ICYMI Multiple Sclerosis

COPENHAGEN—Time to severe disability in progressive multiple sclerosis (MS) is independently accelerated by both pre- and post-progression relapses, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Miguel M. Paz Soldan, MD, and colleagues examined the impact of relapses—both before and after progression onset—on the tempo of post-progression disability accumulation. The researchers studied two cohorts fulfilling McDonald diagnostic criteria for MS: a population-based prevalence cohort from Olmsted County, Minnesota (n = 221), and a clinic-based progressive cohort (n = 859). Progressive disease course was classified as either primary (PPMS), secondary (SPMS), or following a single clinical attack (SAPMS). Disability was assigned per Kurtzke Expanded Disability Status Scale (EDSS). The impact of relapses was studied using a multivariate Cox regression analysis. Gender, age at progression onset, and immunomodulatory medication use were modeled as covariates. Kaplan–Meier analysis was used to generate survival curves to an EDSS score of 6.

Presence of pre-progression relapses (hazard ratio 2.20) predicted shorter time from progression onset to an EDSS score of 6. Post-progression disability accumulation was slowest in patients with PPMS (50% of patients in 10 years), followed by patients with SAPMS (50% in seven years), and fastest in patients with SPMS (50% in four years). Post-progression relapses were more common in patients with SPMS (29.5%) than in patients with SAPMS (10.7%) and patients with PPMS (3.1%), reflecting the pre-progression relapse status in these groups. Ongoing relapses after onset of progressive disease course (17.1%; hazard ratio, 1.48) independently predicted shorter time from progression onset to EDSS score of 6, which was about two years faster. Most post-progression relapses happened within five years (91.6%) after onset of progression and before age 55 (95.2%).

“Our results suggest that continuation of immunomodulation for five years after progression onset or until age 55, whichever comes first, is a reasonable approach in SPMS,” the researchers stated. “However, given the paucity of ongoing relapses, this may not be indicated in SAPMS and PPMS.”

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Time to severe disability in progressive multiple sclerosis (MS) is independently accelerated by both pre- and post-progression relapses, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Miguel M. Paz Soldan, MD, and colleagues examined the impact of relapses—both before and after progression onset—on the tempo of post-progression disability accumulation. The researchers studied two cohorts fulfilling McDonald diagnostic criteria for MS: a population-based prevalence cohort from Olmsted County, Minnesota (n = 221), and a clinic-based progressive cohort (n = 859). Progressive disease course was classified as either primary (PPMS), secondary (SPMS), or following a single clinical attack (SAPMS). Disability was assigned per Kurtzke Expanded Disability Status Scale (EDSS). The impact of relapses was studied using a multivariate Cox regression analysis. Gender, age at progression onset, and immunomodulatory medication use were modeled as covariates. Kaplan–Meier analysis was used to generate survival curves to an EDSS score of 6.

Presence of pre-progression relapses (hazard ratio 2.20) predicted shorter time from progression onset to an EDSS score of 6. Post-progression disability accumulation was slowest in patients with PPMS (50% of patients in 10 years), followed by patients with SAPMS (50% in seven years), and fastest in patients with SPMS (50% in four years). Post-progression relapses were more common in patients with SPMS (29.5%) than in patients with SAPMS (10.7%) and patients with PPMS (3.1%), reflecting the pre-progression relapse status in these groups. Ongoing relapses after onset of progressive disease course (17.1%; hazard ratio, 1.48) independently predicted shorter time from progression onset to EDSS score of 6, which was about two years faster. Most post-progression relapses happened within five years (91.6%) after onset of progression and before age 55 (95.2%).

“Our results suggest that continuation of immunomodulation for five years after progression onset or until age 55, whichever comes first, is a reasonable approach in SPMS,” the researchers stated. “However, given the paucity of ongoing relapses, this may not be indicated in SAPMS and PPMS.”

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Time to severe disability in progressive multiple sclerosis (MS) is independently accelerated by both pre- and post-progression relapses, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Miguel M. Paz Soldan, MD, and colleagues examined the impact of relapses—both before and after progression onset—on the tempo of post-progression disability accumulation. The researchers studied two cohorts fulfilling McDonald diagnostic criteria for MS: a population-based prevalence cohort from Olmsted County, Minnesota (n = 221), and a clinic-based progressive cohort (n = 859). Progressive disease course was classified as either primary (PPMS), secondary (SPMS), or following a single clinical attack (SAPMS). Disability was assigned per Kurtzke Expanded Disability Status Scale (EDSS). The impact of relapses was studied using a multivariate Cox regression analysis. Gender, age at progression onset, and immunomodulatory medication use were modeled as covariates. Kaplan–Meier analysis was used to generate survival curves to an EDSS score of 6.

Presence of pre-progression relapses (hazard ratio 2.20) predicted shorter time from progression onset to an EDSS score of 6. Post-progression disability accumulation was slowest in patients with PPMS (50% of patients in 10 years), followed by patients with SAPMS (50% in seven years), and fastest in patients with SPMS (50% in four years). Post-progression relapses were more common in patients with SPMS (29.5%) than in patients with SAPMS (10.7%) and patients with PPMS (3.1%), reflecting the pre-progression relapse status in these groups. Ongoing relapses after onset of progressive disease course (17.1%; hazard ratio, 1.48) independently predicted shorter time from progression onset to EDSS score of 6, which was about two years faster. Most post-progression relapses happened within five years (91.6%) after onset of progression and before age 55 (95.2%).

“Our results suggest that continuation of immunomodulation for five years after progression onset or until age 55, whichever comes first, is a reasonable approach in SPMS,” the researchers stated. “However, given the paucity of ongoing relapses, this may not be indicated in SAPMS and PPMS.”

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Lipid-specific IgM bands contribute to identify JCV-positive patients at lower risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment, according to a report presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Lipid-specific IgM bands are associated with a suboptimal response to interferon beta in patients with MS. Consequently, many patients treated with natalizumab show these antibodies in their CSF. Luisa Maria Villar, PhD, from the Multiple Sclerosis Unit, Department of Immunology, Ramón y Cajal University Hospital, Madrid, and colleagues sought to determine whether PML risk may change in patients with and without these antibodies. The researchers conducted a multicenter study that included 307 patients with MS treated with natalizumab in 20 European hospitals. Anti-JC antibodies were measured in serum by a two-step enzyme-linked immunosorbent assay (ELISA). Lipid-specific IgM bands were measured by isoelectrofocusing and affinity blot in paired serum and CSF samples. Previous treatments with immunosuppressant drugs and treatment duration were recorded.

Nineteen patients developed PML during natalizumab treatment. Only one of them had lipid-specific IgM bands. However, 194 of the 288 patients (67.3%) who did not develop PML had these antibodies. The researchers then analyzed the risk of PML and observed a protective effect of lipid-specific IgM bands (odds ratio, 36.8). As described previously, the absence of anti-JC antibodies also showed a protective effect (odds ratio, 19.4).

To study the effect of the combination of the two variables, Dr. Villar and colleagues further classified anti-JC–positive patients according to lipid-specific IgM bands status. The researchers found that 65% had lipid-specific IgM bands, and 35% (47 patients) lacked these antibodies (anti-JC–positive, lipid-specific IgM band–negative). Seventeen patients of this group developed PML. When PML risk was analyzed, no differences were found between anti-JC–negative patients and anti-JC–positive, lipid-specific IgM band–positive ones. In contrast, the researchers found clear differences between these groups and anti-JC–positive, lipid-specific IgM band–negative patients, which accounted for 90% of PML cases (odds ratio, 59.8).

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Lipid-specific IgM bands contribute to identify JCV-positive patients at lower risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment, according to a report presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Lipid-specific IgM bands are associated with a suboptimal response to interferon beta in patients with MS. Consequently, many patients treated with natalizumab show these antibodies in their CSF. Luisa Maria Villar, PhD, from the Multiple Sclerosis Unit, Department of Immunology, Ramón y Cajal University Hospital, Madrid, and colleagues sought to determine whether PML risk may change in patients with and without these antibodies. The researchers conducted a multicenter study that included 307 patients with MS treated with natalizumab in 20 European hospitals. Anti-JC antibodies were measured in serum by a two-step enzyme-linked immunosorbent assay (ELISA). Lipid-specific IgM bands were measured by isoelectrofocusing and affinity blot in paired serum and CSF samples. Previous treatments with immunosuppressant drugs and treatment duration were recorded.

Nineteen patients developed PML during natalizumab treatment. Only one of them had lipid-specific IgM bands. However, 194 of the 288 patients (67.3%) who did not develop PML had these antibodies. The researchers then analyzed the risk of PML and observed a protective effect of lipid-specific IgM bands (odds ratio, 36.8). As described previously, the absence of anti-JC antibodies also showed a protective effect (odds ratio, 19.4).

To study the effect of the combination of the two variables, Dr. Villar and colleagues further classified anti-JC–positive patients according to lipid-specific IgM bands status. The researchers found that 65% had lipid-specific IgM bands, and 35% (47 patients) lacked these antibodies (anti-JC–positive, lipid-specific IgM band–negative). Seventeen patients of this group developed PML. When PML risk was analyzed, no differences were found between anti-JC–negative patients and anti-JC–positive, lipid-specific IgM band–positive ones. In contrast, the researchers found clear differences between these groups and anti-JC–positive, lipid-specific IgM band–negative patients, which accounted for 90% of PML cases (odds ratio, 59.8).

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Lipid-specific IgM bands contribute to identify JCV-positive patients at lower risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment, according to a report presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Lipid-specific IgM bands are associated with a suboptimal response to interferon beta in patients with MS. Consequently, many patients treated with natalizumab show these antibodies in their CSF. Luisa Maria Villar, PhD, from the Multiple Sclerosis Unit, Department of Immunology, Ramón y Cajal University Hospital, Madrid, and colleagues sought to determine whether PML risk may change in patients with and without these antibodies. The researchers conducted a multicenter study that included 307 patients with MS treated with natalizumab in 20 European hospitals. Anti-JC antibodies were measured in serum by a two-step enzyme-linked immunosorbent assay (ELISA). Lipid-specific IgM bands were measured by isoelectrofocusing and affinity blot in paired serum and CSF samples. Previous treatments with immunosuppressant drugs and treatment duration were recorded.

Nineteen patients developed PML during natalizumab treatment. Only one of them had lipid-specific IgM bands. However, 194 of the 288 patients (67.3%) who did not develop PML had these antibodies. The researchers then analyzed the risk of PML and observed a protective effect of lipid-specific IgM bands (odds ratio, 36.8). As described previously, the absence of anti-JC antibodies also showed a protective effect (odds ratio, 19.4).

To study the effect of the combination of the two variables, Dr. Villar and colleagues further classified anti-JC–positive patients according to lipid-specific IgM bands status. The researchers found that 65% had lipid-specific IgM bands, and 35% (47 patients) lacked these antibodies (anti-JC–positive, lipid-specific IgM band–negative). Seventeen patients of this group developed PML. When PML risk was analyzed, no differences were found between anti-JC–negative patients and anti-JC–positive, lipid-specific IgM band–positive ones. In contrast, the researchers found clear differences between these groups and anti-JC–positive, lipid-specific IgM band–negative patients, which accounted for 90% of PML cases (odds ratio, 59.8).

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Among patients with multiple sclerosis (MS) in the United States, the rate of relapses was substantially lower in patients who switched from interferon therapy to fingolimod, compared with those who switched to glatiramer acetate, according to a retrospective US claims database analysis presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Niklas Bergvall, PhD, from Novartis Pharma, Basel, Switzerland, and colleagues used US administrative claims data from the IMS PharMetrics Plus Database to compare relapse rates among patients with MS who switched from interferon to fingolimod or glatiramer acetate between October 1, 2010, and September 30, 2011. According to the researchers’ retrospective analysis study protocol, patients needed to switch within 90 days of discontinuing interferon therapy. In addition, patients must have had a diagnosis code for MS within 360 days of the switch (ie, the total period during which the patients were followed).

The occurrence of any type of relapse (identified using a claims-based algorithm) while persistent to fingolimod or glatiramer acetate (period prior to a gap of more than 60 days or switch to another disease-modifying therapy) was measured over 360 days following the switch. The probability of having one or more relapses was estimated using a multivariate logistic regression model, and differences in the rate of relapses were assessed using a multivariate generalized linear model with a negative binomial distribution.

The total sample included 408 patients—198 patients who switched to fingolimod and 210 patients who switched to glatiramer acetate. Before switching, 32.3% and 49.0% of patients had one or more relapses in the fingolimod and glatiramer acetate cohorts, respectively.

In unadjusted analyses, the proportion of patients with one or more relapses during the persistence period was lower for patients treated with fingolimod (16.7%) than for those treated with glatiramer acetate (29.5%) despite a longer mean persistence period (307 vs 282 days for the fingolimod and glatiramer acetate cohorts, respectively). In the persistence period, annualized relapse rates were lower in the fingolimod cohort (0.27) than in the glatiramer acetate cohort (0.55).

After adjusting for baseline differences, the researchers found that patients treated with fingolimod had a 61% reduced probability of having a relapse and 53% fewer relapses per year during the persistence period, compared with patients who switched to glatiramer acetate.

In a related study, Dr. Bergvall and colleagues used the same claims database to compare relapse rates among patients with MS with a history of relapses who were initiated on fingolimod versus interferon or glatiramer acetate.

This study included patients with one or more prescription or administration claims for fingolimod, any interferon, or glatiramer acetate during the same time frame as the previous study (between October 1, 2010, and September 30, 2011). Again, patients had to have an MS diagnosis code and one or more relapses in the 360 days before disease-modifying therapy was initiated and no claim for disease-modifying therapy in the previous 360 days. Patients with prior evidence of fingolimod and another disease-modifying therapy were preferentially assigned to the fingolimod cohort to preserve sample size.

The number of relapses observed while persistent on index disease-modifying therapy (period before a gap of more than 60 days or switch to another disease-modifying therapy) was measured for patients with a 540-day follow-up. The adjusted probability of having one or more relapse was estimated using a logistic regression model, and differences in relapse rates were assessed using a generalized linear model with a negative binomial distribution.

This study included 525 patients (128 on fingolimod and 397 on interferon or glatiramer acetate). Annualized relapse rates in the 360-day pre-index period were 1.70 and 1.26, respectively. In unadjusted analyses, the proportion of patients with one or more relapses during the persistence period was marginally lower in patients treated with fingolimod, compared with interferon or glatiramer acetate (31.3% vs 34.0%), despite a longer mean persistence period (382 vs 341 days, respectively). Annualized relapses over the persistence period were also lower in the fingolimod cohort (0.50), compared with the interferon or glatiramer acetate cohort (0.55) in unadjusted analyses.

After controlling for baseline differences, the investigators found that fingolimod was associated with a 52% reduced probability of experiencing a relapse and 50% fewer relapses, compared with interferon or glatiramer acetate. Point estimates from comparisons of fingolimod versus separate interferon and glatiramer acetate cohorts were identical (50% reduction in relapses).

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Among patients with multiple sclerosis (MS) in the United States, the rate of relapses was substantially lower in patients who switched from interferon therapy to fingolimod, compared with those who switched to glatiramer acetate, according to a retrospective US claims database analysis presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Niklas Bergvall, PhD, from Novartis Pharma, Basel, Switzerland, and colleagues used US administrative claims data from the IMS PharMetrics Plus Database to compare relapse rates among patients with MS who switched from interferon to fingolimod or glatiramer acetate between October 1, 2010, and September 30, 2011. According to the researchers’ retrospective analysis study protocol, patients needed to switch within 90 days of discontinuing interferon therapy. In addition, patients must have had a diagnosis code for MS within 360 days of the switch (ie, the total period during which the patients were followed).

The occurrence of any type of relapse (identified using a claims-based algorithm) while persistent to fingolimod or glatiramer acetate (period prior to a gap of more than 60 days or switch to another disease-modifying therapy) was measured over 360 days following the switch. The probability of having one or more relapses was estimated using a multivariate logistic regression model, and differences in the rate of relapses were assessed using a multivariate generalized linear model with a negative binomial distribution.

The total sample included 408 patients—198 patients who switched to fingolimod and 210 patients who switched to glatiramer acetate. Before switching, 32.3% and 49.0% of patients had one or more relapses in the fingolimod and glatiramer acetate cohorts, respectively.

In unadjusted analyses, the proportion of patients with one or more relapses during the persistence period was lower for patients treated with fingolimod (16.7%) than for those treated with glatiramer acetate (29.5%) despite a longer mean persistence period (307 vs 282 days for the fingolimod and glatiramer acetate cohorts, respectively). In the persistence period, annualized relapse rates were lower in the fingolimod cohort (0.27) than in the glatiramer acetate cohort (0.55).

After adjusting for baseline differences, the researchers found that patients treated with fingolimod had a 61% reduced probability of having a relapse and 53% fewer relapses per year during the persistence period, compared with patients who switched to glatiramer acetate.

In a related study, Dr. Bergvall and colleagues used the same claims database to compare relapse rates among patients with MS with a history of relapses who were initiated on fingolimod versus interferon or glatiramer acetate.

This study included patients with one or more prescription or administration claims for fingolimod, any interferon, or glatiramer acetate during the same time frame as the previous study (between October 1, 2010, and September 30, 2011). Again, patients had to have an MS diagnosis code and one or more relapses in the 360 days before disease-modifying therapy was initiated and no claim for disease-modifying therapy in the previous 360 days. Patients with prior evidence of fingolimod and another disease-modifying therapy were preferentially assigned to the fingolimod cohort to preserve sample size.

The number of relapses observed while persistent on index disease-modifying therapy (period before a gap of more than 60 days or switch to another disease-modifying therapy) was measured for patients with a 540-day follow-up. The adjusted probability of having one or more relapse was estimated using a logistic regression model, and differences in relapse rates were assessed using a generalized linear model with a negative binomial distribution.

This study included 525 patients (128 on fingolimod and 397 on interferon or glatiramer acetate). Annualized relapse rates in the 360-day pre-index period were 1.70 and 1.26, respectively. In unadjusted analyses, the proportion of patients with one or more relapses during the persistence period was marginally lower in patients treated with fingolimod, compared with interferon or glatiramer acetate (31.3% vs 34.0%), despite a longer mean persistence period (382 vs 341 days, respectively). Annualized relapses over the persistence period were also lower in the fingolimod cohort (0.50), compared with the interferon or glatiramer acetate cohort (0.55) in unadjusted analyses.

After controlling for baseline differences, the investigators found that fingolimod was associated with a 52% reduced probability of experiencing a relapse and 50% fewer relapses, compared with interferon or glatiramer acetate. Point estimates from comparisons of fingolimod versus separate interferon and glatiramer acetate cohorts were identical (50% reduction in relapses).

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Among patients with multiple sclerosis (MS) in the United States, the rate of relapses was substantially lower in patients who switched from interferon therapy to fingolimod, compared with those who switched to glatiramer acetate, according to a retrospective US claims database analysis presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Niklas Bergvall, PhD, from Novartis Pharma, Basel, Switzerland, and colleagues used US administrative claims data from the IMS PharMetrics Plus Database to compare relapse rates among patients with MS who switched from interferon to fingolimod or glatiramer acetate between October 1, 2010, and September 30, 2011. According to the researchers’ retrospective analysis study protocol, patients needed to switch within 90 days of discontinuing interferon therapy. In addition, patients must have had a diagnosis code for MS within 360 days of the switch (ie, the total period during which the patients were followed).

The occurrence of any type of relapse (identified using a claims-based algorithm) while persistent to fingolimod or glatiramer acetate (period prior to a gap of more than 60 days or switch to another disease-modifying therapy) was measured over 360 days following the switch. The probability of having one or more relapses was estimated using a multivariate logistic regression model, and differences in the rate of relapses were assessed using a multivariate generalized linear model with a negative binomial distribution.

The total sample included 408 patients—198 patients who switched to fingolimod and 210 patients who switched to glatiramer acetate. Before switching, 32.3% and 49.0% of patients had one or more relapses in the fingolimod and glatiramer acetate cohorts, respectively.

In unadjusted analyses, the proportion of patients with one or more relapses during the persistence period was lower for patients treated with fingolimod (16.7%) than for those treated with glatiramer acetate (29.5%) despite a longer mean persistence period (307 vs 282 days for the fingolimod and glatiramer acetate cohorts, respectively). In the persistence period, annualized relapse rates were lower in the fingolimod cohort (0.27) than in the glatiramer acetate cohort (0.55).

After adjusting for baseline differences, the researchers found that patients treated with fingolimod had a 61% reduced probability of having a relapse and 53% fewer relapses per year during the persistence period, compared with patients who switched to glatiramer acetate.

In a related study, Dr. Bergvall and colleagues used the same claims database to compare relapse rates among patients with MS with a history of relapses who were initiated on fingolimod versus interferon or glatiramer acetate.

This study included patients with one or more prescription or administration claims for fingolimod, any interferon, or glatiramer acetate during the same time frame as the previous study (between October 1, 2010, and September 30, 2011). Again, patients had to have an MS diagnosis code and one or more relapses in the 360 days before disease-modifying therapy was initiated and no claim for disease-modifying therapy in the previous 360 days. Patients with prior evidence of fingolimod and another disease-modifying therapy were preferentially assigned to the fingolimod cohort to preserve sample size.

The number of relapses observed while persistent on index disease-modifying therapy (period before a gap of more than 60 days or switch to another disease-modifying therapy) was measured for patients with a 540-day follow-up. The adjusted probability of having one or more relapse was estimated using a logistic regression model, and differences in relapse rates were assessed using a generalized linear model with a negative binomial distribution.

This study included 525 patients (128 on fingolimod and 397 on interferon or glatiramer acetate). Annualized relapse rates in the 360-day pre-index period were 1.70 and 1.26, respectively. In unadjusted analyses, the proportion of patients with one or more relapses during the persistence period was marginally lower in patients treated with fingolimod, compared with interferon or glatiramer acetate (31.3% vs 34.0%), despite a longer mean persistence period (382 vs 341 days, respectively). Annualized relapses over the persistence period were also lower in the fingolimod cohort (0.50), compared with the interferon or glatiramer acetate cohort (0.55) in unadjusted analyses.

After controlling for baseline differences, the investigators found that fingolimod was associated with a 52% reduced probability of experiencing a relapse and 50% fewer relapses, compared with interferon or glatiramer acetate. Point estimates from comparisons of fingolimod versus separate interferon and glatiramer acetate cohorts were identical (50% reduction in relapses).

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) is meeting for its 29th Annual Congress in Copenhagen from October 2 to 5. Conference organizers estimate approximately 8,000 participants are attending, making it the world’s premier conference on the science, research, and management of MS.

“I am very pleased about the development of our Congress,” said ECTRIMS President Maria Trojano, MD. The ECTRIMS meeting “has indisputably become the number one international event, as reflected in the record number of submissions from non-European countries and in participant registrations,” she said.

This year’s ECTRIMS Congress features four days of scientific sessions and includes more than 1,000 presentations selected from 1,500 abstracts submitted. The number of abstracts submitted this year represents a 10% increase over last year’s number. The conference program features 29 oral sessions, 14 teaching courses, and 12 satellite symposiums. Thirty companies are exhibiting at the meeting.

Topics that were discussed included genetics and gender differences in MS, including a possible explanation for the increase in women with MS over the past several decades. Also discussed were the mechanism of inflammation and tissue damage and the subsequent remyelination, as well as new scanning techniques for imaging the brain.

Several sessions were devoted to state-of-the-art management of MS with new and future treatments. Treatment of progressive forms of MS was also covered. This year’s ECTRIMS Congress is held in conjunction with the 18th Annual Conference of Rehabilitation in Multiple Sclerosis (RIMS). This joint sponsorship brings opportunities to discuss neuropsychologic challenges and progress in MS rehabilitation. Another special feature of this year’s meeting was the debut of two sessions developed with and for nurses, focusing on how to support families affected by MS.

Hot topics at ECTRIMS 2013 included gene environment interactions, micro RNA, and the effect of the gut microbiome on the susceptibility to MS. A session focused on functional imaging, and researchers debated on whether immunomodulatory treatment can change the natural history of MS.

The 2013 meeting marks the second time that Copenhagen has hosted an ECTRIMS Congress. To commemorate the event, the opening ceremony included a welcome address given by Her Majesty Margrethe II, Queen of Denmark.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) is meeting for its 29th Annual Congress in Copenhagen from October 2 to 5. Conference organizers estimate approximately 8,000 participants are attending, making it the world’s premier conference on the science, research, and management of MS.

“I am very pleased about the development of our Congress,” said ECTRIMS President Maria Trojano, MD. The ECTRIMS meeting “has indisputably become the number one international event, as reflected in the record number of submissions from non-European countries and in participant registrations,” she said.

This year’s ECTRIMS Congress features four days of scientific sessions and includes more than 1,000 presentations selected from 1,500 abstracts submitted. The number of abstracts submitted this year represents a 10% increase over last year’s number. The conference program features 29 oral sessions, 14 teaching courses, and 12 satellite symposiums. Thirty companies are exhibiting at the meeting.

Topics that were discussed included genetics and gender differences in MS, including a possible explanation for the increase in women with MS over the past several decades. Also discussed were the mechanism of inflammation and tissue damage and the subsequent remyelination, as well as new scanning techniques for imaging the brain.

Several sessions were devoted to state-of-the-art management of MS with new and future treatments. Treatment of progressive forms of MS was also covered. This year’s ECTRIMS Congress is held in conjunction with the 18th Annual Conference of Rehabilitation in Multiple Sclerosis (RIMS). This joint sponsorship brings opportunities to discuss neuropsychologic challenges and progress in MS rehabilitation. Another special feature of this year’s meeting was the debut of two sessions developed with and for nurses, focusing on how to support families affected by MS.

Hot topics at ECTRIMS 2013 included gene environment interactions, micro RNA, and the effect of the gut microbiome on the susceptibility to MS. A session focused on functional imaging, and researchers debated on whether immunomodulatory treatment can change the natural history of MS.

The 2013 meeting marks the second time that Copenhagen has hosted an ECTRIMS Congress. To commemorate the event, the opening ceremony included a welcome address given by Her Majesty Margrethe II, Queen of Denmark.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) is meeting for its 29th Annual Congress in Copenhagen from October 2 to 5. Conference organizers estimate approximately 8,000 participants are attending, making it the world’s premier conference on the science, research, and management of MS.

“I am very pleased about the development of our Congress,” said ECTRIMS President Maria Trojano, MD. The ECTRIMS meeting “has indisputably become the number one international event, as reflected in the record number of submissions from non-European countries and in participant registrations,” she said.

This year’s ECTRIMS Congress features four days of scientific sessions and includes more than 1,000 presentations selected from 1,500 abstracts submitted. The number of abstracts submitted this year represents a 10% increase over last year’s number. The conference program features 29 oral sessions, 14 teaching courses, and 12 satellite symposiums. Thirty companies are exhibiting at the meeting.

Topics that were discussed included genetics and gender differences in MS, including a possible explanation for the increase in women with MS over the past several decades. Also discussed were the mechanism of inflammation and tissue damage and the subsequent remyelination, as well as new scanning techniques for imaging the brain.

Several sessions were devoted to state-of-the-art management of MS with new and future treatments. Treatment of progressive forms of MS was also covered. This year’s ECTRIMS Congress is held in conjunction with the 18th Annual Conference of Rehabilitation in Multiple Sclerosis (RIMS). This joint sponsorship brings opportunities to discuss neuropsychologic challenges and progress in MS rehabilitation. Another special feature of this year’s meeting was the debut of two sessions developed with and for nurses, focusing on how to support families affected by MS.

Hot topics at ECTRIMS 2013 included gene environment interactions, micro RNA, and the effect of the gut microbiome on the susceptibility to MS. A session focused on functional imaging, and researchers debated on whether immunomodulatory treatment can change the natural history of MS.

The 2013 meeting marks the second time that Copenhagen has hosted an ECTRIMS Congress. To commemorate the event, the opening ceremony included a welcome address given by Her Majesty Margrethe II, Queen of Denmark.

—Glenn S. Williams
Vice President/Group Editor

ORLANDO—Patients with secondary progressive multiple sclerosis (SPMS) have impaired regulation, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Compared with healthy subjects, patients with SPMS have reduced frequencies of Tr1 precursors, Tr1 cells, and nT_reg cells. The nT_reg cells in patients with SPMS, however, maintain levels of FOXP3 and CD39 similar to those of healthy controls.

Healthy subjects examined with multicolor flow cytometry had greater numbers of inhibitory PD-L1+ and HLA-G+ monocytes than did patients with SPMS, said Lauren W. Collison, PhD, Director of Immunology at Opexa Therapeutics in The Woodlands, Texas. In patients with SPMS, the memory T cell compartment had increased levels of Th17 and decreased numbers of Th2 cells, compared with controls. Controls had higher levels of Th1 cells than of Th17 cells, but the opposite was true for patients with SPMS.

Using an acoustic focusing flow cytometer, Dr. Collison and colleagues characterized peripheral blood mononuclear cells from healthy subjects and patients with SPMS. They analyzed the samples with multicolor flow cytometry using 16 six-color marker panels.

The researchers determined specificity by comparing test molecules to isotype-matched controls or by preincubating test molecules with clonally matched purified blocking monoclonal antibodies. They performed t-test analysis to determine the statistical significance of any difference between means of healthy donors and of patients with SPMS.

The number of regulatory T cells, both adaptive/peripherally generated TR1 cells and natural/thymic derived nT_reg cells, was determined in healthy subjects and patients with SPMS. The mean percentage of TR1 precursor cells (CD4+CD18^brightCD49b+) and TR1 cells (CD4+CD45RA-LAG3+CD49b+) was significantly greater among healthy subjects, when compared to patients with SPMS. Non-TR1 cell numbers (CD8+CD18^brightCD49b+ or CD4+CD45RA-LAG3+CD49b+) were similar for both groups.

Healthy donors also trended toward a greater frequency of CD4+ nT_regs. A greater percentage of CD4+ T cells were FOXP3 nT_reg cells in controls, compared with patients with SPMS. The mean fluorescence intensity of FOXP3 nT_reg cells was similar for both subject groups.

Similarly, a greater percentage of CD4+ T cells in healthy donors was CD25^bright nT_reg cells, when compared with patients with SPMS. However, among CD4+ nT_reg cells, CD39 expression was comparable in healthy donors and subjects with SPMS.

—Erik Greb
Senior Associate Editor

ORLANDO—Patients with secondary progressive multiple sclerosis (SPMS) have impaired regulation, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Compared with healthy subjects, patients with SPMS have reduced frequencies of Tr1 precursors, Tr1 cells, and nT_reg cells. The nT_reg cells in patients with SPMS, however, maintain levels of FOXP3 and CD39 similar to those of healthy controls.

Healthy subjects examined with multicolor flow cytometry had greater numbers of inhibitory PD-L1+ and HLA-G+ monocytes than did patients with SPMS, said Lauren W. Collison, PhD, Director of Immunology at Opexa Therapeutics in The Woodlands, Texas. In patients with SPMS, the memory T cell compartment had increased levels of Th17 and decreased numbers of Th2 cells, compared with controls. Controls had higher levels of Th1 cells than of Th17 cells, but the opposite was true for patients with SPMS.

Using an acoustic focusing flow cytometer, Dr. Collison and colleagues characterized peripheral blood mononuclear cells from healthy subjects and patients with SPMS. They analyzed the samples with multicolor flow cytometry using 16 six-color marker panels.

The researchers determined specificity by comparing test molecules to isotype-matched controls or by preincubating test molecules with clonally matched purified blocking monoclonal antibodies. They performed t-test analysis to determine the statistical significance of any difference between means of healthy donors and of patients with SPMS.

The number of regulatory T cells, both adaptive/peripherally generated TR1 cells and natural/thymic derived nT_reg cells, was determined in healthy subjects and patients with SPMS. The mean percentage of TR1 precursor cells (CD4+CD18^brightCD49b+) and TR1 cells (CD4+CD45RA-LAG3+CD49b+) was significantly greater among healthy subjects, when compared to patients with SPMS. Non-TR1 cell numbers (CD8+CD18^brightCD49b+ or CD4+CD45RA-LAG3+CD49b+) were similar for both groups.

Healthy donors also trended toward a greater frequency of CD4+ nT_regs. A greater percentage of CD4+ T cells were FOXP3 nT_reg cells in controls, compared with patients with SPMS. The mean fluorescence intensity of FOXP3 nT_reg cells was similar for both subject groups.

Similarly, a greater percentage of CD4+ T cells in healthy donors was CD25^bright nT_reg cells, when compared with patients with SPMS. However, among CD4+ nT_reg cells, CD39 expression was comparable in healthy donors and subjects with SPMS.

—Erik Greb
Senior Associate Editor

ORLANDO—Patients with secondary progressive multiple sclerosis (SPMS) have impaired regulation, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Compared with healthy subjects, patients with SPMS have reduced frequencies of Tr1 precursors, Tr1 cells, and nT_reg cells. The nT_reg cells in patients with SPMS, however, maintain levels of FOXP3 and CD39 similar to those of healthy controls.

Healthy subjects examined with multicolor flow cytometry had greater numbers of inhibitory PD-L1+ and HLA-G+ monocytes than did patients with SPMS, said Lauren W. Collison, PhD, Director of Immunology at Opexa Therapeutics in The Woodlands, Texas. In patients with SPMS, the memory T cell compartment had increased levels of Th17 and decreased numbers of Th2 cells, compared with controls. Controls had higher levels of Th1 cells than of Th17 cells, but the opposite was true for patients with SPMS.

Using an acoustic focusing flow cytometer, Dr. Collison and colleagues characterized peripheral blood mononuclear cells from healthy subjects and patients with SPMS. They analyzed the samples with multicolor flow cytometry using 16 six-color marker panels.

The researchers determined specificity by comparing test molecules to isotype-matched controls or by preincubating test molecules with clonally matched purified blocking monoclonal antibodies. They performed t-test analysis to determine the statistical significance of any difference between means of healthy donors and of patients with SPMS.

The number of regulatory T cells, both adaptive/peripherally generated TR1 cells and natural/thymic derived nT_reg cells, was determined in healthy subjects and patients with SPMS. The mean percentage of TR1 precursor cells (CD4+CD18^brightCD49b+) and TR1 cells (CD4+CD45RA-LAG3+CD49b+) was significantly greater among healthy subjects, when compared to patients with SPMS. Non-TR1 cell numbers (CD8+CD18^brightCD49b+ or CD4+CD45RA-LAG3+CD49b+) were similar for both groups.

Healthy donors also trended toward a greater frequency of CD4+ nT_regs. A greater percentage of CD4+ T cells were FOXP3 nT_reg cells in controls, compared with patients with SPMS. The mean fluorescence intensity of FOXP3 nT_reg cells was similar for both subject groups.

Similarly, a greater percentage of CD4+ T cells in healthy donors was CD25^bright nT_reg cells, when compared with patients with SPMS. However, among CD4+ nT_reg cells, CD39 expression was comparable in healthy donors and subjects with SPMS.

—Erik Greb
Senior Associate Editor

A large multicenter study published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry points to the complementary value of brain atrophy and lesion volumes for predicting long-term disability in multiple sclerosis (MS).

Although predictors of short- and medium-term clinical progression have been identified, the longer-term clinical prognostic value of brain atrophy measures and lesion volumes has been studied less extensively. “Our finding may help develop predictors of future disability in MS that could be used in clinical trials and eventually also for predicting the evolution of individual patients,” the researchers said.

Veronica Popescu, MD, MSc, of the Department of Radiology and Nuclear Medicine at VU University Medical Center in Amsterdam, and colleagues from the MAGNIMS study group sought to determine the prognostic value for 10-year disability of whole brain atrophy, central brain atrophy, and T2 lesion volumes in a large MS patient group, taking into account disease type, disease-modifying treatment, and initial clinical status. The researchers conducted a longitudinal, retrospective study with short-term serial MRI data and long-term clinical follow-up. Inclusion criteria comprised two MRI scans performed using the same protocol with a one- to two-year interval, baseline scan before January 1, 2000, and an MS diagnosis at 10 years of follow-up according to the McDonald criteria.

The researchers investigated long-term clinical associations with retrospective MR disease measures in 261 patients drawn from a multicenter MS group with all major disease subtypes and clinical follow-up at 10 years. Patients were categorized by baseline diagnosis as primary progressive (n = 77), secondary progressive (n = 69), relapsing-remitting (n = 97), and clinically isolated syndromes (n = 18). Relapse onset patients were classified as minimally impaired or moderately impaired based on their baseline disability, regardless of disease type.

Despite the characteristic variability among patients with MS, the most prominent predictive value was attributed to clinical variables such as baseline Expanded Disability Status Scale (EDSS), disease type, treatment, and imaging protocol. However, the researchers noted associations between MR measures—both cross-sectional and longitudinal—and clinical status 10 years later.

In the whole group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS, and treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS in the whole group and in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients, lesion volumes in moderately impaired relapse onset patients, and whole brain atrophy in primary progressive MS.

—Glenn S. Williams
Vice President/Group Editor

A large multicenter study published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry points to the complementary value of brain atrophy and lesion volumes for predicting long-term disability in multiple sclerosis (MS).

Although predictors of short- and medium-term clinical progression have been identified, the longer-term clinical prognostic value of brain atrophy measures and lesion volumes has been studied less extensively. “Our finding may help develop predictors of future disability in MS that could be used in clinical trials and eventually also for predicting the evolution of individual patients,” the researchers said.

Veronica Popescu, MD, MSc, of the Department of Radiology and Nuclear Medicine at VU University Medical Center in Amsterdam, and colleagues from the MAGNIMS study group sought to determine the prognostic value for 10-year disability of whole brain atrophy, central brain atrophy, and T2 lesion volumes in a large MS patient group, taking into account disease type, disease-modifying treatment, and initial clinical status. The researchers conducted a longitudinal, retrospective study with short-term serial MRI data and long-term clinical follow-up. Inclusion criteria comprised two MRI scans performed using the same protocol with a one- to two-year interval, baseline scan before January 1, 2000, and an MS diagnosis at 10 years of follow-up according to the McDonald criteria.

The researchers investigated long-term clinical associations with retrospective MR disease measures in 261 patients drawn from a multicenter MS group with all major disease subtypes and clinical follow-up at 10 years. Patients were categorized by baseline diagnosis as primary progressive (n = 77), secondary progressive (n = 69), relapsing-remitting (n = 97), and clinically isolated syndromes (n = 18). Relapse onset patients were classified as minimally impaired or moderately impaired based on their baseline disability, regardless of disease type.

Despite the characteristic variability among patients with MS, the most prominent predictive value was attributed to clinical variables such as baseline Expanded Disability Status Scale (EDSS), disease type, treatment, and imaging protocol. However, the researchers noted associations between MR measures—both cross-sectional and longitudinal—and clinical status 10 years later.

In the whole group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS, and treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS in the whole group and in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients, lesion volumes in moderately impaired relapse onset patients, and whole brain atrophy in primary progressive MS.

—Glenn S. Williams
Vice President/Group Editor

A large multicenter study published in the October issue of the Journal of Neurology, Neurosurgery and Psychiatry points to the complementary value of brain atrophy and lesion volumes for predicting long-term disability in multiple sclerosis (MS).

Although predictors of short- and medium-term clinical progression have been identified, the longer-term clinical prognostic value of brain atrophy measures and lesion volumes has been studied less extensively. “Our finding may help develop predictors of future disability in MS that could be used in clinical trials and eventually also for predicting the evolution of individual patients,” the researchers said.

Veronica Popescu, MD, MSc, of the Department of Radiology and Nuclear Medicine at VU University Medical Center in Amsterdam, and colleagues from the MAGNIMS study group sought to determine the prognostic value for 10-year disability of whole brain atrophy, central brain atrophy, and T2 lesion volumes in a large MS patient group, taking into account disease type, disease-modifying treatment, and initial clinical status. The researchers conducted a longitudinal, retrospective study with short-term serial MRI data and long-term clinical follow-up. Inclusion criteria comprised two MRI scans performed using the same protocol with a one- to two-year interval, baseline scan before January 1, 2000, and an MS diagnosis at 10 years of follow-up according to the McDonald criteria.

The researchers investigated long-term clinical associations with retrospective MR disease measures in 261 patients drawn from a multicenter MS group with all major disease subtypes and clinical follow-up at 10 years. Patients were categorized by baseline diagnosis as primary progressive (n = 77), secondary progressive (n = 69), relapsing-remitting (n = 97), and clinically isolated syndromes (n = 18). Relapse onset patients were classified as minimally impaired or moderately impaired based on their baseline disability, regardless of disease type.

Despite the characteristic variability among patients with MS, the most prominent predictive value was attributed to clinical variables such as baseline Expanded Disability Status Scale (EDSS), disease type, treatment, and imaging protocol. However, the researchers noted associations between MR measures—both cross-sectional and longitudinal—and clinical status 10 years later.

In the whole group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS, and treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10-year EDSS in the whole group and in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients, lesion volumes in moderately impaired relapse onset patients, and whole brain atrophy in primary progressive MS.

—Glenn S. Williams
Vice President/Group Editor

The first case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) treated with fingolimod who had not also been treated with natalizumab, according to the FDA.

The patient was diagnosed with PML after almost eight months of treatment with fingolimod, a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient received one month of treatment with interferon beta-1a and azathioprine prior to beginning fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with “multiple courses” of IV corticosteroids for several months before and during treatment with fingolimod.

Treatment with fingolimod was discontinued after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in CSF, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

After several PML cases were reported in patients with MS treated with natalizumab months after it was approved in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis, the drug’s manufacturer, to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug “may therefore increase the risk of infections, some serious in nature,” but PML is not mentioned. The label also says that the drug has not been administered with antineoplastic, immunosuppressive, or immune-modulating therapies used to treat MS and that use of fingolimod with any of these treatments “would be expected to increase the risk of immunosuppression.”

Fingolimod was approved with a risk evaluation and mitigation strategy addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

—Elizabeth Mechcatie
IMNG Medical News

The first case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) treated with fingolimod who had not also been treated with natalizumab, according to the FDA.

The patient was diagnosed with PML after almost eight months of treatment with fingolimod, a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient received one month of treatment with interferon beta-1a and azathioprine prior to beginning fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with “multiple courses” of IV corticosteroids for several months before and during treatment with fingolimod.

Treatment with fingolimod was discontinued after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in CSF, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

After several PML cases were reported in patients with MS treated with natalizumab months after it was approved in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis, the drug’s manufacturer, to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug “may therefore increase the risk of infections, some serious in nature,” but PML is not mentioned. The label also says that the drug has not been administered with antineoplastic, immunosuppressive, or immune-modulating therapies used to treat MS and that use of fingolimod with any of these treatments “would be expected to increase the risk of immunosuppression.”

Fingolimod was approved with a risk evaluation and mitigation strategy addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

—Elizabeth Mechcatie
IMNG Medical News

The first case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient with multiple sclerosis (MS) treated with fingolimod who had not also been treated with natalizumab, according to the FDA.

The patient was diagnosed with PML after almost eight months of treatment with fingolimod, a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient received one month of treatment with interferon beta-1a and azathioprine prior to beginning fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with “multiple courses” of IV corticosteroids for several months before and during treatment with fingolimod.

Treatment with fingolimod was discontinued after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in CSF, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

After several PML cases were reported in patients with MS treated with natalizumab months after it was approved in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis, the drug’s manufacturer, to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug “may therefore increase the risk of infections, some serious in nature,” but PML is not mentioned. The label also says that the drug has not been administered with antineoplastic, immunosuppressive, or immune-modulating therapies used to treat MS and that use of fingolimod with any of these treatments “would be expected to increase the risk of immunosuppression.”

Fingolimod was approved with a risk evaluation and mitigation strategy addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

—Elizabeth Mechcatie
IMNG Medical News

ORLANDO—Cannabis may be a safe and effective therapy for pain and spasticity in patients with multiple sclerosis (MS), according to an overview presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. The route of administration and the dose influence the drug’s physical and psychotropic effects.

Approximately 46% of patients with MS smoke marijuana for pain, tremor, insomnia, bladder problems, or spasticity, said Heidi Maloni, PhD, nurse practitioner at the Veterans Affairs Medical Center in Washington, DC. Although smoking the herbal form of cannabis is associated with several health concerns, oral and buccal sprays appear to entail fewer risks.

Nabiximols May Receive FDA Approval Soon
Nabiximols, a liquid extract of two strains of cloned Cannabis sativa, is formulated as an oromucosal spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. THC is the psychoactive chemical in marijuana, and CBD counteracts this psychoactive effect. Each spray of nabiximols contains 100 µL of cannabis, and the suggested maximum dose is 33.8 mg/day.

Three clinical trials conducted since 2010 suggest that nabiximols effectively reduces MS-related pain that otherwise resists pharmacologic intervention. Patients did not develop tolerance to nabiximols, and cessation of treatment was not associated with symptoms of withdrawal. In several clinical trials that included 930 patients who took nabiximols, 27.5% of patients who took the drug had dizziness, 13.1% had diarrhea, and 11% had fatigue. Less than 1% of patients had a cannabis high. Slow titration of the drug over 10 days helped to reduce the occurrence of serious adverse events.

Unlike smoked cannabis, nabiximols was not associated with memory impairment, sedation, or intoxication. The drug’s effect on pain intensity generally is evident within four weeks of treatment. The cost efficacy of nabiximols remains to be established, however. Authorities in the United Kingdom do not consider nabiximols to be cost effective when compared with baclofen and tizanidine.

The drug is an approved treatment for MS-related spasticity and pain in the United Kingdom, Canada, New Zealand, and eight European countries. The FDA is expected to approve the drug in December 2013, said Dr. Maloni.

Smoked Cannabis Is Associated With Cognitive Impairment
Unlike cannabis-based extracts such as nabiximols, which generally take 90 minutes to reach the brain and cause an effect, smoked cannabis reaches its peak concentration in the body in 10 minutes. In clinical trials of smoked cannabis, during which patients received between 4 and 128 mg/day of THC, pain intensity decreased by at least 30% for all participants. This result reflected an important improvement on quality of life, said Dr. Maloni. The medium dose of THC was as effective as the high dose.

In a 2012 study, scores on the visual analog scale of pain decreased by five points—a “huge” difference—among patients who smoked cannabis for MS-related pain, said Dr. Maloni. Mean scores on the Paced Auditory Serial Addition Test, however, decreased by eight points among patients who smoked cannabis, compared with controls.

A Canadian study published in Neurology compared patients with MS who smoked cannabis with patients who did not smoke it. Participants underwent cognitive testing after a 12-hour period during which no subject smoked cannabis. Scores on all aspects of cognition, including visuospatial ability, executive function, and short-term memory, were 30% worse for patients who smoked cannabis than for controls. Because MS itself can entail cognitive problems, smoked cannabis can be problematic for patients with the disease, said Dr. Maloni.

Smoked cannabis also entails other concerns. About 10% of people who smoke the drug develop dependence, and people who stop smoking it may have withdrawal symptoms. Smoked cannabis is associated with tachycardia, cardiovascular disease, and elevated blood pressure and heart rate. And because cannabis is an anticholinergic, it can cause problems for MS patients’ eyes. “You want to be careful with anything that’s going to dry them out,” said Dr. Maloni.

Oral Cannabis Is Least Popular Among Patients
Synthetic cannabis is available in oral tablets and capsules, but patients express the least satisfaction with this form of the drug because it is subject to the cytochrome P450 system and is metabolized by the liver, said Dr. Maloni. The bioavailability of oral cannabis ranges between 5% and 20%.

Dronabinol, a synthetic THC, is available in 2.5-, 5-, and 10-mg oral capsules. A 10- to 20-mg dose of THC has an analgesic effect equivalent to that of 60 to 120 mg of codeine. In one study, dronabinol was associated with subjective improvement in spasticity, pain, and relapse rate in patients with MS. Dronabinol is approved in the United States for the treatment of chemotherapy-related nausea and vomiting and the treatment of weight loss related to wasting syndromes.

Nabilone, a synthetic CB1 and CB2 receptor agonist, is also approved in the US for the treatment of chemotherapy-related nausea and vomiting. Studies of 0.5- to 1-mg doses of nabilone in patients with MS have not been robust, but the drug may have an effect in patients with fibromyalgia, said Dr. Maloni. A meta-analysis suggested that nabilone and dronabinol were associated with statistically significant differences in pain intensity.

Cannabis May Be an Alternative to Opioids
Physicians need guidance on prescribing cannabis for their patients, said Dr. Maloni. “Cannabis in an oral or buccal spray is safe, tolerable, and effective,” she added. The drug could provide an alternative to opioids and should be considered as a treatment for pain in MS when other accepted options have failed. Patients should be fully informed about their treatment, which should take place in the context of an ongoing relationship with their physician.

—Erik Greb
Senior Associate Editor

ORLANDO—Cannabis may be a safe and effective therapy for pain and spasticity in patients with multiple sclerosis (MS), according to an overview presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. The route of administration and the dose influence the drug’s physical and psychotropic effects.

Approximately 46% of patients with MS smoke marijuana for pain, tremor, insomnia, bladder problems, or spasticity, said Heidi Maloni, PhD, nurse practitioner at the Veterans Affairs Medical Center in Washington, DC. Although smoking the herbal form of cannabis is associated with several health concerns, oral and buccal sprays appear to entail fewer risks.

Nabiximols May Receive FDA Approval Soon
Nabiximols, a liquid extract of two strains of cloned Cannabis sativa, is formulated as an oromucosal spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. THC is the psychoactive chemical in marijuana, and CBD counteracts this psychoactive effect. Each spray of nabiximols contains 100 µL of cannabis, and the suggested maximum dose is 33.8 mg/day.

Three clinical trials conducted since 2010 suggest that nabiximols effectively reduces MS-related pain that otherwise resists pharmacologic intervention. Patients did not develop tolerance to nabiximols, and cessation of treatment was not associated with symptoms of withdrawal. In several clinical trials that included 930 patients who took nabiximols, 27.5% of patients who took the drug had dizziness, 13.1% had diarrhea, and 11% had fatigue. Less than 1% of patients had a cannabis high. Slow titration of the drug over 10 days helped to reduce the occurrence of serious adverse events.

Unlike smoked cannabis, nabiximols was not associated with memory impairment, sedation, or intoxication. The drug’s effect on pain intensity generally is evident within four weeks of treatment. The cost efficacy of nabiximols remains to be established, however. Authorities in the United Kingdom do not consider nabiximols to be cost effective when compared with baclofen and tizanidine.

The drug is an approved treatment for MS-related spasticity and pain in the United Kingdom, Canada, New Zealand, and eight European countries. The FDA is expected to approve the drug in December 2013, said Dr. Maloni.

Smoked Cannabis Is Associated With Cognitive Impairment
Unlike cannabis-based extracts such as nabiximols, which generally take 90 minutes to reach the brain and cause an effect, smoked cannabis reaches its peak concentration in the body in 10 minutes. In clinical trials of smoked cannabis, during which patients received between 4 and 128 mg/day of THC, pain intensity decreased by at least 30% for all participants. This result reflected an important improvement on quality of life, said Dr. Maloni. The medium dose of THC was as effective as the high dose.

In a 2012 study, scores on the visual analog scale of pain decreased by five points—a “huge” difference—among patients who smoked cannabis for MS-related pain, said Dr. Maloni. Mean scores on the Paced Auditory Serial Addition Test, however, decreased by eight points among patients who smoked cannabis, compared with controls.

A Canadian study published in Neurology compared patients with MS who smoked cannabis with patients who did not smoke it. Participants underwent cognitive testing after a 12-hour period during which no subject smoked cannabis. Scores on all aspects of cognition, including visuospatial ability, executive function, and short-term memory, were 30% worse for patients who smoked cannabis than for controls. Because MS itself can entail cognitive problems, smoked cannabis can be problematic for patients with the disease, said Dr. Maloni.

Smoked cannabis also entails other concerns. About 10% of people who smoke the drug develop dependence, and people who stop smoking it may have withdrawal symptoms. Smoked cannabis is associated with tachycardia, cardiovascular disease, and elevated blood pressure and heart rate. And because cannabis is an anticholinergic, it can cause problems for MS patients’ eyes. “You want to be careful with anything that’s going to dry them out,” said Dr. Maloni.

Oral Cannabis Is Least Popular Among Patients
Synthetic cannabis is available in oral tablets and capsules, but patients express the least satisfaction with this form of the drug because it is subject to the cytochrome P450 system and is metabolized by the liver, said Dr. Maloni. The bioavailability of oral cannabis ranges between 5% and 20%.

Dronabinol, a synthetic THC, is available in 2.5-, 5-, and 10-mg oral capsules. A 10- to 20-mg dose of THC has an analgesic effect equivalent to that of 60 to 120 mg of codeine. In one study, dronabinol was associated with subjective improvement in spasticity, pain, and relapse rate in patients with MS. Dronabinol is approved in the United States for the treatment of chemotherapy-related nausea and vomiting and the treatment of weight loss related to wasting syndromes.

Nabilone, a synthetic CB1 and CB2 receptor agonist, is also approved in the US for the treatment of chemotherapy-related nausea and vomiting. Studies of 0.5- to 1-mg doses of nabilone in patients with MS have not been robust, but the drug may have an effect in patients with fibromyalgia, said Dr. Maloni. A meta-analysis suggested that nabilone and dronabinol were associated with statistically significant differences in pain intensity.

Cannabis May Be an Alternative to Opioids
Physicians need guidance on prescribing cannabis for their patients, said Dr. Maloni. “Cannabis in an oral or buccal spray is safe, tolerable, and effective,” she added. The drug could provide an alternative to opioids and should be considered as a treatment for pain in MS when other accepted options have failed. Patients should be fully informed about their treatment, which should take place in the context of an ongoing relationship with their physician.

—Erik Greb
Senior Associate Editor

ORLANDO—Cannabis may be a safe and effective therapy for pain and spasticity in patients with multiple sclerosis (MS), according to an overview presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. The route of administration and the dose influence the drug’s physical and psychotropic effects.

Approximately 46% of patients with MS smoke marijuana for pain, tremor, insomnia, bladder problems, or spasticity, said Heidi Maloni, PhD, nurse practitioner at the Veterans Affairs Medical Center in Washington, DC. Although smoking the herbal form of cannabis is associated with several health concerns, oral and buccal sprays appear to entail fewer risks.

Nabiximols May Receive FDA Approval Soon
Nabiximols, a liquid extract of two strains of cloned Cannabis sativa, is formulated as an oromucosal spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio. THC is the psychoactive chemical in marijuana, and CBD counteracts this psychoactive effect. Each spray of nabiximols contains 100 µL of cannabis, and the suggested maximum dose is 33.8 mg/day.

Three clinical trials conducted since 2010 suggest that nabiximols effectively reduces MS-related pain that otherwise resists pharmacologic intervention. Patients did not develop tolerance to nabiximols, and cessation of treatment was not associated with symptoms of withdrawal. In several clinical trials that included 930 patients who took nabiximols, 27.5% of patients who took the drug had dizziness, 13.1% had diarrhea, and 11% had fatigue. Less than 1% of patients had a cannabis high. Slow titration of the drug over 10 days helped to reduce the occurrence of serious adverse events.

Unlike smoked cannabis, nabiximols was not associated with memory impairment, sedation, or intoxication. The drug’s effect on pain intensity generally is evident within four weeks of treatment. The cost efficacy of nabiximols remains to be established, however. Authorities in the United Kingdom do not consider nabiximols to be cost effective when compared with baclofen and tizanidine.

The drug is an approved treatment for MS-related spasticity and pain in the United Kingdom, Canada, New Zealand, and eight European countries. The FDA is expected to approve the drug in December 2013, said Dr. Maloni.

Smoked Cannabis Is Associated With Cognitive Impairment
Unlike cannabis-based extracts such as nabiximols, which generally take 90 minutes to reach the brain and cause an effect, smoked cannabis reaches its peak concentration in the body in 10 minutes. In clinical trials of smoked cannabis, during which patients received between 4 and 128 mg/day of THC, pain intensity decreased by at least 30% for all participants. This result reflected an important improvement on quality of life, said Dr. Maloni. The medium dose of THC was as effective as the high dose.

In a 2012 study, scores on the visual analog scale of pain decreased by five points—a “huge” difference—among patients who smoked cannabis for MS-related pain, said Dr. Maloni. Mean scores on the Paced Auditory Serial Addition Test, however, decreased by eight points among patients who smoked cannabis, compared with controls.

A Canadian study published in Neurology compared patients with MS who smoked cannabis with patients who did not smoke it. Participants underwent cognitive testing after a 12-hour period during which no subject smoked cannabis. Scores on all aspects of cognition, including visuospatial ability, executive function, and short-term memory, were 30% worse for patients who smoked cannabis than for controls. Because MS itself can entail cognitive problems, smoked cannabis can be problematic for patients with the disease, said Dr. Maloni.

Smoked cannabis also entails other concerns. About 10% of people who smoke the drug develop dependence, and people who stop smoking it may have withdrawal symptoms. Smoked cannabis is associated with tachycardia, cardiovascular disease, and elevated blood pressure and heart rate. And because cannabis is an anticholinergic, it can cause problems for MS patients’ eyes. “You want to be careful with anything that’s going to dry them out,” said Dr. Maloni.

Oral Cannabis Is Least Popular Among Patients
Synthetic cannabis is available in oral tablets and capsules, but patients express the least satisfaction with this form of the drug because it is subject to the cytochrome P450 system and is metabolized by the liver, said Dr. Maloni. The bioavailability of oral cannabis ranges between 5% and 20%.

Dronabinol, a synthetic THC, is available in 2.5-, 5-, and 10-mg oral capsules. A 10- to 20-mg dose of THC has an analgesic effect equivalent to that of 60 to 120 mg of codeine. In one study, dronabinol was associated with subjective improvement in spasticity, pain, and relapse rate in patients with MS. Dronabinol is approved in the United States for the treatment of chemotherapy-related nausea and vomiting and the treatment of weight loss related to wasting syndromes.

Nabilone, a synthetic CB1 and CB2 receptor agonist, is also approved in the US for the treatment of chemotherapy-related nausea and vomiting. Studies of 0.5- to 1-mg doses of nabilone in patients with MS have not been robust, but the drug may have an effect in patients with fibromyalgia, said Dr. Maloni. A meta-analysis suggested that nabilone and dronabinol were associated with statistically significant differences in pain intensity.

Cannabis May Be an Alternative to Opioids
Physicians need guidance on prescribing cannabis for their patients, said Dr. Maloni. “Cannabis in an oral or buccal spray is safe, tolerable, and effective,” she added. The drug could provide an alternative to opioids and should be considered as a treatment for pain in MS when other accepted options have failed. Patients should be fully informed about their treatment, which should take place in the context of an ongoing relationship with their physician.

—Erik Greb
Senior Associate Editor

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

Upcoming Oral Agents
The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule for which two phase III clinical trials have been completed. The European Medicines Agency is reviewing the drug for marketing approval. Teva, the drug’s manufacturer, has not yet applied to the FDA for approval in the United States.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively, and thus to entail a lower risk of compromising the immune system, than fingolimod. These agents include siponimod, ponesimod, and ONO-4641.

—Bruce Jancin
IMNG Medical News

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

Upcoming Oral Agents
The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule for which two phase III clinical trials have been completed. The European Medicines Agency is reviewing the drug for marketing approval. Teva, the drug’s manufacturer, has not yet applied to the FDA for approval in the United States.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively, and thus to entail a lower risk of compromising the immune system, than fingolimod. These agents include siponimod, ponesimod, and ONO-4641.

—Bruce Jancin
IMNG Medical News

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line [treatments] that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line [drugs] because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral [medication] will be better than a failed injectable [medication] has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

Upcoming Oral Agents
The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule for which two phase III clinical trials have been completed. The European Medicines Agency is reviewing the drug for marketing approval. Teva, the drug’s manufacturer, has not yet applied to the FDA for approval in the United States.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively, and thus to entail a lower risk of compromising the immune system, than fingolimod. These agents include siponimod, ponesimod, and ONO-4641.

—Bruce Jancin
IMNG Medical News

ORLANDO—Among patients with multiple sclerosis (MS), treatment with a disease-modifying therapy (DMT) may be associated with more rapid development of autoimmune disease than remaining untreated, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. In addition, irritable bowel syndrome (IBS) may be more prevalent among patients with MS who receive a DMT than among untreated patients.

Lynn Chouhfeh, MD, medical resident at the University at Buffalo, New York, and colleagues analyzed data from the New York State MS Consortium (NYSMSC) longitudinal registry to investigate the type and prevalence of comorbid autoimmune diseases in patients with MS treated with various DMTs. Eligible patients had at least five years of follow-up and clinically definite MS according to McDonald criteria. Patients with unknown DMT use before enrollment were excluded, as were patients with an autoimmune disease at the time of entry into the registry.

Of the 2,047 eligible patients, 281 developed an autoimmune disease after DMT initiation, and 33 patients who were DMT naïve developed an autoimmune disease. Autoimmune diseases included Crohn’s disease, myasthenia gravis, IBS, psoriasis, and rheumatoid arthritis, among others. DMT types included interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab, among others.

Rheumatoid Arthritis Was More Common Among Untreated Patients
The researchers found no demographic differences between the treated and untreated patients with MS. Approximately 91% of untreated patients were female, compared with 85% of treated patients. Mean age at registration was approximately 61 for untreated patients and 52 for patients who later received a DMT.

Thyroid disease was the most common autoimmune disease in both groups. The mean time from MS symptom onset to first comorbid autoimmune disease was significantly shorter among patients who received DMTs (192 months) than among untreated patients (262 months). The effect remained after adjusting for covariates in logistic regression modeling.

IBS was more common in the group of DMT users, compared with patients who were treatment naïve. Rheumatoid arthritis, however, was more common among untreated patients than among patients who received a DMT.

“Identifying risk factors associated with the development of autoimmune disease in the context of DMT use merits further understanding,” said Dr. Chouhfeh. “Our study results may contribute to identifying more appropriate personalized therapeutic management decisions for MS patients.”

Comorbid Autoimmune Disease May Increase Odds of MS Progression
A related study presented at the same meeting suggested that having a comorbid autoimmune disease significantly increases the odds of disease progression among patients with MS. Among individuals with relapsing-remitting MS, about 22% of patients with comorbid autoimmune disease developed secondary progressive MS, compared with 18% of patients without comorbid autoimmune disease. After adjusting for confounders, the investigators found that patients with comorbid autoimmune disease were 1.4 times as likely to develop secondary progressive MS than patients without comorbid autoimmune disease.

Katelyn S. Kavak, research scientist at the University at Buffalo, and colleagues analyzed data from the NYSMSC registry for 3,292 subjects with clinically definite relapsing-remitting MS and at least one follow-up. Eight types of autoimmune disease were reported in the database, including thryroid, lupus, psoriasis, and rheumatoid arthritis. Participants were considered to have a comorbid autoimmune disease if they ever reported having one or more such diseases at study enrollment or at follow-up.

The researchers compared subjects who reported having an autoimmune disease with those who did not to determine the effects of autoimmune disease on MS progression. The team conducted logistic regression analysis and controlled for age at symptom onset, sex, Expanded Disability Status Scale (EDSS) score at enrollment, and DMT use.

Progression Was More Prevalent Among Patients Using DMT
Compared with patients without comorbid autoimmune disease, patients with comorbid autoimmune disease were older at MS symptom onset (33 vs 31) and more likely to be female (84% vs 75%). EDSS score at enrollment did not differ between the two groups, but it was higher at the most recent follow-up among patients with comorbid autoimmune disease than among subjects without.

The researchers found no difference in race, education, or DMT use between the groups. But after results were stratified by DMT use, progression was significantly more prevalent in subjects using DMT than among subjects who did not use DMT.

“The increased susceptibility patients with MS have to other autoimmune diseases might be due to the effects of DMT use, as others have reported an increased susceptibility to thyroid issues in patients with MS after interferon treatment,” said Ms. Kavak. “Causality cannot be assumed in this study, and it has to be considered that subjects with a comorbid autoimmune disease might be different from those without a comorbid autoimmune disease. Subjects with a more severe form of relapsing-remitting MS may have a higher prevalence of medication use, which may not necessarily stop disease progression, but might induce autoimmune disease,” she added. “It would be of interest to investigate whether treating the autoimmune disease comorbidity would improve MS disease course.”

—Erik Greb
Senior Associate Editor

ORLANDO—Among patients with multiple sclerosis (MS), treatment with a disease-modifying therapy (DMT) may be associated with more rapid development of autoimmune disease than remaining untreated, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. In addition, irritable bowel syndrome (IBS) may be more prevalent among patients with MS who receive a DMT than among untreated patients.

Lynn Chouhfeh, MD, medical resident at the University at Buffalo, New York, and colleagues analyzed data from the New York State MS Consortium (NYSMSC) longitudinal registry to investigate the type and prevalence of comorbid autoimmune diseases in patients with MS treated with various DMTs. Eligible patients had at least five years of follow-up and clinically definite MS according to McDonald criteria. Patients with unknown DMT use before enrollment were excluded, as were patients with an autoimmune disease at the time of entry into the registry.

Of the 2,047 eligible patients, 281 developed an autoimmune disease after DMT initiation, and 33 patients who were DMT naïve developed an autoimmune disease. Autoimmune diseases included Crohn’s disease, myasthenia gravis, IBS, psoriasis, and rheumatoid arthritis, among others. DMT types included interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab, among others.

Rheumatoid Arthritis Was More Common Among Untreated Patients
The researchers found no demographic differences between the treated and untreated patients with MS. Approximately 91% of untreated patients were female, compared with 85% of treated patients. Mean age at registration was approximately 61 for untreated patients and 52 for patients who later received a DMT.

Thyroid disease was the most common autoimmune disease in both groups. The mean time from MS symptom onset to first comorbid autoimmune disease was significantly shorter among patients who received DMTs (192 months) than among untreated patients (262 months). The effect remained after adjusting for covariates in logistic regression modeling.

IBS was more common in the group of DMT users, compared with patients who were treatment naïve. Rheumatoid arthritis, however, was more common among untreated patients than among patients who received a DMT.

“Identifying risk factors associated with the development of autoimmune disease in the context of DMT use merits further understanding,” said Dr. Chouhfeh. “Our study results may contribute to identifying more appropriate personalized therapeutic management decisions for MS patients.”

Comorbid Autoimmune Disease May Increase Odds of MS Progression
A related study presented at the same meeting suggested that having a comorbid autoimmune disease significantly increases the odds of disease progression among patients with MS. Among individuals with relapsing-remitting MS, about 22% of patients with comorbid autoimmune disease developed secondary progressive MS, compared with 18% of patients without comorbid autoimmune disease. After adjusting for confounders, the investigators found that patients with comorbid autoimmune disease were 1.4 times as likely to develop secondary progressive MS than patients without comorbid autoimmune disease.

Katelyn S. Kavak, research scientist at the University at Buffalo, and colleagues analyzed data from the NYSMSC registry for 3,292 subjects with clinically definite relapsing-remitting MS and at least one follow-up. Eight types of autoimmune disease were reported in the database, including thryroid, lupus, psoriasis, and rheumatoid arthritis. Participants were considered to have a comorbid autoimmune disease if they ever reported having one or more such diseases at study enrollment or at follow-up.

The researchers compared subjects who reported having an autoimmune disease with those who did not to determine the effects of autoimmune disease on MS progression. The team conducted logistic regression analysis and controlled for age at symptom onset, sex, Expanded Disability Status Scale (EDSS) score at enrollment, and DMT use.

Progression Was More Prevalent Among Patients Using DMT
Compared with patients without comorbid autoimmune disease, patients with comorbid autoimmune disease were older at MS symptom onset (33 vs 31) and more likely to be female (84% vs 75%). EDSS score at enrollment did not differ between the two groups, but it was higher at the most recent follow-up among patients with comorbid autoimmune disease than among subjects without.

The researchers found no difference in race, education, or DMT use between the groups. But after results were stratified by DMT use, progression was significantly more prevalent in subjects using DMT than among subjects who did not use DMT.

“The increased susceptibility patients with MS have to other autoimmune diseases might be due to the effects of DMT use, as others have reported an increased susceptibility to thyroid issues in patients with MS after interferon treatment,” said Ms. Kavak. “Causality cannot be assumed in this study, and it has to be considered that subjects with a comorbid autoimmune disease might be different from those without a comorbid autoimmune disease. Subjects with a more severe form of relapsing-remitting MS may have a higher prevalence of medication use, which may not necessarily stop disease progression, but might induce autoimmune disease,” she added. “It would be of interest to investigate whether treating the autoimmune disease comorbidity would improve MS disease course.”

—Erik Greb
Senior Associate Editor

ORLANDO—Among patients with multiple sclerosis (MS), treatment with a disease-modifying therapy (DMT) may be associated with more rapid development of autoimmune disease than remaining untreated, according to data presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. In addition, irritable bowel syndrome (IBS) may be more prevalent among patients with MS who receive a DMT than among untreated patients.

Lynn Chouhfeh, MD, medical resident at the University at Buffalo, New York, and colleagues analyzed data from the New York State MS Consortium (NYSMSC) longitudinal registry to investigate the type and prevalence of comorbid autoimmune diseases in patients with MS treated with various DMTs. Eligible patients had at least five years of follow-up and clinically definite MS according to McDonald criteria. Patients with unknown DMT use before enrollment were excluded, as were patients with an autoimmune disease at the time of entry into the registry.

Of the 2,047 eligible patients, 281 developed an autoimmune disease after DMT initiation, and 33 patients who were DMT naïve developed an autoimmune disease. Autoimmune diseases included Crohn’s disease, myasthenia gravis, IBS, psoriasis, and rheumatoid arthritis, among others. DMT types included interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab, among others.

Rheumatoid Arthritis Was More Common Among Untreated Patients
The researchers found no demographic differences between the treated and untreated patients with MS. Approximately 91% of untreated patients were female, compared with 85% of treated patients. Mean age at registration was approximately 61 for untreated patients and 52 for patients who later received a DMT.

Thyroid disease was the most common autoimmune disease in both groups. The mean time from MS symptom onset to first comorbid autoimmune disease was significantly shorter among patients who received DMTs (192 months) than among untreated patients (262 months). The effect remained after adjusting for covariates in logistic regression modeling.

IBS was more common in the group of DMT users, compared with patients who were treatment naïve. Rheumatoid arthritis, however, was more common among untreated patients than among patients who received a DMT.

“Identifying risk factors associated with the development of autoimmune disease in the context of DMT use merits further understanding,” said Dr. Chouhfeh. “Our study results may contribute to identifying more appropriate personalized therapeutic management decisions for MS patients.”

Comorbid Autoimmune Disease May Increase Odds of MS Progression
A related study presented at the same meeting suggested that having a comorbid autoimmune disease significantly increases the odds of disease progression among patients with MS. Among individuals with relapsing-remitting MS, about 22% of patients with comorbid autoimmune disease developed secondary progressive MS, compared with 18% of patients without comorbid autoimmune disease. After adjusting for confounders, the investigators found that patients with comorbid autoimmune disease were 1.4 times as likely to develop secondary progressive MS than patients without comorbid autoimmune disease.

Katelyn S. Kavak, research scientist at the University at Buffalo, and colleagues analyzed data from the NYSMSC registry for 3,292 subjects with clinically definite relapsing-remitting MS and at least one follow-up. Eight types of autoimmune disease were reported in the database, including thryroid, lupus, psoriasis, and rheumatoid arthritis. Participants were considered to have a comorbid autoimmune disease if they ever reported having one or more such diseases at study enrollment or at follow-up.

The researchers compared subjects who reported having an autoimmune disease with those who did not to determine the effects of autoimmune disease on MS progression. The team conducted logistic regression analysis and controlled for age at symptom onset, sex, Expanded Disability Status Scale (EDSS) score at enrollment, and DMT use.

Progression Was More Prevalent Among Patients Using DMT
Compared with patients without comorbid autoimmune disease, patients with comorbid autoimmune disease were older at MS symptom onset (33 vs 31) and more likely to be female (84% vs 75%). EDSS score at enrollment did not differ between the two groups, but it was higher at the most recent follow-up among patients with comorbid autoimmune disease than among subjects without.

The researchers found no difference in race, education, or DMT use between the groups. But after results were stratified by DMT use, progression was significantly more prevalent in subjects using DMT than among subjects who did not use DMT.

“The increased susceptibility patients with MS have to other autoimmune diseases might be due to the effects of DMT use, as others have reported an increased susceptibility to thyroid issues in patients with MS after interferon treatment,” said Ms. Kavak. “Causality cannot be assumed in this study, and it has to be considered that subjects with a comorbid autoimmune disease might be different from those without a comorbid autoimmune disease. Subjects with a more severe form of relapsing-remitting MS may have a higher prevalence of medication use, which may not necessarily stop disease progression, but might induce autoimmune disease,” she added. “It would be of interest to investigate whether treating the autoimmune disease comorbidity would improve MS disease course.”

—Erik Greb
Senior Associate Editor