Jeff Evans

BOSTON – Brain-training with a video game appears to improve cognitive abilities in multiple sclerosis patients with cognitive impairment by increasing thalamo-cortical connectivity in the brain, according to Dr. Laura De Giglio.

She and her colleagues at Sapienza University of Rome conducted functional MRI scans of patients before and after 8 weeks of using "Dr. Kawashima's Brain Training" video game and compared them against patients who had been assigned to a wait-list group in a small, pilot, randomized study. They found improvements in processing speed and some aspects of working memory that correlated with increased functional connectivity between the thalamus and parts of the cortex.

In a video interview at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, Dr. De Giglio explained the rationale behind the study and how it might be applied further.

[email protected]

BOSTON – Brain-training with a video game appears to improve cognitive abilities in multiple sclerosis patients with cognitive impairment by increasing thalamo-cortical connectivity in the brain, according to Dr. Laura De Giglio.

She and her colleagues at Sapienza University of Rome conducted functional MRI scans of patients before and after 8 weeks of using "Dr. Kawashima's Brain Training" video game and compared them against patients who had been assigned to a wait-list group in a small, pilot, randomized study. They found improvements in processing speed and some aspects of working memory that correlated with increased functional connectivity between the thalamus and parts of the cortex.

In a video interview at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, Dr. De Giglio explained the rationale behind the study and how it might be applied further.

[email protected]

BOSTON – Brain-training with a video game appears to improve cognitive abilities in multiple sclerosis patients with cognitive impairment by increasing thalamo-cortical connectivity in the brain, according to Dr. Laura De Giglio.

She and her colleagues at Sapienza University of Rome conducted functional MRI scans of patients before and after 8 weeks of using "Dr. Kawashima's Brain Training" video game and compared them against patients who had been assigned to a wait-list group in a small, pilot, randomized study. They found improvements in processing speed and some aspects of working memory that correlated with increased functional connectivity between the thalamus and parts of the cortex.

In a video interview at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, Dr. De Giglio explained the rationale behind the study and how it might be applied further.

[email protected]

BOSTON – Multiple sclerosis patients with cognitive impairment who played a brain-training video game on a regular basis had significant improvement in cognitive test results that correlated with an increase in functional connectivity between the thalamus and cortex in a small, randomized pilot study.

The results of the study provide some preliminary evidence that improvement in measures of the functional connectivity between thalamic and cortical areas serve as the functional substrate underlying clinical recovery, Dr. Laura De Giglio said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Dr. De Giglio and her associates at Sapienza University of Rome based the premise of the current study on their research team’s recent functional MRI study in MS patients with cognitive impairment, which indicated that worse performance on cognitive testing is associated with increased functional thalamo-cortical connectivity in the thalamic resting state network (Radiology 2014 June [doi:http://dx.doi.org/10.1148/radiol.14131688]). That association could be interpreted to mean that "there are some neuroplastic changes in the thalamic resting state in MS that are not able to fully compensate for tissue damage to prevent cognitive dysfunction," Dr. De Giglio said.

Given the success of recent studies in cognitive rehabilitation of MS patients with face-to-face, computer-assisted, and home-based treatments, she and her colleagues sought to understand how this might work by randomizing 24 patients with cognitive impairment to 8 weeks of training with the video game, "Dr. Kawashimas Brain Training," or to a wait-list group that later received the same training after the study period. Patients used the Italian version of the video game at home for 30 minutes per day, 5 days per week during an 8-week period; their compliance with its use was recorded on the console. The patients had a similar mean level of education (14 years), disease duration (13 years), and Expanded Disability Status score (2).

The investigators assessed attention, processing speed, and working memory before and after the video game training with the Paced Auditory Serial Addition Test (PASAT) with a 3-second pace (0-60, higher scores better), the Symbol Digit Modalities Test (SDMT; 0-110, higher scores better), and the Stroop Test (higher scores better) while patients underwent 3-Tesla functional MRI.

The investigators defined cognitive impairment as failure on at least one of the three neuropsychological tests, based on a score below the 10th percentile of normative data in the Italian population.

Mean scores improved significantly in the intervention group, compared with the wait-list group, on the PASAT (from 35.5 to 46.2 vs. from 32.64 to 36.60) and the Stroop Test (from 22.83 to 28.83 vs. from 24.43 to 25.36). The intervention led to numerically greater mean improvement on the SDMT, but the results were not statistically significant.

Improvement on the PASAT correlated with patterns of increased thalamic connectivity to the left superior temporal gyrus and bilateral locations in the lingual, fusiform, and pre-central gyri. On the Stroop Test, improvement was correlated with improved connectivity between the right angular and supramarginal gyri and the thalamus. Improvement on the SDMT was associated with increased thalamic connectivity to bilateral locations on the temporal, occipital, and lateral parietal cortex.

The investigators observed no relapses or worsening of Expanded Disability Status Scale scores in the patients.

Dr. De Giglio had nothing to disclose. Two coauthors had consulting or lecture fees from pharmaceutical companies marketing MS therapies.

[email protected]

BOSTON – Multiple sclerosis patients with cognitive impairment who played a brain-training video game on a regular basis had significant improvement in cognitive test results that correlated with an increase in functional connectivity between the thalamus and cortex in a small, randomized pilot study.

The results of the study provide some preliminary evidence that improvement in measures of the functional connectivity between thalamic and cortical areas serve as the functional substrate underlying clinical recovery, Dr. Laura De Giglio said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Dr. De Giglio and her associates at Sapienza University of Rome based the premise of the current study on their research team’s recent functional MRI study in MS patients with cognitive impairment, which indicated that worse performance on cognitive testing is associated with increased functional thalamo-cortical connectivity in the thalamic resting state network (Radiology 2014 June [doi:http://dx.doi.org/10.1148/radiol.14131688]). That association could be interpreted to mean that "there are some neuroplastic changes in the thalamic resting state in MS that are not able to fully compensate for tissue damage to prevent cognitive dysfunction," Dr. De Giglio said.

Given the success of recent studies in cognitive rehabilitation of MS patients with face-to-face, computer-assisted, and home-based treatments, she and her colleagues sought to understand how this might work by randomizing 24 patients with cognitive impairment to 8 weeks of training with the video game, "Dr. Kawashimas Brain Training," or to a wait-list group that later received the same training after the study period. Patients used the Italian version of the video game at home for 30 minutes per day, 5 days per week during an 8-week period; their compliance with its use was recorded on the console. The patients had a similar mean level of education (14 years), disease duration (13 years), and Expanded Disability Status score (2).

The investigators assessed attention, processing speed, and working memory before and after the video game training with the Paced Auditory Serial Addition Test (PASAT) with a 3-second pace (0-60, higher scores better), the Symbol Digit Modalities Test (SDMT; 0-110, higher scores better), and the Stroop Test (higher scores better) while patients underwent 3-Tesla functional MRI.

The investigators defined cognitive impairment as failure on at least one of the three neuropsychological tests, based on a score below the 10th percentile of normative data in the Italian population.

Mean scores improved significantly in the intervention group, compared with the wait-list group, on the PASAT (from 35.5 to 46.2 vs. from 32.64 to 36.60) and the Stroop Test (from 22.83 to 28.83 vs. from 24.43 to 25.36). The intervention led to numerically greater mean improvement on the SDMT, but the results were not statistically significant.

Improvement on the PASAT correlated with patterns of increased thalamic connectivity to the left superior temporal gyrus and bilateral locations in the lingual, fusiform, and pre-central gyri. On the Stroop Test, improvement was correlated with improved connectivity between the right angular and supramarginal gyri and the thalamus. Improvement on the SDMT was associated with increased thalamic connectivity to bilateral locations on the temporal, occipital, and lateral parietal cortex.

The investigators observed no relapses or worsening of Expanded Disability Status Scale scores in the patients.

Dr. De Giglio had nothing to disclose. Two coauthors had consulting or lecture fees from pharmaceutical companies marketing MS therapies.

[email protected]

BOSTON – Multiple sclerosis patients with cognitive impairment who played a brain-training video game on a regular basis had significant improvement in cognitive test results that correlated with an increase in functional connectivity between the thalamus and cortex in a small, randomized pilot study.

The results of the study provide some preliminary evidence that improvement in measures of the functional connectivity between thalamic and cortical areas serve as the functional substrate underlying clinical recovery, Dr. Laura De Giglio said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Dr. De Giglio and her associates at Sapienza University of Rome based the premise of the current study on their research team’s recent functional MRI study in MS patients with cognitive impairment, which indicated that worse performance on cognitive testing is associated with increased functional thalamo-cortical connectivity in the thalamic resting state network (Radiology 2014 June [doi:http://dx.doi.org/10.1148/radiol.14131688]). That association could be interpreted to mean that "there are some neuroplastic changes in the thalamic resting state in MS that are not able to fully compensate for tissue damage to prevent cognitive dysfunction," Dr. De Giglio said.

Given the success of recent studies in cognitive rehabilitation of MS patients with face-to-face, computer-assisted, and home-based treatments, she and her colleagues sought to understand how this might work by randomizing 24 patients with cognitive impairment to 8 weeks of training with the video game, "Dr. Kawashimas Brain Training," or to a wait-list group that later received the same training after the study period. Patients used the Italian version of the video game at home for 30 minutes per day, 5 days per week during an 8-week period; their compliance with its use was recorded on the console. The patients had a similar mean level of education (14 years), disease duration (13 years), and Expanded Disability Status score (2).

The investigators assessed attention, processing speed, and working memory before and after the video game training with the Paced Auditory Serial Addition Test (PASAT) with a 3-second pace (0-60, higher scores better), the Symbol Digit Modalities Test (SDMT; 0-110, higher scores better), and the Stroop Test (higher scores better) while patients underwent 3-Tesla functional MRI.

The investigators defined cognitive impairment as failure on at least one of the three neuropsychological tests, based on a score below the 10th percentile of normative data in the Italian population.

Mean scores improved significantly in the intervention group, compared with the wait-list group, on the PASAT (from 35.5 to 46.2 vs. from 32.64 to 36.60) and the Stroop Test (from 22.83 to 28.83 vs. from 24.43 to 25.36). The intervention led to numerically greater mean improvement on the SDMT, but the results were not statistically significant.

Improvement on the PASAT correlated with patterns of increased thalamic connectivity to the left superior temporal gyrus and bilateral locations in the lingual, fusiform, and pre-central gyri. On the Stroop Test, improvement was correlated with improved connectivity between the right angular and supramarginal gyri and the thalamus. Improvement on the SDMT was associated with increased thalamic connectivity to bilateral locations on the temporal, occipital, and lateral parietal cortex.

The investigators observed no relapses or worsening of Expanded Disability Status Scale scores in the patients.

Dr. De Giglio had nothing to disclose. Two coauthors had consulting or lecture fees from pharmaceutical companies marketing MS therapies.

[email protected]

As powerful new drugs enter the market for the treatment of multiple sclerosis, methods are emerging for stratifying patients’ risk of progressive multifocal leukoencephalopathy.

Researchers are looking to immunosuppressive history and specific biomarkers to detect progressive multifocal leukoencephalopathy (PML) in its early stages. Also, they are gaining a better understanding of PML’s pathogenesis. At the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston, researchers will discuss each of these areas.

PML risk stratification

Two recently developed methods for determining a patient’s risk for PML while taking natalizumab – an anti–JC virus antibody index greater than 0.9 and a finding of less than 21.6% of CD4-positive T cells with l-selectin (CD62L) – may be best used for risk stratification when patients’ previous immunosuppressive drug use is known, according to research that Dr. Heinz Wiendl of the University of Münster in Germany will present Sept. 11. He and his colleagues’ analysis of nearly 2,000 natalizumab-treated MS patients found a statistical correlation between the anti-JCV antibody index and CD62L that existed only in patients who had previously been on immunosuppression. In addition, there was a stronger correlation between CD62L values and treatment duration in patients with previous immunosuppression, "suggesting CD62L as a first biological marker explaining why [previously immunosuppressed] patients are at higher risk to develop PML over time," the investigators wrote in their abstract.

Diagnosing PML regardless of etiology

A hypointense T2* band at the gray-white junction with variable thickness that at least partially encompasses the characteristic PML lesion sign of asymmetric hyperintensities on T2*-weight imaging may be helpful in detecting PML irrespective of the underlying etiology, according to new research from the National Institute of Neurological Disorders and Stroke that will be presented during the same session on Sept. 11. Dr. Varun Sethi and his colleagues at NINDS used a 3-T scanner to evaluate nine PML patients, including four with natalizumab-treated MS, two with lymphoma, one with idiopathic low CD4 T-cell count, and two with HIV infection. The band was never seen in association with preexisting MS lesions and had a tendency to spread over time in the five patients who had an additional scan 1-7 months after the first scan.

Insight into JC virus reactivation

On Sept. 11, Dr. Spyridon Chalkias of Beth Israel Deaconess Medical Center, Boston, will describe a study he led that provides further insight into how JC virus is reactivated in patients taking natalizumab, which has a mechanism of action that prevents trafficking of leukocytes out of the bloodstream. Dr. Chalkias and his colleagues found that JCV-seropositive patients taking natalizumab could be clinically asymptomatic and free of radiographic findings of PML despite evidence of JCV reactivation in the cerebrospinal fluid or in specific leukocyte populations. The researchers enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy for greater than 18 months, 6 on interferon beta-1a monotherapy for greater than 36 months, and 5 untreated controls. Of 27 natalizumab-treated patients who were asymptomatic and MRI-negative for PML, 2 had JCV DNA detected in their cerebrospinal fluid. Overall, the investigators found JCV DNA in the blood of 12 (28%) of the 43 patients. The two natalizumab-treated patients with JCV DNA in CSF did not have JCV DNA in blood or urine; however, the investigators detected JCV-specific CD4-positive T cells ex vivo more frequently in natalizumab-treated patients who were viremic, and in vitro stimulation led to more frequent detection of JCV-specific CD4-positive T cells than of CD8-positive T cells, indicating that "viremia might trigger a JCV-specific CD4-positive mediated response."

PML after natalizumab switchover to fingolimod

An analysis of a Novartis safety reporting database for fingolimod points to no new risk for PML that can be attributed to the drug, although 11 new cases have been reported in patients who switched from natalizumab to fingolimod. The study, to be presented by Dr. Norman Putzki of Novartis on Sept. 12, is based on 135,800 patient-years of fingolimod exposure in MS patients through February 2014. About 15%-20% of patients in the database had previously been on natalizumab. The 11 natalizumab-associated PML cases have been reported following 4 years’ mean duration of natalizumab use, and in all cases the onset of PML was either confirmed prior to the switch (in retrospect) or occurred within 6 months after the switch to fingolimod. In one additional case, a patient who had not been exposed to natalizumab was reported to have PML after 7 months of fingolimod treatment based on the results of a low JCV copy number in cerebrospinal fluid, but it was later determined that the patient’s clinical features and MRI evolution were consistent with neuromyelitis optica.

[email protected]

As powerful new drugs enter the market for the treatment of multiple sclerosis, methods are emerging for stratifying patients’ risk of progressive multifocal leukoencephalopathy.

Researchers are looking to immunosuppressive history and specific biomarkers to detect progressive multifocal leukoencephalopathy (PML) in its early stages. Also, they are gaining a better understanding of PML’s pathogenesis. At the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston, researchers will discuss each of these areas.

PML risk stratification

Two recently developed methods for determining a patient’s risk for PML while taking natalizumab – an anti–JC virus antibody index greater than 0.9 and a finding of less than 21.6% of CD4-positive T cells with l-selectin (CD62L) – may be best used for risk stratification when patients’ previous immunosuppressive drug use is known, according to research that Dr. Heinz Wiendl of the University of Münster in Germany will present Sept. 11. He and his colleagues’ analysis of nearly 2,000 natalizumab-treated MS patients found a statistical correlation between the anti-JCV antibody index and CD62L that existed only in patients who had previously been on immunosuppression. In addition, there was a stronger correlation between CD62L values and treatment duration in patients with previous immunosuppression, "suggesting CD62L as a first biological marker explaining why [previously immunosuppressed] patients are at higher risk to develop PML over time," the investigators wrote in their abstract.

Diagnosing PML regardless of etiology

A hypointense T2* band at the gray-white junction with variable thickness that at least partially encompasses the characteristic PML lesion sign of asymmetric hyperintensities on T2*-weight imaging may be helpful in detecting PML irrespective of the underlying etiology, according to new research from the National Institute of Neurological Disorders and Stroke that will be presented during the same session on Sept. 11. Dr. Varun Sethi and his colleagues at NINDS used a 3-T scanner to evaluate nine PML patients, including four with natalizumab-treated MS, two with lymphoma, one with idiopathic low CD4 T-cell count, and two with HIV infection. The band was never seen in association with preexisting MS lesions and had a tendency to spread over time in the five patients who had an additional scan 1-7 months after the first scan.

Insight into JC virus reactivation

On Sept. 11, Dr. Spyridon Chalkias of Beth Israel Deaconess Medical Center, Boston, will describe a study he led that provides further insight into how JC virus is reactivated in patients taking natalizumab, which has a mechanism of action that prevents trafficking of leukocytes out of the bloodstream. Dr. Chalkias and his colleagues found that JCV-seropositive patients taking natalizumab could be clinically asymptomatic and free of radiographic findings of PML despite evidence of JCV reactivation in the cerebrospinal fluid or in specific leukocyte populations. The researchers enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy for greater than 18 months, 6 on interferon beta-1a monotherapy for greater than 36 months, and 5 untreated controls. Of 27 natalizumab-treated patients who were asymptomatic and MRI-negative for PML, 2 had JCV DNA detected in their cerebrospinal fluid. Overall, the investigators found JCV DNA in the blood of 12 (28%) of the 43 patients. The two natalizumab-treated patients with JCV DNA in CSF did not have JCV DNA in blood or urine; however, the investigators detected JCV-specific CD4-positive T cells ex vivo more frequently in natalizumab-treated patients who were viremic, and in vitro stimulation led to more frequent detection of JCV-specific CD4-positive T cells than of CD8-positive T cells, indicating that "viremia might trigger a JCV-specific CD4-positive mediated response."

PML after natalizumab switchover to fingolimod

An analysis of a Novartis safety reporting database for fingolimod points to no new risk for PML that can be attributed to the drug, although 11 new cases have been reported in patients who switched from natalizumab to fingolimod. The study, to be presented by Dr. Norman Putzki of Novartis on Sept. 12, is based on 135,800 patient-years of fingolimod exposure in MS patients through February 2014. About 15%-20% of patients in the database had previously been on natalizumab. The 11 natalizumab-associated PML cases have been reported following 4 years’ mean duration of natalizumab use, and in all cases the onset of PML was either confirmed prior to the switch (in retrospect) or occurred within 6 months after the switch to fingolimod. In one additional case, a patient who had not been exposed to natalizumab was reported to have PML after 7 months of fingolimod treatment based on the results of a low JCV copy number in cerebrospinal fluid, but it was later determined that the patient’s clinical features and MRI evolution were consistent with neuromyelitis optica.

[email protected]

As powerful new drugs enter the market for the treatment of multiple sclerosis, methods are emerging for stratifying patients’ risk of progressive multifocal leukoencephalopathy.

Researchers are looking to immunosuppressive history and specific biomarkers to detect progressive multifocal leukoencephalopathy (PML) in its early stages. Also, they are gaining a better understanding of PML’s pathogenesis. At the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston, researchers will discuss each of these areas.

PML risk stratification

Two recently developed methods for determining a patient’s risk for PML while taking natalizumab – an anti–JC virus antibody index greater than 0.9 and a finding of less than 21.6% of CD4-positive T cells with l-selectin (CD62L) – may be best used for risk stratification when patients’ previous immunosuppressive drug use is known, according to research that Dr. Heinz Wiendl of the University of Münster in Germany will present Sept. 11. He and his colleagues’ analysis of nearly 2,000 natalizumab-treated MS patients found a statistical correlation between the anti-JCV antibody index and CD62L that existed only in patients who had previously been on immunosuppression. In addition, there was a stronger correlation between CD62L values and treatment duration in patients with previous immunosuppression, "suggesting CD62L as a first biological marker explaining why [previously immunosuppressed] patients are at higher risk to develop PML over time," the investigators wrote in their abstract.

Diagnosing PML regardless of etiology

A hypointense T2* band at the gray-white junction with variable thickness that at least partially encompasses the characteristic PML lesion sign of asymmetric hyperintensities on T2*-weight imaging may be helpful in detecting PML irrespective of the underlying etiology, according to new research from the National Institute of Neurological Disorders and Stroke that will be presented during the same session on Sept. 11. Dr. Varun Sethi and his colleagues at NINDS used a 3-T scanner to evaluate nine PML patients, including four with natalizumab-treated MS, two with lymphoma, one with idiopathic low CD4 T-cell count, and two with HIV infection. The band was never seen in association with preexisting MS lesions and had a tendency to spread over time in the five patients who had an additional scan 1-7 months after the first scan.

Insight into JC virus reactivation

On Sept. 11, Dr. Spyridon Chalkias of Beth Israel Deaconess Medical Center, Boston, will describe a study he led that provides further insight into how JC virus is reactivated in patients taking natalizumab, which has a mechanism of action that prevents trafficking of leukocytes out of the bloodstream. Dr. Chalkias and his colleagues found that JCV-seropositive patients taking natalizumab could be clinically asymptomatic and free of radiographic findings of PML despite evidence of JCV reactivation in the cerebrospinal fluid or in specific leukocyte populations. The researchers enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy for greater than 18 months, 6 on interferon beta-1a monotherapy for greater than 36 months, and 5 untreated controls. Of 27 natalizumab-treated patients who were asymptomatic and MRI-negative for PML, 2 had JCV DNA detected in their cerebrospinal fluid. Overall, the investigators found JCV DNA in the blood of 12 (28%) of the 43 patients. The two natalizumab-treated patients with JCV DNA in CSF did not have JCV DNA in blood or urine; however, the investigators detected JCV-specific CD4-positive T cells ex vivo more frequently in natalizumab-treated patients who were viremic, and in vitro stimulation led to more frequent detection of JCV-specific CD4-positive T cells than of CD8-positive T cells, indicating that "viremia might trigger a JCV-specific CD4-positive mediated response."

PML after natalizumab switchover to fingolimod

An analysis of a Novartis safety reporting database for fingolimod points to no new risk for PML that can be attributed to the drug, although 11 new cases have been reported in patients who switched from natalizumab to fingolimod. The study, to be presented by Dr. Norman Putzki of Novartis on Sept. 12, is based on 135,800 patient-years of fingolimod exposure in MS patients through February 2014. About 15%-20% of patients in the database had previously been on natalizumab. The 11 natalizumab-associated PML cases have been reported following 4 years’ mean duration of natalizumab use, and in all cases the onset of PML was either confirmed prior to the switch (in retrospect) or occurred within 6 months after the switch to fingolimod. In one additional case, a patient who had not been exposed to natalizumab was reported to have PML after 7 months of fingolimod treatment based on the results of a low JCV copy number in cerebrospinal fluid, but it was later determined that the patient’s clinical features and MRI evolution were consistent with neuromyelitis optica.

[email protected]

Generic glatiramer acetate provided reductions in gadolinium-enhancing lesions and annualized relapse rate that were similar to the brand-name version of the drug, Copaxone, in patients with relapsing-remitting multiple sclerosis without any additional safety concerns in a phase III trial.

The combined number of gadolinium-enhancing lesions over months 7, 8, and 9 of the 9-month, double-blind, placebo-controlled, randomized GATE trial, sponsored by Synthon BV, served as the primary endpoint and indicated equivalent efficacy based on the predefined equivalence margin for the ratio of new lesions between generic glatiramer acetate and Copaxone in the study of 794 total patients. Both drugs reduced the number of new lesions, compared with placebo. The annualized relapse rates were comparable across all the groups: 0.31 (generic glatiramer acetate), 0.41 (Copaxone), and 0.39 (placebo).

The active treatment groups had similar incidence, spectrum, and severity of reported adverse events, including injection site reactions. Dr. Jeffrey A. Cohen, director of the experimental therapeutics program at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, will report the results on Sept. 12 at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston.

On Sept. 11, Dr. Cohen also will speak about the need for generic equivalents to drugs that will soon be coming off patent protection. Although there is great potential for "cost savings to patients and third-party payers based on the more limited testing required for approval and resultant reduced development costs," Dr. Cohen wrote in his abstract that there are many difficulties in the process of developing these generics. As is the case for the highly complex peptide mixture that constitutes glatiramer acetate, interferons or monoclonal antibodies are biologics with highly complex chemical structures whose properties are vulnerable to changes on many levels that are difficult to predict without thorough testing. However, it will probably be necessary for developers to use more sensitive biologic markers of drug response, such as MRI, that have been previously well characterized for the original innovator product, as well as trials that use new designs and statistical analyses, he wrote.

[email protected]

Generic glatiramer acetate provided reductions in gadolinium-enhancing lesions and annualized relapse rate that were similar to the brand-name version of the drug, Copaxone, in patients with relapsing-remitting multiple sclerosis without any additional safety concerns in a phase III trial.

The combined number of gadolinium-enhancing lesions over months 7, 8, and 9 of the 9-month, double-blind, placebo-controlled, randomized GATE trial, sponsored by Synthon BV, served as the primary endpoint and indicated equivalent efficacy based on the predefined equivalence margin for the ratio of new lesions between generic glatiramer acetate and Copaxone in the study of 794 total patients. Both drugs reduced the number of new lesions, compared with placebo. The annualized relapse rates were comparable across all the groups: 0.31 (generic glatiramer acetate), 0.41 (Copaxone), and 0.39 (placebo).

The active treatment groups had similar incidence, spectrum, and severity of reported adverse events, including injection site reactions. Dr. Jeffrey A. Cohen, director of the experimental therapeutics program at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, will report the results on Sept. 12 at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston.

On Sept. 11, Dr. Cohen also will speak about the need for generic equivalents to drugs that will soon be coming off patent protection. Although there is great potential for "cost savings to patients and third-party payers based on the more limited testing required for approval and resultant reduced development costs," Dr. Cohen wrote in his abstract that there are many difficulties in the process of developing these generics. As is the case for the highly complex peptide mixture that constitutes glatiramer acetate, interferons or monoclonal antibodies are biologics with highly complex chemical structures whose properties are vulnerable to changes on many levels that are difficult to predict without thorough testing. However, it will probably be necessary for developers to use more sensitive biologic markers of drug response, such as MRI, that have been previously well characterized for the original innovator product, as well as trials that use new designs and statistical analyses, he wrote.

[email protected]

Generic glatiramer acetate provided reductions in gadolinium-enhancing lesions and annualized relapse rate that were similar to the brand-name version of the drug, Copaxone, in patients with relapsing-remitting multiple sclerosis without any additional safety concerns in a phase III trial.

The combined number of gadolinium-enhancing lesions over months 7, 8, and 9 of the 9-month, double-blind, placebo-controlled, randomized GATE trial, sponsored by Synthon BV, served as the primary endpoint and indicated equivalent efficacy based on the predefined equivalence margin for the ratio of new lesions between generic glatiramer acetate and Copaxone in the study of 794 total patients. Both drugs reduced the number of new lesions, compared with placebo. The annualized relapse rates were comparable across all the groups: 0.31 (generic glatiramer acetate), 0.41 (Copaxone), and 0.39 (placebo).

The active treatment groups had similar incidence, spectrum, and severity of reported adverse events, including injection site reactions. Dr. Jeffrey A. Cohen, director of the experimental therapeutics program at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, will report the results on Sept. 12 at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston.

On Sept. 11, Dr. Cohen also will speak about the need for generic equivalents to drugs that will soon be coming off patent protection. Although there is great potential for "cost savings to patients and third-party payers based on the more limited testing required for approval and resultant reduced development costs," Dr. Cohen wrote in his abstract that there are many difficulties in the process of developing these generics. As is the case for the highly complex peptide mixture that constitutes glatiramer acetate, interferons or monoclonal antibodies are biologics with highly complex chemical structures whose properties are vulnerable to changes on many levels that are difficult to predict without thorough testing. However, it will probably be necessary for developers to use more sensitive biologic markers of drug response, such as MRI, that have been previously well characterized for the original innovator product, as well as trials that use new designs and statistical analyses, he wrote.

[email protected]

Cognitive impairment continues to be a growing area of research in patients with multiple sclerosis, and the scientific program of the joint meeting of the European and Americas committees for Treatment and Research in Multiple Sclerosis has plenty to offer.

In the first young investigators session on Sept. 10, a multicenter study will provide evidence in support of the view that regional thalamic structural connectivity abnormalities play a significant role in cognitive impairment in relapsing-remitting MS patients. Dr. Alvino Bisecco of Vita-Salute San Raffaele University in Milan, Italy, and his colleagues will show that particular patterns of damage to gray matter (viewed as increased fractional anisotropy on diffusion tensor MR imaging) and to white matter (decreased fractional anisotropy) in thalamic subregions contributes to cognitive impairment in MS, compared with patterns observed in healthy control patients.

Another group, led by Dr. Prejaas Tewarie of VU University Medical Center in Amsterdam also will report on Sept. 11 evidence linking thalamic atrophy with disrupted cortical function in MS patients with cognitive impairment. Dr. Tewarie will present data indicating that in MS patients, reduced thalamic volume on MRI is positively associated with a shift in functional network topology between the thalamus and cortex on magnetoencephalography and increased thalamocortical functional connectivity, compared with healthy controls, that proved to be associated with worse cognition and functional status on the Kurtzke Expanded Disability Status Scale.

However, these abnormalities in thalamic functional connectivity could be treated with a brain-training video game, according to a study also to be presented at the first young investigators session on Sept. 10. An 8-week training period in patients who had failing results on at least one cognitive test led to improved test results and a significantly changed pattern of thalamocortical resting-state functional connectivity on MRI, when compared with a wait-list control group. Lead investigator Dr. Laura De Giglio and her associates at Sapienza University of Rome had previously shown that thalamocortical resting-state functional connectivity is disrupted in MS.

During the Sept. 11 hot topics session on symptomatic and rehabilitation strategies, Dr. Maria Pia Amato of the University of Florence (Italy) will review promising results coming from well-designed studies involving behavioral treatment and computerized training, as well as findings from other interventions on cognition, including modest improvement with interferon treatments in patients with relapsing-remitting disease and negative or inconsistent results seen with symptomatic therapies.

Finally, in the second young investigators session on Sept. 10, a unique study will reveal how patients with pediatric-onset and adult-onset relapsing-remitting MS appear to have similar cognitive outcomes at the same age in young adulthood. At mean ages of about 26-27 years in patients who were matched for level of education and physical disability, there were similar mean scores on neuropsychological tests, similar numbers of failed tests, and no difference in the percentage of patients classified as cognitively impaired (14% among pediatric-onset and 27% for adult-onset disease), according to data that will be presented by Dr. Bahia Hakiki of the University of Florence. Because "disease onset in a period of active brain growth and maturation may render pediatric-onset subjects more vulnerable to cognitive issues, our findings suggest good compensatory/recovery abilities in these subjects, possibly related with enhanced brain plasticity in early life," Dr. Hakiki and colleagues wrote.

[email protected]

Cognitive impairment continues to be a growing area of research in patients with multiple sclerosis, and the scientific program of the joint meeting of the European and Americas committees for Treatment and Research in Multiple Sclerosis has plenty to offer.

In the first young investigators session on Sept. 10, a multicenter study will provide evidence in support of the view that regional thalamic structural connectivity abnormalities play a significant role in cognitive impairment in relapsing-remitting MS patients. Dr. Alvino Bisecco of Vita-Salute San Raffaele University in Milan, Italy, and his colleagues will show that particular patterns of damage to gray matter (viewed as increased fractional anisotropy on diffusion tensor MR imaging) and to white matter (decreased fractional anisotropy) in thalamic subregions contributes to cognitive impairment in MS, compared with patterns observed in healthy control patients.

Another group, led by Dr. Prejaas Tewarie of VU University Medical Center in Amsterdam also will report on Sept. 11 evidence linking thalamic atrophy with disrupted cortical function in MS patients with cognitive impairment. Dr. Tewarie will present data indicating that in MS patients, reduced thalamic volume on MRI is positively associated with a shift in functional network topology between the thalamus and cortex on magnetoencephalography and increased thalamocortical functional connectivity, compared with healthy controls, that proved to be associated with worse cognition and functional status on the Kurtzke Expanded Disability Status Scale.

However, these abnormalities in thalamic functional connectivity could be treated with a brain-training video game, according to a study also to be presented at the first young investigators session on Sept. 10. An 8-week training period in patients who had failing results on at least one cognitive test led to improved test results and a significantly changed pattern of thalamocortical resting-state functional connectivity on MRI, when compared with a wait-list control group. Lead investigator Dr. Laura De Giglio and her associates at Sapienza University of Rome had previously shown that thalamocortical resting-state functional connectivity is disrupted in MS.

During the Sept. 11 hot topics session on symptomatic and rehabilitation strategies, Dr. Maria Pia Amato of the University of Florence (Italy) will review promising results coming from well-designed studies involving behavioral treatment and computerized training, as well as findings from other interventions on cognition, including modest improvement with interferon treatments in patients with relapsing-remitting disease and negative or inconsistent results seen with symptomatic therapies.

Finally, in the second young investigators session on Sept. 10, a unique study will reveal how patients with pediatric-onset and adult-onset relapsing-remitting MS appear to have similar cognitive outcomes at the same age in young adulthood. At mean ages of about 26-27 years in patients who were matched for level of education and physical disability, there were similar mean scores on neuropsychological tests, similar numbers of failed tests, and no difference in the percentage of patients classified as cognitively impaired (14% among pediatric-onset and 27% for adult-onset disease), according to data that will be presented by Dr. Bahia Hakiki of the University of Florence. Because "disease onset in a period of active brain growth and maturation may render pediatric-onset subjects more vulnerable to cognitive issues, our findings suggest good compensatory/recovery abilities in these subjects, possibly related with enhanced brain plasticity in early life," Dr. Hakiki and colleagues wrote.

[email protected]

Cognitive impairment continues to be a growing area of research in patients with multiple sclerosis, and the scientific program of the joint meeting of the European and Americas committees for Treatment and Research in Multiple Sclerosis has plenty to offer.

In the first young investigators session on Sept. 10, a multicenter study will provide evidence in support of the view that regional thalamic structural connectivity abnormalities play a significant role in cognitive impairment in relapsing-remitting MS patients. Dr. Alvino Bisecco of Vita-Salute San Raffaele University in Milan, Italy, and his colleagues will show that particular patterns of damage to gray matter (viewed as increased fractional anisotropy on diffusion tensor MR imaging) and to white matter (decreased fractional anisotropy) in thalamic subregions contributes to cognitive impairment in MS, compared with patterns observed in healthy control patients.

Another group, led by Dr. Prejaas Tewarie of VU University Medical Center in Amsterdam also will report on Sept. 11 evidence linking thalamic atrophy with disrupted cortical function in MS patients with cognitive impairment. Dr. Tewarie will present data indicating that in MS patients, reduced thalamic volume on MRI is positively associated with a shift in functional network topology between the thalamus and cortex on magnetoencephalography and increased thalamocortical functional connectivity, compared with healthy controls, that proved to be associated with worse cognition and functional status on the Kurtzke Expanded Disability Status Scale.

However, these abnormalities in thalamic functional connectivity could be treated with a brain-training video game, according to a study also to be presented at the first young investigators session on Sept. 10. An 8-week training period in patients who had failing results on at least one cognitive test led to improved test results and a significantly changed pattern of thalamocortical resting-state functional connectivity on MRI, when compared with a wait-list control group. Lead investigator Dr. Laura De Giglio and her associates at Sapienza University of Rome had previously shown that thalamocortical resting-state functional connectivity is disrupted in MS.

During the Sept. 11 hot topics session on symptomatic and rehabilitation strategies, Dr. Maria Pia Amato of the University of Florence (Italy) will review promising results coming from well-designed studies involving behavioral treatment and computerized training, as well as findings from other interventions on cognition, including modest improvement with interferon treatments in patients with relapsing-remitting disease and negative or inconsistent results seen with symptomatic therapies.

Finally, in the second young investigators session on Sept. 10, a unique study will reveal how patients with pediatric-onset and adult-onset relapsing-remitting MS appear to have similar cognitive outcomes at the same age in young adulthood. At mean ages of about 26-27 years in patients who were matched for level of education and physical disability, there were similar mean scores on neuropsychological tests, similar numbers of failed tests, and no difference in the percentage of patients classified as cognitively impaired (14% among pediatric-onset and 27% for adult-onset disease), according to data that will be presented by Dr. Bahia Hakiki of the University of Florence. Because "disease onset in a period of active brain growth and maturation may render pediatric-onset subjects more vulnerable to cognitive issues, our findings suggest good compensatory/recovery abilities in these subjects, possibly related with enhanced brain plasticity in early life," Dr. Hakiki and colleagues wrote.

[email protected]

The presence of antibodies against the NR2 subtype of N-methyl-d-aspartate receptor in cerebrospinal fluid had a significantly negative effect on the gray matter volume of the hippocampus of patients with systemic lupus erythematosus or primary Sjögren’s syndrome in a single-center, prospective, cross-sectional study.

Anti-NR2 antibodies have been found, albeit inconsistently, to be associated with cognitive dysfunction and memory impairment in previous studies of both patients with systemic lupus erythematosus (SLE) and those with primary Sjögren’s syndrome (pSS). The NR2 subtype of N-methyl-d-aspartate (NMDA) receptor is widespread in the brain, but it occurs at a high density in the hippocampus, the brain’s vital structure for memory formation and learning.

Dr. Maria B. Lauvsnes of Stavanger (Norway) University Hospital and her associates recruited 50 patients (mean age, 44 years) who had had SLE for an average of 12.5 years; 8 (16%) had anti-NR2 antibodies in cerebrospinal fluid. A separate group of 50 patients (mean age, 57 years) had had pSS for an average of 6.6 years; 6 (12%) had anti-NR2 antibodies.

Although anti-NR2 antibodies were associated with smaller hippocampal gray matter volume on 1.5 T MRI, there was no significant effect on this volume according to disease group (SLE or pSS), the presence of antiphospholipid antibodies, disease duration, or present use of corticosteroids. Disease group also did not act as a confounder of the association between anti-NR2 antibodies and hippocampal gray matter volume (Arthritis Rheumatol. 2014 Aug. 22 [doi: 10.1002/art.38852]).

A whole-brain analysis showed that no regions outside the hippocampus had significant gray matter loss in association with the presence of anti-NR2 antibodies.

"The reason for this localized loss of gray matter could be due to the high density in the hippocampus of NR2 receptors, allowing only atrophy of these structures to reach statistical significance. Another explanation could be that other disease factors not tested for in this study, such as anti-ribosomal P protein (anti-P) antibodies, might have an additive effect with anti-NR2 antibodies in the hippocampus," the investigators wrote.

They noted that in vitro studies have shown that anti-NR2 antibodies enhance the normal influx of calcium through the receptor’s ion channel and thereby cause cytotoxic intracellular levels of calcium that leads to neuronal apoptosis.

Studies in a mouse model of SLE have demonstrated that anti-NR2 antibodies cause cognitive impairment and altered emotional behavior. In both SLE and pSS patients, anti-NR2 antibodies have been linked to memory impairment, Dr. Lauvsnes and her associates said.

The authors acknowledged that the study did not track if anti-NR2 levels fluctuated over time, and could not determine an origin for the antibodies.

None of the authors had relevant conflicts of interest to report. Dr. Lauvsnes received funding support as a doctoral research fellow from the Western Norway Regional Health Authority.

[email protected]

The presence of antibodies against the NR2 subtype of N-methyl-d-aspartate receptor in cerebrospinal fluid had a significantly negative effect on the gray matter volume of the hippocampus of patients with systemic lupus erythematosus or primary Sjögren’s syndrome in a single-center, prospective, cross-sectional study.

Anti-NR2 antibodies have been found, albeit inconsistently, to be associated with cognitive dysfunction and memory impairment in previous studies of both patients with systemic lupus erythematosus (SLE) and those with primary Sjögren’s syndrome (pSS). The NR2 subtype of N-methyl-d-aspartate (NMDA) receptor is widespread in the brain, but it occurs at a high density in the hippocampus, the brain’s vital structure for memory formation and learning.

Dr. Maria B. Lauvsnes of Stavanger (Norway) University Hospital and her associates recruited 50 patients (mean age, 44 years) who had had SLE for an average of 12.5 years; 8 (16%) had anti-NR2 antibodies in cerebrospinal fluid. A separate group of 50 patients (mean age, 57 years) had had pSS for an average of 6.6 years; 6 (12%) had anti-NR2 antibodies.

Although anti-NR2 antibodies were associated with smaller hippocampal gray matter volume on 1.5 T MRI, there was no significant effect on this volume according to disease group (SLE or pSS), the presence of antiphospholipid antibodies, disease duration, or present use of corticosteroids. Disease group also did not act as a confounder of the association between anti-NR2 antibodies and hippocampal gray matter volume (Arthritis Rheumatol. 2014 Aug. 22 [doi: 10.1002/art.38852]).

A whole-brain analysis showed that no regions outside the hippocampus had significant gray matter loss in association with the presence of anti-NR2 antibodies.

"The reason for this localized loss of gray matter could be due to the high density in the hippocampus of NR2 receptors, allowing only atrophy of these structures to reach statistical significance. Another explanation could be that other disease factors not tested for in this study, such as anti-ribosomal P protein (anti-P) antibodies, might have an additive effect with anti-NR2 antibodies in the hippocampus," the investigators wrote.

They noted that in vitro studies have shown that anti-NR2 antibodies enhance the normal influx of calcium through the receptor’s ion channel and thereby cause cytotoxic intracellular levels of calcium that leads to neuronal apoptosis.

Studies in a mouse model of SLE have demonstrated that anti-NR2 antibodies cause cognitive impairment and altered emotional behavior. In both SLE and pSS patients, anti-NR2 antibodies have been linked to memory impairment, Dr. Lauvsnes and her associates said.

The authors acknowledged that the study did not track if anti-NR2 levels fluctuated over time, and could not determine an origin for the antibodies.

None of the authors had relevant conflicts of interest to report. Dr. Lauvsnes received funding support as a doctoral research fellow from the Western Norway Regional Health Authority.

[email protected]

The presence of antibodies against the NR2 subtype of N-methyl-d-aspartate receptor in cerebrospinal fluid had a significantly negative effect on the gray matter volume of the hippocampus of patients with systemic lupus erythematosus or primary Sjögren’s syndrome in a single-center, prospective, cross-sectional study.

Anti-NR2 antibodies have been found, albeit inconsistently, to be associated with cognitive dysfunction and memory impairment in previous studies of both patients with systemic lupus erythematosus (SLE) and those with primary Sjögren’s syndrome (pSS). The NR2 subtype of N-methyl-d-aspartate (NMDA) receptor is widespread in the brain, but it occurs at a high density in the hippocampus, the brain’s vital structure for memory formation and learning.

Dr. Maria B. Lauvsnes of Stavanger (Norway) University Hospital and her associates recruited 50 patients (mean age, 44 years) who had had SLE for an average of 12.5 years; 8 (16%) had anti-NR2 antibodies in cerebrospinal fluid. A separate group of 50 patients (mean age, 57 years) had had pSS for an average of 6.6 years; 6 (12%) had anti-NR2 antibodies.

Although anti-NR2 antibodies were associated with smaller hippocampal gray matter volume on 1.5 T MRI, there was no significant effect on this volume according to disease group (SLE or pSS), the presence of antiphospholipid antibodies, disease duration, or present use of corticosteroids. Disease group also did not act as a confounder of the association between anti-NR2 antibodies and hippocampal gray matter volume (Arthritis Rheumatol. 2014 Aug. 22 [doi: 10.1002/art.38852]).

A whole-brain analysis showed that no regions outside the hippocampus had significant gray matter loss in association with the presence of anti-NR2 antibodies.

"The reason for this localized loss of gray matter could be due to the high density in the hippocampus of NR2 receptors, allowing only atrophy of these structures to reach statistical significance. Another explanation could be that other disease factors not tested for in this study, such as anti-ribosomal P protein (anti-P) antibodies, might have an additive effect with anti-NR2 antibodies in the hippocampus," the investigators wrote.

They noted that in vitro studies have shown that anti-NR2 antibodies enhance the normal influx of calcium through the receptor’s ion channel and thereby cause cytotoxic intracellular levels of calcium that leads to neuronal apoptosis.

Studies in a mouse model of SLE have demonstrated that anti-NR2 antibodies cause cognitive impairment and altered emotional behavior. In both SLE and pSS patients, anti-NR2 antibodies have been linked to memory impairment, Dr. Lauvsnes and her associates said.

The authors acknowledged that the study did not track if anti-NR2 levels fluctuated over time, and could not determine an origin for the antibodies.

None of the authors had relevant conflicts of interest to report. Dr. Lauvsnes received funding support as a doctoral research fellow from the Western Norway Regional Health Authority.

[email protected]

PARIS – Thanks to microarray analysis of gene expression in patients with juvenile idiopathic arthritis, response to treatment at 12 months can be predicted after just 4 months of therapy, based on a longitudinal analysis of whole blood samples from children participating in the TREAT study.

The prediction of active versus inactive disease could be made even more strongly when stratifying patients based on the presence of rheumatoid factor (RF), which is an "exciting" finding, study investigator Dr. James Jarvis said in a video interview at the annual European Congress of Rheumatology. "We’ve known for a long time that children with rheumatoid factor–positive disease are just harder to treat."

The National Institutes of Health–funded TREAT (Trial of Early Aggressive Drug Therapy in Juvenile Idiopathic Arthritis) study compared treatment with methotrexate alone against methotrexate plus etanercept for children with newly diagnosed juvenile idiopathic arthritis. The current analysis found that treatment in RF-positive patients led to changes in fewer genes than in RF-negative patients, and also changed the expression of different genes than in those with RF-negative disease. Dr. Jarvis is chief of allergy/immunology and rheumatology in the pediatrics department at the University at Buffalo, The State University of New York.

[email protected]

PARIS – Thanks to microarray analysis of gene expression in patients with juvenile idiopathic arthritis, response to treatment at 12 months can be predicted after just 4 months of therapy, based on a longitudinal analysis of whole blood samples from children participating in the TREAT study.

The prediction of active versus inactive disease could be made even more strongly when stratifying patients based on the presence of rheumatoid factor (RF), which is an "exciting" finding, study investigator Dr. James Jarvis said in a video interview at the annual European Congress of Rheumatology. "We’ve known for a long time that children with rheumatoid factor–positive disease are just harder to treat."

The National Institutes of Health–funded TREAT (Trial of Early Aggressive Drug Therapy in Juvenile Idiopathic Arthritis) study compared treatment with methotrexate alone against methotrexate plus etanercept for children with newly diagnosed juvenile idiopathic arthritis. The current analysis found that treatment in RF-positive patients led to changes in fewer genes than in RF-negative patients, and also changed the expression of different genes than in those with RF-negative disease. Dr. Jarvis is chief of allergy/immunology and rheumatology in the pediatrics department at the University at Buffalo, The State University of New York.

[email protected]

PARIS – Thanks to microarray analysis of gene expression in patients with juvenile idiopathic arthritis, response to treatment at 12 months can be predicted after just 4 months of therapy, based on a longitudinal analysis of whole blood samples from children participating in the TREAT study.

The prediction of active versus inactive disease could be made even more strongly when stratifying patients based on the presence of rheumatoid factor (RF), which is an "exciting" finding, study investigator Dr. James Jarvis said in a video interview at the annual European Congress of Rheumatology. "We’ve known for a long time that children with rheumatoid factor–positive disease are just harder to treat."

The National Institutes of Health–funded TREAT (Trial of Early Aggressive Drug Therapy in Juvenile Idiopathic Arthritis) study compared treatment with methotrexate alone against methotrexate plus etanercept for children with newly diagnosed juvenile idiopathic arthritis. The current analysis found that treatment in RF-positive patients led to changes in fewer genes than in RF-negative patients, and also changed the expression of different genes than in those with RF-negative disease. Dr. Jarvis is chief of allergy/immunology and rheumatology in the pediatrics department at the University at Buffalo, The State University of New York.

[email protected]

Treatment with tumor necrosis factor inhibitors does not appear to increase the rate of breast cancer recurrence among patients with rheumatoid arthritis, according to findings from a Swedish case-control study.

The study’s results help to allay concerns about the potential for tumor necrosis factor (TNF) inhibitors to promote cancer recurrence, but it still leaves the agents’ possible effect on much more recently diagnosed cancer or cancers with poor prognosis unknown, said lead investigator Dr. Pauline Raaschou of the Karolinska Institute, Stockholm, and her colleagues in the ARTIS Study Group.

Although two previous studies have examined the risk of recurrence of any type of cancer in patients treated with a TNF inhibitor, it was unclear to the investigators how much the baseline risk of recurrence played a role and how much "channeling" of high-risk patients away from TNF inhibitors has potentially contributed to selection bias in such studies. Breast cancer seemed an ideal cancer type to study in this regard, the investigators said, because of women’s high lifetime risk and the dovetailing of peak age of onset of both breast cancer and RA at around age 60 years.

The researchers matched 120 patients who were treated with TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) to 120 patients who had never received treatment with a biologic. The patients had started TNF inhibitors or began follow-up a median of 9.4 years after their breast cancer diagnosis. The patients had a mean age of 66-67 years and their cancers were in remission at the start of follow-up (Ann. Rheum. Dis. 2014 Aug. 8 [doi:10.1136/annrheumdis-2014-205745]).

During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years. This gave a hazard ratio of 0.8 with a 95% confidence interval of 0.3-2.1.

The risk did not change appreciably in different models that adjusted for small differences in prognostic factors for breast cancer recurrence and RA-related characteristics. There also were no differences in the risk of recurrence between individuals with a history of breast cancer within 5 years or later – a time frame in which many guidelines recommend using caution in starting TNF inhibitors – but only 15% of the patients started a TNF inhibitor within 5 years of their breast cancer, according to the investigators.

Dr. Raaschou and her associates noted that although their study is the largest on the topic to date, it still has limited power because at an alpha of .05, "a study of our design would require approximately 120 patients in each treatment group [i.e., our sample size] to have 80% power to detect a doubled risk, but 350 patients in each treatment group to detect a 50% increased risk."

This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.

[email protected]

Treatment with tumor necrosis factor inhibitors does not appear to increase the rate of breast cancer recurrence among patients with rheumatoid arthritis, according to findings from a Swedish case-control study.

The study’s results help to allay concerns about the potential for tumor necrosis factor (TNF) inhibitors to promote cancer recurrence, but it still leaves the agents’ possible effect on much more recently diagnosed cancer or cancers with poor prognosis unknown, said lead investigator Dr. Pauline Raaschou of the Karolinska Institute, Stockholm, and her colleagues in the ARTIS Study Group.

Although two previous studies have examined the risk of recurrence of any type of cancer in patients treated with a TNF inhibitor, it was unclear to the investigators how much the baseline risk of recurrence played a role and how much "channeling" of high-risk patients away from TNF inhibitors has potentially contributed to selection bias in such studies. Breast cancer seemed an ideal cancer type to study in this regard, the investigators said, because of women’s high lifetime risk and the dovetailing of peak age of onset of both breast cancer and RA at around age 60 years.

The researchers matched 120 patients who were treated with TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) to 120 patients who had never received treatment with a biologic. The patients had started TNF inhibitors or began follow-up a median of 9.4 years after their breast cancer diagnosis. The patients had a mean age of 66-67 years and their cancers were in remission at the start of follow-up (Ann. Rheum. Dis. 2014 Aug. 8 [doi:10.1136/annrheumdis-2014-205745]).

During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years. This gave a hazard ratio of 0.8 with a 95% confidence interval of 0.3-2.1.

The risk did not change appreciably in different models that adjusted for small differences in prognostic factors for breast cancer recurrence and RA-related characteristics. There also were no differences in the risk of recurrence between individuals with a history of breast cancer within 5 years or later – a time frame in which many guidelines recommend using caution in starting TNF inhibitors – but only 15% of the patients started a TNF inhibitor within 5 years of their breast cancer, according to the investigators.

Dr. Raaschou and her associates noted that although their study is the largest on the topic to date, it still has limited power because at an alpha of .05, "a study of our design would require approximately 120 patients in each treatment group [i.e., our sample size] to have 80% power to detect a doubled risk, but 350 patients in each treatment group to detect a 50% increased risk."

This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.

[email protected]

Treatment with tumor necrosis factor inhibitors does not appear to increase the rate of breast cancer recurrence among patients with rheumatoid arthritis, according to findings from a Swedish case-control study.

The study’s results help to allay concerns about the potential for tumor necrosis factor (TNF) inhibitors to promote cancer recurrence, but it still leaves the agents’ possible effect on much more recently diagnosed cancer or cancers with poor prognosis unknown, said lead investigator Dr. Pauline Raaschou of the Karolinska Institute, Stockholm, and her colleagues in the ARTIS Study Group.

Although two previous studies have examined the risk of recurrence of any type of cancer in patients treated with a TNF inhibitor, it was unclear to the investigators how much the baseline risk of recurrence played a role and how much "channeling" of high-risk patients away from TNF inhibitors has potentially contributed to selection bias in such studies. Breast cancer seemed an ideal cancer type to study in this regard, the investigators said, because of women’s high lifetime risk and the dovetailing of peak age of onset of both breast cancer and RA at around age 60 years.

The researchers matched 120 patients who were treated with TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) to 120 patients who had never received treatment with a biologic. The patients had started TNF inhibitors or began follow-up a median of 9.4 years after their breast cancer diagnosis. The patients had a mean age of 66-67 years and their cancers were in remission at the start of follow-up (Ann. Rheum. Dis. 2014 Aug. 8 [doi:10.1136/annrheumdis-2014-205745]).

During 592 person-years of follow-up, nine patients treated with a TNF inhibitor developed a breast cancer recurrence for a crude incidence rate of 15/1,000 person-years, compared with nine of the biologic-naive patients during 550 person-years of follow-up for a rate of 16/1,000 person-years. This gave a hazard ratio of 0.8 with a 95% confidence interval of 0.3-2.1.

The risk did not change appreciably in different models that adjusted for small differences in prognostic factors for breast cancer recurrence and RA-related characteristics. There also were no differences in the risk of recurrence between individuals with a history of breast cancer within 5 years or later – a time frame in which many guidelines recommend using caution in starting TNF inhibitors – but only 15% of the patients started a TNF inhibitor within 5 years of their breast cancer, according to the investigators.

Dr. Raaschou and her associates noted that although their study is the largest on the topic to date, it still has limited power because at an alpha of .05, "a study of our design would require approximately 120 patients in each treatment group [i.e., our sample size] to have 80% power to detect a doubled risk, but 350 patients in each treatment group to detect a 50% increased risk."

This research was funded by a variety of Swedish medical societies, foundations, and programs. One author reported receiving research grants from Pfizer and AstraZeneca as part of a public-private research consortium and speaker’s honoraria from Merck. The Swedish Biologics Register, ARTIS, is maintained in part by funding from Abbott Laboratories, Bristol-Myers Squibb, Merck, Pfizer, Roche, SOBI, and UCB.

[email protected]

The joints of patients with early arthritis that showed subclinical inflammation on MRI had an increased risk of radiographic progression in the first year after disease presentation, particularly those with bone marrow edema, according to findings from the first study to look at the radiographic outcome of such joints.

A total of 179 patients at the Leiden Early Arthritis Clinic, a population-based inception cohort including patients with confirmed clinical arthritis and symptoms for less than 2 years, underwent 1.5T extremity MRI at baseline of the metacarpophalangeal 2-5, wrist, and metatarsophalangeal 1-5 joints on the side with the most severe symptoms or the dominant side in cases in which both sides were equally affected. At 1-year follow-up, 113 had radiographs taken. Close to half of these patients (46.9%) fulfilled the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) at baseline, and those who did not have follow-up at 1 year were diagnosed with RA less often. Other patients had unclassified arthritis (32.7%), psoriatic arthritis (9.7%), inflammatory osteoarthritis (3.5%), spondylarthritis (2.7%), or other diagnoses (4.4%). Within the first year, 77% of all patients received treatment with a disease-modifying antirheumatic drug, including 93% of all patients with RA, said Dr. Annemarie Krabben and her colleagues at Leiden University Medical Center, the Netherlands (Ann. Rheum. Dis. 2014 July 29 [doi:10.1136/annrheumdis-2014-205208]).

Of the 1,130 joints studied, 932 were clinically free of swelling at baseline, and, of these, 232 (26%) had subclinical inflammation on MRI, including 17% with bone marrow edema, 16% with synovitis, and 21% with tenosynovitis. Overall, only 2% of the unswollen joints had radiographic progression at 1 year, compared with 8% of clinically swollen joints. The relative risk for radiographic progression in unswollen joints with subclinical inflammation on MRI was 3.5 (95% confidence interval, 1.3-9.6) based on radiographic progression in 4% of those with subclinical inflammation and 1% of those without it. The relative risk was highest for nonswollen joints with bone marrow edema (RR, 5.3; 95% CI, 2.0-14.0) and also significant for those with synovitis (RR, 3.4; 95% CI, 1.2-9.3), but not for those with tenosynovitis (RR, 3.0; 95% CI, 0.7-12.7). The relative risk was comparable for joints that were both nonswollen and nontender, although the 95% CI was broader.

"Our observation that the total level of MRI inflammation [in both swollen and unswollen joints] was an independent predictor for radiographic progression fits with previous findings," the investigators wrote. "Furthermore, our finding that subclinical inflammation at disease onset is associated with radiographic progression is in line with previous findings on subclinical inflammation in patients with RA in clinical remission."

The authors noted that their "study mainly increases the comprehension of the connection between inflammation and structural damage early in the disease. Whether subclinical MRI inflammation is relevant to clinical practice remains a question, as rheumatologists treat patients and not joints. Information on subclinical inflamed joints would affect treatment decisions most when patients have few clinically swollen joints."

The size of the study’s patient sample limits the applicability of the findings, particularly in regard to the moderate number of patients with RA, who had broad 95% CI estimates for the risk of radiographic progression. Other limits to the study included the relative infrequency of radiographic progression at 3% of all joints (4% of joints in patients with RA) and the relatively small increase of 1 or greater on the Sharp-van der Heijde score that was used to define radiographic progression.

The study was supported by the Dutch Arthritis Foundation, the Dutch Organization of Health Research and Development, the Center for Translational Molecular Medicine, and by a grant within the European Community Seventh Framework Programme FP7 (Masterswitch). The authors had no competing interests to declare.

[email protected]

The joints of patients with early arthritis that showed subclinical inflammation on MRI had an increased risk of radiographic progression in the first year after disease presentation, particularly those with bone marrow edema, according to findings from the first study to look at the radiographic outcome of such joints.

A total of 179 patients at the Leiden Early Arthritis Clinic, a population-based inception cohort including patients with confirmed clinical arthritis and symptoms for less than 2 years, underwent 1.5T extremity MRI at baseline of the metacarpophalangeal 2-5, wrist, and metatarsophalangeal 1-5 joints on the side with the most severe symptoms or the dominant side in cases in which both sides were equally affected. At 1-year follow-up, 113 had radiographs taken. Close to half of these patients (46.9%) fulfilled the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) at baseline, and those who did not have follow-up at 1 year were diagnosed with RA less often. Other patients had unclassified arthritis (32.7%), psoriatic arthritis (9.7%), inflammatory osteoarthritis (3.5%), spondylarthritis (2.7%), or other diagnoses (4.4%). Within the first year, 77% of all patients received treatment with a disease-modifying antirheumatic drug, including 93% of all patients with RA, said Dr. Annemarie Krabben and her colleagues at Leiden University Medical Center, the Netherlands (Ann. Rheum. Dis. 2014 July 29 [doi:10.1136/annrheumdis-2014-205208]).

Of the 1,130 joints studied, 932 were clinically free of swelling at baseline, and, of these, 232 (26%) had subclinical inflammation on MRI, including 17% with bone marrow edema, 16% with synovitis, and 21% with tenosynovitis. Overall, only 2% of the unswollen joints had radiographic progression at 1 year, compared with 8% of clinically swollen joints. The relative risk for radiographic progression in unswollen joints with subclinical inflammation on MRI was 3.5 (95% confidence interval, 1.3-9.6) based on radiographic progression in 4% of those with subclinical inflammation and 1% of those without it. The relative risk was highest for nonswollen joints with bone marrow edema (RR, 5.3; 95% CI, 2.0-14.0) and also significant for those with synovitis (RR, 3.4; 95% CI, 1.2-9.3), but not for those with tenosynovitis (RR, 3.0; 95% CI, 0.7-12.7). The relative risk was comparable for joints that were both nonswollen and nontender, although the 95% CI was broader.

"Our observation that the total level of MRI inflammation [in both swollen and unswollen joints] was an independent predictor for radiographic progression fits with previous findings," the investigators wrote. "Furthermore, our finding that subclinical inflammation at disease onset is associated with radiographic progression is in line with previous findings on subclinical inflammation in patients with RA in clinical remission."

The authors noted that their "study mainly increases the comprehension of the connection between inflammation and structural damage early in the disease. Whether subclinical MRI inflammation is relevant to clinical practice remains a question, as rheumatologists treat patients and not joints. Information on subclinical inflamed joints would affect treatment decisions most when patients have few clinically swollen joints."

The size of the study’s patient sample limits the applicability of the findings, particularly in regard to the moderate number of patients with RA, who had broad 95% CI estimates for the risk of radiographic progression. Other limits to the study included the relative infrequency of radiographic progression at 3% of all joints (4% of joints in patients with RA) and the relatively small increase of 1 or greater on the Sharp-van der Heijde score that was used to define radiographic progression.

The study was supported by the Dutch Arthritis Foundation, the Dutch Organization of Health Research and Development, the Center for Translational Molecular Medicine, and by a grant within the European Community Seventh Framework Programme FP7 (Masterswitch). The authors had no competing interests to declare.

[email protected]

The joints of patients with early arthritis that showed subclinical inflammation on MRI had an increased risk of radiographic progression in the first year after disease presentation, particularly those with bone marrow edema, according to findings from the first study to look at the radiographic outcome of such joints.

A total of 179 patients at the Leiden Early Arthritis Clinic, a population-based inception cohort including patients with confirmed clinical arthritis and symptoms for less than 2 years, underwent 1.5T extremity MRI at baseline of the metacarpophalangeal 2-5, wrist, and metatarsophalangeal 1-5 joints on the side with the most severe symptoms or the dominant side in cases in which both sides were equally affected. At 1-year follow-up, 113 had radiographs taken. Close to half of these patients (46.9%) fulfilled the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) at baseline, and those who did not have follow-up at 1 year were diagnosed with RA less often. Other patients had unclassified arthritis (32.7%), psoriatic arthritis (9.7%), inflammatory osteoarthritis (3.5%), spondylarthritis (2.7%), or other diagnoses (4.4%). Within the first year, 77% of all patients received treatment with a disease-modifying antirheumatic drug, including 93% of all patients with RA, said Dr. Annemarie Krabben and her colleagues at Leiden University Medical Center, the Netherlands (Ann. Rheum. Dis. 2014 July 29 [doi:10.1136/annrheumdis-2014-205208]).

Of the 1,130 joints studied, 932 were clinically free of swelling at baseline, and, of these, 232 (26%) had subclinical inflammation on MRI, including 17% with bone marrow edema, 16% with synovitis, and 21% with tenosynovitis. Overall, only 2% of the unswollen joints had radiographic progression at 1 year, compared with 8% of clinically swollen joints. The relative risk for radiographic progression in unswollen joints with subclinical inflammation on MRI was 3.5 (95% confidence interval, 1.3-9.6) based on radiographic progression in 4% of those with subclinical inflammation and 1% of those without it. The relative risk was highest for nonswollen joints with bone marrow edema (RR, 5.3; 95% CI, 2.0-14.0) and also significant for those with synovitis (RR, 3.4; 95% CI, 1.2-9.3), but not for those with tenosynovitis (RR, 3.0; 95% CI, 0.7-12.7). The relative risk was comparable for joints that were both nonswollen and nontender, although the 95% CI was broader.

"Our observation that the total level of MRI inflammation [in both swollen and unswollen joints] was an independent predictor for radiographic progression fits with previous findings," the investigators wrote. "Furthermore, our finding that subclinical inflammation at disease onset is associated with radiographic progression is in line with previous findings on subclinical inflammation in patients with RA in clinical remission."

The authors noted that their "study mainly increases the comprehension of the connection between inflammation and structural damage early in the disease. Whether subclinical MRI inflammation is relevant to clinical practice remains a question, as rheumatologists treat patients and not joints. Information on subclinical inflamed joints would affect treatment decisions most when patients have few clinically swollen joints."

The size of the study’s patient sample limits the applicability of the findings, particularly in regard to the moderate number of patients with RA, who had broad 95% CI estimates for the risk of radiographic progression. Other limits to the study included the relative infrequency of radiographic progression at 3% of all joints (4% of joints in patients with RA) and the relatively small increase of 1 or greater on the Sharp-van der Heijde score that was used to define radiographic progression.

The study was supported by the Dutch Arthritis Foundation, the Dutch Organization of Health Research and Development, the Center for Translational Molecular Medicine, and by a grant within the European Community Seventh Framework Programme FP7 (Masterswitch). The authors had no competing interests to declare.

[email protected]