Neuromuscular Disorders

ORLANDO – An investigational pegylated formulation of subcutaneous interferon beta-1a appears to offer the efficacy and safety of currently available interferon therapy for relapsing-remitting multiple sclerosis with the advantage of less frequent injections, a study has shown.

In the phase III, double-blind ADVANCE trial, peginterferon beta-1a at 125 mcg self-administered subcutaneously every 2 weeks for 1 year consistently provided statistically significant advantages over placebo for all clinical and radiologic outcomes, Dr. Peter A. Calabresi reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Peginterferon beta-1a dosed every 4 weeks was less effective than every 2 weeks. It bested placebo on some but not all endpoints, added Dr. Calabresi, professor of neurology and director of the multiple sclerosis center at Johns Hopkins University, Baltimore.

Bruce Jancin/IMNG Medical Media

The ADVANCE trial involved 1,516 randomized patients with relapsing-remitting MS, 86% of whom had a baseline Expanded Disability Status Scale (EDSS) score of less than 4.

The primary endpoint was the annualized relapse rate at 1 year: 0.397 with placebo; 0.2888 with peginterferon beta-1a every 4 weeks, for a 27.5% reduction compared with placebo; and 0.256 with biweekly therapy, for a 35.6% reduction. The 1-year incidence of relapse was reduced by 26% with monthly dosing and by 39% with biweekly dosing of peginterferon beta-1a, compared with placebo.

A key secondary outcome measure, disability progression during year 1 as defined by at least a 1-point increase in the EDSS sustained for 12 weeks or more, was reduced by 38% in both peginterferon beta-1a arms, compared with placebo.

In terms of MRI outcomes reflecting disease activity, the mean number of new or enlarging T2 lesions at 1 year was 10.9 with placebo, 7.9 with peginterferon every 4 weeks, and 3.6 – a 67% reduction compared with placebo – with biweekly therapy. The mean number of gadolinium-enhancing MRI lesions was 1.4 with placebo, 0.9 with peginterferon every 4 weeks, and 0.2 with biweekly peginterferon, an 86% reduction compared with placebo.

The incidence of interferon-neutralizing antibodies believed capable of interfering with the effect of the drug was reassuringly low at less than 1% in all three study arms at 1 year.

The adverse events profile of peginterferon beta-1a would be familiar to physicians who prescribe other interferons: injection site reactions, flulike illness, and headaches, for example – all typically rated mild and lasting less than 48 hours, Dr. Calabresi continued.

One audience member, noting that peginterferon beta-1a every 2 weeks was clearly more effective than every 4 weeks, asked why once-weekly injections weren’t studied. Dr. Calabresi replied that the every-2-week regimen appears to provide a reduction in the relapse rate that’s roughly equivalent to that achieved with standard nonpegylated interferon beta-1a given more frequently. For patients who’ve done well on interferon therapy for years, the idea of switching from Avonex given intramuscularly once weekly or Rebif given subcutaneously three times per week to an every 2-week dosing regimen that provides the efficacy and safety they’re accustomed to is likely to be very attractive, he added.

Pegylation is a strategy for increasing the half-life and pharmacodynamic effects of a drug. Less frequent dosing means greater convenience for patients and possibly improved adherence as well. Ninety-one percent of the placebo group completed year 1 of ADVANCE, as did 88% on peginterferon beta-1a given every 4 weeks and 86% on biweekly dosing.

The ADVANCE study is now in its second and final year, during which patients continue on the same peginterferon dosing schedule they had in year 1, while patients formerly on placebo are randomized to a year on one of the two peginterferon dosing regimens. After the 2 years of ADVANCE are completed, there will be a 2-year extension study called ATTAIN.

The ADVANCE trial is sponsored by Biogen Idec. Dr. Calabresi reported receiving grant support from that company and serving as a consultant to Vaccinex, Abbott, and Vertex.

[email protected]

ORLANDO – An investigational pegylated formulation of subcutaneous interferon beta-1a appears to offer the efficacy and safety of currently available interferon therapy for relapsing-remitting multiple sclerosis with the advantage of less frequent injections, a study has shown.

In the phase III, double-blind ADVANCE trial, peginterferon beta-1a at 125 mcg self-administered subcutaneously every 2 weeks for 1 year consistently provided statistically significant advantages over placebo for all clinical and radiologic outcomes, Dr. Peter A. Calabresi reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Peginterferon beta-1a dosed every 4 weeks was less effective than every 2 weeks. It bested placebo on some but not all endpoints, added Dr. Calabresi, professor of neurology and director of the multiple sclerosis center at Johns Hopkins University, Baltimore.

Bruce Jancin/IMNG Medical Media

The ADVANCE trial involved 1,516 randomized patients with relapsing-remitting MS, 86% of whom had a baseline Expanded Disability Status Scale (EDSS) score of less than 4.

The primary endpoint was the annualized relapse rate at 1 year: 0.397 with placebo; 0.2888 with peginterferon beta-1a every 4 weeks, for a 27.5% reduction compared with placebo; and 0.256 with biweekly therapy, for a 35.6% reduction. The 1-year incidence of relapse was reduced by 26% with monthly dosing and by 39% with biweekly dosing of peginterferon beta-1a, compared with placebo.

A key secondary outcome measure, disability progression during year 1 as defined by at least a 1-point increase in the EDSS sustained for 12 weeks or more, was reduced by 38% in both peginterferon beta-1a arms, compared with placebo.

In terms of MRI outcomes reflecting disease activity, the mean number of new or enlarging T2 lesions at 1 year was 10.9 with placebo, 7.9 with peginterferon every 4 weeks, and 3.6 – a 67% reduction compared with placebo – with biweekly therapy. The mean number of gadolinium-enhancing MRI lesions was 1.4 with placebo, 0.9 with peginterferon every 4 weeks, and 0.2 with biweekly peginterferon, an 86% reduction compared with placebo.

The incidence of interferon-neutralizing antibodies believed capable of interfering with the effect of the drug was reassuringly low at less than 1% in all three study arms at 1 year.

The adverse events profile of peginterferon beta-1a would be familiar to physicians who prescribe other interferons: injection site reactions, flulike illness, and headaches, for example – all typically rated mild and lasting less than 48 hours, Dr. Calabresi continued.

One audience member, noting that peginterferon beta-1a every 2 weeks was clearly more effective than every 4 weeks, asked why once-weekly injections weren’t studied. Dr. Calabresi replied that the every-2-week regimen appears to provide a reduction in the relapse rate that’s roughly equivalent to that achieved with standard nonpegylated interferon beta-1a given more frequently. For patients who’ve done well on interferon therapy for years, the idea of switching from Avonex given intramuscularly once weekly or Rebif given subcutaneously three times per week to an every 2-week dosing regimen that provides the efficacy and safety they’re accustomed to is likely to be very attractive, he added.

Pegylation is a strategy for increasing the half-life and pharmacodynamic effects of a drug. Less frequent dosing means greater convenience for patients and possibly improved adherence as well. Ninety-one percent of the placebo group completed year 1 of ADVANCE, as did 88% on peginterferon beta-1a given every 4 weeks and 86% on biweekly dosing.

The ADVANCE study is now in its second and final year, during which patients continue on the same peginterferon dosing schedule they had in year 1, while patients formerly on placebo are randomized to a year on one of the two peginterferon dosing regimens. After the 2 years of ADVANCE are completed, there will be a 2-year extension study called ATTAIN.

The ADVANCE trial is sponsored by Biogen Idec. Dr. Calabresi reported receiving grant support from that company and serving as a consultant to Vaccinex, Abbott, and Vertex.

[email protected]

ORLANDO – An investigational pegylated formulation of subcutaneous interferon beta-1a appears to offer the efficacy and safety of currently available interferon therapy for relapsing-remitting multiple sclerosis with the advantage of less frequent injections, a study has shown.

In the phase III, double-blind ADVANCE trial, peginterferon beta-1a at 125 mcg self-administered subcutaneously every 2 weeks for 1 year consistently provided statistically significant advantages over placebo for all clinical and radiologic outcomes, Dr. Peter A. Calabresi reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Peginterferon beta-1a dosed every 4 weeks was less effective than every 2 weeks. It bested placebo on some but not all endpoints, added Dr. Calabresi, professor of neurology and director of the multiple sclerosis center at Johns Hopkins University, Baltimore.

Bruce Jancin/IMNG Medical Media

The ADVANCE trial involved 1,516 randomized patients with relapsing-remitting MS, 86% of whom had a baseline Expanded Disability Status Scale (EDSS) score of less than 4.

The primary endpoint was the annualized relapse rate at 1 year: 0.397 with placebo; 0.2888 with peginterferon beta-1a every 4 weeks, for a 27.5% reduction compared with placebo; and 0.256 with biweekly therapy, for a 35.6% reduction. The 1-year incidence of relapse was reduced by 26% with monthly dosing and by 39% with biweekly dosing of peginterferon beta-1a, compared with placebo.

A key secondary outcome measure, disability progression during year 1 as defined by at least a 1-point increase in the EDSS sustained for 12 weeks or more, was reduced by 38% in both peginterferon beta-1a arms, compared with placebo.

In terms of MRI outcomes reflecting disease activity, the mean number of new or enlarging T2 lesions at 1 year was 10.9 with placebo, 7.9 with peginterferon every 4 weeks, and 3.6 – a 67% reduction compared with placebo – with biweekly therapy. The mean number of gadolinium-enhancing MRI lesions was 1.4 with placebo, 0.9 with peginterferon every 4 weeks, and 0.2 with biweekly peginterferon, an 86% reduction compared with placebo.

The incidence of interferon-neutralizing antibodies believed capable of interfering with the effect of the drug was reassuringly low at less than 1% in all three study arms at 1 year.

The adverse events profile of peginterferon beta-1a would be familiar to physicians who prescribe other interferons: injection site reactions, flulike illness, and headaches, for example – all typically rated mild and lasting less than 48 hours, Dr. Calabresi continued.

One audience member, noting that peginterferon beta-1a every 2 weeks was clearly more effective than every 4 weeks, asked why once-weekly injections weren’t studied. Dr. Calabresi replied that the every-2-week regimen appears to provide a reduction in the relapse rate that’s roughly equivalent to that achieved with standard nonpegylated interferon beta-1a given more frequently. For patients who’ve done well on interferon therapy for years, the idea of switching from Avonex given intramuscularly once weekly or Rebif given subcutaneously three times per week to an every 2-week dosing regimen that provides the efficacy and safety they’re accustomed to is likely to be very attractive, he added.

Pegylation is a strategy for increasing the half-life and pharmacodynamic effects of a drug. Less frequent dosing means greater convenience for patients and possibly improved adherence as well. Ninety-one percent of the placebo group completed year 1 of ADVANCE, as did 88% on peginterferon beta-1a given every 4 weeks and 86% on biweekly dosing.

The ADVANCE study is now in its second and final year, during which patients continue on the same peginterferon dosing schedule they had in year 1, while patients formerly on placebo are randomized to a year on one of the two peginterferon dosing regimens. After the 2 years of ADVANCE are completed, there will be a 2-year extension study called ATTAIN.

The ADVANCE trial is sponsored by Biogen Idec. Dr. Calabresi reported receiving grant support from that company and serving as a consultant to Vaccinex, Abbott, and Vertex.

[email protected]

A study that tracked the incidence of Guillain-Barré syndrome in Californians over the course of more than 30 million person-years found no evidence that risk that immunization increased the risk for the disorder, according to a report published online in Clinical Infectious Diseases.

This retrospective study could not definitively exclude a possible weak association between vaccines and GBS, partly because the rarity of the disorder limited the study’s power to fully assess this risk. But the findings "provide reassurance that the risk of GBS following any vaccine ... is extremely low," said Dr. Roger Baxter of the Kaiser Permanente Vaccine Study Center, Oakland, Calif., and his associates.

DesignPics.com

Concern about a link between vaccinations and GBS have "flourished" since a study found a small but significant increase in cases during the 6 weeks following immunization against the 1976 Swine flu. Since that time, studies assessing GBS risk after seasonal flu vaccinations "have shown either no risk or a very small attributable risk of approximately one case per million doses," the investigators wrote (Clin. Infect. Dis. 2013;57:197-204 [doi:10.1093/cid/cit222]).

Similarly, no conclusive evidence has been found linking GBS with other vaccines, but there have been a small number of case reports in which the disorder developed following tetanus, rabies, polio, or hepatitis B vaccination.

In contrast, the evidence is clear that GBS is temporally associated with infectious diseases. "Most published case series report that approximately two-thirds of all cases are preceded by a gastrointestinal or respiratory infection within the prior 3 months. Campylobacter enteritis is the most common trigger, but influenza, cytomegalovirus, Epstein Barr virus, HIV, and Mycoplasma pneumoniae, among others, have been implicated as well," Dr. Baxter and his colleagues said.

They used information from Kaiser’s database of electronic medical records and its immunization tracking system to examine a possible association between GBS and immunizations. The researchers identified 415 patients who were hospitalized with GBS between 1994 and 2006 and had received any vaccination during the year preceding symptom onset.

During 32,734,642 person-years of observation, the overall incidence was 1.27 cases of GBS/100,000 person-years. This rate is comparable with that reported in previous studies of GBS incidence.

As has been reported in previous studies, the majority (59%) of cases in this study occurred in males.

The mean age of GBS patients was 49 years (range, 5-87 years). Two-thirds of cases (67%) had a documented respiratory or gastrointestinal illness during the 90 days preceding onset of GBS.

Only 25 of these 415 patients had received any vaccine during the 6 weeks before symptom onset. This included 18 patients who had received influenza vaccines, and one to three patients each of whom had received vaccines against pneumococcus, tetanus-diphtheria, hepatitis A, or hepatitis B, Dr. Baxter and his associates said.

Of the 18 patients who developed GBS within 6 weeks of receiving an influenza vaccine, 13 had known respiratory or gastrointestinal illness during that period, which also may have predisposed them to GBS. These 18 cases also occurred against a backdrop of 6,841,901 flu immunizations given during that interval.

Six of the remaining seven patients who developed GBS within 6 weeks of a noninfluenza vaccination also had respiratory or gastrointestinal illness during that interval.

There was no association between GBS and any of the vaccines typically administered during childhood, despite the extremely large number of doses given: For example, 1.2 million doses of oral polio vaccine, 1.6 million of MMR, and 764,000 varicella vaccine were dispensed.

There was no significant difference in the rate of GBS among people vaccinated up to 6 weeks prior to symptom onset and those vaccinated from 6 weeks to 12 months prior to symptom onset, judging from the findings of a secondary cohort analysis.

GBS was significantly more likely to occur during the winter months than during any other season.

This study was supported by America\'s Health Insurance Plans and the Centers for Disease Control and Prevention. Dr. Baxter and one of his associates reported ties to GlaxoSmithKline, MedImmune, Merck, Novartis Vaccines, Pfizer, and Sanofi-Pasteur.

A study that tracked the incidence of Guillain-Barré syndrome in Californians over the course of more than 30 million person-years found no evidence that risk that immunization increased the risk for the disorder, according to a report published online in Clinical Infectious Diseases.

This retrospective study could not definitively exclude a possible weak association between vaccines and GBS, partly because the rarity of the disorder limited the study’s power to fully assess this risk. But the findings "provide reassurance that the risk of GBS following any vaccine ... is extremely low," said Dr. Roger Baxter of the Kaiser Permanente Vaccine Study Center, Oakland, Calif., and his associates.

DesignPics.com

Concern about a link between vaccinations and GBS have "flourished" since a study found a small but significant increase in cases during the 6 weeks following immunization against the 1976 Swine flu. Since that time, studies assessing GBS risk after seasonal flu vaccinations "have shown either no risk or a very small attributable risk of approximately one case per million doses," the investigators wrote (Clin. Infect. Dis. 2013;57:197-204 [doi:10.1093/cid/cit222]).

Similarly, no conclusive evidence has been found linking GBS with other vaccines, but there have been a small number of case reports in which the disorder developed following tetanus, rabies, polio, or hepatitis B vaccination.

In contrast, the evidence is clear that GBS is temporally associated with infectious diseases. "Most published case series report that approximately two-thirds of all cases are preceded by a gastrointestinal or respiratory infection within the prior 3 months. Campylobacter enteritis is the most common trigger, but influenza, cytomegalovirus, Epstein Barr virus, HIV, and Mycoplasma pneumoniae, among others, have been implicated as well," Dr. Baxter and his colleagues said.

They used information from Kaiser’s database of electronic medical records and its immunization tracking system to examine a possible association between GBS and immunizations. The researchers identified 415 patients who were hospitalized with GBS between 1994 and 2006 and had received any vaccination during the year preceding symptom onset.

During 32,734,642 person-years of observation, the overall incidence was 1.27 cases of GBS/100,000 person-years. This rate is comparable with that reported in previous studies of GBS incidence.

As has been reported in previous studies, the majority (59%) of cases in this study occurred in males.

The mean age of GBS patients was 49 years (range, 5-87 years). Two-thirds of cases (67%) had a documented respiratory or gastrointestinal illness during the 90 days preceding onset of GBS.

Only 25 of these 415 patients had received any vaccine during the 6 weeks before symptom onset. This included 18 patients who had received influenza vaccines, and one to three patients each of whom had received vaccines against pneumococcus, tetanus-diphtheria, hepatitis A, or hepatitis B, Dr. Baxter and his associates said.

Of the 18 patients who developed GBS within 6 weeks of receiving an influenza vaccine, 13 had known respiratory or gastrointestinal illness during that period, which also may have predisposed them to GBS. These 18 cases also occurred against a backdrop of 6,841,901 flu immunizations given during that interval.

Six of the remaining seven patients who developed GBS within 6 weeks of a noninfluenza vaccination also had respiratory or gastrointestinal illness during that interval.

There was no association between GBS and any of the vaccines typically administered during childhood, despite the extremely large number of doses given: For example, 1.2 million doses of oral polio vaccine, 1.6 million of MMR, and 764,000 varicella vaccine were dispensed.

There was no significant difference in the rate of GBS among people vaccinated up to 6 weeks prior to symptom onset and those vaccinated from 6 weeks to 12 months prior to symptom onset, judging from the findings of a secondary cohort analysis.

GBS was significantly more likely to occur during the winter months than during any other season.

This study was supported by America\'s Health Insurance Plans and the Centers for Disease Control and Prevention. Dr. Baxter and one of his associates reported ties to GlaxoSmithKline, MedImmune, Merck, Novartis Vaccines, Pfizer, and Sanofi-Pasteur.

A study that tracked the incidence of Guillain-Barré syndrome in Californians over the course of more than 30 million person-years found no evidence that risk that immunization increased the risk for the disorder, according to a report published online in Clinical Infectious Diseases.

This retrospective study could not definitively exclude a possible weak association between vaccines and GBS, partly because the rarity of the disorder limited the study’s power to fully assess this risk. But the findings "provide reassurance that the risk of GBS following any vaccine ... is extremely low," said Dr. Roger Baxter of the Kaiser Permanente Vaccine Study Center, Oakland, Calif., and his associates.

DesignPics.com

Concern about a link between vaccinations and GBS have "flourished" since a study found a small but significant increase in cases during the 6 weeks following immunization against the 1976 Swine flu. Since that time, studies assessing GBS risk after seasonal flu vaccinations "have shown either no risk or a very small attributable risk of approximately one case per million doses," the investigators wrote (Clin. Infect. Dis. 2013;57:197-204 [doi:10.1093/cid/cit222]).

Similarly, no conclusive evidence has been found linking GBS with other vaccines, but there have been a small number of case reports in which the disorder developed following tetanus, rabies, polio, or hepatitis B vaccination.

In contrast, the evidence is clear that GBS is temporally associated with infectious diseases. "Most published case series report that approximately two-thirds of all cases are preceded by a gastrointestinal or respiratory infection within the prior 3 months. Campylobacter enteritis is the most common trigger, but influenza, cytomegalovirus, Epstein Barr virus, HIV, and Mycoplasma pneumoniae, among others, have been implicated as well," Dr. Baxter and his colleagues said.

They used information from Kaiser’s database of electronic medical records and its immunization tracking system to examine a possible association between GBS and immunizations. The researchers identified 415 patients who were hospitalized with GBS between 1994 and 2006 and had received any vaccination during the year preceding symptom onset.

During 32,734,642 person-years of observation, the overall incidence was 1.27 cases of GBS/100,000 person-years. This rate is comparable with that reported in previous studies of GBS incidence.

As has been reported in previous studies, the majority (59%) of cases in this study occurred in males.

The mean age of GBS patients was 49 years (range, 5-87 years). Two-thirds of cases (67%) had a documented respiratory or gastrointestinal illness during the 90 days preceding onset of GBS.

Only 25 of these 415 patients had received any vaccine during the 6 weeks before symptom onset. This included 18 patients who had received influenza vaccines, and one to three patients each of whom had received vaccines against pneumococcus, tetanus-diphtheria, hepatitis A, or hepatitis B, Dr. Baxter and his associates said.

Of the 18 patients who developed GBS within 6 weeks of receiving an influenza vaccine, 13 had known respiratory or gastrointestinal illness during that period, which also may have predisposed them to GBS. These 18 cases also occurred against a backdrop of 6,841,901 flu immunizations given during that interval.

Six of the remaining seven patients who developed GBS within 6 weeks of a noninfluenza vaccination also had respiratory or gastrointestinal illness during that interval.

There was no association between GBS and any of the vaccines typically administered during childhood, despite the extremely large number of doses given: For example, 1.2 million doses of oral polio vaccine, 1.6 million of MMR, and 764,000 varicella vaccine were dispensed.

There was no significant difference in the rate of GBS among people vaccinated up to 6 weeks prior to symptom onset and those vaccinated from 6 weeks to 12 months prior to symptom onset, judging from the findings of a secondary cohort analysis.

GBS was significantly more likely to occur during the winter months than during any other season.

This study was supported by America\'s Health Insurance Plans and the Centers for Disease Control and Prevention. Dr. Baxter and one of his associates reported ties to GlaxoSmithKline, MedImmune, Merck, Novartis Vaccines, Pfizer, and Sanofi-Pasteur.

ORLANDO – Sepsis, pulmonary infections, aspiration, and ischemic heart disease accounted for the bulk of excess mortality seen in patients with multiple sclerosis, compared with the matched general population, in a large U.S. study.

"Increased awareness of these potentially fatal conditions for patients with MS can improve patient care by increasing physician vigilance and facilitating early intervention," Dr. Michael J. Corwin said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Because MS is a chronic, progressive, incurable disease, the death certificates of MS patients often list MS as the underlying cause of death. Accepting that at face value would mean nearly two-thirds of excess mortality seen in the study was because of advanced MS, said Dr. Corwin. But with the use of a novel cause-of-death algorithm, he and his colleagues were able to identify key intermediate and potentially interruptible steps on the pathway from end-stage MS to death.

He presented a retrospective matched cohort study of 30,402 patients with MS and 89,818 matched non-MS comparators, all drawn from a large, national, U.S. commercial health-plan database. The mortality rate was doubled among the MS population: 5.2%, compared with 2.6% in controls. This translated to a death rate of 899 per 100,000 person-years in the MS group and 446 per 100,000 person-years in the control group, reported Dr. Corwin, an associate professor of pediatrics and epidemiology at Boston University’s Schools of Medicine and Public Health.

The study entailed detailed analysis of the death records of 1,579 MS patients and 2,332 matched controls. Because of the notorious lack of uniformity in the way death certificate data are recorded, it can be difficult to determine the immediate cause of death from these records, noted Dr. Corwin. Therefore, he and his coinvestigators developed the algorithm for doing so.

Specifically, the algorithm showed that infection accounted for 21% of the excess mortality in the MS population, cardiovascular disease 13%, and pulmonary disease 10%. Collectively, these three causes of death accounted for 44% of the excess mortality. Another 29% of the excess remained attributable to late-stage MS because of the lack of additional death record data that might have allowed a more specific categorization.

Delving more deeply into the principal causes of death, the investigators determined that sepsis was the No. 1 contributor to the excess mortality seen in the MS population. It accounted for 45 of the 453 excess deaths per 100,000 person-years. Sepsis was followed by pulmonary infection at 41, pulmonary aspiration at 27, and ischemic heart disease at 17.

The prominent role of pulmonary infections in contributing to excess mortality in patients with MS seen in this study confirms a finding from the 21-year follow-up of the landmark, multicenter, interferon beta-1b randomized treatment trial (BMJ Open 2012 Nov 30;2(6). pii: e001972 [doi: 10.1136/bmjopen-2012-001972]). Respiratory diseases were also the top cause of excess mortality found among MS patients in a recent, large, British, national population-based registry (Eur. J. Neurol. 2012;19:1007-14).

Dr. Corwin is a principal in Care-Safe, a consulting firm contracted by Bayer HealthCare Pharmaceuticals to conduct the U.S. study.

[email protected]

ORLANDO – Sepsis, pulmonary infections, aspiration, and ischemic heart disease accounted for the bulk of excess mortality seen in patients with multiple sclerosis, compared with the matched general population, in a large U.S. study.

"Increased awareness of these potentially fatal conditions for patients with MS can improve patient care by increasing physician vigilance and facilitating early intervention," Dr. Michael J. Corwin said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Because MS is a chronic, progressive, incurable disease, the death certificates of MS patients often list MS as the underlying cause of death. Accepting that at face value would mean nearly two-thirds of excess mortality seen in the study was because of advanced MS, said Dr. Corwin. But with the use of a novel cause-of-death algorithm, he and his colleagues were able to identify key intermediate and potentially interruptible steps on the pathway from end-stage MS to death.

He presented a retrospective matched cohort study of 30,402 patients with MS and 89,818 matched non-MS comparators, all drawn from a large, national, U.S. commercial health-plan database. The mortality rate was doubled among the MS population: 5.2%, compared with 2.6% in controls. This translated to a death rate of 899 per 100,000 person-years in the MS group and 446 per 100,000 person-years in the control group, reported Dr. Corwin, an associate professor of pediatrics and epidemiology at Boston University’s Schools of Medicine and Public Health.

The study entailed detailed analysis of the death records of 1,579 MS patients and 2,332 matched controls. Because of the notorious lack of uniformity in the way death certificate data are recorded, it can be difficult to determine the immediate cause of death from these records, noted Dr. Corwin. Therefore, he and his coinvestigators developed the algorithm for doing so.

Specifically, the algorithm showed that infection accounted for 21% of the excess mortality in the MS population, cardiovascular disease 13%, and pulmonary disease 10%. Collectively, these three causes of death accounted for 44% of the excess mortality. Another 29% of the excess remained attributable to late-stage MS because of the lack of additional death record data that might have allowed a more specific categorization.

Delving more deeply into the principal causes of death, the investigators determined that sepsis was the No. 1 contributor to the excess mortality seen in the MS population. It accounted for 45 of the 453 excess deaths per 100,000 person-years. Sepsis was followed by pulmonary infection at 41, pulmonary aspiration at 27, and ischemic heart disease at 17.

The prominent role of pulmonary infections in contributing to excess mortality in patients with MS seen in this study confirms a finding from the 21-year follow-up of the landmark, multicenter, interferon beta-1b randomized treatment trial (BMJ Open 2012 Nov 30;2(6). pii: e001972 [doi: 10.1136/bmjopen-2012-001972]). Respiratory diseases were also the top cause of excess mortality found among MS patients in a recent, large, British, national population-based registry (Eur. J. Neurol. 2012;19:1007-14).

Dr. Corwin is a principal in Care-Safe, a consulting firm contracted by Bayer HealthCare Pharmaceuticals to conduct the U.S. study.

[email protected]

ORLANDO – Sepsis, pulmonary infections, aspiration, and ischemic heart disease accounted for the bulk of excess mortality seen in patients with multiple sclerosis, compared with the matched general population, in a large U.S. study.

"Increased awareness of these potentially fatal conditions for patients with MS can improve patient care by increasing physician vigilance and facilitating early intervention," Dr. Michael J. Corwin said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Because MS is a chronic, progressive, incurable disease, the death certificates of MS patients often list MS as the underlying cause of death. Accepting that at face value would mean nearly two-thirds of excess mortality seen in the study was because of advanced MS, said Dr. Corwin. But with the use of a novel cause-of-death algorithm, he and his colleagues were able to identify key intermediate and potentially interruptible steps on the pathway from end-stage MS to death.

He presented a retrospective matched cohort study of 30,402 patients with MS and 89,818 matched non-MS comparators, all drawn from a large, national, U.S. commercial health-plan database. The mortality rate was doubled among the MS population: 5.2%, compared with 2.6% in controls. This translated to a death rate of 899 per 100,000 person-years in the MS group and 446 per 100,000 person-years in the control group, reported Dr. Corwin, an associate professor of pediatrics and epidemiology at Boston University’s Schools of Medicine and Public Health.

The study entailed detailed analysis of the death records of 1,579 MS patients and 2,332 matched controls. Because of the notorious lack of uniformity in the way death certificate data are recorded, it can be difficult to determine the immediate cause of death from these records, noted Dr. Corwin. Therefore, he and his coinvestigators developed the algorithm for doing so.

Specifically, the algorithm showed that infection accounted for 21% of the excess mortality in the MS population, cardiovascular disease 13%, and pulmonary disease 10%. Collectively, these three causes of death accounted for 44% of the excess mortality. Another 29% of the excess remained attributable to late-stage MS because of the lack of additional death record data that might have allowed a more specific categorization.

Delving more deeply into the principal causes of death, the investigators determined that sepsis was the No. 1 contributor to the excess mortality seen in the MS population. It accounted for 45 of the 453 excess deaths per 100,000 person-years. Sepsis was followed by pulmonary infection at 41, pulmonary aspiration at 27, and ischemic heart disease at 17.

The prominent role of pulmonary infections in contributing to excess mortality in patients with MS seen in this study confirms a finding from the 21-year follow-up of the landmark, multicenter, interferon beta-1b randomized treatment trial (BMJ Open 2012 Nov 30;2(6). pii: e001972 [doi: 10.1136/bmjopen-2012-001972]). Respiratory diseases were also the top cause of excess mortality found among MS patients in a recent, large, British, national population-based registry (Eur. J. Neurol. 2012;19:1007-14).

Dr. Corwin is a principal in Care-Safe, a consulting firm contracted by Bayer HealthCare Pharmaceuticals to conduct the U.S. study.

[email protected]

There has been much progress in multiple sclerosis research in the past decade. Researchers are now armed with more evidence that halting inflammation in the early stages of the disease can protect patients decades down the road. Dr. Stephen L. Hauser, chair of the department of neurology at the University of California, San Francisco, talks about the current state of MS research, the challenges, and the opportunities for progress.

There has been much progress in multiple sclerosis research in the past decade. Researchers are now armed with more evidence that halting inflammation in the early stages of the disease can protect patients decades down the road. Dr. Stephen L. Hauser, chair of the department of neurology at the University of California, San Francisco, talks about the current state of MS research, the challenges, and the opportunities for progress.

There has been much progress in multiple sclerosis research in the past decade. Researchers are now armed with more evidence that halting inflammation in the early stages of the disease can protect patients decades down the road. Dr. Stephen L. Hauser, chair of the department of neurology at the University of California, San Francisco, talks about the current state of MS research, the challenges, and the opportunities for progress.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

[email protected]

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

[email protected]

SAN DIEGO – Fingolimod slows brain atrophy in patients with multiple sclerosis and is the only approved drug that does so within the first 6 months of treatment, according to Dr. Jeffrey Cohen of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

The findings come from a combined analysis of the drug’s three clinical trials: FREEDOMS (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis) and FREEDOMS II, which pitted 0.5 mg and 1.25 mg daily against placebo for 2 years, and TRANSFORMS (FREEDOMS With Optional Extension Phase), which pitted those doses against weekly intramuscular interferon beta-1a (Avonex) for a year. Brain volumes were assessed by MRI SIENA (structural image evaluation, using normalization, of atrophy) at baseline and 6, 12, and 24 months. More than 3,000 patients 18-55 years old with clinically active relapsing-remitting MS participated.

"There was a consistent" 31%-36% reduction in the rate of brain volume loss with both doses of fingolimod (Gilenya) "as compared to placebo and interferon beta-1a. There was no clear-cut dose effect between the two" doses, said Dr. Cohen, the lead investigator and the director of the Mellen center’s experimental therapeutics program.

In the two trials with placebo arms, fingolimod patients had volume losses of about 0.85%, compared with 1.31% in placebo patients. In the remaining trial, brain volume loss was about 0.31% with fingolimod and about 0.45% with interferon beta-1a.

The "benefit was seen as early as 6 months, in both FREEDOMS and FREEDOMS II. In this analysis of the overall study cohort, there was no apparent early acceleration of brain volume loss, in other words, no pseudoatrophy," Dr. Cohen said at the annual meeting of the American Academy of Neurology.

Other approved MS therapies have shown either no significant effect on brain atrophy or a benefit only in the second year of treatment, as with natalizumab (Tysabri) and glatiramer acetate (Copaxone), he said.

The study investigators found that baseline brain atrophy correlated best with baseline T1 and T2 lesion volume, disability, age, and disease duration and severity. Both high baseline T2 lesion volume and active gadolinium-enhancing T1 lesions predicted brain volume loss during the trial. Volume loss in the study correlated best with worsening disability and increasing numbers of T2 lesions.

The drug seemed to protect brain volume in patients who got it, regardless of baseline characteristics.

There were weak correlations between accumulations of T2 lesions and disability during the study, perhaps because "brain volume and measures of disability don’t change much over 2 years," Dr. Cohen said.

Novartis, the maker of fingolimod, paid for the study. Dr. Cohen disclosed compensation or research support from Novartis, Biogen Idec, Genzyme, Lilly, Serono, and Teva.

[email protected]

Induced pluripotent stem cell lines that are created from the somatic cells of people with neurological diseases are beginning to pave a pathway for researchers to understand pathophysiology and screen for new drug candidates.

Recent work has characterized disease phenotypes and, in some cases, tested therapies in neurons that were differentiated from induced pluripotent stem cells (iPSCs) derived from patients with sporadic and familial Alzheimer’s disease, Huntington’s disease, and familial Parkinson’s disease.

These are heady times for this field in general and for neurological disease in particular. "It is really exciting when you start to be able to see relevant pathophysiologies in the dish," said Matthew Huentelman, Ph.D., head of the neurobehavioral research unit in the neurogenomics division at the Translational Genomics Research Institute, Phoenix.

Other investigators are trying to avoid one of the problems that has been plaguing this line of research: cell teratoma formation in vivo iPSC and embryonic stem cells. Their current approach is to reprogram fibroblasts into multipotent induced neural stem cells (iNSCs) that can then be differentiated into whatever neural progenitor cells the investigators wish to culture (neurons, oligodendroglia, and astroglia). This method also may lead to more efficient differentiation into the desired cell type, according to Dr. Yadong Huang, an associate investigator at the Gladstone Institute of Neurological Disease at the University of California, San Francisco.

Dr. Huang was the senior author on a study that used a single factor, rather than three or more, to directly reprogram human fibroblasts into multipotent iNSCs that can self-renew for 40-50 generations. This self-renewal ability, which is not present in the direct reprogramming of fibroblasts into neurons, makes them better to use for pathophysiology and drug testing studies (Cell Stem Cell 2012;11:100-9).

Only in the past year or so have people begun working in this middle ground between iPSCs and directly induced neuronal cells, so "it is important for studies in all three techniques to go forward now in parallel because each has advantages and disadvantages, at least at this point," Dr. Huang said in an interview.

"These initial studies ... are really encouraging because [they set us up] to dream about how we might leverage these cellular technologies to perform high-throughput drug screening," noted Dr. Huentelman.

In one study of Alzheimer’s disease, investigators developed iPSC cell lines from one patient with sporadic disease and two patients with familial disease caused by a mutation in the gene for amyloid precursor protein (APP). In each case, the investigators observed three major biochemical markers of Alzheimer’s (Nature 2012 Jan. 25 [doi:10.1038/nature10821]).

A separate study of familial Alzheimer’s disease with patients with presenilin-1 mutations, which was recently presented at the Alzheimer’s Association International Conference 2012, found substantial phenotypic differences between control neurons derived from iPSCs from unaffected family members, such as an increased ratio of amyloid-beta-42 to amyloid-beta-40 and an enhanced cell death response to apoptotic stimuli.

Even greater success has been reported with human Huntington’s disease neurons derived from iPSCs. In one study, researchers correlated the severity of phenotype in neurons with the number of CAG expansions observed in the huntingtin gene, as is observed in humans. However, some of the phenotypes were observed only in cell lines with the longest CAG expansion (Cell Stem Cell 2012 June 28 [doi:10.1016/j.stem.2012.04.027]). A separate group of researchers reported success in replacing the CAG expansion with a normal repeat length, which corrected the Huntington’s disease phenotype of mitochondrial deficits, lower levels of brain-derived neurotrophic factor, and altered cell signaling proteins (Cell Stem Cell 2012 June 28 [doi:10.1016/j.stem.2012.04.026]).

Another group of investigators reported the pharmacologic rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease caused by mutations in either PINK1 or LRRK2. Neural cells with PINK1 mutations that received low doses of mitochondrial stressors were rescued by both the antioxidant coenzyme Q10 and an LRRK2 inhibitor, whereas those with an LRRK2 mutation were partially rescued by rapamycin or an LRRK2 inhibitor. The researchers said that they hope to apply their observations on cellular responses to stress in mutation-carrying, iPSC-derived neural cells to sporadic forms of Parkinson’s disease (Sci. Transl. Med. 2012 July 4 [doi:10.1126/scitranslmed.3003985]).

"I think where the real excitement might come is how relevant these models systems are in helping us dissect the more sporadic forms of these diseases, because, frankly, that’s where we need some additional ability to control our investigations," Dr. Huentelman said.

However, he noted that iPSC-derived cell lines take a lot of time and money to produce. In addition, all of the studies reported so far suffer from a small sample size – mostly one or two patients – as well as the potential for diagnostic inaccuracy. "Accuracy is good for these disorders, but it is not 100%," he said.

"Most researchers are taking biopsies from living patients with a diagnosis. That’s fine, maybe, with familial cases of [Parkinson’s disease, Alzheimer’s disease], and Huntington’s because you see the family structure and you can follow the genetics," but it becomes more difficult with sporadic cases, he added.

Researchers at Dr. Huentelman’s institution have partnered with the Banner Sun Health Brain and Tissue Bank to make iPSCs from whole-body donors to that program, so that their cell studies are backed with a neuropathological diagnosis.

Neither Dr. Huang nor Dr. Huentelman had relevant disclosures.

Induced pluripotent stem cell lines that are created from the somatic cells of people with neurological diseases are beginning to pave a pathway for researchers to understand pathophysiology and screen for new drug candidates.

Recent work has characterized disease phenotypes and, in some cases, tested therapies in neurons that were differentiated from induced pluripotent stem cells (iPSCs) derived from patients with sporadic and familial Alzheimer’s disease, Huntington’s disease, and familial Parkinson’s disease.

These are heady times for this field in general and for neurological disease in particular. "It is really exciting when you start to be able to see relevant pathophysiologies in the dish," said Matthew Huentelman, Ph.D., head of the neurobehavioral research unit in the neurogenomics division at the Translational Genomics Research Institute, Phoenix.

Other investigators are trying to avoid one of the problems that has been plaguing this line of research: cell teratoma formation in vivo iPSC and embryonic stem cells. Their current approach is to reprogram fibroblasts into multipotent induced neural stem cells (iNSCs) that can then be differentiated into whatever neural progenitor cells the investigators wish to culture (neurons, oligodendroglia, and astroglia). This method also may lead to more efficient differentiation into the desired cell type, according to Dr. Yadong Huang, an associate investigator at the Gladstone Institute of Neurological Disease at the University of California, San Francisco.

Dr. Huang was the senior author on a study that used a single factor, rather than three or more, to directly reprogram human fibroblasts into multipotent iNSCs that can self-renew for 40-50 generations. This self-renewal ability, which is not present in the direct reprogramming of fibroblasts into neurons, makes them better to use for pathophysiology and drug testing studies (Cell Stem Cell 2012;11:100-9).

Only in the past year or so have people begun working in this middle ground between iPSCs and directly induced neuronal cells, so "it is important for studies in all three techniques to go forward now in parallel because each has advantages and disadvantages, at least at this point," Dr. Huang said in an interview.

"These initial studies ... are really encouraging because [they set us up] to dream about how we might leverage these cellular technologies to perform high-throughput drug screening," noted Dr. Huentelman.

In one study of Alzheimer’s disease, investigators developed iPSC cell lines from one patient with sporadic disease and two patients with familial disease caused by a mutation in the gene for amyloid precursor protein (APP). In each case, the investigators observed three major biochemical markers of Alzheimer’s (Nature 2012 Jan. 25 [doi:10.1038/nature10821]).

A separate study of familial Alzheimer’s disease with patients with presenilin-1 mutations, which was recently presented at the Alzheimer’s Association International Conference 2012, found substantial phenotypic differences between control neurons derived from iPSCs from unaffected family members, such as an increased ratio of amyloid-beta-42 to amyloid-beta-40 and an enhanced cell death response to apoptotic stimuli.

Even greater success has been reported with human Huntington’s disease neurons derived from iPSCs. In one study, researchers correlated the severity of phenotype in neurons with the number of CAG expansions observed in the huntingtin gene, as is observed in humans. However, some of the phenotypes were observed only in cell lines with the longest CAG expansion (Cell Stem Cell 2012 June 28 [doi:10.1016/j.stem.2012.04.027]). A separate group of researchers reported success in replacing the CAG expansion with a normal repeat length, which corrected the Huntington’s disease phenotype of mitochondrial deficits, lower levels of brain-derived neurotrophic factor, and altered cell signaling proteins (Cell Stem Cell 2012 June 28 [doi:10.1016/j.stem.2012.04.026]).

Another group of investigators reported the pharmacologic rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease caused by mutations in either PINK1 or LRRK2. Neural cells with PINK1 mutations that received low doses of mitochondrial stressors were rescued by both the antioxidant coenzyme Q10 and an LRRK2 inhibitor, whereas those with an LRRK2 mutation were partially rescued by rapamycin or an LRRK2 inhibitor. The researchers said that they hope to apply their observations on cellular responses to stress in mutation-carrying, iPSC-derived neural cells to sporadic forms of Parkinson’s disease (Sci. Transl. Med. 2012 July 4 [doi:10.1126/scitranslmed.3003985]).

"I think where the real excitement might come is how relevant these models systems are in helping us dissect the more sporadic forms of these diseases, because, frankly, that’s where we need some additional ability to control our investigations," Dr. Huentelman said.

However, he noted that iPSC-derived cell lines take a lot of time and money to produce. In addition, all of the studies reported so far suffer from a small sample size – mostly one or two patients – as well as the potential for diagnostic inaccuracy. "Accuracy is good for these disorders, but it is not 100%," he said.

"Most researchers are taking biopsies from living patients with a diagnosis. That’s fine, maybe, with familial cases of [Parkinson’s disease, Alzheimer’s disease], and Huntington’s because you see the family structure and you can follow the genetics," but it becomes more difficult with sporadic cases, he added.

Researchers at Dr. Huentelman’s institution have partnered with the Banner Sun Health Brain and Tissue Bank to make iPSCs from whole-body donors to that program, so that their cell studies are backed with a neuropathological diagnosis.

Neither Dr. Huang nor Dr. Huentelman had relevant disclosures.

Induced pluripotent stem cell lines that are created from the somatic cells of people with neurological diseases are beginning to pave a pathway for researchers to understand pathophysiology and screen for new drug candidates.

Recent work has characterized disease phenotypes and, in some cases, tested therapies in neurons that were differentiated from induced pluripotent stem cells (iPSCs) derived from patients with sporadic and familial Alzheimer’s disease, Huntington’s disease, and familial Parkinson’s disease.

These are heady times for this field in general and for neurological disease in particular. "It is really exciting when you start to be able to see relevant pathophysiologies in the dish," said Matthew Huentelman, Ph.D., head of the neurobehavioral research unit in the neurogenomics division at the Translational Genomics Research Institute, Phoenix.

Other investigators are trying to avoid one of the problems that has been plaguing this line of research: cell teratoma formation in vivo iPSC and embryonic stem cells. Their current approach is to reprogram fibroblasts into multipotent induced neural stem cells (iNSCs) that can then be differentiated into whatever neural progenitor cells the investigators wish to culture (neurons, oligodendroglia, and astroglia). This method also may lead to more efficient differentiation into the desired cell type, according to Dr. Yadong Huang, an associate investigator at the Gladstone Institute of Neurological Disease at the University of California, San Francisco.

Dr. Huang was the senior author on a study that used a single factor, rather than three or more, to directly reprogram human fibroblasts into multipotent iNSCs that can self-renew for 40-50 generations. This self-renewal ability, which is not present in the direct reprogramming of fibroblasts into neurons, makes them better to use for pathophysiology and drug testing studies (Cell Stem Cell 2012;11:100-9).

Only in the past year or so have people begun working in this middle ground between iPSCs and directly induced neuronal cells, so "it is important for studies in all three techniques to go forward now in parallel because each has advantages and disadvantages, at least at this point," Dr. Huang said in an interview.

"These initial studies ... are really encouraging because [they set us up] to dream about how we might leverage these cellular technologies to perform high-throughput drug screening," noted Dr. Huentelman.

In one study of Alzheimer’s disease, investigators developed iPSC cell lines from one patient with sporadic disease and two patients with familial disease caused by a mutation in the gene for amyloid precursor protein (APP). In each case, the investigators observed three major biochemical markers of Alzheimer’s (Nature 2012 Jan. 25 [doi:10.1038/nature10821]).

A separate study of familial Alzheimer’s disease with patients with presenilin-1 mutations, which was recently presented at the Alzheimer’s Association International Conference 2012, found substantial phenotypic differences between control neurons derived from iPSCs from unaffected family members, such as an increased ratio of amyloid-beta-42 to amyloid-beta-40 and an enhanced cell death response to apoptotic stimuli.

Even greater success has been reported with human Huntington’s disease neurons derived from iPSCs. In one study, researchers correlated the severity of phenotype in neurons with the number of CAG expansions observed in the huntingtin gene, as is observed in humans. However, some of the phenotypes were observed only in cell lines with the longest CAG expansion (Cell Stem Cell 2012 June 28 [doi:10.1016/j.stem.2012.04.027]). A separate group of researchers reported success in replacing the CAG expansion with a normal repeat length, which corrected the Huntington’s disease phenotype of mitochondrial deficits, lower levels of brain-derived neurotrophic factor, and altered cell signaling proteins (Cell Stem Cell 2012 June 28 [doi:10.1016/j.stem.2012.04.026]).

Another group of investigators reported the pharmacologic rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease caused by mutations in either PINK1 or LRRK2. Neural cells with PINK1 mutations that received low doses of mitochondrial stressors were rescued by both the antioxidant coenzyme Q10 and an LRRK2 inhibitor, whereas those with an LRRK2 mutation were partially rescued by rapamycin or an LRRK2 inhibitor. The researchers said that they hope to apply their observations on cellular responses to stress in mutation-carrying, iPSC-derived neural cells to sporadic forms of Parkinson’s disease (Sci. Transl. Med. 2012 July 4 [doi:10.1126/scitranslmed.3003985]).

"I think where the real excitement might come is how relevant these models systems are in helping us dissect the more sporadic forms of these diseases, because, frankly, that’s where we need some additional ability to control our investigations," Dr. Huentelman said.

However, he noted that iPSC-derived cell lines take a lot of time and money to produce. In addition, all of the studies reported so far suffer from a small sample size – mostly one or two patients – as well as the potential for diagnostic inaccuracy. "Accuracy is good for these disorders, but it is not 100%," he said.

"Most researchers are taking biopsies from living patients with a diagnosis. That’s fine, maybe, with familial cases of [Parkinson’s disease, Alzheimer’s disease], and Huntington’s because you see the family structure and you can follow the genetics," but it becomes more difficult with sporadic cases, he added.

Researchers at Dr. Huentelman’s institution have partnered with the Banner Sun Health Brain and Tissue Bank to make iPSCs from whole-body donors to that program, so that their cell studies are backed with a neuropathological diagnosis.

Neither Dr. Huang nor Dr. Huentelman had relevant disclosures.

SAN FRANCISCO – Successful outcomes in 74 of 79 patients who underwent robotic-assisted thymectomy suggest that the technology is safe and feasible, results of a multicenter European study demonstrate.

Dr. Franca Melfi, of the University of Pisa in Italy, and her colleagues studied 79 patients with early thymoma who were surgically treated at multiple centers in Europe between 2002 and 2011. More than half, 45 patients, had myasthenia gravis. The mean operating time was 155 minutes. At last follow-up, 74 patients were still alive and free from recurrence. One patient died of a diffuse intrathoracic recurrence and the others died of causes unrelated to thymoma, Dr. Melfi said at the annual meeting of the American Association for Thoracic Surgery.

Improved depth perception and precise movements facilitated by articulated instruments are among the benefits of the robotic approach. The robot facilitates safe access to the thymus in the upper mediastinal area where the space is small and there are numerous vessels. This approach also allows a prolonged thymectomy when removal of all the fat is required, she explained.

The 608 reported robotic-assisted thymectomies worldwide come from 43 papers published since 2003, but most feature a small number of patients and/or a short follow-up, Dr. Melfi said. One of the few larger studies of robotic-assisted thymectomy included 106 patients with myasthenia gravis (Ann. N.Y. Acad. Sci. 2008:1132:329-35). Researchers in this prospective study reported a mean operative time of 186 minutes, a 1% conversion rate, and a 30-day mortality of 0%. They had a low overall postoperative morbidity rate (2 of 95 patients): one instance of bleeding and one nerve injury.

A greater than 40% complete and stable remission rate for myasthenia gravis was "a real interesting result," Dr. Melfi said, noting that the mean follow-up was 20 months. Most participants reported improved quality of life, she added.

Additional clinical experience and refinements to robotic-assisted thymectomy are warranted, Dr. Melfi said, acknowledging the need for prospective, randomized trials.

Dr. Melfi said she had no relevant financial disclosures.

SAN FRANCISCO – Successful outcomes in 74 of 79 patients who underwent robotic-assisted thymectomy suggest that the technology is safe and feasible, results of a multicenter European study demonstrate.

Dr. Franca Melfi, of the University of Pisa in Italy, and her colleagues studied 79 patients with early thymoma who were surgically treated at multiple centers in Europe between 2002 and 2011. More than half, 45 patients, had myasthenia gravis. The mean operating time was 155 minutes. At last follow-up, 74 patients were still alive and free from recurrence. One patient died of a diffuse intrathoracic recurrence and the others died of causes unrelated to thymoma, Dr. Melfi said at the annual meeting of the American Association for Thoracic Surgery.

Improved depth perception and precise movements facilitated by articulated instruments are among the benefits of the robotic approach. The robot facilitates safe access to the thymus in the upper mediastinal area where the space is small and there are numerous vessels. This approach also allows a prolonged thymectomy when removal of all the fat is required, she explained.

The 608 reported robotic-assisted thymectomies worldwide come from 43 papers published since 2003, but most feature a small number of patients and/or a short follow-up, Dr. Melfi said. One of the few larger studies of robotic-assisted thymectomy included 106 patients with myasthenia gravis (Ann. N.Y. Acad. Sci. 2008:1132:329-35). Researchers in this prospective study reported a mean operative time of 186 minutes, a 1% conversion rate, and a 30-day mortality of 0%. They had a low overall postoperative morbidity rate (2 of 95 patients): one instance of bleeding and one nerve injury.

A greater than 40% complete and stable remission rate for myasthenia gravis was "a real interesting result," Dr. Melfi said, noting that the mean follow-up was 20 months. Most participants reported improved quality of life, she added.

Additional clinical experience and refinements to robotic-assisted thymectomy are warranted, Dr. Melfi said, acknowledging the need for prospective, randomized trials.

Dr. Melfi said she had no relevant financial disclosures.

SAN FRANCISCO – Successful outcomes in 74 of 79 patients who underwent robotic-assisted thymectomy suggest that the technology is safe and feasible, results of a multicenter European study demonstrate.

Dr. Franca Melfi, of the University of Pisa in Italy, and her colleagues studied 79 patients with early thymoma who were surgically treated at multiple centers in Europe between 2002 and 2011. More than half, 45 patients, had myasthenia gravis. The mean operating time was 155 minutes. At last follow-up, 74 patients were still alive and free from recurrence. One patient died of a diffuse intrathoracic recurrence and the others died of causes unrelated to thymoma, Dr. Melfi said at the annual meeting of the American Association for Thoracic Surgery.

Improved depth perception and precise movements facilitated by articulated instruments are among the benefits of the robotic approach. The robot facilitates safe access to the thymus in the upper mediastinal area where the space is small and there are numerous vessels. This approach also allows a prolonged thymectomy when removal of all the fat is required, she explained.

The 608 reported robotic-assisted thymectomies worldwide come from 43 papers published since 2003, but most feature a small number of patients and/or a short follow-up, Dr. Melfi said. One of the few larger studies of robotic-assisted thymectomy included 106 patients with myasthenia gravis (Ann. N.Y. Acad. Sci. 2008:1132:329-35). Researchers in this prospective study reported a mean operative time of 186 minutes, a 1% conversion rate, and a 30-day mortality of 0%. They had a low overall postoperative morbidity rate (2 of 95 patients): one instance of bleeding and one nerve injury.

A greater than 40% complete and stable remission rate for myasthenia gravis was "a real interesting result," Dr. Melfi said, noting that the mean follow-up was 20 months. Most participants reported improved quality of life, she added.

Additional clinical experience and refinements to robotic-assisted thymectomy are warranted, Dr. Melfi said, acknowledging the need for prospective, randomized trials.

Dr. Melfi said she had no relevant financial disclosures.

DESTIN, FLA. – An increasing number of patients are presenting with muscular dystrophy in adulthood.

"We’re now finding more and more patients who are presenting with muscular dystrophy [and] becoming symptomatic in adulthood, not just at age 20, but even at age 30, 40, or 50 years old," Dr. Robert Wortmann said at the Congress of Clinical Rheumatology.

In one case, a patient was diagnosed with a limb-girdle muscular dystrophy at 82 years of age, said Dr. Wortmann, professor of medicine at Dartmouth Medical School, Lebanon, N.H.

"So these are more common, more prevalent, and we’re learning a lot more about this disease," he added.

As an example, Dr. Wortmann presented one case involving a 20-year-old Brazilian exchange student with a 6-month history of progressive proximal muscle weakness. She had creatine phosphokinase (CPK) values that ranged between 20 and 60 times the upper limit of normal; a muscle biopsy showed lymphocytic inflammation. Corticosteroid and methotrexate treatment did not improve her condition.

She was found to have an autosomal recessive limb-girdle muscular dystrophy associated with dysferlin deficiency (limb-girdle muscular dystrophy type 2B, or LGMD2B). Dysferlin is one of the most common proteins to be deficient in this type of muscular dystrophy, Dr. Wortmann said.

Characteristics of LGMD2B include symmetric proximal myopathy, onset at 11-48 years of age (which has been expanded from an earlier identified range of late teens to early 20s), and very high CPK levels.

Caused by genetic defects in muscle cell proteins, muscular dystrophies are typically characterized by proximal muscle weakness, and later by muscle wasting. Early on in dystrophy, histology will look very similar to that of polymyositis.

"It may not be as profound a lymphocytic infiltrate, but it’s the same cells and the same distribution within the tissue," he said.

In fact, about 30% of cases in one series were first diagnosed with polymyositis, he said, noting that patients may even have some response to steroids.

Over time, however, this inflammation tends to decrease, and the muscle wastes and is replaced by fibrous tissue and fat," he said.

The muscle wasting represents an important distinction between polymyositis and muscular dystrophies, noted Dr. Wortmann.

The roles of various proteins in the associated genetic abnormalities continue to be defined, and limb-girdle muscular dystrophy is now considered to have 7 different autosomal dominant forms with different gene mutations, and 11 autosomal recessive forms that affect different structured proteins in the muscle and result in the identical presentation to polymyositis – including the LGMD2B disease identified in the case patient.

Not all patients with limb-girdle muscular dystrophy present with proximal myopathy, however.

In some cases, Miyoshi myopathy occurs, which is distal, late-onset myopathy. In other cases, there is mixed proximal and distal myopathy, he said.

"One thing I don’t understand – and I hope we learn some day why – is that some genetic disease that affects muscle will cause one phenotypic expression in one patient, and the same genetic defect in another patient will cause a different presentation," Dr. Wortmann said, adding that those that first appear to be polymyositis are generally the cases referred to rheumatologists and those with distal myopathy are generally those referred to neurologists.

Dr. Wortmann disclosed a financial relationship with Questcor.

DESTIN, FLA. – An increasing number of patients are presenting with muscular dystrophy in adulthood.

"We’re now finding more and more patients who are presenting with muscular dystrophy [and] becoming symptomatic in adulthood, not just at age 20, but even at age 30, 40, or 50 years old," Dr. Robert Wortmann said at the Congress of Clinical Rheumatology.

In one case, a patient was diagnosed with a limb-girdle muscular dystrophy at 82 years of age, said Dr. Wortmann, professor of medicine at Dartmouth Medical School, Lebanon, N.H.

"So these are more common, more prevalent, and we’re learning a lot more about this disease," he added.

As an example, Dr. Wortmann presented one case involving a 20-year-old Brazilian exchange student with a 6-month history of progressive proximal muscle weakness. She had creatine phosphokinase (CPK) values that ranged between 20 and 60 times the upper limit of normal; a muscle biopsy showed lymphocytic inflammation. Corticosteroid and methotrexate treatment did not improve her condition.

She was found to have an autosomal recessive limb-girdle muscular dystrophy associated with dysferlin deficiency (limb-girdle muscular dystrophy type 2B, or LGMD2B). Dysferlin is one of the most common proteins to be deficient in this type of muscular dystrophy, Dr. Wortmann said.

Characteristics of LGMD2B include symmetric proximal myopathy, onset at 11-48 years of age (which has been expanded from an earlier identified range of late teens to early 20s), and very high CPK levels.

Caused by genetic defects in muscle cell proteins, muscular dystrophies are typically characterized by proximal muscle weakness, and later by muscle wasting. Early on in dystrophy, histology will look very similar to that of polymyositis.

"It may not be as profound a lymphocytic infiltrate, but it’s the same cells and the same distribution within the tissue," he said.

In fact, about 30% of cases in one series were first diagnosed with polymyositis, he said, noting that patients may even have some response to steroids.

Over time, however, this inflammation tends to decrease, and the muscle wastes and is replaced by fibrous tissue and fat," he said.

The muscle wasting represents an important distinction between polymyositis and muscular dystrophies, noted Dr. Wortmann.

The roles of various proteins in the associated genetic abnormalities continue to be defined, and limb-girdle muscular dystrophy is now considered to have 7 different autosomal dominant forms with different gene mutations, and 11 autosomal recessive forms that affect different structured proteins in the muscle and result in the identical presentation to polymyositis – including the LGMD2B disease identified in the case patient.

Not all patients with limb-girdle muscular dystrophy present with proximal myopathy, however.

In some cases, Miyoshi myopathy occurs, which is distal, late-onset myopathy. In other cases, there is mixed proximal and distal myopathy, he said.

"One thing I don’t understand – and I hope we learn some day why – is that some genetic disease that affects muscle will cause one phenotypic expression in one patient, and the same genetic defect in another patient will cause a different presentation," Dr. Wortmann said, adding that those that first appear to be polymyositis are generally the cases referred to rheumatologists and those with distal myopathy are generally those referred to neurologists.

Dr. Wortmann disclosed a financial relationship with Questcor.

DESTIN, FLA. – An increasing number of patients are presenting with muscular dystrophy in adulthood.

"We’re now finding more and more patients who are presenting with muscular dystrophy [and] becoming symptomatic in adulthood, not just at age 20, but even at age 30, 40, or 50 years old," Dr. Robert Wortmann said at the Congress of Clinical Rheumatology.

In one case, a patient was diagnosed with a limb-girdle muscular dystrophy at 82 years of age, said Dr. Wortmann, professor of medicine at Dartmouth Medical School, Lebanon, N.H.

"So these are more common, more prevalent, and we’re learning a lot more about this disease," he added.

As an example, Dr. Wortmann presented one case involving a 20-year-old Brazilian exchange student with a 6-month history of progressive proximal muscle weakness. She had creatine phosphokinase (CPK) values that ranged between 20 and 60 times the upper limit of normal; a muscle biopsy showed lymphocytic inflammation. Corticosteroid and methotrexate treatment did not improve her condition.

She was found to have an autosomal recessive limb-girdle muscular dystrophy associated with dysferlin deficiency (limb-girdle muscular dystrophy type 2B, or LGMD2B). Dysferlin is one of the most common proteins to be deficient in this type of muscular dystrophy, Dr. Wortmann said.

Characteristics of LGMD2B include symmetric proximal myopathy, onset at 11-48 years of age (which has been expanded from an earlier identified range of late teens to early 20s), and very high CPK levels.

Caused by genetic defects in muscle cell proteins, muscular dystrophies are typically characterized by proximal muscle weakness, and later by muscle wasting. Early on in dystrophy, histology will look very similar to that of polymyositis.

"It may not be as profound a lymphocytic infiltrate, but it’s the same cells and the same distribution within the tissue," he said.

In fact, about 30% of cases in one series were first diagnosed with polymyositis, he said, noting that patients may even have some response to steroids.

Over time, however, this inflammation tends to decrease, and the muscle wastes and is replaced by fibrous tissue and fat," he said.

The muscle wasting represents an important distinction between polymyositis and muscular dystrophies, noted Dr. Wortmann.

The roles of various proteins in the associated genetic abnormalities continue to be defined, and limb-girdle muscular dystrophy is now considered to have 7 different autosomal dominant forms with different gene mutations, and 11 autosomal recessive forms that affect different structured proteins in the muscle and result in the identical presentation to polymyositis – including the LGMD2B disease identified in the case patient.

Not all patients with limb-girdle muscular dystrophy present with proximal myopathy, however.

In some cases, Miyoshi myopathy occurs, which is distal, late-onset myopathy. In other cases, there is mixed proximal and distal myopathy, he said.

"One thing I don’t understand – and I hope we learn some day why – is that some genetic disease that affects muscle will cause one phenotypic expression in one patient, and the same genetic defect in another patient will cause a different presentation," Dr. Wortmann said, adding that those that first appear to be polymyositis are generally the cases referred to rheumatologists and those with distal myopathy are generally those referred to neurologists.

Dr. Wortmann disclosed a financial relationship with Questcor.

SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A single study of the investigational drug tafamidis provided enough evidence of its effectiveness as a treatment for polyneuropathy in patients with a rare form of hereditary amyloidosis to meet Food and Drug Administration criteria for an accelerated approval of a drug, the majority of an advisory panel has agreed.

At a May 24th meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 13-4 that the results of a small placebo-controlled study of tafamidis provided enough evidence that it was effective, based on surrogate end points that were considered "reasonably likely" to predict a clinical benefit in patients with this disease. That is the basis of an accelerated approval the FDA grants to drugs for diseases for which there is an unmet need, under the condition that the company conduct another study to confirm the clinical benefit, before full approval. If follow-up studies fail to confirm a benefit, the FDA can rescind approval.

The panel also voted 13-4 that the results of the study were not strong enough to provide evidence that was comparable to the evidence required for a full approval of a drug, two studies with evidence of effectiveness on clinical end points.

The proposed indication for tafamidis – a capsule formulation taken once daily – is for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with symptomatic polyneuropathy, with the aim of delaying neurologic impairment. Tafamidis is thought to prevent the formation of abnormal amyloid protein that is deposited on peripheral nerves, which causes polyneuropathy in patients with the progressive neurodegenerative disease. There are no approved treatments for the disease; the only treatment option is a liver transplant, since TTR is primarily synthesized in the liver. An autosomal dominant disease, FAP is one of the two types of familial amyloidosis (the other is familial amyloid cardiomyopathy), which affects fewer than 10,000 people worldwide, including about 2,500 cases in the United States. Cases are clustered in Portugal, Sweden, and Japan.

The randomized, placebo-controlled study, conducted by FoldRx Pharmaceuticals, a subsidiary of Pfizer, enrolled patients in relatively early stages of the disease outside the United States, comparing treatment with 20 mg once a day of tafamidis in 65 patients with placebo in 63 patients. At 18 months, 45% of those on the drug had less than a two-point change in neuropathy impairment scores from baseline (the primary efficacy end point), compared with 29.5% of those on placebo, which was not statistically significant. There was also evidence that those patients on tafamidis experienced less deterioration in quality of life over 18 months, compared with those on placebo.

About 20% of the patients in the study dropped out early to undergo a liver transplant, and more than half the study patients were treated at one site in Portugal, which were limitations of the study. The most common adverse events affecting at least 10% of patients on the drug were urinary tract infections, diarrhea, extremity pain, and upper abdominal pain.

Major issues raised by FDA reviewers and panelists included the lack of statistical significance of the primary end point, the lack of a beneficial effect when the patients at the Portuguese site were excluded, generalizability to the U.S. population, and lower baseline neuropathy scores in the treatment group.

But panelists supporting the accelerated approval cited evidence of efficacy on some surrogate end points, including evidence of improvements in muscle strength, although they had concerns about the strength of the data. Panelists had no particular safety concerns, but they pointed out the number of patients studied was small, and one panelist noted that the duration of treatment for patients would be much longer than the time in the study.

Tafamidis was approved in Europe for this indication in November 2011, under an "exceptional circumstances" provision. If approved in the United States, the drug will be marketed as Vyndaquel; it would be the first pharmacologic treatment approved in the United States and the first treatment that would be available immediately after a patient is diagnosed, according to Pfizer.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.