents the approved dosage. The glatiramer acetate arm was excluded from the parent analysis of newly diagnosed patients in DEFINE or CONFIRM.

“Newly diagnosed” was defined as MS diagnosis within one year prior to parent study entry and patients were either treatment-naïve or previously treated with corticosteroids alone. Minimum follow-up (data as of May 14, 2014) was approximately five years; patients who received active treatment bid in previous studies (bid/bid) remaining on study received approximately five years or more of continuous delayed-release dimethyl fumarate treatment; patients receiving placebo bid remaining on study received two years of placebo in DEFINE or CONFIRM, followed by approximately three years of delayed-release dimethyl fumarate in the ENDORSE trial (delayed treatment).

The newly diagnosed population included 144 bid and 85 placebo bid patients. At five years (ENDORSE Year 3), the annualized relapse rate in the newly diagnosed population was 0.137 in the bid patient group and 0.169 in the placebo bid group. Although the annualized relapse rate at five years was lower in the bid patient group compared with those who received delayed treatment (placebo followed by delayed-release dimethyl fumarate bid), those patients who switched to active treatment demonstrated improvements after switching to delayed-release dimethyl fumarate in ENDORSE: annualized relapse rate was 0.244 from years zero to two (DEFINE and CONFIRM), and 0.102 from years three to five (ENDORSE). The Kaplan–Meier estimated proportion of patients with 24-week confirmed disability progression at five years was 8.1% in those who remained on bid dosing and 20.4% in those who switched from placebo to active treatment.

Six-Year Data
New long-term data from the six years of study—two years in DEFINE or CONFIRM followed by four years in the safety extension ENDORSE study—showed that the annualized relapse rate for the 144 newly diagnosed patients who started delayed-release dimethyl fumarate at the beginning of the study remained low (0.14). In those 85 patients who switched from placebo to active treatment, researchers saw that the annualized relapse rate was reduced from 0.26 during the placebo period to 0.1 in years three to six on delayed-release dimethyl fumarate treatment, which represents a 61% reduction. The proportion of patients with a 24-week confirmed disability after six years of treatment was 15.7%, compared with 24.3% in those who switched to active treatment in year three.

The overall risk/benefit profile of delayed-release dimethyl fumarate remained consistent across all patients treated up to six years. “Early initiation of delayed-release dimethyl fumarate therapy does confer a long-term benefit for patients,” the researchers concluded.

BARCELONA—Long-term treatment with delayed-release dimethyl fumarate demonstrated strong and sustained effects on relapses and disability progression among patients newly diagnosed with relapsing-remitting multiple sclerosis (MS), according to data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Delayed-release dimethyl fumarate demonstrated efficacy and safety in patients with relapsing-remitting MS in the phase III DEFINE and CONFIRM studies. ENDORSE is an eight-year extension of DEFINE and CONFIRM. In an integrated analysis of the DEFINE, CONFIRM, and ENDORSE trials, Jing Marantz, MD, PhD, and colleagues reported six-year outcomes with delayed-release dimethyl fumarate in newly diagnosed patients with relapsing-remitting MS.

Five-Year Data
In ENDORSE, patients randomized in DEFINE or CONFIRM to delayed-release dimethyl fumarate 240 mg bid or tid continued on the same dosage. Patients randomized to placebo or glatiramer acetate (CONFIRM only) were re-randomized 1:1 to delayed-release dimethyl fumarate bid or tid. Results for the 240 mg bid dose were reported in the integrated analysis, as this represents the approved dosage. The glatiramer acetate arm was excluded from the parent analysis of newly diagnosed patients in DEFINE or CONFIRM.

“Newly diagnosed” was defined as MS diagnosis within one year prior to parent study entry and patients were either treatment-naïve or previously treated with corticosteroids alone. Minimum follow-up (data as of May 14, 2014) was approximately five years; patients who received active treatment bid in previous studies (bid/bid) remaining on study received approximately five years or more of continuous delayed-release dimethyl fumarate treatment; patients receiving placebo bid remaining on study received two years of placebo in DEFINE or CONFIRM, followed by approximately three years of delayed-release dimethyl fumarate in the ENDORSE trial (delayed treatment).

The newly diagnosed population included 144 bid and 85 placebo bid patients. At five years (ENDORSE Year 3), the annualized relapse rate in the newly diagnosed population was 0.137 in the bid patient group and 0.169 in the placebo bid group. Although the annualized relapse rate at five years was lower in the bid patient group compared with those who received delayed treatment (placebo followed by delayed-release dimethyl fumarate bid), those patients who switched to active treatment demonstrated improvements after switching to delayed-release dimethyl fumarate in ENDORSE: annualized relapse rate was 0.244 from years zero to two (DEFINE and CONFIRM), and 0.102 from years three to five (ENDORSE). The Kaplan–Meier estimated proportion of patients with 24-week confirmed disability progression at five years was 8.1% in those who remained on bid dosing and 20.4% in those who switched from placebo to active treatment.

Six-Year Data
New long-term data from the six years of study—two years in DEFINE or CONFIRM followed by four years in the safety extension ENDORSE study—showed that the annualized relapse rate for the 144 newly diagnosed patients who started delayed-release dimethyl fumarate at the beginning of the study remained low (0.14). In those 85 patients who switched from placebo to active treatment, researchers saw that the annualized relapse rate was reduced from 0.26 during the placebo period to 0.1 in years three to six on delayed-release dimethyl fumarate treatment, which represents a 61% reduction. The proportion of patients with a 24-week confirmed disability after six years of treatment was 15.7%, compared with 24.3% in those who switched to active treatment in year three.

The overall risk/benefit profile of delayed-release dimethyl fumarate remained consistent across all patients treated up to six years. “Early initiation of delayed-release dimethyl fumarate therapy does confer a long-term benefit for patients,” the researchers concluded.

BARCELONA—Prolonged-release fampridine improves objective and subjective measures of walking in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The drug also may improve patients’ quality of life.

Rachel Farrell, PhD, a consultant at the National Hospital for Neurology and Neurosurgery in London, and colleagues enrolled 133 patients (93 females) with MS and severe walking impairment into a study to examine the long-term efficacy of prolonged-release fampridine on walking, quality of life, and functional ability when used in routine clinical practice. Participants were examined by neurologists and specialist physiotherapists in a specialist ambulation clinic. Study outcomes included Timed 25-Foot Walk (T25FW), MS Walking Scale (MSWS-12), the EuroQol 5-dimension instrument (EQ-5D-5L), functional goals of treatment, and walking aid use. Patients whose T25FW speed increased by 20% or more from baseline and whose MSWS-12 scores also improved were considered responders.

Participants’ mean Expanded Disability Status Scale score at baseline was 6.41. In all, 105 patients achieved responder status at two weeks. Mean baseline T25FW speed was 0.822 ft/s for responders and 0.934 ft/s for nonresponders.

At two weeks, mean T25FW speed improved by 83.3% from baseline in the responder group, compared with a deterioration of 2.73% among nonresponders. Responders continued to walk faster at 22 months (0.920 ft/s) than at baseline. The researchers also observed significant improvements in the MSWS-12 among responders (-21.7), but not among nonresponders (+5.7).

In addition, the EQ-5D-5L index improved significantly among responders (+0.114), compared with nonresponders (-0.046). Responders reported more anxiety or depression on EQ-5L-5D at baseline than nonresponders, but scored better on the other four domains of the index. After four months, 79% of patients had achieved their goals (eg, walking to the corner shop, reducing falls, increasing social activities, or doing housework). After 10 months, 55% of patients had maintained their goals, and a further 38% had achieved their goals.

The majority of patients required the same walking aids at the end of the study period. A total of 17 patients required fewer aids, and three patients required more assistance. “This [result] suggests that prolonged-release fampridine responders perform better functionally for up to 22 months of treatment,” said Dr. Farrell.

Side effects reported in the study were the same as those described in phase III and IV trials of fampridine. They included insomnia, urinary tract infections, gastrointestinal side effects, dizziness, and headaches.

“This cohort has a higher responder rate than that of pivotal trials. This [result] may be due to the severity of their walking impairment and the open-label nature of this study,” said Dr. Farrell. “This [finding] brings into question the current practice of using a 20% improvement as the threshold for clinical significance.” Overall, “the results of this study validate the utility of prolonged-release fampridine in improving walking of people with MS in routine clinical practice,” she concluded.

BARCELONA—Prolonged-release fampridine improves objective and subjective measures of walking in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The drug also may improve patients’ quality of life.

Rachel Farrell, PhD, a consultant at the National Hospital for Neurology and Neurosurgery in London, and colleagues enrolled 133 patients (93 females) with MS and severe walking impairment into a study to examine the long-term efficacy of prolonged-release fampridine on walking, quality of life, and functional ability when used in routine clinical practice. Participants were examined by neurologists and specialist physiotherapists in a specialist ambulation clinic. Study outcomes included Timed 25-Foot Walk (T25FW), MS Walking Scale (MSWS-12), the EuroQol 5-dimension instrument (EQ-5D-5L), functional goals of treatment, and walking aid use. Patients whose T25FW speed increased by 20% or more from baseline and whose MSWS-12 scores also improved were considered responders.

Participants’ mean Expanded Disability Status Scale score at baseline was 6.41. In all, 105 patients achieved responder status at two weeks. Mean baseline T25FW speed was 0.822 ft/s for responders and 0.934 ft/s for nonresponders.

At two weeks, mean T25FW speed improved by 83.3% from baseline in the responder group, compared with a deterioration of 2.73% among nonresponders. Responders continued to walk faster at 22 months (0.920 ft/s) than at baseline. The researchers also observed significant improvements in the MSWS-12 among responders (-21.7), but not among nonresponders (+5.7).

In addition, the EQ-5D-5L index improved significantly among responders (+0.114), compared with nonresponders (-0.046). Responders reported more anxiety or depression on EQ-5L-5D at baseline than nonresponders, but scored better on the other four domains of the index. After four months, 79% of patients had achieved their goals (eg, walking to the corner shop, reducing falls, increasing social activities, or doing housework). After 10 months, 55% of patients had maintained their goals, and a further 38% had achieved their goals.

The majority of patients required the same walking aids at the end of the study period. A total of 17 patients required fewer aids, and three patients required more assistance. “This [result] suggests that prolonged-release fampridine responders perform better functionally for up to 22 months of treatment,” said Dr. Farrell.

Side effects reported in the study were the same as those described in phase III and IV trials of fampridine. They included insomnia, urinary tract infections, gastrointestinal side effects, dizziness, and headaches.

“This cohort has a higher responder rate than that of pivotal trials. This [result] may be due to the severity of their walking impairment and the open-label nature of this study,” said Dr. Farrell. “This [finding] brings into question the current practice of using a 20% improvement as the threshold for clinical significance.” Overall, “the results of this study validate the utility of prolonged-release fampridine in improving walking of people with MS in routine clinical practice,” she concluded.

BARCELONA—Prolonged-release fampridine improves objective and subjective measures of walking in patients with multiple sclerosis (MS), according to research presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The drug also may improve patients’ quality of life.

Rachel Farrell, PhD, a consultant at the National Hospital for Neurology and Neurosurgery in London, and colleagues enrolled 133 patients (93 females) with MS and severe walking impairment into a study to examine the long-term efficacy of prolonged-release fampridine on walking, quality of life, and functional ability when used in routine clinical practice. Participants were examined by neurologists and specialist physiotherapists in a specialist ambulation clinic. Study outcomes included Timed 25-Foot Walk (T25FW), MS Walking Scale (MSWS-12), the EuroQol 5-dimension instrument (EQ-5D-5L), functional goals of treatment, and walking aid use. Patients whose T25FW speed increased by 20% or more from baseline and whose MSWS-12 scores also improved were considered responders.

Participants’ mean Expanded Disability Status Scale score at baseline was 6.41. In all, 105 patients achieved responder status at two weeks. Mean baseline T25FW speed was 0.822 ft/s for responders and 0.934 ft/s for nonresponders.

At two weeks, mean T25FW speed improved by 83.3% from baseline in the responder group, compared with a deterioration of 2.73% among nonresponders. Responders continued to walk faster at 22 months (0.920 ft/s) than at baseline. The researchers also observed significant improvements in the MSWS-12 among responders (-21.7), but not among nonresponders (+5.7).

In addition, the EQ-5D-5L index improved significantly among responders (+0.114), compared with nonresponders (-0.046). Responders reported more anxiety or depression on EQ-5L-5D at baseline than nonresponders, but scored better on the other four domains of the index. After four months, 79% of patients had achieved their goals (eg, walking to the corner shop, reducing falls, increasing social activities, or doing housework). After 10 months, 55% of patients had maintained their goals, and a further 38% had achieved their goals.

The majority of patients required the same walking aids at the end of the study period. A total of 17 patients required fewer aids, and three patients required more assistance. “This [result] suggests that prolonged-release fampridine responders perform better functionally for up to 22 months of treatment,” said Dr. Farrell.

Side effects reported in the study were the same as those described in phase III and IV trials of fampridine. They included insomnia, urinary tract infections, gastrointestinal side effects, dizziness, and headaches.

“This cohort has a higher responder rate than that of pivotal trials. This [result] may be due to the severity of their walking impairment and the open-label nature of this study,” said Dr. Farrell. “This [finding] brings into question the current practice of using a 20% improvement as the threshold for clinical significance.” Overall, “the results of this study validate the utility of prolonged-release fampridine in improving walking of people with MS in routine clinical practice,” she concluded.

BARCELONA—Alemtuzumab’s benefits for patients with relapsing-remitting multiple sclerosis (MS) may persist for five years, according to data from an extension study presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Participants who received alemtuzumab in the phase III pivotal studies CARE-MS I and CARE-MS II had positive outcomes throughout the course of the two-year trials. These benefits were maintained through three additional years in the extension study. In the pivotal studies, courses of treatment were administered at month zero and at month 12. After the initial two courses of treatment, 68% of treated patients from CARE-MS I and 60% of treated patients from CARE-MS II did not receive additional alemtuzumab during the following four years (ie, through month 60).

The low annualized relapse rates observed in patients who received alemtuzumab in CARE-MS I (0.18) and CARE-MS II (0.27) were maintained from year three (0.19 and 0.22, respectively) to year five (0.15 and 0.18, respectively). Through year five, 80% and 76% of patients who received alemtuzumab in CARE-MS I and CARE-MS II, respectively, did not have worsening of disability progression confirmed over six months, as measured by the Expanded Disability Status Scale (EDSS). Through year five, 33% and 43% of patients who had disability before receiving alemtuzumab in CARE-MS I and CARE-MS II, respectively, had improvement in EDSS score confirmed over at least six months, as compared with pretreatment baseline.

Furthermore, through year five, patients who received alemtuzumab in CARE-MS I and II had a slowing of brain atrophy, as measured by brain parenchymal fraction on MRI. In years three, four, and five, the median yearly brain volume loss was 0.20% or less, which was lower than the rate observed during the two-year pivotal studies. In each of years three, four, and five, most patients had no evidence of MRI disease activity (70–72% in CARE-MS I and 68–70% in CARE-MS II).

Through year five, the incidence of most adverse events during the extension study was comparable to or lower than that of the pivotal studies. The frequency of thyroid adverse events was highest in year three and declined in the subsequent years.

The phase III trials of alemtuzumab were randomized, rater-blinded, two-year pivotal studies comparing alemtuzumab with high-dose subcutaneous interferon beta-1a in patients with relapsing-remitting MS who had active disease and were either new to treatment (ie, in CARE-MS I) or who had had an inadequate response to another therapy (ie, in CARE-MS II).

More than 90% of the patients who received alemtuzumab in the CARE-MS phase III trials enrolled in the extension study. These patients were eligible to receive additional treatment with alemtuzumab in the extension study if they had at least one relapse or at least two new or enlarging brain or spinal cord lesions.

“These data illustrate that most alemtuzumab patients experienced sustained effects of treatment, despite the absence of additional treatment courses,” said Eva Havrdová, MD, PhD, Professor of Neurology at Charles University in Prague. “It is encouraging to see consistent effects maintained across multiple meaningful outcomes through five years.”

Serious side effects associated with alemtuzumab included infusion-associated reactions, autoimmune disorders (eg, thyroid disease, autoimmune cytopenias, and nephropathies), infections, and pneumonitis. The most common side effects of alemtuzumab are rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in an extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.

BARCELONA—Alemtuzumab’s benefits for patients with relapsing-remitting multiple sclerosis (MS) may persist for five years, according to data from an extension study presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Participants who received alemtuzumab in the phase III pivotal studies CARE-MS I and CARE-MS II had positive outcomes throughout the course of the two-year trials. These benefits were maintained through three additional years in the extension study. In the pivotal studies, courses of treatment were administered at month zero and at month 12. After the initial two courses of treatment, 68% of treated patients from CARE-MS I and 60% of treated patients from CARE-MS II did not receive additional alemtuzumab during the following four years (ie, through month 60).

The low annualized relapse rates observed in patients who received alemtuzumab in CARE-MS I (0.18) and CARE-MS II (0.27) were maintained from year three (0.19 and 0.22, respectively) to year five (0.15 and 0.18, respectively). Through year five, 80% and 76% of patients who received alemtuzumab in CARE-MS I and CARE-MS II, respectively, did not have worsening of disability progression confirmed over six months, as measured by the Expanded Disability Status Scale (EDSS). Through year five, 33% and 43% of patients who had disability before receiving alemtuzumab in CARE-MS I and CARE-MS II, respectively, had improvement in EDSS score confirmed over at least six months, as compared with pretreatment baseline.

Furthermore, through year five, patients who received alemtuzumab in CARE-MS I and II had a slowing of brain atrophy, as measured by brain parenchymal fraction on MRI. In years three, four, and five, the median yearly brain volume loss was 0.20% or less, which was lower than the rate observed during the two-year pivotal studies. In each of years three, four, and five, most patients had no evidence of MRI disease activity (70–72% in CARE-MS I and 68–70% in CARE-MS II).

Through year five, the incidence of most adverse events during the extension study was comparable to or lower than that of the pivotal studies. The frequency of thyroid adverse events was highest in year three and declined in the subsequent years.

The phase III trials of alemtuzumab were randomized, rater-blinded, two-year pivotal studies comparing alemtuzumab with high-dose subcutaneous interferon beta-1a in patients with relapsing-remitting MS who had active disease and were either new to treatment (ie, in CARE-MS I) or who had had an inadequate response to another therapy (ie, in CARE-MS II).

More than 90% of the patients who received alemtuzumab in the CARE-MS phase III trials enrolled in the extension study. These patients were eligible to receive additional treatment with alemtuzumab in the extension study if they had at least one relapse or at least two new or enlarging brain or spinal cord lesions.

“These data illustrate that most alemtuzumab patients experienced sustained effects of treatment, despite the absence of additional treatment courses,” said Eva Havrdová, MD, PhD, Professor of Neurology at Charles University in Prague. “It is encouraging to see consistent effects maintained across multiple meaningful outcomes through five years.”

Serious side effects associated with alemtuzumab included infusion-associated reactions, autoimmune disorders (eg, thyroid disease, autoimmune cytopenias, and nephropathies), infections, and pneumonitis. The most common side effects of alemtuzumab are rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in an extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.

BARCELONA—Alemtuzumab’s benefits for patients with relapsing-remitting multiple sclerosis (MS) may persist for five years, according to data from an extension study presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Participants who received alemtuzumab in the phase III pivotal studies CARE-MS I and CARE-MS II had positive outcomes throughout the course of the two-year trials. These benefits were maintained through three additional years in the extension study. In the pivotal studies, courses of treatment were administered at month zero and at month 12. After the initial two courses of treatment, 68% of treated patients from CARE-MS I and 60% of treated patients from CARE-MS II did not receive additional alemtuzumab during the following four years (ie, through month 60).

The low annualized relapse rates observed in patients who received alemtuzumab in CARE-MS I (0.18) and CARE-MS II (0.27) were maintained from year three (0.19 and 0.22, respectively) to year five (0.15 and 0.18, respectively). Through year five, 80% and 76% of patients who received alemtuzumab in CARE-MS I and CARE-MS II, respectively, did not have worsening of disability progression confirmed over six months, as measured by the Expanded Disability Status Scale (EDSS). Through year five, 33% and 43% of patients who had disability before receiving alemtuzumab in CARE-MS I and CARE-MS II, respectively, had improvement in EDSS score confirmed over at least six months, as compared with pretreatment baseline.

Furthermore, through year five, patients who received alemtuzumab in CARE-MS I and II had a slowing of brain atrophy, as measured by brain parenchymal fraction on MRI. In years three, four, and five, the median yearly brain volume loss was 0.20% or less, which was lower than the rate observed during the two-year pivotal studies. In each of years three, four, and five, most patients had no evidence of MRI disease activity (70–72% in CARE-MS I and 68–70% in CARE-MS II).

Through year five, the incidence of most adverse events during the extension study was comparable to or lower than that of the pivotal studies. The frequency of thyroid adverse events was highest in year three and declined in the subsequent years.

The phase III trials of alemtuzumab were randomized, rater-blinded, two-year pivotal studies comparing alemtuzumab with high-dose subcutaneous interferon beta-1a in patients with relapsing-remitting MS who had active disease and were either new to treatment (ie, in CARE-MS I) or who had had an inadequate response to another therapy (ie, in CARE-MS II).

More than 90% of the patients who received alemtuzumab in the CARE-MS phase III trials enrolled in the extension study. These patients were eligible to receive additional treatment with alemtuzumab in the extension study if they had at least one relapse or at least two new or enlarging brain or spinal cord lesions.

“These data illustrate that most alemtuzumab patients experienced sustained effects of treatment, despite the absence of additional treatment courses,” said Eva Havrdová, MD, PhD, Professor of Neurology at Charles University in Prague. “It is encouraging to see consistent effects maintained across multiple meaningful outcomes through five years.”

Serious side effects associated with alemtuzumab included infusion-associated reactions, autoimmune disorders (eg, thyroid disease, autoimmune cytopenias, and nephropathies), infections, and pneumonitis. The most common side effects of alemtuzumab are rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in an extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.

BARCELONA—Initial findings from a global initiative called vs.MS were presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Sponsored by Genzyme and aimed at fostering better informed care, the survey aimed at uncovering the often unspoken emotional and physical challenges faced by patients living with relapsing-remitting multiple sclerosis (MS) and their caregivers.

The vs.MS survey was developed with input and guidance from a steering committee of leading global neurologists specializing in MS. The online survey addressed topics such as progression and disability, cognitive challenges, relationship and intimacy issues, emotional burden, fatigue and sensitivity, bladder and bowel challenges, and the impact of MS on careers.

The vs.MS survey was fielded among more than 1,500 people in seven countries, including patients with relapsing-remitting MS and their caregivers.

An initial set of data from the vs.MS global survey elucidate the impact that the disease may have on various aspects of day-to-day life for people living with relapsing-remitting MS. For example, half of respondents feel their ability to progress in their career has changed for the worse since they were diagnosed with relapsing-remitting MS, and 40% are concerned about being able to keep their job.

The vs.MS survey also revealed the effect of MS on the emotional well-being of those living with the disease and their caregivers. For example, more than half of respondents living with relapsing-remitting MS feel lonely or isolated because of their MS, while more than half of caregivers do not discuss their fear of MS progressing to avoid upsetting the person they care for.

“The results of this global survey offer a unique look into the realities of relapsing MS, including the challenges that people living with MS and their care partners deal with on a daily basis,” said Barry Singer, MD, Director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis, and a vs.MS steering committee member. “We are hopeful that insight into the daily struggles of those living with MS will result in better disease management.”

While at ECTRIMS, Genzyme brought together people from across the MS community—people living with MS, health care providers specializing in the disease, and advocacy groups—to review the full vs.MS survey findings and begin developing a program that will be introduced to the community.

In the coming months, Genzyme will reveal the full vs.MS data set and partner with the MS community to encourage behavior and attitude shifts in an effort to yield better outcomes for those affected by the disease.

BARCELONA—Initial findings from a global initiative called vs.MS were presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Sponsored by Genzyme and aimed at fostering better informed care, the survey aimed at uncovering the often unspoken emotional and physical challenges faced by patients living with relapsing-remitting multiple sclerosis (MS) and their caregivers.

The vs.MS survey was developed with input and guidance from a steering committee of leading global neurologists specializing in MS. The online survey addressed topics such as progression and disability, cognitive challenges, relationship and intimacy issues, emotional burden, fatigue and sensitivity, bladder and bowel challenges, and the impact of MS on careers.

The vs.MS survey was fielded among more than 1,500 people in seven countries, including patients with relapsing-remitting MS and their caregivers.

An initial set of data from the vs.MS global survey elucidate the impact that the disease may have on various aspects of day-to-day life for people living with relapsing-remitting MS. For example, half of respondents feel their ability to progress in their career has changed for the worse since they were diagnosed with relapsing-remitting MS, and 40% are concerned about being able to keep their job.

The vs.MS survey also revealed the effect of MS on the emotional well-being of those living with the disease and their caregivers. For example, more than half of respondents living with relapsing-remitting MS feel lonely or isolated because of their MS, while more than half of caregivers do not discuss their fear of MS progressing to avoid upsetting the person they care for.

“The results of this global survey offer a unique look into the realities of relapsing MS, including the challenges that people living with MS and their care partners deal with on a daily basis,” said Barry Singer, MD, Director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis, and a vs.MS steering committee member. “We are hopeful that insight into the daily struggles of those living with MS will result in better disease management.”

While at ECTRIMS, Genzyme brought together people from across the MS community—people living with MS, health care providers specializing in the disease, and advocacy groups—to review the full vs.MS survey findings and begin developing a program that will be introduced to the community.

In the coming months, Genzyme will reveal the full vs.MS data set and partner with the MS community to encourage behavior and attitude shifts in an effort to yield better outcomes for those affected by the disease.

BARCELONA—Initial findings from a global initiative called vs.MS were presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Sponsored by Genzyme and aimed at fostering better informed care, the survey aimed at uncovering the often unspoken emotional and physical challenges faced by patients living with relapsing-remitting multiple sclerosis (MS) and their caregivers.

The vs.MS survey was developed with input and guidance from a steering committee of leading global neurologists specializing in MS. The online survey addressed topics such as progression and disability, cognitive challenges, relationship and intimacy issues, emotional burden, fatigue and sensitivity, bladder and bowel challenges, and the impact of MS on careers.

The vs.MS survey was fielded among more than 1,500 people in seven countries, including patients with relapsing-remitting MS and their caregivers.

An initial set of data from the vs.MS global survey elucidate the impact that the disease may have on various aspects of day-to-day life for people living with relapsing-remitting MS. For example, half of respondents feel their ability to progress in their career has changed for the worse since they were diagnosed with relapsing-remitting MS, and 40% are concerned about being able to keep their job.

The vs.MS survey also revealed the effect of MS on the emotional well-being of those living with the disease and their caregivers. For example, more than half of respondents living with relapsing-remitting MS feel lonely or isolated because of their MS, while more than half of caregivers do not discuss their fear of MS progressing to avoid upsetting the person they care for.

“The results of this global survey offer a unique look into the realities of relapsing MS, including the challenges that people living with MS and their care partners deal with on a daily basis,” said Barry Singer, MD, Director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis, and a vs.MS steering committee member. “We are hopeful that insight into the daily struggles of those living with MS will result in better disease management.”

While at ECTRIMS, Genzyme brought together people from across the MS community—people living with MS, health care providers specializing in the disease, and advocacy groups—to review the full vs.MS survey findings and begin developing a program that will be introduced to the community.

In the coming months, Genzyme will reveal the full vs.MS data set and partner with the MS community to encourage behavior and attitude shifts in an effort to yield better outcomes for those affected by the disease.

BARCELONA—Teriflunomide significantly slows brain-volume loss, compared with placebo, over two years in people with relapsing-remitting multiple sclerosis (MS), according to new data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In this analysis, researchers examined MRI data from the TEMSO study using Structural Image Evaluation Using Normalization of Atrophy (SIENA).

In the phase III TEMSO study, 1,088 participants with relapsing-remitting MS between ages 18 and 55 were randomly assigned to daily oral doses of placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide for 108 weeks. The treatment arms were approximately equal in size, and randomization was stratified according to the baseline Expanded Disability Status Scale score and according to trial site, with a block size of six. Researchers regularly assessed the patients’ change in brain volume from baseline. The study’s primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks. A total of 796 patients completed the study, with similar proportions of patients in the three study groups.

By month 12, median reduction from baseline in brain volume was 0.39%, 0.40%, and 0.61% for patients receiving 14 mg of teriflunomide, 7 mg of teriflunomide, and placebo, respectively. This change was lower for both teriflunomide groups, compared with placebo. For patients receiving 14 mg of teriflunomide, the change in volume was 36.9% lower than that for placebo. For patients receiving 7 mg of teriflunomide, the change in volume was 34.4% lower than that for placebo.

The significant difference in reduction of brain atrophy for teriflunomide versus placebo was maintained at month 24. Median reduction in brain volume from baseline was 0.90%, 0.94%, and 1.29% for 14 mg of teriflunomide, 7 mg of teriflunomide, and placebo, respectively. This change was lower for both teriflunomide groups versus placebo. For patients receiving 14 mg of teriflunomide, the change was 30.6% lower than that for placebo. For patients receiving 7 mg of teriflunomide, the change was 27.6% lower than that for placebo. In the MS clinical studies of teriflunomide, including TEMSO, the incidence of serious adverse events was similar between patients who received teriflunomide and those treated with placebo.

“Control or prevention of brain atrophy is an important target for MS treatment,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland. “These data help provide further insight into teriflunomide’s potential effects.”

BARCELONA—Teriflunomide significantly slows brain-volume loss, compared with placebo, over two years in people with relapsing-remitting multiple sclerosis (MS), according to new data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In this analysis, researchers examined MRI data from the TEMSO study using Structural Image Evaluation Using Normalization of Atrophy (SIENA).

In the phase III TEMSO study, 1,088 participants with relapsing-remitting MS between ages 18 and 55 were randomly assigned to daily oral doses of placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide for 108 weeks. The treatment arms were approximately equal in size, and randomization was stratified according to the baseline Expanded Disability Status Scale score and according to trial site, with a block size of six. Researchers regularly assessed the patients’ change in brain volume from baseline. The study’s primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks. A total of 796 patients completed the study, with similar proportions of patients in the three study groups.

By month 12, median reduction from baseline in brain volume was 0.39%, 0.40%, and 0.61% for patients receiving 14 mg of teriflunomide, 7 mg of teriflunomide, and placebo, respectively. This change was lower for both teriflunomide groups, compared with placebo. For patients receiving 14 mg of teriflunomide, the change in volume was 36.9% lower than that for placebo. For patients receiving 7 mg of teriflunomide, the change in volume was 34.4% lower than that for placebo.

The significant difference in reduction of brain atrophy for teriflunomide versus placebo was maintained at month 24. Median reduction in brain volume from baseline was 0.90%, 0.94%, and 1.29% for 14 mg of teriflunomide, 7 mg of teriflunomide, and placebo, respectively. This change was lower for both teriflunomide groups versus placebo. For patients receiving 14 mg of teriflunomide, the change was 30.6% lower than that for placebo. For patients receiving 7 mg of teriflunomide, the change was 27.6% lower than that for placebo. In the MS clinical studies of teriflunomide, including TEMSO, the incidence of serious adverse events was similar between patients who received teriflunomide and those treated with placebo.

“Control or prevention of brain atrophy is an important target for MS treatment,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland. “These data help provide further insight into teriflunomide’s potential effects.”

BARCELONA—Teriflunomide significantly slows brain-volume loss, compared with placebo, over two years in people with relapsing-remitting multiple sclerosis (MS), according to new data presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). In this analysis, researchers examined MRI data from the TEMSO study using Structural Image Evaluation Using Normalization of Atrophy (SIENA).

In the phase III TEMSO study, 1,088 participants with relapsing-remitting MS between ages 18 and 55 were randomly assigned to daily oral doses of placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide for 108 weeks. The treatment arms were approximately equal in size, and randomization was stratified according to the baseline Expanded Disability Status Scale score and according to trial site, with a block size of six. Researchers regularly assessed the patients’ change in brain volume from baseline. The study’s primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks. A total of 796 patients completed the study, with similar proportions of patients in the three study groups.

By month 12, median reduction from baseline in brain volume was 0.39%, 0.40%, and 0.61% for patients receiving 14 mg of teriflunomide, 7 mg of teriflunomide, and placebo, respectively. This change was lower for both teriflunomide groups, compared with placebo. For patients receiving 14 mg of teriflunomide, the change in volume was 36.9% lower than that for placebo. For patients receiving 7 mg of teriflunomide, the change in volume was 34.4% lower than that for placebo.

The significant difference in reduction of brain atrophy for teriflunomide versus placebo was maintained at month 24. Median reduction in brain volume from baseline was 0.90%, 0.94%, and 1.29% for 14 mg of teriflunomide, 7 mg of teriflunomide, and placebo, respectively. This change was lower for both teriflunomide groups versus placebo. For patients receiving 14 mg of teriflunomide, the change was 30.6% lower than that for placebo. For patients receiving 7 mg of teriflunomide, the change was 27.6% lower than that for placebo. In the MS clinical studies of teriflunomide, including TEMSO, the incidence of serious adverse events was similar between patients who received teriflunomide and those treated with placebo.

“Control or prevention of brain atrophy is an important target for MS treatment,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital Basel in Switzerland. “These data help provide further insight into teriflunomide’s potential effects.”

BARCELONA—In people with primary progressive multiple sclerosis (MS), treatment with ocrelizumab may significantly reduce the progression of clinical disability sustained for at least 12 weeks, compared with placebo, according to results from a pivotal phase III study presented at the 31st Congress of ECTRIMS. In the study, which is called ORATORIO, clinical disability was measured by the Expanded Disability Status Scale (EDSS).

Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a type of immune cell thought to be a key contributor to myelin damage and axonal damage. Preclinical studies suggest that ocrelizumab binds to CD20 cell-surface proteins expressed on certain B cells, but not on stem cells or plasma cells, thus potentially preserving important functions of the immune system.

The ORATORIO trial was a randomized, double-blind, global multicenter study. Researchers administered placebo or 600 mg of ocrelizumab by IV infusion every six months to 732 people with primary progressive MS. The doses of ocrelizumab were given as two 300-mg infusions two weeks apart. The primary end point of the study was time to onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

Overall, the incidence of adverse events associated with ocrelizumab was similar to that of placebo. The most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to that of placebo.

“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said Sandra Horning, MD, Chief Medical Officer and head of Global Product Development for Genentech, the developer of the therapy. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”

In addition to ORATORIO, the phase III clinical development program for ocrelizumab includes OPERA I and OPERA II, which are randomized, double-blind, double-dummy, global multicenter studies in people with relapsing forms of MS. The results of the studies appear to validate the hypothesis that B cells are central to the underlying biology of MS. Genentech plans to pursue marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS. The company will submit data from the OPERA I and II studies and from the ORATORIO study to the FDA in early 2016.

BARCELONA—In people with primary progressive multiple sclerosis (MS), treatment with ocrelizumab may significantly reduce the progression of clinical disability sustained for at least 12 weeks, compared with placebo, according to results from a pivotal phase III study presented at the 31st Congress of ECTRIMS. In the study, which is called ORATORIO, clinical disability was measured by the Expanded Disability Status Scale (EDSS).

Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a type of immune cell thought to be a key contributor to myelin damage and axonal damage. Preclinical studies suggest that ocrelizumab binds to CD20 cell-surface proteins expressed on certain B cells, but not on stem cells or plasma cells, thus potentially preserving important functions of the immune system.

The ORATORIO trial was a randomized, double-blind, global multicenter study. Researchers administered placebo or 600 mg of ocrelizumab by IV infusion every six months to 732 people with primary progressive MS. The doses of ocrelizumab were given as two 300-mg infusions two weeks apart. The primary end point of the study was time to onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

Overall, the incidence of adverse events associated with ocrelizumab was similar to that of placebo. The most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to that of placebo.

“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said Sandra Horning, MD, Chief Medical Officer and head of Global Product Development for Genentech, the developer of the therapy. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”

In addition to ORATORIO, the phase III clinical development program for ocrelizumab includes OPERA I and OPERA II, which are randomized, double-blind, double-dummy, global multicenter studies in people with relapsing forms of MS. The results of the studies appear to validate the hypothesis that B cells are central to the underlying biology of MS. Genentech plans to pursue marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS. The company will submit data from the OPERA I and II studies and from the ORATORIO study to the FDA in early 2016.

BARCELONA—In people with primary progressive multiple sclerosis (MS), treatment with ocrelizumab may significantly reduce the progression of clinical disability sustained for at least 12 weeks, compared with placebo, according to results from a pivotal phase III study presented at the 31st Congress of ECTRIMS. In the study, which is called ORATORIO, clinical disability was measured by the Expanded Disability Status Scale (EDSS).

Ocrelizumab is an investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a type of immune cell thought to be a key contributor to myelin damage and axonal damage. Preclinical studies suggest that ocrelizumab binds to CD20 cell-surface proteins expressed on certain B cells, but not on stem cells or plasma cells, thus potentially preserving important functions of the immune system.

The ORATORIO trial was a randomized, double-blind, global multicenter study. Researchers administered placebo or 600 mg of ocrelizumab by IV infusion every six months to 732 people with primary progressive MS. The doses of ocrelizumab were given as two 300-mg infusions two weeks apart. The primary end point of the study was time to onset of confirmed disability progression, defined as an increase in EDSS that is sustained for at least 12 weeks.

Overall, the incidence of adverse events associated with ocrelizumab was similar to that of placebo. The most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to that of placebo.

“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said Sandra Horning, MD, Chief Medical Officer and head of Global Product Development for Genentech, the developer of the therapy. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”

In addition to ORATORIO, the phase III clinical development program for ocrelizumab includes OPERA I and OPERA II, which are randomized, double-blind, double-dummy, global multicenter studies in people with relapsing forms of MS. The results of the studies appear to validate the hypothesis that B cells are central to the underlying biology of MS. Genentech plans to pursue marketing authorization for ocrelizumab in relapsing MS and in primary progressive MS. The company will submit data from the OPERA I and II studies and from the ORATORIO study to the FDA in early 2016.

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

A peptide derived from erythropoietin (EPO) demonstrated potent clinical benefits in animal models of multiple sclerosis (MS) without inducing hematologic side effects, according to research published online ahead of print August 14 in Neurotherapeutics. The peptide, JM-4, reduced disability and protected against demyelination in mice with experimental autoimmune encephalomyelitis (EAE). Unlike full-length EPO, JM-4 did not elevate hematocrit in mice with EAE, said RuiRong Yuan, MD, of the VA Medical Center of East Orange and the Department of Neurology and Neurosciences at Rutgers New Jersey Medical School in Newark.

JM-4 “may hold considerable potential for direct clinical application in the treatment of neuroinflammatory diseases, demyelinating illnesses, CNS trauma, and stroke, as well as in the treatment of inflammatory/immune diseases of non-neural origins,” said Dr. Yuan and her research colleagues.

Dissecting EPO

Prior studies have found that full-length EPO may be tissue-protective in several animal models of neurologic injuries, including traumatic brain injury and stroke, but EPO may induce hazardous increases in red cell mass, which can lead to cardiovascular complications. Dr. Yuan and colleagues hypothesized that the erythropoietic and tissue-protective elements of EPO reside in different domains of the molecule and the tissue-protective domains could be separated from the regions responsible for erythropoiesis.

To test their hypothesis, the researchers generated a set of EPO-derived small peptides that contain one or two cysteines within a 7- to 25-mer peptide. They screened these peptides for biologic activity and stability in vitro. They then studied whether the peptides retained their tissue-protective properties in two mouse models of EAE: C57BL/6 mice with EAE induced by immunization with proteolipid protein (PLP) and SJL/J mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG).

Peptides Did Not Elevate Hematocrit

The investigators previously reported that full-length EPO demonstrated beneficial effects in EAE C57BL/6 mice without significantly altering hematocrit. In EAE SJL/J mice, however, half of the animals rapidly developed clinical symptoms related to erythrocytosis and died after less than seven days of EPO therapy.

In studying the EPO-derived peptides, researchers compared SJL/J mice that were treated with full-length EPO or EPO-derived peptides, and a control group that received phosphate-buffered saline (PBS) as a sham treatment. Hematocrit increased dramatically after whole EPO treatment for seven days, rising to approximately 75% by day 14, said Dr. Yuan. In contrast, hematocrit levels in groups treated with PBS or the peptides, including JM-4, remained unchanged at approximately 51% over the five-week follow-up period.

JM-4 Reduced Disability

The investigators found that the 19-mer JM-4 peptide possessed more consistent beneficial effects than all of the other EPO-derived peptides in their set. To determine if JM-4 could prevent disease exacerbation, SJL/J mice were first immunized with a suboptimal dose of PLP, which induced significant neurologic disability by day 10. Symptomatic mice were then treated with IV JM-4 at 250 μg/kg/day in 200 μL of PBS, or sham-treated with PBS for seven days. Early sustained clinical improvement occurred in the JM-4 treated group compared with the group receiving sham treatment.

Similar results were observed in experiments using the monophasic C57BL/6 EAE disease model. Significant clinical improvement was observed in both the EPO- and JM-4-treated groups, compared with the control group.

Modifying Flare-Ups

To see if JM-4 could modify recurrent disease flare-ups and if symptom improvement could be sustained after termination of therapy, the researchers employed a relapsing-remitting model of EAE. The investigators immunized SJL/J mice with a suboptimal dose of PLP and allowed the animals to recover without intervention. The recovered mice were then separated into two groups that received treatment with JM-4 or PBS for seven days before being challenged with a second immunization containing the same amount of PLP antigen. Previous JM-4 therapy delayed the onset of disease and significantly reduced EAE-induced motor dysfunction compared with the sham-treated mice. Over the following five weeks, the sham-treated group continued to exhibit protracted relapses and more pronounced neurologic deficit, while the JM-4-treated mice had mild disease with little or no hindlimb impairment.

Further examination revealed that JM-4 treatment protected against demyelination and axonal damage in the acute EAE spinal cord, compared with sham treatment. JM-4 treatment also modulated inflammatory and immune reaction within the peripheral lymphatic tissue. In addition, the peptide suppressed proinflammatory cytokine production in MOG peptide enriched T cells and provided neuroprotection against cytotoxic insult, said the researchers.

Potential in a Range of Diseases?

It was important that JM-4 demonstrated therapeutic effect during early neurologic presentation in the EAE animal models because that time point more accurately reflects the human clinical situation.

“Therapies that are effective at symptom onset and provoke long-term resolution of subsequent relapses would be desirable for MS treatment,” Dr. Yuan and colleagues said. “In the preclinical animal model data presented here, our agents have performed satisfactorily in this regard.” The JM-4 peptide “shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation,” concluded the researchers.

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Patients who continue smoking after they have been diagnosed with multiple sclerosis (MS) may progress to secondary progressive MS earlier than patients who quit smoking, according to research published online ahead of print September 8 in JAMA Neurology. The findings suggest that physicians should advise patients to stop smoking to avoid aggravating MS-related disability, said Jan Hillert, MD, PhD, of the Karolinska Institutet at Karolinska University Hospital Solna in Stockholm.

“Evidence clearly supports advising patients with MS who smoke to quit,” said Dr. Hillert and colleagues. “Health care services for patients with MS should be organized to support such a lifestyle change.”

A Cross-Sectional Analysis

Cigarette smoking is a known risk factor for MS, with an odds ratio between 1.2 and 1.5, but investigators had not assessed whether quitting smoking after diagnosis affects the course of the disease. To clarify the impact of smoking continuation and cessation on time to conversion from relapsing-remitting MS to secondary progressive MS, Dr. Hillert and colleagues performed a cross-sectional study of patients in the Genes and Environment in Multiple Sclerosis (GEMS) Study in Sweden, a population-based case–control study that includes patients with prevalent MS from the Swedish National MS Registry. Researchers included in their main analysis 728 patients who smoked at diagnosis and who completed questionnaires from November 2009 to March 2011 about their smoking habits.

Researchers categorized 332 of these patients as continuous smokers (ie, they averaged at least one cigarette per day every year from the year after diagnosis) and 118 as quitters. Intermittent smokers were not considered in the primary outcome. An optimized accelerated failure time survival model showed that each additional year of smoking after diagnosis accelerated the time to conversion to secondary progressive MS by 4.7%. Uncorrected Kaplan–Meier plots showed that those who continued to smoke each year after diagnosis converted to secondary progressive MS at a median age of 48, compared with a median age of 56 for those who quit smoking, said the researchers. Smoking measured by pack-years had similar associations with time to conversion as years of active smoking, suggesting that these measures may be approximate proxies of each other.

Potential Confounder

Confounders can exist in any association study, and there might be variables associated with smoking that were not captured in this study, the researchers said.

While the groups were well balanced across most measures, those who quit smoking had shorter time to MS treatment than those who continued smoking, which is a potential confounder in the difference in time of secondary progressive MS onset, said Myla D. Goldman, MD, of the University of Virginia in Charlottesville, and Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center at Dallas, in an editorial commentary published with the study.

In addition, the broad categories of patient smoking levels “unfortunately prohibited any granularity about any dose effect of smoking on progression,” Drs. Goldman and Stüve said. “Thus, it remains unclear whether simply cutting back on the amount one is smoking could provide any benefit.”

A Risk Factor Worth Modifying

About 60% of Swedish patients with MS are smokers, reflecting a potentially large overall health benefit to smoking cessation efforts, Dr. Hillert and colleagues said.

“Most importantly, [this study] provides the first evidence, to our knowledge, that quitting smoking appears to delay onset of secondary progressive MS and provide protective benefit,” said Drs. Goldman and Stüve. “Therefore, even after MS diagnosis, smoking is a risk factor worth modifying.”

—Jake Remaly

Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology, according to an analysis of 1,220 tissue blocks from 120 patients with MS. Researchers found:

• Active plaques were most often found in early disease.

• In later stages, smoldering, inactive, and shadow plaques predominated.

• Early active plaques rapidly declined with disease duration.

• Plaque type distribution differed significantly by clinical course.

• The majority of plaques in acute monophasic  and relapsing-remitting MS were active.

• In secondary progressive MS (SPMS) with attacks, all plaque types could be distinguished.

• In SPMS without attacks, inactive plaques predominated.

• Smoldering plaques were found almost exclusively in progressive MS.

• At 47 years of age, equilibrium was seen between active and inactive plaques and smoldering plaques began to peak.

• Men displayed a higher proportion of smoldering plaques.

Citation: Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. [Published online ahead of print August 3, 2015]. Ann Neurol. doi: 10.1002/ana.24497.

Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology, according to an analysis of 1,220 tissue blocks from 120 patients with MS. Researchers found:

• Active plaques were most often found in early disease.

• In later stages, smoldering, inactive, and shadow plaques predominated.

• Early active plaques rapidly declined with disease duration.

• Plaque type distribution differed significantly by clinical course.

• The majority of plaques in acute monophasic  and relapsing-remitting MS were active.

• In secondary progressive MS (SPMS) with attacks, all plaque types could be distinguished.

• In SPMS without attacks, inactive plaques predominated.

• Smoldering plaques were found almost exclusively in progressive MS.

• At 47 years of age, equilibrium was seen between active and inactive plaques and smoldering plaques began to peak.

• Men displayed a higher proportion of smoldering plaques.

Citation: Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. [Published online ahead of print August 3, 2015]. Ann Neurol. doi: 10.1002/ana.24497.

Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology, according to an analysis of 1,220 tissue blocks from 120 patients with MS. Researchers found:

• Active plaques were most often found in early disease.

• In later stages, smoldering, inactive, and shadow plaques predominated.

• Early active plaques rapidly declined with disease duration.

• Plaque type distribution differed significantly by clinical course.

• The majority of plaques in acute monophasic  and relapsing-remitting MS were active.

• In secondary progressive MS (SPMS) with attacks, all plaque types could be distinguished.

• In SPMS without attacks, inactive plaques predominated.

• Smoldering plaques were found almost exclusively in progressive MS.

• At 47 years of age, equilibrium was seen between active and inactive plaques and smoldering plaques began to peak.

• Men displayed a higher proportion of smoldering plaques.

Citation: Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. [Published online ahead of print August 3, 2015]. Ann Neurol. doi: 10.1002/ana.24497.