Multiple Sclerosis Hub

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—In patients with multiple sclerosis (MS), telerehabilitation is a convenient and practical method of performing physical therapy with efficacy comparable to that of conventional in-person physical therapy, as measured by objective outcomes of gait and balance. Telerehabilitation should be investigated further and used more extensively as a means of improving function and quality of life in MS, according to researchers who spoke at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS).

MS often results in physical and cognitive disability. Rehabilitation methods that include physical therapy can achieve functional improvement of established physical deficits. Factors such as availability, geographical distance, mobility, transportation, and cost, however, limit access to specialized rehabilitation services. Telecommunication technology opens the possibility of supervising and directing a physical therapy program remotely through audio and visual communication in real time.

Gabriel Pardo, MD, Director of the Oklahoma Medical Research Foundation MS Center of Excellence in Oklahoma City, and colleagues sought to demonstrate the feasibility of a tele-health rehabilitation program in individuals with ambulatory deficits secondary to MS. The researchers also intended to evaluate the efficacy of the tele-health rehabilitation program and compare it with that of conventional physical therapy.

Dr. Pardo and colleagues included 30 individuals in a single-center, prospective, randomized, three-arm, evaluator-blinded study that lasted for eight weeks. About 69% of participants were female, and the population’s mean age was 54.7. Approximately 60% of participants had relapsing-remitting MS, 23% had secondary progressive MS, and 17% had primary progressive MS. The population’s mean Expanded Disability Status Scale (EDSS) score was 4.3.

All participants performed a home-based exercise program (HEP) unsupervised on five days per week for eight weeks. Participants were randomized to three intervention groups. Group 1 underwent HEP alone. Group 2 underwent HEP plus remote physical therapy supervised via audio and visual real-time telecommunication two to three times per week. Group 3 underwent HEP plus in-person physical therapy at the medical facility two to three times per week. The study outcomes were multiple measurements of gait and balance, as well as patient-reported outcomes. Selected outcomes were performed with a computerized system (ie, Neurocom SmartBalance).

Functional gait assessment improved from baseline in all groups. Improvements were no different between the telerehabilitation and the conventional PT groups, but this finding was not statistically significant. Other outcomes that were similar for Groups 2 and 3 were the Timed 25-Foot Walk, stride length, the Berg balance scale, step width, tandem sway, tandem width, limits of stability, and the sensory organization test. One participant dropped out of the study because of an MS relapse.

The researchers observed no problems with adherence in any of the groups. “If we are to demonstrate a more significant intergroup difference, we need [larger] cohorts, and consequently, further research is needed,” Dr. Pardo concluded.

LONDON—In patients with multiple sclerosis (MS), telerehabilitation is a convenient and practical method of performing physical therapy with efficacy comparable to that of conventional in-person physical therapy, as measured by objective outcomes of gait and balance. Telerehabilitation should be investigated further and used more extensively as a means of improving function and quality of life in MS, according to researchers who spoke at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS).

MS often results in physical and cognitive disability. Rehabilitation methods that include physical therapy can achieve functional improvement of established physical deficits. Factors such as availability, geographical distance, mobility, transportation, and cost, however, limit access to specialized rehabilitation services. Telecommunication technology opens the possibility of supervising and directing a physical therapy program remotely through audio and visual communication in real time.

Gabriel Pardo, MD, Director of the Oklahoma Medical Research Foundation MS Center of Excellence in Oklahoma City, and colleagues sought to demonstrate the feasibility of a tele-health rehabilitation program in individuals with ambulatory deficits secondary to MS. The researchers also intended to evaluate the efficacy of the tele-health rehabilitation program and compare it with that of conventional physical therapy.

Dr. Pardo and colleagues included 30 individuals in a single-center, prospective, randomized, three-arm, evaluator-blinded study that lasted for eight weeks. About 69% of participants were female, and the population’s mean age was 54.7. Approximately 60% of participants had relapsing-remitting MS, 23% had secondary progressive MS, and 17% had primary progressive MS. The population’s mean Expanded Disability Status Scale (EDSS) score was 4.3.

All participants performed a home-based exercise program (HEP) unsupervised on five days per week for eight weeks. Participants were randomized to three intervention groups. Group 1 underwent HEP alone. Group 2 underwent HEP plus remote physical therapy supervised via audio and visual real-time telecommunication two to three times per week. Group 3 underwent HEP plus in-person physical therapy at the medical facility two to three times per week. The study outcomes were multiple measurements of gait and balance, as well as patient-reported outcomes. Selected outcomes were performed with a computerized system (ie, Neurocom SmartBalance).

Functional gait assessment improved from baseline in all groups. Improvements were no different between the telerehabilitation and the conventional PT groups, but this finding was not statistically significant. Other outcomes that were similar for Groups 2 and 3 were the Timed 25-Foot Walk, stride length, the Berg balance scale, step width, tandem sway, tandem width, limits of stability, and the sensory organization test. One participant dropped out of the study because of an MS relapse.

The researchers observed no problems with adherence in any of the groups. “If we are to demonstrate a more significant intergroup difference, we need [larger] cohorts, and consequently, further research is needed,” Dr. Pardo concluded.

LONDON—In patients with multiple sclerosis (MS), telerehabilitation is a convenient and practical method of performing physical therapy with efficacy comparable to that of conventional in-person physical therapy, as measured by objective outcomes of gait and balance. Telerehabilitation should be investigated further and used more extensively as a means of improving function and quality of life in MS, according to researchers who spoke at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS).

MS often results in physical and cognitive disability. Rehabilitation methods that include physical therapy can achieve functional improvement of established physical deficits. Factors such as availability, geographical distance, mobility, transportation, and cost, however, limit access to specialized rehabilitation services. Telecommunication technology opens the possibility of supervising and directing a physical therapy program remotely through audio and visual communication in real time.

Gabriel Pardo, MD, Director of the Oklahoma Medical Research Foundation MS Center of Excellence in Oklahoma City, and colleagues sought to demonstrate the feasibility of a tele-health rehabilitation program in individuals with ambulatory deficits secondary to MS. The researchers also intended to evaluate the efficacy of the tele-health rehabilitation program and compare it with that of conventional physical therapy.

Dr. Pardo and colleagues included 30 individuals in a single-center, prospective, randomized, three-arm, evaluator-blinded study that lasted for eight weeks. About 69% of participants were female, and the population’s mean age was 54.7. Approximately 60% of participants had relapsing-remitting MS, 23% had secondary progressive MS, and 17% had primary progressive MS. The population’s mean Expanded Disability Status Scale (EDSS) score was 4.3.

All participants performed a home-based exercise program (HEP) unsupervised on five days per week for eight weeks. Participants were randomized to three intervention groups. Group 1 underwent HEP alone. Group 2 underwent HEP plus remote physical therapy supervised via audio and visual real-time telecommunication two to three times per week. Group 3 underwent HEP plus in-person physical therapy at the medical facility two to three times per week. The study outcomes were multiple measurements of gait and balance, as well as patient-reported outcomes. Selected outcomes were performed with a computerized system (ie, Neurocom SmartBalance).

Functional gait assessment improved from baseline in all groups. Improvements were no different between the telerehabilitation and the conventional PT groups, but this finding was not statistically significant. Other outcomes that were similar for Groups 2 and 3 were the Timed 25-Foot Walk, stride length, the Berg balance scale, step width, tandem sway, tandem width, limits of stability, and the sensory organization test. One participant dropped out of the study because of an MS relapse.

The researchers observed no problems with adherence in any of the groups. “If we are to demonstrate a more significant intergroup difference, we need [larger] cohorts, and consequently, further research is needed,” Dr. Pardo concluded.

LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.

Measures of retinal layer thicknesses obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thicknesses as assessed by OCT predicts disability in MS 10 years later.

A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007.  During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thicknesses at baseline predict EDSS scores after 10 years.

The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean differences = 21.5 years and 11.7 years, respectively) and that patients with SPMS patients had a longer disease duration than patients with RRMS and PPMS (mean differences = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts (0%). Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm³ lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.

—Glenn S. Williams

LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.

Measures of retinal layer thicknesses obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thicknesses as assessed by OCT predicts disability in MS 10 years later.

A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007.  During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thicknesses at baseline predict EDSS scores after 10 years.

The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean differences = 21.5 years and 11.7 years, respectively) and that patients with SPMS patients had a longer disease duration than patients with RRMS and PPMS (mean differences = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts (0%). Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm³ lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.

—Glenn S. Williams

LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.

Measures of retinal layer thicknesses obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thicknesses as assessed by OCT predicts disability in MS 10 years later.

A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007.  During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thicknesses at baseline predict EDSS scores after 10 years.

The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean differences = 21.5 years and 11.7 years, respectively) and that patients with SPMS patients had a longer disease duration than patients with RRMS and PPMS (mean differences = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts (0%). Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm³ lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.

—Glenn S. Williams

LONDON—Significant treatment effect versus placebo of cladribine tablets given to patients with clinically isolated syndrome during the initial treatment period continues to be observed in patients who convert to clinically definite multiple sclerosis (MS) and switch to treatment with a different disease modifying drug (ie, subcutaneous interferon beta-1a), according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Giancarlo Comi, MD, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan, Italy, and colleagues reported that patients with clinically isolated syndrome who had been treated with cladribine tablets and who had converted to MS during the Oral Cladribine in Early Multiple Sclerosis (ORACLE-MS) initial treatment period had lower annualized relapse rates during the open-label maintenance period, relative to those patients who had received placebo during the ORACLE-MS initial treatment period.  

The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study in patients with active MS showed that annualized relapse rates and sustained disability worsening were reduced in patients treated with cladribine tablets annually for two years in short-duration courses, compared with placebo. The efficacy observed in CLARITY was maintained without further active treatment during the CLARITY extension study. In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of conversion to clinically definite MS, compared with placebo. If clinically definite MS occurred in the double-blinded, initial treatment period, patients were treated with subcutaneous interferon beta-1a in an open-label maintenance period.

The present study was designed to assess the annualized relapse rate during the ORACLE-MS open-label maintenance period in patients randomized to cladribine (3.5 mg/kg and 5.25 mg/kg) or placebo in the initial treatment period.

Similar to previous trials, participation in the ORACLE-MS open-label maintenance period was dependent upon the clinical course of the patient’s disease in the initial treatment period. Patients in ORACLE-MS who converted to clinically definite MS (according to Poser criteria) during the initial treatment period entered the open-label maintenance period and were treated with subcutaneous interferon beta-1a (titrated over four weeks up to the dose of 44 μg) administered three times per week.

A total of 109 patients in ORACLE-MS converted to clinically definite MS in the initial treatment period and received at least one dose of interferon beta-1a. The median time on interferon beta-1a was 56.0 weeks. Estimated annualized relapse rates in the open-label maintenance period were 0.14 for patients (n = 25) originally treated with cladribine 3.5 mg/kg, 0.24 for patients (n = 24) originally treated with cladribine 5.25 mg/kg, and 0.42 for patients (n = 60) who originally received placebo in the initial treatment period.

According to the researchers, durable efficacy of cladribine tablets in ORACLE-MS into the open-label maintenance period is consistent with results of the CLARITY and CLARITY extension studies.

This study was sponsored by EMD Serono Inc.

—Glenn S. Williams

LONDON—Significant treatment effect versus placebo of cladribine tablets given to patients with clinically isolated syndrome during the initial treatment period continues to be observed in patients who convert to clinically definite multiple sclerosis (MS) and switch to treatment with a different disease modifying drug (ie, subcutaneous interferon beta-1a), according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Giancarlo Comi, MD, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan, Italy, and colleagues reported that patients with clinically isolated syndrome who had been treated with cladribine tablets and who had converted to MS during the Oral Cladribine in Early Multiple Sclerosis (ORACLE-MS) initial treatment period had lower annualized relapse rates during the open-label maintenance period, relative to those patients who had received placebo during the ORACLE-MS initial treatment period.  

The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study in patients with active MS showed that annualized relapse rates and sustained disability worsening were reduced in patients treated with cladribine tablets annually for two years in short-duration courses, compared with placebo. The efficacy observed in CLARITY was maintained without further active treatment during the CLARITY extension study. In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of conversion to clinically definite MS, compared with placebo. If clinically definite MS occurred in the double-blinded, initial treatment period, patients were treated with subcutaneous interferon beta-1a in an open-label maintenance period.

The present study was designed to assess the annualized relapse rate during the ORACLE-MS open-label maintenance period in patients randomized to cladribine (3.5 mg/kg and 5.25 mg/kg) or placebo in the initial treatment period.

Similar to previous trials, participation in the ORACLE-MS open-label maintenance period was dependent upon the clinical course of the patient’s disease in the initial treatment period. Patients in ORACLE-MS who converted to clinically definite MS (according to Poser criteria) during the initial treatment period entered the open-label maintenance period and were treated with subcutaneous interferon beta-1a (titrated over four weeks up to the dose of 44 μg) administered three times per week.

A total of 109 patients in ORACLE-MS converted to clinically definite MS in the initial treatment period and received at least one dose of interferon beta-1a. The median time on interferon beta-1a was 56.0 weeks. Estimated annualized relapse rates in the open-label maintenance period were 0.14 for patients (n = 25) originally treated with cladribine 3.5 mg/kg, 0.24 for patients (n = 24) originally treated with cladribine 5.25 mg/kg, and 0.42 for patients (n = 60) who originally received placebo in the initial treatment period.

According to the researchers, durable efficacy of cladribine tablets in ORACLE-MS into the open-label maintenance period is consistent with results of the CLARITY and CLARITY extension studies.

This study was sponsored by EMD Serono Inc.

—Glenn S. Williams

LONDON—Significant treatment effect versus placebo of cladribine tablets given to patients with clinically isolated syndrome during the initial treatment period continues to be observed in patients who convert to clinically definite multiple sclerosis (MS) and switch to treatment with a different disease modifying drug (ie, subcutaneous interferon beta-1a), according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Giancarlo Comi, MD, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan, Italy, and colleagues reported that patients with clinically isolated syndrome who had been treated with cladribine tablets and who had converted to MS during the Oral Cladribine in Early Multiple Sclerosis (ORACLE-MS) initial treatment period had lower annualized relapse rates during the open-label maintenance period, relative to those patients who had received placebo during the ORACLE-MS initial treatment period.  

The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study in patients with active MS showed that annualized relapse rates and sustained disability worsening were reduced in patients treated with cladribine tablets annually for two years in short-duration courses, compared with placebo. The efficacy observed in CLARITY was maintained without further active treatment during the CLARITY extension study. In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of conversion to clinically definite MS, compared with placebo. If clinically definite MS occurred in the double-blinded, initial treatment period, patients were treated with subcutaneous interferon beta-1a in an open-label maintenance period.

The present study was designed to assess the annualized relapse rate during the ORACLE-MS open-label maintenance period in patients randomized to cladribine (3.5 mg/kg and 5.25 mg/kg) or placebo in the initial treatment period.

Similar to previous trials, participation in the ORACLE-MS open-label maintenance period was dependent upon the clinical course of the patient’s disease in the initial treatment period. Patients in ORACLE-MS who converted to clinically definite MS (according to Poser criteria) during the initial treatment period entered the open-label maintenance period and were treated with subcutaneous interferon beta-1a (titrated over four weeks up to the dose of 44 μg) administered three times per week.

A total of 109 patients in ORACLE-MS converted to clinically definite MS in the initial treatment period and received at least one dose of interferon beta-1a. The median time on interferon beta-1a was 56.0 weeks. Estimated annualized relapse rates in the open-label maintenance period were 0.14 for patients (n = 25) originally treated with cladribine 3.5 mg/kg, 0.24 for patients (n = 24) originally treated with cladribine 5.25 mg/kg, and 0.42 for patients (n = 60) who originally received placebo in the initial treatment period.

According to the researchers, durable efficacy of cladribine tablets in ORACLE-MS into the open-label maintenance period is consistent with results of the CLARITY and CLARITY extension studies.

This study was sponsored by EMD Serono Inc.

—Glenn S. Williams

LONDON—Strong evidence suggests an association between pediatric CNS demyelinating diseases and psychiatric disorders, according to a population-based study presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Mental health professionals need to be involved early with patients with MS as part of a multidisciplinary care approach, said the researchers.

In adults, MS is associated with various psychiatric disorders. When MS onset occurs in children, particularly when the pathophysiology occurs during a key period of CNS development, MS may be associated with a different set of psychiatric disorders, compared with those in adults.

To assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa, Julia Pakpoor, academic and clinical trainee at the University of Oxford in the United Kingdom, and colleagues analyzed linked English Hospital Episode Statistics and mortality data for the years 1999 to 2011. Cohorts were constructed of children (ie, patients younger than 18) admitted with MS and other CNS demyelinating diseases. The investigators searched for any subsequent episode of care with psychiatric disorders in these cohorts, and compared them to a reference cohort.

The researchers included 201 children in the MS cohort, 1,097 children in the CNS demyelinating-diseases cohort, and more than 1.1 million children in the reference cohort. Children with a demyelinating disease had an increased risk of psychotic disorders (standardized rate ratio [RR] 5.77); anxiety, stress-related, and somatoform disorders (RR, 2.38); intellectual disability (RR, 6.56); and other behavioral disorders (RR, 8.99), as well as an elevated rate of any of the psychiatric disorders studied (RR, 1.56). These findings remained significant with a one-year minimum interval between the first demyelinating disease episode and the first psychiatric disorder episode. They remained significant for psychotic disorders, intellectual disability, and other behavioral disorders with a minimum five-year interval.

In an analysis of the pediatric MS cohort as the exposure, the researchers observed elevated rates of psychotic disorders (RR, 10.76), mood disorders (RR, 2.57), and intellectual disability (RR, 6.08). In reverse analyses, the researchers found elevated rates of demyelinating diseases after anxiety, stress-related, and somatoform disorders (RR, 3.15); ADHD (RR, 3.88); autism (RR, 3.80); intellectual disability (RR, 6.33); other behavioral disorders (RR, 8.30); and any of the psychiatric disorders studied (RR, 2.15).

“What this study and what many other studies of comorbidities in MS demonstrate is that it’s high time to abandon the single-disease approach, which has perhaps been the approach for a long time not only in medical research, but also medical care and medical education,” said Ms. Pakpoor. “What we clearly need to do is develop more comprehensive algorithms to identify psychiatric comorbidities for a broad range of these individuals.”

—Erik Greb

LONDON—Strong evidence suggests an association between pediatric CNS demyelinating diseases and psychiatric disorders, according to a population-based study presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Mental health professionals need to be involved early with patients with MS as part of a multidisciplinary care approach, said the researchers.

In adults, MS is associated with various psychiatric disorders. When MS onset occurs in children, particularly when the pathophysiology occurs during a key period of CNS development, MS may be associated with a different set of psychiatric disorders, compared with those in adults.

To assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa, Julia Pakpoor, academic and clinical trainee at the University of Oxford in the United Kingdom, and colleagues analyzed linked English Hospital Episode Statistics and mortality data for the years 1999 to 2011. Cohorts were constructed of children (ie, patients younger than 18) admitted with MS and other CNS demyelinating diseases. The investigators searched for any subsequent episode of care with psychiatric disorders in these cohorts, and compared them to a reference cohort.

The researchers included 201 children in the MS cohort, 1,097 children in the CNS demyelinating-diseases cohort, and more than 1.1 million children in the reference cohort. Children with a demyelinating disease had an increased risk of psychotic disorders (standardized rate ratio [RR] 5.77); anxiety, stress-related, and somatoform disorders (RR, 2.38); intellectual disability (RR, 6.56); and other behavioral disorders (RR, 8.99), as well as an elevated rate of any of the psychiatric disorders studied (RR, 1.56). These findings remained significant with a one-year minimum interval between the first demyelinating disease episode and the first psychiatric disorder episode. They remained significant for psychotic disorders, intellectual disability, and other behavioral disorders with a minimum five-year interval.

In an analysis of the pediatric MS cohort as the exposure, the researchers observed elevated rates of psychotic disorders (RR, 10.76), mood disorders (RR, 2.57), and intellectual disability (RR, 6.08). In reverse analyses, the researchers found elevated rates of demyelinating diseases after anxiety, stress-related, and somatoform disorders (RR, 3.15); ADHD (RR, 3.88); autism (RR, 3.80); intellectual disability (RR, 6.33); other behavioral disorders (RR, 8.30); and any of the psychiatric disorders studied (RR, 2.15).

“What this study and what many other studies of comorbidities in MS demonstrate is that it’s high time to abandon the single-disease approach, which has perhaps been the approach for a long time not only in medical research, but also medical care and medical education,” said Ms. Pakpoor. “What we clearly need to do is develop more comprehensive algorithms to identify psychiatric comorbidities for a broad range of these individuals.”

—Erik Greb

LONDON—Strong evidence suggests an association between pediatric CNS demyelinating diseases and psychiatric disorders, according to a population-based study presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Mental health professionals need to be involved early with patients with MS as part of a multidisciplinary care approach, said the researchers.

In adults, MS is associated with various psychiatric disorders. When MS onset occurs in children, particularly when the pathophysiology occurs during a key period of CNS development, MS may be associated with a different set of psychiatric disorders, compared with those in adults.

To assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa, Julia Pakpoor, academic and clinical trainee at the University of Oxford in the United Kingdom, and colleagues analyzed linked English Hospital Episode Statistics and mortality data for the years 1999 to 2011. Cohorts were constructed of children (ie, patients younger than 18) admitted with MS and other CNS demyelinating diseases. The investigators searched for any subsequent episode of care with psychiatric disorders in these cohorts, and compared them to a reference cohort.

The researchers included 201 children in the MS cohort, 1,097 children in the CNS demyelinating-diseases cohort, and more than 1.1 million children in the reference cohort. Children with a demyelinating disease had an increased risk of psychotic disorders (standardized rate ratio [RR] 5.77); anxiety, stress-related, and somatoform disorders (RR, 2.38); intellectual disability (RR, 6.56); and other behavioral disorders (RR, 8.99), as well as an elevated rate of any of the psychiatric disorders studied (RR, 1.56). These findings remained significant with a one-year minimum interval between the first demyelinating disease episode and the first psychiatric disorder episode. They remained significant for psychotic disorders, intellectual disability, and other behavioral disorders with a minimum five-year interval.

In an analysis of the pediatric MS cohort as the exposure, the researchers observed elevated rates of psychotic disorders (RR, 10.76), mood disorders (RR, 2.57), and intellectual disability (RR, 6.08). In reverse analyses, the researchers found elevated rates of demyelinating diseases after anxiety, stress-related, and somatoform disorders (RR, 3.15); ADHD (RR, 3.88); autism (RR, 3.80); intellectual disability (RR, 6.33); other behavioral disorders (RR, 8.30); and any of the psychiatric disorders studied (RR, 2.15).

“What this study and what many other studies of comorbidities in MS demonstrate is that it’s high time to abandon the single-disease approach, which has perhaps been the approach for a long time not only in medical research, but also medical care and medical education,” said Ms. Pakpoor. “What we clearly need to do is develop more comprehensive algorithms to identify psychiatric comorbidities for a broad range of these individuals.”

—Erik Greb

LONDON—Evaluation of cortical lesions improves specificity of the diagnostic criteria for multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Assessment of cortical lesions, in concert with current McDonald criteria, also preserved a high level of diagnostic sensitivity and accuracy in a multicentric cohort of patients with clinically isolated syndrome, reported Paolo Preziosa, MD, Neuroimaging Research Unit at the Institute of Experimental Neurology and Division of Neuroscience at San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and his research colleagues.

Since the publication of the 2010 revised McDonald criteria, new data regarding the application of MRI for the diagnosis of MS have become available. In a single-center study, adding the assessment of cortical lesions has been shown to modify the diagnostic algorithm resulting in higher specificity.

In the present study, Dr. Preziosa and colleagues sought to test the performance of different sets of imaging criteria, including the assessment of cortical lesions, for the development of MS in a multicentric cohort of patients with clinically isolated syndrome.

The researchers analyzed brain double inversion recovery and brain and cord T2-weighted and post-contrast T1-weighted sequences acquired from 72 patients with clinically isolated syndrome from five European centers (Barcelona, Belgrade, Mainz, Milan, and Verona) within three months and after 12 months from disease onset. Patients were followed clinically for 24 or more months or until the development of clinically defined MS. Median follow-up was 24.2 months. Sensitivity, specificity, and accuracy of the different dissemination in space MRI criteria for the development of MS were tested.

At follow-up, 65 patients (90%) had clinically and/or radiologically definite MS. The sensitivity of all criteria was high (McDonald 2005, 83%; McDonald 2010, 92%; Filippi 2010, 80%). Specificity of Filippi 2010 was higher (67%) compared with the others (50% for McDonald 2005 and 2010). The accuracy of all criteria was high (McDonald 2005, 81%; McDonald 2010, 89%; Filippi 2010, 79%).

“The detection of cortical lesions in vivo using MRI should be considered in future clinical trials,” Dr. Preziosa said.

—Glenn S. Williams

LONDON—Evaluation of cortical lesions improves specificity of the diagnostic criteria for multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Assessment of cortical lesions, in concert with current McDonald criteria, also preserved a high level of diagnostic sensitivity and accuracy in a multicentric cohort of patients with clinically isolated syndrome, reported Paolo Preziosa, MD, Neuroimaging Research Unit at the Institute of Experimental Neurology and Division of Neuroscience at San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and his research colleagues.

Since the publication of the 2010 revised McDonald criteria, new data regarding the application of MRI for the diagnosis of MS have become available. In a single-center study, adding the assessment of cortical lesions has been shown to modify the diagnostic algorithm resulting in higher specificity.

In the present study, Dr. Preziosa and colleagues sought to test the performance of different sets of imaging criteria, including the assessment of cortical lesions, for the development of MS in a multicentric cohort of patients with clinically isolated syndrome.

The researchers analyzed brain double inversion recovery and brain and cord T2-weighted and post-contrast T1-weighted sequences acquired from 72 patients with clinically isolated syndrome from five European centers (Barcelona, Belgrade, Mainz, Milan, and Verona) within three months and after 12 months from disease onset. Patients were followed clinically for 24 or more months or until the development of clinically defined MS. Median follow-up was 24.2 months. Sensitivity, specificity, and accuracy of the different dissemination in space MRI criteria for the development of MS were tested.

At follow-up, 65 patients (90%) had clinically and/or radiologically definite MS. The sensitivity of all criteria was high (McDonald 2005, 83%; McDonald 2010, 92%; Filippi 2010, 80%). Specificity of Filippi 2010 was higher (67%) compared with the others (50% for McDonald 2005 and 2010). The accuracy of all criteria was high (McDonald 2005, 81%; McDonald 2010, 89%; Filippi 2010, 79%).

“The detection of cortical lesions in vivo using MRI should be considered in future clinical trials,” Dr. Preziosa said.

—Glenn S. Williams

LONDON—Evaluation of cortical lesions improves specificity of the diagnostic criteria for multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Assessment of cortical lesions, in concert with current McDonald criteria, also preserved a high level of diagnostic sensitivity and accuracy in a multicentric cohort of patients with clinically isolated syndrome, reported Paolo Preziosa, MD, Neuroimaging Research Unit at the Institute of Experimental Neurology and Division of Neuroscience at San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and his research colleagues.

Since the publication of the 2010 revised McDonald criteria, new data regarding the application of MRI for the diagnosis of MS have become available. In a single-center study, adding the assessment of cortical lesions has been shown to modify the diagnostic algorithm resulting in higher specificity.

In the present study, Dr. Preziosa and colleagues sought to test the performance of different sets of imaging criteria, including the assessment of cortical lesions, for the development of MS in a multicentric cohort of patients with clinically isolated syndrome.

The researchers analyzed brain double inversion recovery and brain and cord T2-weighted and post-contrast T1-weighted sequences acquired from 72 patients with clinically isolated syndrome from five European centers (Barcelona, Belgrade, Mainz, Milan, and Verona) within three months and after 12 months from disease onset. Patients were followed clinically for 24 or more months or until the development of clinically defined MS. Median follow-up was 24.2 months. Sensitivity, specificity, and accuracy of the different dissemination in space MRI criteria for the development of MS were tested.

At follow-up, 65 patients (90%) had clinically and/or radiologically definite MS. The sensitivity of all criteria was high (McDonald 2005, 83%; McDonald 2010, 92%; Filippi 2010, 80%). Specificity of Filippi 2010 was higher (67%) compared with the others (50% for McDonald 2005 and 2010). The accuracy of all criteria was high (McDonald 2005, 81%; McDonald 2010, 89%; Filippi 2010, 79%).

“The detection of cortical lesions in vivo using MRI should be considered in future clinical trials,” Dr. Preziosa said.

—Glenn S. Williams

LONDON—Data suggest a selective activation of Th17 cells in the intestinal mucosa of patients with multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The findings validate previous reports in preclinical models of MS and provide the first evidence that gut immunity modulates MS pathogenesis in humans, according to the authors.

Animal models of MS have provided evidence that gut immunity and immune regulation are instrumental to maintaining immune tolerance towards the body’s own tissues. Immune regulation also helps to avoid inflammatory conditions in the intestine and at distal sites, thus helping to prevent organ-specific autoimmune diseases such as MS. Investigators hypothesize that by altering gut immunity, environmental factors acting at the intestinal level (eg, diet and microbiota modifications) increase the risk of developing autoimmune diseases such as MS in genetically at-risk individuals. Gloria Dalla Costa, MD, neurology resident at San Raffaele Hospital in Milan, and colleagues conducted a study to assess the potential role of gut immunity and microbiota modifications in MS pathogenesis.

The investigators analyzed gut immune cell subsets in intestinal mucosal samples isolated from 23 patients with relapsing-remitting MS and 16 age- and sex-matched healthy controls. Participants underwent esophago-gastro-duodenal endoscopy (EGDS) for diagnostic purposes. All patients with MS had not received corticosteroid treatments in the six months before EGDS, and had not received antibiotic treatment four weeks before EGDS. Patients with MS were receiving treatment with various disease-modifying drugs.

Dr. Dalla Costa and colleagues performed a multiparametric fluorescence-activated cell sorting analysis and measured the relative percentages of different T helper and Treg cell subsets in the small intestinal mucosa and peripheral blood. In the same patients with MS and healthy controls, the researchers performed a 16S metagenomic analysis of microbiota composition to correlate the activation of Th17 cells to a specific microbiota profile.

The investigators found that effector Th17 cells that play a crucial role in the pathogenesis of MS were present in the intestinal mucosa, but not in peripheral blood. Th22 cells were also detected only in the intestinal mucosa. In addition, patients with MS showed an increased percentage of activated Th17 cells (eg, IL-17, IL-22, and T cells) in the intestinal mucosa, with an increased Th17:FoxP3+Treg cell ratio, compared with healthy controls. This finding indicated activation of effector Th17 cells in the gut mucosa.

“Our next goal is to determine how environmental factors such as diet can modulate MS pathogenesis through alterations of gut microbiota composition and intestinal immunity,” said Dr. Dalla Costa.

LONDON—Data suggest a selective activation of Th17 cells in the intestinal mucosa of patients with multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The findings validate previous reports in preclinical models of MS and provide the first evidence that gut immunity modulates MS pathogenesis in humans, according to the authors.

Animal models of MS have provided evidence that gut immunity and immune regulation are instrumental to maintaining immune tolerance towards the body’s own tissues. Immune regulation also helps to avoid inflammatory conditions in the intestine and at distal sites, thus helping to prevent organ-specific autoimmune diseases such as MS. Investigators hypothesize that by altering gut immunity, environmental factors acting at the intestinal level (eg, diet and microbiota modifications) increase the risk of developing autoimmune diseases such as MS in genetically at-risk individuals. Gloria Dalla Costa, MD, neurology resident at San Raffaele Hospital in Milan, and colleagues conducted a study to assess the potential role of gut immunity and microbiota modifications in MS pathogenesis.

The investigators analyzed gut immune cell subsets in intestinal mucosal samples isolated from 23 patients with relapsing-remitting MS and 16 age- and sex-matched healthy controls. Participants underwent esophago-gastro-duodenal endoscopy (EGDS) for diagnostic purposes. All patients with MS had not received corticosteroid treatments in the six months before EGDS, and had not received antibiotic treatment four weeks before EGDS. Patients with MS were receiving treatment with various disease-modifying drugs.

Dr. Dalla Costa and colleagues performed a multiparametric fluorescence-activated cell sorting analysis and measured the relative percentages of different T helper and Treg cell subsets in the small intestinal mucosa and peripheral blood. In the same patients with MS and healthy controls, the researchers performed a 16S metagenomic analysis of microbiota composition to correlate the activation of Th17 cells to a specific microbiota profile.

The investigators found that effector Th17 cells that play a crucial role in the pathogenesis of MS were present in the intestinal mucosa, but not in peripheral blood. Th22 cells were also detected only in the intestinal mucosa. In addition, patients with MS showed an increased percentage of activated Th17 cells (eg, IL-17, IL-22, and T cells) in the intestinal mucosa, with an increased Th17:FoxP3+Treg cell ratio, compared with healthy controls. This finding indicated activation of effector Th17 cells in the gut mucosa.

“Our next goal is to determine how environmental factors such as diet can modulate MS pathogenesis through alterations of gut microbiota composition and intestinal immunity,” said Dr. Dalla Costa.

LONDON—Data suggest a selective activation of Th17 cells in the intestinal mucosa of patients with multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The findings validate previous reports in preclinical models of MS and provide the first evidence that gut immunity modulates MS pathogenesis in humans, according to the authors.

Animal models of MS have provided evidence that gut immunity and immune regulation are instrumental to maintaining immune tolerance towards the body’s own tissues. Immune regulation also helps to avoid inflammatory conditions in the intestine and at distal sites, thus helping to prevent organ-specific autoimmune diseases such as MS. Investigators hypothesize that by altering gut immunity, environmental factors acting at the intestinal level (eg, diet and microbiota modifications) increase the risk of developing autoimmune diseases such as MS in genetically at-risk individuals. Gloria Dalla Costa, MD, neurology resident at San Raffaele Hospital in Milan, and colleagues conducted a study to assess the potential role of gut immunity and microbiota modifications in MS pathogenesis.

The investigators analyzed gut immune cell subsets in intestinal mucosal samples isolated from 23 patients with relapsing-remitting MS and 16 age- and sex-matched healthy controls. Participants underwent esophago-gastro-duodenal endoscopy (EGDS) for diagnostic purposes. All patients with MS had not received corticosteroid treatments in the six months before EGDS, and had not received antibiotic treatment four weeks before EGDS. Patients with MS were receiving treatment with various disease-modifying drugs.

Dr. Dalla Costa and colleagues performed a multiparametric fluorescence-activated cell sorting analysis and measured the relative percentages of different T helper and Treg cell subsets in the small intestinal mucosa and peripheral blood. In the same patients with MS and healthy controls, the researchers performed a 16S metagenomic analysis of microbiota composition to correlate the activation of Th17 cells to a specific microbiota profile.

The investigators found that effector Th17 cells that play a crucial role in the pathogenesis of MS were present in the intestinal mucosa, but not in peripheral blood. Th22 cells were also detected only in the intestinal mucosa. In addition, patients with MS showed an increased percentage of activated Th17 cells (eg, IL-17, IL-22, and T cells) in the intestinal mucosa, with an increased Th17:FoxP3+Treg cell ratio, compared with healthy controls. This finding indicated activation of effector Th17 cells in the gut mucosa.

“Our next goal is to determine how environmental factors such as diet can modulate MS pathogenesis through alterations of gut microbiota composition and intestinal immunity,” said Dr. Dalla Costa.

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

—Jeff Evans

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

—Jeff Evans

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

—Jeff Evans