Jeff Evans

MRI T2 hyperintensities in the hippocampi of children after febrile status epilepticus often evolved to visual appearance of hippocampal sclerosis after a median follow-up of 1 year in a prospective, observational cohort study of 226 children.

Even children who had a normal MRI after an episode of febrile status epilepticus (FSE) had smaller mean size of hippocampi and abnormal, decreased right/left hippocampal volume ratios, compared with a control group of 38 children who had a simple febrile seizure and normal MRIs. The visually normal hippocampi in children with FSE also grew more slowly than in children with a simple febrile seizure, suggesting "a subtle acute hippocampal injury," according to lead investigator Darrell V. Lewis of the department of pediatrics at Duke University, Durham, N.C., and his associates.

Most of the cohort was derived from patients in the ongoing FEBSTAT study, which along with other previous studies have shown that FSE can result in acute hippocampal injury visible on MRI. This injury is suspected to cause hippocampal sclerosis, which is a common feature of temporal lobe epilepsy. Dr. Lewis and his colleagues’ study aimed to determine whether radiologically defined hippocampal sclerosis (as noted by an increased hippocampal signal and visual confirmation of atrophy) can be first detected on MRI in the days after an initial FSE episode and evolve further on later follow-up MRI.

Ultimately, the goal of this research is to find biomarkers for temporal lobe epilepsy following FSE that would allow clinicians to identify patients who could undergo an as yet unknown antiepileptogenic intervention, but until further follow-up is available from FEBSTAT and other studies, researchers can only look for biomarkers for hippocampal sclerosis because temporal lobe epilepsy may arise 10 or more years after FSE, according to Dr. Lewis and his associates.

The study involved 226 children with FSE aged 1 month to 6 years, including subjects from the FEBSTAT study, the Duke FEBSTAT pilot study, and the Columbia first FS study. In this cohort, 67% underwent an initial MRI within 3 days of FSE and 88% within 7 days (Ann. Neurol. 2013 Dec. 7 [doi:10.1002/ana.24081]).

At baseline, 22 of the 226 (9.7%) children with FSE had an abnormal hippocampal signal, most of which (15) were right-sided except for 6 on the left side and 1 that was bilateral. The side in which 21 patients had unilateral T2 hyperintensities was larger than the contralateral side in 13 patients (62%). Hyperintense hippocampi also had significantly larger mean volume than did contralateral hippocampi in these patients, excluding three children with preexisting small hippocampi.

Two children had visually small hippocampi that also measured small in volume and hyperintense at baseline and at follow-up. This finding was "unexpected and supports the suggestion that [hippocampal sclerosis] might occasionally precede FSE made by others," the investigators said. The other child with a preexisting small, hyperintense hippocampus also had a small, schizencephalic hemisphere on the same side.

On follow-up MRIs conducted a median of 1 year later (range, 1 month to 2.5 years) in 14 of the 22 patients with hippocampal abnormalities, 10 met visual criteria for hippocampal sclerosis (including 1 patient with hippocampal sclerosis on the initial MRI). Volume loss also occurred in 13 of 15 hyperintense hippocampi (including the one patient with bilateral hyperintense hippocampi).

During follow-up, 5 of the 22 (23%) patients with hippocampal hyperintensity developed epilepsy early, mostly not temporal lobe epilepsy, and all returned for follow-up. Of the 14 with follow-up MRIs, 3 (23%) developed epilepsy. Only one of the eight (12.5%) patients without follow-up MRIs is known to have epilepsy. Another 11 FSE patients with normal baseline MRIs later developed epilepsy.

Patients who had normal baseline MRIs later appeared to have small changes potentially indicating hippocampal injury. In 116 patients with both initial and follow-up MRIs, only 1 developed abnormal signal on follow-up after a second episode of FSE; none had radiologic evidence of hippocampal sclerosis.

However, hippocampi in FSE patients that were normal at baseline appeared to show subtle signs of injury on follow-up MRIs at 6-24 months. Follow-up MRIs in 59 (26%) FSE patients with completely normal MRIs at baseline showed a significantly lower right/left volume ratio estimate than 38 control patients with a simple febrile seizure who had completely normal baseline MRIs, after controlling for age and gender. Similarly, right and left hippocampal volumes were significantly lower among the FSE patients on follow-up MRIs, and their hippocampi appeared to grow more slowly.

"The combined decreased right hippocampal volume of the FSE hippocampi and the predominance of hyperintensity on the right suggest volume asymmetry may signify hippocampal vulnerability present before FSE, as has been suggested previously," the investigators wrote.

Differences in follow-up did not appear to bias the results. Among the patients with hippocampal abnormalities at baseline, there were no significant differences between patients with or without MRI follow-up for status epilepticus duration, T2 scores, presence of developmental delay, focal status, and abnormal acute EEG. However, in both patients with hippocampal abnormalities at baseline and in the FSE cohort overall, patients with multiple conditions that affect well-being, such as developmental delay, epilepsy, or recurrent status epilepticus, seemed to be more likely to undergo follow-up MRI.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. No financial disclosures were reported.

[email protected]

MRI T2 hyperintensities in the hippocampi of children after febrile status epilepticus often evolved to visual appearance of hippocampal sclerosis after a median follow-up of 1 year in a prospective, observational cohort study of 226 children.

Even children who had a normal MRI after an episode of febrile status epilepticus (FSE) had smaller mean size of hippocampi and abnormal, decreased right/left hippocampal volume ratios, compared with a control group of 38 children who had a simple febrile seizure and normal MRIs. The visually normal hippocampi in children with FSE also grew more slowly than in children with a simple febrile seizure, suggesting "a subtle acute hippocampal injury," according to lead investigator Darrell V. Lewis of the department of pediatrics at Duke University, Durham, N.C., and his associates.

Most of the cohort was derived from patients in the ongoing FEBSTAT study, which along with other previous studies have shown that FSE can result in acute hippocampal injury visible on MRI. This injury is suspected to cause hippocampal sclerosis, which is a common feature of temporal lobe epilepsy. Dr. Lewis and his colleagues’ study aimed to determine whether radiologically defined hippocampal sclerosis (as noted by an increased hippocampal signal and visual confirmation of atrophy) can be first detected on MRI in the days after an initial FSE episode and evolve further on later follow-up MRI.

Ultimately, the goal of this research is to find biomarkers for temporal lobe epilepsy following FSE that would allow clinicians to identify patients who could undergo an as yet unknown antiepileptogenic intervention, but until further follow-up is available from FEBSTAT and other studies, researchers can only look for biomarkers for hippocampal sclerosis because temporal lobe epilepsy may arise 10 or more years after FSE, according to Dr. Lewis and his associates.

The study involved 226 children with FSE aged 1 month to 6 years, including subjects from the FEBSTAT study, the Duke FEBSTAT pilot study, and the Columbia first FS study. In this cohort, 67% underwent an initial MRI within 3 days of FSE and 88% within 7 days (Ann. Neurol. 2013 Dec. 7 [doi:10.1002/ana.24081]).

At baseline, 22 of the 226 (9.7%) children with FSE had an abnormal hippocampal signal, most of which (15) were right-sided except for 6 on the left side and 1 that was bilateral. The side in which 21 patients had unilateral T2 hyperintensities was larger than the contralateral side in 13 patients (62%). Hyperintense hippocampi also had significantly larger mean volume than did contralateral hippocampi in these patients, excluding three children with preexisting small hippocampi.

Two children had visually small hippocampi that also measured small in volume and hyperintense at baseline and at follow-up. This finding was "unexpected and supports the suggestion that [hippocampal sclerosis] might occasionally precede FSE made by others," the investigators said. The other child with a preexisting small, hyperintense hippocampus also had a small, schizencephalic hemisphere on the same side.

On follow-up MRIs conducted a median of 1 year later (range, 1 month to 2.5 years) in 14 of the 22 patients with hippocampal abnormalities, 10 met visual criteria for hippocampal sclerosis (including 1 patient with hippocampal sclerosis on the initial MRI). Volume loss also occurred in 13 of 15 hyperintense hippocampi (including the one patient with bilateral hyperintense hippocampi).

During follow-up, 5 of the 22 (23%) patients with hippocampal hyperintensity developed epilepsy early, mostly not temporal lobe epilepsy, and all returned for follow-up. Of the 14 with follow-up MRIs, 3 (23%) developed epilepsy. Only one of the eight (12.5%) patients without follow-up MRIs is known to have epilepsy. Another 11 FSE patients with normal baseline MRIs later developed epilepsy.

Patients who had normal baseline MRIs later appeared to have small changes potentially indicating hippocampal injury. In 116 patients with both initial and follow-up MRIs, only 1 developed abnormal signal on follow-up after a second episode of FSE; none had radiologic evidence of hippocampal sclerosis.

However, hippocampi in FSE patients that were normal at baseline appeared to show subtle signs of injury on follow-up MRIs at 6-24 months. Follow-up MRIs in 59 (26%) FSE patients with completely normal MRIs at baseline showed a significantly lower right/left volume ratio estimate than 38 control patients with a simple febrile seizure who had completely normal baseline MRIs, after controlling for age and gender. Similarly, right and left hippocampal volumes were significantly lower among the FSE patients on follow-up MRIs, and their hippocampi appeared to grow more slowly.

"The combined decreased right hippocampal volume of the FSE hippocampi and the predominance of hyperintensity on the right suggest volume asymmetry may signify hippocampal vulnerability present before FSE, as has been suggested previously," the investigators wrote.

Differences in follow-up did not appear to bias the results. Among the patients with hippocampal abnormalities at baseline, there were no significant differences between patients with or without MRI follow-up for status epilepticus duration, T2 scores, presence of developmental delay, focal status, and abnormal acute EEG. However, in both patients with hippocampal abnormalities at baseline and in the FSE cohort overall, patients with multiple conditions that affect well-being, such as developmental delay, epilepsy, or recurrent status epilepticus, seemed to be more likely to undergo follow-up MRI.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. No financial disclosures were reported.

[email protected]

MRI T2 hyperintensities in the hippocampi of children after febrile status epilepticus often evolved to visual appearance of hippocampal sclerosis after a median follow-up of 1 year in a prospective, observational cohort study of 226 children.

Even children who had a normal MRI after an episode of febrile status epilepticus (FSE) had smaller mean size of hippocampi and abnormal, decreased right/left hippocampal volume ratios, compared with a control group of 38 children who had a simple febrile seizure and normal MRIs. The visually normal hippocampi in children with FSE also grew more slowly than in children with a simple febrile seizure, suggesting "a subtle acute hippocampal injury," according to lead investigator Darrell V. Lewis of the department of pediatrics at Duke University, Durham, N.C., and his associates.

Most of the cohort was derived from patients in the ongoing FEBSTAT study, which along with other previous studies have shown that FSE can result in acute hippocampal injury visible on MRI. This injury is suspected to cause hippocampal sclerosis, which is a common feature of temporal lobe epilepsy. Dr. Lewis and his colleagues’ study aimed to determine whether radiologically defined hippocampal sclerosis (as noted by an increased hippocampal signal and visual confirmation of atrophy) can be first detected on MRI in the days after an initial FSE episode and evolve further on later follow-up MRI.

Ultimately, the goal of this research is to find biomarkers for temporal lobe epilepsy following FSE that would allow clinicians to identify patients who could undergo an as yet unknown antiepileptogenic intervention, but until further follow-up is available from FEBSTAT and other studies, researchers can only look for biomarkers for hippocampal sclerosis because temporal lobe epilepsy may arise 10 or more years after FSE, according to Dr. Lewis and his associates.

The study involved 226 children with FSE aged 1 month to 6 years, including subjects from the FEBSTAT study, the Duke FEBSTAT pilot study, and the Columbia first FS study. In this cohort, 67% underwent an initial MRI within 3 days of FSE and 88% within 7 days (Ann. Neurol. 2013 Dec. 7 [doi:10.1002/ana.24081]).

At baseline, 22 of the 226 (9.7%) children with FSE had an abnormal hippocampal signal, most of which (15) were right-sided except for 6 on the left side and 1 that was bilateral. The side in which 21 patients had unilateral T2 hyperintensities was larger than the contralateral side in 13 patients (62%). Hyperintense hippocampi also had significantly larger mean volume than did contralateral hippocampi in these patients, excluding three children with preexisting small hippocampi.

Two children had visually small hippocampi that also measured small in volume and hyperintense at baseline and at follow-up. This finding was "unexpected and supports the suggestion that [hippocampal sclerosis] might occasionally precede FSE made by others," the investigators said. The other child with a preexisting small, hyperintense hippocampus also had a small, schizencephalic hemisphere on the same side.

On follow-up MRIs conducted a median of 1 year later (range, 1 month to 2.5 years) in 14 of the 22 patients with hippocampal abnormalities, 10 met visual criteria for hippocampal sclerosis (including 1 patient with hippocampal sclerosis on the initial MRI). Volume loss also occurred in 13 of 15 hyperintense hippocampi (including the one patient with bilateral hyperintense hippocampi).

During follow-up, 5 of the 22 (23%) patients with hippocampal hyperintensity developed epilepsy early, mostly not temporal lobe epilepsy, and all returned for follow-up. Of the 14 with follow-up MRIs, 3 (23%) developed epilepsy. Only one of the eight (12.5%) patients without follow-up MRIs is known to have epilepsy. Another 11 FSE patients with normal baseline MRIs later developed epilepsy.

Patients who had normal baseline MRIs later appeared to have small changes potentially indicating hippocampal injury. In 116 patients with both initial and follow-up MRIs, only 1 developed abnormal signal on follow-up after a second episode of FSE; none had radiologic evidence of hippocampal sclerosis.

However, hippocampi in FSE patients that were normal at baseline appeared to show subtle signs of injury on follow-up MRIs at 6-24 months. Follow-up MRIs in 59 (26%) FSE patients with completely normal MRIs at baseline showed a significantly lower right/left volume ratio estimate than 38 control patients with a simple febrile seizure who had completely normal baseline MRIs, after controlling for age and gender. Similarly, right and left hippocampal volumes were significantly lower among the FSE patients on follow-up MRIs, and their hippocampi appeared to grow more slowly.

"The combined decreased right hippocampal volume of the FSE hippocampi and the predominance of hyperintensity on the right suggest volume asymmetry may signify hippocampal vulnerability present before FSE, as has been suggested previously," the investigators wrote.

Differences in follow-up did not appear to bias the results. Among the patients with hippocampal abnormalities at baseline, there were no significant differences between patients with or without MRI follow-up for status epilepticus duration, T2 scores, presence of developmental delay, focal status, and abnormal acute EEG. However, in both patients with hippocampal abnormalities at baseline and in the FSE cohort overall, patients with multiple conditions that affect well-being, such as developmental delay, epilepsy, or recurrent status epilepticus, seemed to be more likely to undergo follow-up MRI.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. No financial disclosures were reported.

[email protected]

Psychological distress and physical disability have decreased in patients with rheumatoid arthritis over the past 2 decades, at least partly because of reduced disease activity with earlier and more intensive treatment and shifting recommendations for physical activity, according to an analysis of 1,151 Dutch patients who were monitored at diagnosis and after 3-5 years of treatment during 1990-2011.

Although prior studies have found this trend for improvement for shorter time periods, they had few cross-sectional cohorts and did not examine recent years, said Cécile L. Overman and colleagues at Utrecht (the Netherlands) University and Utrecht University Medical Center.

The investigators assembled the study cohort from a median of 47 patients older than 16 years with a duration of rheumatoid arthritis of less than 1 year who presented each year during 1990-2001 to rheumatology departments across the Netherlands. The patients originally had consented to participate in one of several prospective trials comparing the effectiveness of different drug treatment strategies, including strategies that were conventional at the time.

The rate of depressed mood among patients at the time of diagnosis declined from 43% in 1990-1994 to 32% in 2004-2008, and the corresponding rate at follow-up declined from 25% to 14%. For anxiety, the rate at the time of diagnosis shifted from 34% to 21% and at follow-up changed from 23% to 12%. Physical disability rates at diagnosis decreased from 64% to 60% and at follow-up from 53% to 31% (Arthritis Care Res. 2013 Dec. 3 [doi:10.1002/acr.22211]).

Across the 21 years of the study, there were small, but statistically significant decreases in depressed mood and physical disability and a moderate decline in anxiety. During treatment, these changes were not significant for depressed mood but were significant, yet small for anxiety and moderate to large for physical disability. After time trends were accounted for, measurements associated with decreased disease activity at the time of diagnosis and at follow-up declined over the course of the study, and partly mediated declines in depressed mood, anxiety, and physical disability. Changes in patient composition over time, such as earlier diagnosis over the years as reflected by a decreasing age at the time of diagnosis, increases in education level, and increases in socioeconomic status and life expectancy, were not consistently associated with depressed mood or anxiety or physical disability at diagnosis or follow-up.

"Across the decades, especially the trend of progressively decreasing physical disability after the first years of treatment was noteworthy, and this favorable trend remained significant after having taken account of the reduction of disease activity and change in the composition of patient influx," wrote Ms. Overman, a PhD candidate in the department of clinical and health psychology at the university, and her associates.

The investigators noted that it is impossible to know whether the changes in patient composition played a causal role in affecting psychological distress and physical disability or "only reflect a historic change occurring simultaneously, affecting the improvements statistically but not in real life."

They also suggested that improvements in psychological distress and physical disability might be related not only to pharmacologic reduction of disease activity but also targeted nonpharmacologic therapies such as exercise therapy and cognitive-behavioral therapy as well as "the changed education by rheumatologists and health professionals enhancing physical activity and encouraging patients to live a valued life."

Biologic agents’ inhibition of proinflammatory cytokines and their potential effects on behavior also could have contributed to a reduction in psychological distress and physical disability "not fully explained by reduced disease activity," according to the investigators.

The study was funded by a grant from the Faculty of Social and Behavioral Sciences of Utrecht University and by unrestricted grants from the Dutch Arthritis Foundation. The authors reported no relevant financial conflicts.

[email protected]

Psychological distress and physical disability have decreased in patients with rheumatoid arthritis over the past 2 decades, at least partly because of reduced disease activity with earlier and more intensive treatment and shifting recommendations for physical activity, according to an analysis of 1,151 Dutch patients who were monitored at diagnosis and after 3-5 years of treatment during 1990-2011.

Although prior studies have found this trend for improvement for shorter time periods, they had few cross-sectional cohorts and did not examine recent years, said Cécile L. Overman and colleagues at Utrecht (the Netherlands) University and Utrecht University Medical Center.

The investigators assembled the study cohort from a median of 47 patients older than 16 years with a duration of rheumatoid arthritis of less than 1 year who presented each year during 1990-2001 to rheumatology departments across the Netherlands. The patients originally had consented to participate in one of several prospective trials comparing the effectiveness of different drug treatment strategies, including strategies that were conventional at the time.

The rate of depressed mood among patients at the time of diagnosis declined from 43% in 1990-1994 to 32% in 2004-2008, and the corresponding rate at follow-up declined from 25% to 14%. For anxiety, the rate at the time of diagnosis shifted from 34% to 21% and at follow-up changed from 23% to 12%. Physical disability rates at diagnosis decreased from 64% to 60% and at follow-up from 53% to 31% (Arthritis Care Res. 2013 Dec. 3 [doi:10.1002/acr.22211]).

Across the 21 years of the study, there were small, but statistically significant decreases in depressed mood and physical disability and a moderate decline in anxiety. During treatment, these changes were not significant for depressed mood but were significant, yet small for anxiety and moderate to large for physical disability. After time trends were accounted for, measurements associated with decreased disease activity at the time of diagnosis and at follow-up declined over the course of the study, and partly mediated declines in depressed mood, anxiety, and physical disability. Changes in patient composition over time, such as earlier diagnosis over the years as reflected by a decreasing age at the time of diagnosis, increases in education level, and increases in socioeconomic status and life expectancy, were not consistently associated with depressed mood or anxiety or physical disability at diagnosis or follow-up.

"Across the decades, especially the trend of progressively decreasing physical disability after the first years of treatment was noteworthy, and this favorable trend remained significant after having taken account of the reduction of disease activity and change in the composition of patient influx," wrote Ms. Overman, a PhD candidate in the department of clinical and health psychology at the university, and her associates.

The investigators noted that it is impossible to know whether the changes in patient composition played a causal role in affecting psychological distress and physical disability or "only reflect a historic change occurring simultaneously, affecting the improvements statistically but not in real life."

They also suggested that improvements in psychological distress and physical disability might be related not only to pharmacologic reduction of disease activity but also targeted nonpharmacologic therapies such as exercise therapy and cognitive-behavioral therapy as well as "the changed education by rheumatologists and health professionals enhancing physical activity and encouraging patients to live a valued life."

Biologic agents’ inhibition of proinflammatory cytokines and their potential effects on behavior also could have contributed to a reduction in psychological distress and physical disability "not fully explained by reduced disease activity," according to the investigators.

The study was funded by a grant from the Faculty of Social and Behavioral Sciences of Utrecht University and by unrestricted grants from the Dutch Arthritis Foundation. The authors reported no relevant financial conflicts.

[email protected]

Psychological distress and physical disability have decreased in patients with rheumatoid arthritis over the past 2 decades, at least partly because of reduced disease activity with earlier and more intensive treatment and shifting recommendations for physical activity, according to an analysis of 1,151 Dutch patients who were monitored at diagnosis and after 3-5 years of treatment during 1990-2011.

Although prior studies have found this trend for improvement for shorter time periods, they had few cross-sectional cohorts and did not examine recent years, said Cécile L. Overman and colleagues at Utrecht (the Netherlands) University and Utrecht University Medical Center.

The investigators assembled the study cohort from a median of 47 patients older than 16 years with a duration of rheumatoid arthritis of less than 1 year who presented each year during 1990-2001 to rheumatology departments across the Netherlands. The patients originally had consented to participate in one of several prospective trials comparing the effectiveness of different drug treatment strategies, including strategies that were conventional at the time.

The rate of depressed mood among patients at the time of diagnosis declined from 43% in 1990-1994 to 32% in 2004-2008, and the corresponding rate at follow-up declined from 25% to 14%. For anxiety, the rate at the time of diagnosis shifted from 34% to 21% and at follow-up changed from 23% to 12%. Physical disability rates at diagnosis decreased from 64% to 60% and at follow-up from 53% to 31% (Arthritis Care Res. 2013 Dec. 3 [doi:10.1002/acr.22211]).

Across the 21 years of the study, there were small, but statistically significant decreases in depressed mood and physical disability and a moderate decline in anxiety. During treatment, these changes were not significant for depressed mood but were significant, yet small for anxiety and moderate to large for physical disability. After time trends were accounted for, measurements associated with decreased disease activity at the time of diagnosis and at follow-up declined over the course of the study, and partly mediated declines in depressed mood, anxiety, and physical disability. Changes in patient composition over time, such as earlier diagnosis over the years as reflected by a decreasing age at the time of diagnosis, increases in education level, and increases in socioeconomic status and life expectancy, were not consistently associated with depressed mood or anxiety or physical disability at diagnosis or follow-up.

"Across the decades, especially the trend of progressively decreasing physical disability after the first years of treatment was noteworthy, and this favorable trend remained significant after having taken account of the reduction of disease activity and change in the composition of patient influx," wrote Ms. Overman, a PhD candidate in the department of clinical and health psychology at the university, and her associates.

The investigators noted that it is impossible to know whether the changes in patient composition played a causal role in affecting psychological distress and physical disability or "only reflect a historic change occurring simultaneously, affecting the improvements statistically but not in real life."

They also suggested that improvements in psychological distress and physical disability might be related not only to pharmacologic reduction of disease activity but also targeted nonpharmacologic therapies such as exercise therapy and cognitive-behavioral therapy as well as "the changed education by rheumatologists and health professionals enhancing physical activity and encouraging patients to live a valued life."

Biologic agents’ inhibition of proinflammatory cytokines and their potential effects on behavior also could have contributed to a reduction in psychological distress and physical disability "not fully explained by reduced disease activity," according to the investigators.

The study was funded by a grant from the Faculty of Social and Behavioral Sciences of Utrecht University and by unrestricted grants from the Dutch Arthritis Foundation. The authors reported no relevant financial conflicts.

[email protected]

Sarilumab, an investigational fully human monoclonal antibody against interleukin-6 receptor alpha, proved to have good safety and efficacy for methotrexate-nonresponsive rheumatoid arthritis patients with doses given every 2 weeks in a multicenter, phase II dose-ranging study.

The dosing regimens that appeared to have the best balance between efficacy and safety – 150 mg every 2 weeks and 200 mg every 2 weeks – gave American College of Rheumatology 20 (ACR 20) response rates of 67% and 65%, and as with other biologic drugs, had nonserious infections as the most common adverse events, reported Dr. Tom Huizinga of Leiden (the Netherlands) University Medical Center and his associates.

Sarilumab at those doses also was associated with neutropenia and increases in liver function tests and serum lipids, which are similar to laboratory changes observed with tocilizumab (Actemra), a humanized monoclonal antibody directed against interleukin-6 (IL-6) receptor alpha. Tocilizumab has been approved in the United States for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs.

IL-6 activity is a target for the treatment of rheumatoid arthritis because of the cytokine’s role in driving inflammation and its elevation in the serum and synovial fluid of patients with RA.

Patients in the trial, dubbed SARIL-RA-MOBILITY Part A, had active RA for at least 3 months despite methotrexate treatment for a minimum of 12 weeks on a stable dose (10-25 mg/wk) for at least 6 weeks prior to the screening visit. Participants’ mean age was 52 years (range, 18-75 years), and 79% were women. They continued on methotrexate after being randomized to one of five subcutaneous sarilumab dosing arms or placebo for 12 weeks of treatment plus 6 weeks of posttreatment follow-up.

Of the five active treatment arms in the double-blind, placebo-controlled trial of 306 patients – 100 mg every 2 weeks, 150 mg every 2 weeks, 200 mg every 2 weeks, 100 mg every week, and 150 mg every week – only 100 mg every 2 weeks was ineffective, with an ACR 20 response seen in 49% of patients, compared with 46% of patients who received placebo. The ACR 20 responses in the other sarilumab regimens ranged from 62% at 100 mg every week to 72% at 150 mg every week (Ann. Rheum. Dis. 2013 Dec. 2 [doi: 10.1136/annrheumdis-2013-204405]).

Secondary endpoints in the trial also showed that the lowest dose of sarilumab was ineffective in comparison with placebo, according to ACR 50 and ACR 70 responses, changes from baseline in individual disease activity measures (swollen joint count, tender joint count, physician and patient global assessment of disease activity, patient’s pain score, C-reactive protein levels, and Health Assessment Questionnaire score), as well as Disease Activity Score in 28 joints (DAS28-CRP).

For most of those measures, the doses of 150 mg every 2 weeks and 200 mg every 2 weeks gave results similar to those of two higher doses in terms of statistically significant improvement compared with placebo. In some cases, the responses seen with sarilumab at 200 mg every 2 weeks were numerically similar to or greater than those observed with the highest dose.

"These data, taken together with the more convenient dosing interval, support [biweekly] dosing as optimal for sarilumab when dosed at 150 mg and 200 mg," the investigators wrote.

The investigators were unsure why the placebo arm had such a high ACR 20 response rate (46%), but they noted that investigators in the CHARISMA trial involving tocilizumab suggested that "extending the time period during which patients received stable methotrexate prior to trial entry may reduce the high placebo rate."

Of the 24 patient discontinuations that were due to treatment-emergent adverse events, 22 were a result of neutropenia (as mandated by protocol) and 2 were due to infection (1 Escherichia coli urinary tract infection and 1 herpes zoster infection). Infection rates with sarilumab did not appear to be associated with neutropenia.

All of the efficacious dosing arms increased alanine aminotransferase levels during the dosing period, rising to three to five times the upper limit of normal in seven patients and from 5 to 10 times the upper limit of normal in four patients, most of which resolved on treatment or at the end of the study. Similar rates of increase in aspartate transferase levels were seen with sarilumab treatment.

Increases in the mean total cholesterol level at week 12 ranged from 9% to 21% in the four efficacious treatment arms, compared with 5% in the placebo group.

The trial was funded by Sanofi and Regeneron Pharmaceuticals, which are developing sarilumab. Three investigators reported financial ties to Sanofi and/or Regeneron and other manufacturers of drugs for RA, and the rest are employees and/or shareholders of Sanofi or Regeneron or were during the conduct of the study.

[email protected]

Sarilumab, an investigational fully human monoclonal antibody against interleukin-6 receptor alpha, proved to have good safety and efficacy for methotrexate-nonresponsive rheumatoid arthritis patients with doses given every 2 weeks in a multicenter, phase II dose-ranging study.

The dosing regimens that appeared to have the best balance between efficacy and safety – 150 mg every 2 weeks and 200 mg every 2 weeks – gave American College of Rheumatology 20 (ACR 20) response rates of 67% and 65%, and as with other biologic drugs, had nonserious infections as the most common adverse events, reported Dr. Tom Huizinga of Leiden (the Netherlands) University Medical Center and his associates.

Sarilumab at those doses also was associated with neutropenia and increases in liver function tests and serum lipids, which are similar to laboratory changes observed with tocilizumab (Actemra), a humanized monoclonal antibody directed against interleukin-6 (IL-6) receptor alpha. Tocilizumab has been approved in the United States for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs.

IL-6 activity is a target for the treatment of rheumatoid arthritis because of the cytokine’s role in driving inflammation and its elevation in the serum and synovial fluid of patients with RA.

Patients in the trial, dubbed SARIL-RA-MOBILITY Part A, had active RA for at least 3 months despite methotrexate treatment for a minimum of 12 weeks on a stable dose (10-25 mg/wk) for at least 6 weeks prior to the screening visit. Participants’ mean age was 52 years (range, 18-75 years), and 79% were women. They continued on methotrexate after being randomized to one of five subcutaneous sarilumab dosing arms or placebo for 12 weeks of treatment plus 6 weeks of posttreatment follow-up.

Of the five active treatment arms in the double-blind, placebo-controlled trial of 306 patients – 100 mg every 2 weeks, 150 mg every 2 weeks, 200 mg every 2 weeks, 100 mg every week, and 150 mg every week – only 100 mg every 2 weeks was ineffective, with an ACR 20 response seen in 49% of patients, compared with 46% of patients who received placebo. The ACR 20 responses in the other sarilumab regimens ranged from 62% at 100 mg every week to 72% at 150 mg every week (Ann. Rheum. Dis. 2013 Dec. 2 [doi: 10.1136/annrheumdis-2013-204405]).

Secondary endpoints in the trial also showed that the lowest dose of sarilumab was ineffective in comparison with placebo, according to ACR 50 and ACR 70 responses, changes from baseline in individual disease activity measures (swollen joint count, tender joint count, physician and patient global assessment of disease activity, patient’s pain score, C-reactive protein levels, and Health Assessment Questionnaire score), as well as Disease Activity Score in 28 joints (DAS28-CRP).

For most of those measures, the doses of 150 mg every 2 weeks and 200 mg every 2 weeks gave results similar to those of two higher doses in terms of statistically significant improvement compared with placebo. In some cases, the responses seen with sarilumab at 200 mg every 2 weeks were numerically similar to or greater than those observed with the highest dose.

"These data, taken together with the more convenient dosing interval, support [biweekly] dosing as optimal for sarilumab when dosed at 150 mg and 200 mg," the investigators wrote.

The investigators were unsure why the placebo arm had such a high ACR 20 response rate (46%), but they noted that investigators in the CHARISMA trial involving tocilizumab suggested that "extending the time period during which patients received stable methotrexate prior to trial entry may reduce the high placebo rate."

Of the 24 patient discontinuations that were due to treatment-emergent adverse events, 22 were a result of neutropenia (as mandated by protocol) and 2 were due to infection (1 Escherichia coli urinary tract infection and 1 herpes zoster infection). Infection rates with sarilumab did not appear to be associated with neutropenia.

All of the efficacious dosing arms increased alanine aminotransferase levels during the dosing period, rising to three to five times the upper limit of normal in seven patients and from 5 to 10 times the upper limit of normal in four patients, most of which resolved on treatment or at the end of the study. Similar rates of increase in aspartate transferase levels were seen with sarilumab treatment.

Increases in the mean total cholesterol level at week 12 ranged from 9% to 21% in the four efficacious treatment arms, compared with 5% in the placebo group.

The trial was funded by Sanofi and Regeneron Pharmaceuticals, which are developing sarilumab. Three investigators reported financial ties to Sanofi and/or Regeneron and other manufacturers of drugs for RA, and the rest are employees and/or shareholders of Sanofi or Regeneron or were during the conduct of the study.

[email protected]

Sarilumab, an investigational fully human monoclonal antibody against interleukin-6 receptor alpha, proved to have good safety and efficacy for methotrexate-nonresponsive rheumatoid arthritis patients with doses given every 2 weeks in a multicenter, phase II dose-ranging study.

The dosing regimens that appeared to have the best balance between efficacy and safety – 150 mg every 2 weeks and 200 mg every 2 weeks – gave American College of Rheumatology 20 (ACR 20) response rates of 67% and 65%, and as with other biologic drugs, had nonserious infections as the most common adverse events, reported Dr. Tom Huizinga of Leiden (the Netherlands) University Medical Center and his associates.

Sarilumab at those doses also was associated with neutropenia and increases in liver function tests and serum lipids, which are similar to laboratory changes observed with tocilizumab (Actemra), a humanized monoclonal antibody directed against interleukin-6 (IL-6) receptor alpha. Tocilizumab has been approved in the United States for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs.

IL-6 activity is a target for the treatment of rheumatoid arthritis because of the cytokine’s role in driving inflammation and its elevation in the serum and synovial fluid of patients with RA.

Patients in the trial, dubbed SARIL-RA-MOBILITY Part A, had active RA for at least 3 months despite methotrexate treatment for a minimum of 12 weeks on a stable dose (10-25 mg/wk) for at least 6 weeks prior to the screening visit. Participants’ mean age was 52 years (range, 18-75 years), and 79% were women. They continued on methotrexate after being randomized to one of five subcutaneous sarilumab dosing arms or placebo for 12 weeks of treatment plus 6 weeks of posttreatment follow-up.

Of the five active treatment arms in the double-blind, placebo-controlled trial of 306 patients – 100 mg every 2 weeks, 150 mg every 2 weeks, 200 mg every 2 weeks, 100 mg every week, and 150 mg every week – only 100 mg every 2 weeks was ineffective, with an ACR 20 response seen in 49% of patients, compared with 46% of patients who received placebo. The ACR 20 responses in the other sarilumab regimens ranged from 62% at 100 mg every week to 72% at 150 mg every week (Ann. Rheum. Dis. 2013 Dec. 2 [doi: 10.1136/annrheumdis-2013-204405]).

Secondary endpoints in the trial also showed that the lowest dose of sarilumab was ineffective in comparison with placebo, according to ACR 50 and ACR 70 responses, changes from baseline in individual disease activity measures (swollen joint count, tender joint count, physician and patient global assessment of disease activity, patient’s pain score, C-reactive protein levels, and Health Assessment Questionnaire score), as well as Disease Activity Score in 28 joints (DAS28-CRP).

For most of those measures, the doses of 150 mg every 2 weeks and 200 mg every 2 weeks gave results similar to those of two higher doses in terms of statistically significant improvement compared with placebo. In some cases, the responses seen with sarilumab at 200 mg every 2 weeks were numerically similar to or greater than those observed with the highest dose.

"These data, taken together with the more convenient dosing interval, support [biweekly] dosing as optimal for sarilumab when dosed at 150 mg and 200 mg," the investigators wrote.

The investigators were unsure why the placebo arm had such a high ACR 20 response rate (46%), but they noted that investigators in the CHARISMA trial involving tocilizumab suggested that "extending the time period during which patients received stable methotrexate prior to trial entry may reduce the high placebo rate."

Of the 24 patient discontinuations that were due to treatment-emergent adverse events, 22 were a result of neutropenia (as mandated by protocol) and 2 were due to infection (1 Escherichia coli urinary tract infection and 1 herpes zoster infection). Infection rates with sarilumab did not appear to be associated with neutropenia.

All of the efficacious dosing arms increased alanine aminotransferase levels during the dosing period, rising to three to five times the upper limit of normal in seven patients and from 5 to 10 times the upper limit of normal in four patients, most of which resolved on treatment or at the end of the study. Similar rates of increase in aspartate transferase levels were seen with sarilumab treatment.

Increases in the mean total cholesterol level at week 12 ranged from 9% to 21% in the four efficacious treatment arms, compared with 5% in the placebo group.

The trial was funded by Sanofi and Regeneron Pharmaceuticals, which are developing sarilumab. Three investigators reported financial ties to Sanofi and/or Regeneron and other manufacturers of drugs for RA, and the rest are employees and/or shareholders of Sanofi or Regeneron or were during the conduct of the study.

[email protected]

Dr. Kenneth R. Wilske, an editorial adviser to Rheumatology News since 2003, died unexpectedly Sept. 17 of a pulmonary embolism while playing golf. He was 78.

Dr. Wilske was a leader in rheumatology in the Pacific Northwest and was a driving force in what he called the "step-down bridge" approach to treating rheumatoid arthritis. He also made important contributions to medicine’s understanding of giant cell arteritis and polymyalgia rheumatica.

Until his retirement in 2004, Dr. Wilske served as the section head of the division of rheumatology at the Virginia Mason Clinic in Seattle, which acknowledged his legacy by creating the Wilske Center for Translational Research. He also was a clinical professor of rheumatology at the University of Washington, Seattle, where he had trained as one of the first fellows in the division of rheumatology in 1962-1964 under Dr. John Decker.

Dr. Wilske remained an important member of the clinical faculty at the university in retirement. "We saw him regularly. He would come not only to rheumatology programs, but he was also a faithful attendee of medical grand rounds at the university. He saw patients with our fellows and attended our clinical conferences, and he was an insightful, very positive force in our program," said Dr. Peter A. Simkin, emeritus professor of medicine in the division of rheumatology at the university.

Dr. Wilske played a key role in building the Benaroya Research Institute (BRI) at Virginia Mason Clinic and served on many of its advisory boards and committees. Until his death, Dr. Wilske continued to work on the board of the BRI, which recognized his legacy after his retirement by establishing the Kenneth R. Wilske Lecture Series in Science and Medicine.

He served terms as president of the Northwest Society for Clinical Research and the Northwest Rheumatism Society and as a member of the Food and Drug Administration Arthritis Advisory Committee.

In 2000, the American College of Rheumatology honored him as a Master of Rheumatology and in the following year gave him its Distinguished Rheumatologist Award.

Dr. Wilske’s step-down bridge approach to the treatment of rheumatoid arthritis "was really a paradigm shift at the time," noted Dr. Jeffrey Carlin, who succeeded him as the section head of the division of rheumatology at Virginia Mason. In their original editorial on the subject, Dr. Wilske and his Virginia Mason colleague, Dr. Louis Andrew Healey, wrote that the step-down bridge concept involves taking advantage of different medication’s abilities and mechanisms of action in suppressing inflammation by "employing a combination of drugs to control inflammation in the critical early stages of RA," so that medications can be "sequentially withdrawn in contrast to the traditional pyramid, in which they have been sequentially added," without any greater problem of toxicity (J. Rheumatol. 1989;16:565-7).

"This concept has now become accepted and a standard approach to the therapy of rheumatoid arthritis and is becoming a paradigm and strategy for therapy for other rheumatic diseases and chronic inflammatory disorders," said Dr. Keith B. Elkon, head of the division of rheumatology at the University of Washington.

Dr. Wilske published 75 articles and abstracts. He was best known for his clinical research in polymyalgia rheumatica and giant cell arteritis, much of which was conducted with Dr. Healey. The two researchers "literally wrote the book on giant cell arteritis and made a lot of important contributions when it was really just first finding its way into the rheumatology panoply of conditions that we deal with," Dr. Simkin said.

Many of Dr. Wilske’s colleagues held in high regard not only his clinical acumen but also his interpersonal abilities. "He had a remarkably well-organized mindset, so that if you wanted a list of complications of any drug or the manifestations of any disease, it was always right on the tip of his tongue – just an excellent clinician," Dr. Simkin said.

"He was the kind of guy who could see a ridiculous number of people in the course of a day but somehow everybody felt as though they got his full attention. And yet he could still find time to have lunch and interact with his colleagues. I don’t know how he did it," Dr. Carlin said.

Dr. Wilske is survived by his wife, three daughters, and three granddaughters.

[email protected]

Dr. Kenneth R. Wilske, an editorial adviser to Rheumatology News since 2003, died unexpectedly Sept. 17 of a pulmonary embolism while playing golf. He was 78.

Dr. Wilske was a leader in rheumatology in the Pacific Northwest and was a driving force in what he called the "step-down bridge" approach to treating rheumatoid arthritis. He also made important contributions to medicine’s understanding of giant cell arteritis and polymyalgia rheumatica.

Until his retirement in 2004, Dr. Wilske served as the section head of the division of rheumatology at the Virginia Mason Clinic in Seattle, which acknowledged his legacy by creating the Wilske Center for Translational Research. He also was a clinical professor of rheumatology at the University of Washington, Seattle, where he had trained as one of the first fellows in the division of rheumatology in 1962-1964 under Dr. John Decker.

Dr. Wilske remained an important member of the clinical faculty at the university in retirement. "We saw him regularly. He would come not only to rheumatology programs, but he was also a faithful attendee of medical grand rounds at the university. He saw patients with our fellows and attended our clinical conferences, and he was an insightful, very positive force in our program," said Dr. Peter A. Simkin, emeritus professor of medicine in the division of rheumatology at the university.

Dr. Wilske played a key role in building the Benaroya Research Institute (BRI) at Virginia Mason Clinic and served on many of its advisory boards and committees. Until his death, Dr. Wilske continued to work on the board of the BRI, which recognized his legacy after his retirement by establishing the Kenneth R. Wilske Lecture Series in Science and Medicine.

He served terms as president of the Northwest Society for Clinical Research and the Northwest Rheumatism Society and as a member of the Food and Drug Administration Arthritis Advisory Committee.

In 2000, the American College of Rheumatology honored him as a Master of Rheumatology and in the following year gave him its Distinguished Rheumatologist Award.

Dr. Wilske’s step-down bridge approach to the treatment of rheumatoid arthritis "was really a paradigm shift at the time," noted Dr. Jeffrey Carlin, who succeeded him as the section head of the division of rheumatology at Virginia Mason. In their original editorial on the subject, Dr. Wilske and his Virginia Mason colleague, Dr. Louis Andrew Healey, wrote that the step-down bridge concept involves taking advantage of different medication’s abilities and mechanisms of action in suppressing inflammation by "employing a combination of drugs to control inflammation in the critical early stages of RA," so that medications can be "sequentially withdrawn in contrast to the traditional pyramid, in which they have been sequentially added," without any greater problem of toxicity (J. Rheumatol. 1989;16:565-7).

"This concept has now become accepted and a standard approach to the therapy of rheumatoid arthritis and is becoming a paradigm and strategy for therapy for other rheumatic diseases and chronic inflammatory disorders," said Dr. Keith B. Elkon, head of the division of rheumatology at the University of Washington.

Dr. Wilske published 75 articles and abstracts. He was best known for his clinical research in polymyalgia rheumatica and giant cell arteritis, much of which was conducted with Dr. Healey. The two researchers "literally wrote the book on giant cell arteritis and made a lot of important contributions when it was really just first finding its way into the rheumatology panoply of conditions that we deal with," Dr. Simkin said.

Many of Dr. Wilske’s colleagues held in high regard not only his clinical acumen but also his interpersonal abilities. "He had a remarkably well-organized mindset, so that if you wanted a list of complications of any drug or the manifestations of any disease, it was always right on the tip of his tongue – just an excellent clinician," Dr. Simkin said.

"He was the kind of guy who could see a ridiculous number of people in the course of a day but somehow everybody felt as though they got his full attention. And yet he could still find time to have lunch and interact with his colleagues. I don’t know how he did it," Dr. Carlin said.

Dr. Wilske is survived by his wife, three daughters, and three granddaughters.

[email protected]

Dr. Kenneth R. Wilske, an editorial adviser to Rheumatology News since 2003, died unexpectedly Sept. 17 of a pulmonary embolism while playing golf. He was 78.

Dr. Wilske was a leader in rheumatology in the Pacific Northwest and was a driving force in what he called the "step-down bridge" approach to treating rheumatoid arthritis. He also made important contributions to medicine’s understanding of giant cell arteritis and polymyalgia rheumatica.

Until his retirement in 2004, Dr. Wilske served as the section head of the division of rheumatology at the Virginia Mason Clinic in Seattle, which acknowledged his legacy by creating the Wilske Center for Translational Research. He also was a clinical professor of rheumatology at the University of Washington, Seattle, where he had trained as one of the first fellows in the division of rheumatology in 1962-1964 under Dr. John Decker.

Dr. Wilske remained an important member of the clinical faculty at the university in retirement. "We saw him regularly. He would come not only to rheumatology programs, but he was also a faithful attendee of medical grand rounds at the university. He saw patients with our fellows and attended our clinical conferences, and he was an insightful, very positive force in our program," said Dr. Peter A. Simkin, emeritus professor of medicine in the division of rheumatology at the university.

Dr. Wilske played a key role in building the Benaroya Research Institute (BRI) at Virginia Mason Clinic and served on many of its advisory boards and committees. Until his death, Dr. Wilske continued to work on the board of the BRI, which recognized his legacy after his retirement by establishing the Kenneth R. Wilske Lecture Series in Science and Medicine.

He served terms as president of the Northwest Society for Clinical Research and the Northwest Rheumatism Society and as a member of the Food and Drug Administration Arthritis Advisory Committee.

In 2000, the American College of Rheumatology honored him as a Master of Rheumatology and in the following year gave him its Distinguished Rheumatologist Award.

Dr. Wilske’s step-down bridge approach to the treatment of rheumatoid arthritis "was really a paradigm shift at the time," noted Dr. Jeffrey Carlin, who succeeded him as the section head of the division of rheumatology at Virginia Mason. In their original editorial on the subject, Dr. Wilske and his Virginia Mason colleague, Dr. Louis Andrew Healey, wrote that the step-down bridge concept involves taking advantage of different medication’s abilities and mechanisms of action in suppressing inflammation by "employing a combination of drugs to control inflammation in the critical early stages of RA," so that medications can be "sequentially withdrawn in contrast to the traditional pyramid, in which they have been sequentially added," without any greater problem of toxicity (J. Rheumatol. 1989;16:565-7).

"This concept has now become accepted and a standard approach to the therapy of rheumatoid arthritis and is becoming a paradigm and strategy for therapy for other rheumatic diseases and chronic inflammatory disorders," said Dr. Keith B. Elkon, head of the division of rheumatology at the University of Washington.

Dr. Wilske published 75 articles and abstracts. He was best known for his clinical research in polymyalgia rheumatica and giant cell arteritis, much of which was conducted with Dr. Healey. The two researchers "literally wrote the book on giant cell arteritis and made a lot of important contributions when it was really just first finding its way into the rheumatology panoply of conditions that we deal with," Dr. Simkin said.

Many of Dr. Wilske’s colleagues held in high regard not only his clinical acumen but also his interpersonal abilities. "He had a remarkably well-organized mindset, so that if you wanted a list of complications of any drug or the manifestations of any disease, it was always right on the tip of his tongue – just an excellent clinician," Dr. Simkin said.

"He was the kind of guy who could see a ridiculous number of people in the course of a day but somehow everybody felt as though they got his full attention. And yet he could still find time to have lunch and interact with his colleagues. I don’t know how he did it," Dr. Carlin said.

Dr. Wilske is survived by his wife, three daughters, and three granddaughters.

[email protected]

The Food and Drug Administration has approved eslicarbazepine acetate, a voltage-gated sodium channel inhibitor, as an add-on treatment for adults with partial-onset seizures.

The approval, announced Nov. 8, is based on three phase III, double-blind, randomized placebo-controlled clinical trials of eslicarbazepine at doses of 800 mg and 1,200 mg once daily involving more than 1,400 adults. All patients had partial seizures that were inadequately controlled on one to three concomitant antiepileptic drugs (including carbamazepine, lamotrigine, valproic acid, and levetiracetam). In the studies, 41% of patients taking eslicarbazepine had at least a 50% reduction from baseline in seizure frequency, compared with 22% of placebo-treated patients.

The most common side effects in the studies included dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor, resulting in adverse event discontinuation rates of 14% for the 800-mg dose, 25% for the 1,200-mg dose, and 7% for placebo.

The manufacturer of eslicarbazepine, Sunovion Pharmaceuticals, will market the drug under the brand name Aptiom, an immediate-release formulation taken once daily.

The treatment dose should begin at 400 mg once daily and after 1 week can be increased to the recommended dose of 800 mg once daily, followed by a switch to the maximum recommended dose of 1,200 mg once daily if necessary. The 1,200-mg dose regimen is associated with an increase in adverse reactions and should be started only after a patient has tolerated 800 mg once daily for at least 1 week. However, it may be necessary for some patients to begin treatment at 800 mg once daily if the need for additional seizure reduction outweighs the risk of greater adverse reactions, according to Sunovion.

The company said it expects that Aptiom will be available in U.S. pharmacies in the second quarter of 2014.

[email protected]

The Food and Drug Administration has approved eslicarbazepine acetate, a voltage-gated sodium channel inhibitor, as an add-on treatment for adults with partial-onset seizures.

The approval, announced Nov. 8, is based on three phase III, double-blind, randomized placebo-controlled clinical trials of eslicarbazepine at doses of 800 mg and 1,200 mg once daily involving more than 1,400 adults. All patients had partial seizures that were inadequately controlled on one to three concomitant antiepileptic drugs (including carbamazepine, lamotrigine, valproic acid, and levetiracetam). In the studies, 41% of patients taking eslicarbazepine had at least a 50% reduction from baseline in seizure frequency, compared with 22% of placebo-treated patients.

The most common side effects in the studies included dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor, resulting in adverse event discontinuation rates of 14% for the 800-mg dose, 25% for the 1,200-mg dose, and 7% for placebo.

The manufacturer of eslicarbazepine, Sunovion Pharmaceuticals, will market the drug under the brand name Aptiom, an immediate-release formulation taken once daily.

The treatment dose should begin at 400 mg once daily and after 1 week can be increased to the recommended dose of 800 mg once daily, followed by a switch to the maximum recommended dose of 1,200 mg once daily if necessary. The 1,200-mg dose regimen is associated with an increase in adverse reactions and should be started only after a patient has tolerated 800 mg once daily for at least 1 week. However, it may be necessary for some patients to begin treatment at 800 mg once daily if the need for additional seizure reduction outweighs the risk of greater adverse reactions, according to Sunovion.

The company said it expects that Aptiom will be available in U.S. pharmacies in the second quarter of 2014.

[email protected]

The Food and Drug Administration has approved eslicarbazepine acetate, a voltage-gated sodium channel inhibitor, as an add-on treatment for adults with partial-onset seizures.

The approval, announced Nov. 8, is based on three phase III, double-blind, randomized placebo-controlled clinical trials of eslicarbazepine at doses of 800 mg and 1,200 mg once daily involving more than 1,400 adults. All patients had partial seizures that were inadequately controlled on one to three concomitant antiepileptic drugs (including carbamazepine, lamotrigine, valproic acid, and levetiracetam). In the studies, 41% of patients taking eslicarbazepine had at least a 50% reduction from baseline in seizure frequency, compared with 22% of placebo-treated patients.

The most common side effects in the studies included dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor, resulting in adverse event discontinuation rates of 14% for the 800-mg dose, 25% for the 1,200-mg dose, and 7% for placebo.

The manufacturer of eslicarbazepine, Sunovion Pharmaceuticals, will market the drug under the brand name Aptiom, an immediate-release formulation taken once daily.

The treatment dose should begin at 400 mg once daily and after 1 week can be increased to the recommended dose of 800 mg once daily, followed by a switch to the maximum recommended dose of 1,200 mg once daily if necessary. The 1,200-mg dose regimen is associated with an increase in adverse reactions and should be started only after a patient has tolerated 800 mg once daily for at least 1 week. However, it may be necessary for some patients to begin treatment at 800 mg once daily if the need for additional seizure reduction outweighs the risk of greater adverse reactions, according to Sunovion.

The company said it expects that Aptiom will be available in U.S. pharmacies in the second quarter of 2014.

[email protected]

Using an online self-help tool for 10 weeks improved rheumatoid arthritis patients’ quality of life up to 9 months after the intervention, according to a small, randomized trial.

However, patients didn’t see improvements in health status or pain and other symptoms beyond those of patients who were randomized to a waiting list and didn’t receive the intervention, according to Cheryl L. Shigaki, Ph.D., of the department of health psychology at the University of Missouri, Columbia, and her colleagues (Arthritis Care Res. 2013;65:1573-81).

The only previous study of an online self-management intervention involved patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia, and those with RA showed sustained improvement in self-reported global health and activity limitation at 12 months after beginning the program (Arthritis Rheum. 2008;59:1009-17).

The self-management tool included content delivered via a visual slideshow, as well as access to the online site RAHelp.org, which provided peer support through social networking applications. Patients in the intervention group also had weekly phone calls with a counselor trained in cognitive-behavioral group interventions.

The mean age of the 106 patients who underwent the intervention (54 patients) or went on a wait list (52 patients) was 49 and 50 years, respectively, and 98 of the 106 patients were women. A total of 86% had attended graduate school or at least some college, and 94% of the 106 patients were white.

Immediately after the 10-week intervention period, participants in the treatment group had significantly better scores on the Arthritis Self-Efficacy Scale than did those in the wait-list group (83.9 vs. 68.5, respectively), and that difference was maintained 9 months after the intervention (84.1 vs. 68.6). The effect size associated with the intervention at both time points was large, at 0.92.

The intervention had significantly greater positive effect on quality of life than did being on the waiting list, Dr. Shigaki and her colleagues noted, and had a moderate effect size on Quality of Life Scale scores that was retained from immediately after the intervention (88.4 vs. 84.9) through 9 months later (88.0 vs. 83.1).

The investigators acknowledged that it’s difficult to determine how much of the intervention’s impact was attributable to the online materials and peer support, and how much was because of the phone calls with counselors. However, given the public’s increasing comfort with online communications since the trial began in 2003, they said, "we expect that a future version of RAHelp could be conducted safely and effectively without scheduled phone contacts, and that most, if not all, interactions could be conducted online."

The investigators cautioned that the participants were not blinded to the intervention and may have benefited from an attention effect. The participants also were early adopters of Internet tools and services, and they had a high level of education and income. Thus, their results may not be generalizable to a broader population. But they may represent people "who accept and are comfortable with, or even perhaps prefer, receiving health care services online."

The program could be scaled up by "significantly reducing the amount of clinician phone contact time without introducing untoward risk or consumer rejection," the researchers added.

Reimbursement could be a barrier to expanding similar programs, however. "At this time, there is no clear and consistent way to recoup costs associated with online self-management programming," Dr. Shigaki and her colleagues cautioned. But that could change as Medicare shifts its thinking on reimbursement for behavioral and psychosocial approaches that reduce the overall costs of chronic illness.

The study was funded by a grant from the National Institute on Disability and Rehabilitation Research of the Department of Education. One of the authors reported receiving honoraria from the Association of Rheumatology Health Professionals.

[email protected]

Using an online self-help tool for 10 weeks improved rheumatoid arthritis patients’ quality of life up to 9 months after the intervention, according to a small, randomized trial.

However, patients didn’t see improvements in health status or pain and other symptoms beyond those of patients who were randomized to a waiting list and didn’t receive the intervention, according to Cheryl L. Shigaki, Ph.D., of the department of health psychology at the University of Missouri, Columbia, and her colleagues (Arthritis Care Res. 2013;65:1573-81).

The only previous study of an online self-management intervention involved patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia, and those with RA showed sustained improvement in self-reported global health and activity limitation at 12 months after beginning the program (Arthritis Rheum. 2008;59:1009-17).

The self-management tool included content delivered via a visual slideshow, as well as access to the online site RAHelp.org, which provided peer support through social networking applications. Patients in the intervention group also had weekly phone calls with a counselor trained in cognitive-behavioral group interventions.

The mean age of the 106 patients who underwent the intervention (54 patients) or went on a wait list (52 patients) was 49 and 50 years, respectively, and 98 of the 106 patients were women. A total of 86% had attended graduate school or at least some college, and 94% of the 106 patients were white.

Immediately after the 10-week intervention period, participants in the treatment group had significantly better scores on the Arthritis Self-Efficacy Scale than did those in the wait-list group (83.9 vs. 68.5, respectively), and that difference was maintained 9 months after the intervention (84.1 vs. 68.6). The effect size associated with the intervention at both time points was large, at 0.92.

The intervention had significantly greater positive effect on quality of life than did being on the waiting list, Dr. Shigaki and her colleagues noted, and had a moderate effect size on Quality of Life Scale scores that was retained from immediately after the intervention (88.4 vs. 84.9) through 9 months later (88.0 vs. 83.1).

The investigators acknowledged that it’s difficult to determine how much of the intervention’s impact was attributable to the online materials and peer support, and how much was because of the phone calls with counselors. However, given the public’s increasing comfort with online communications since the trial began in 2003, they said, "we expect that a future version of RAHelp could be conducted safely and effectively without scheduled phone contacts, and that most, if not all, interactions could be conducted online."

The investigators cautioned that the participants were not blinded to the intervention and may have benefited from an attention effect. The participants also were early adopters of Internet tools and services, and they had a high level of education and income. Thus, their results may not be generalizable to a broader population. But they may represent people "who accept and are comfortable with, or even perhaps prefer, receiving health care services online."

The program could be scaled up by "significantly reducing the amount of clinician phone contact time without introducing untoward risk or consumer rejection," the researchers added.

Reimbursement could be a barrier to expanding similar programs, however. "At this time, there is no clear and consistent way to recoup costs associated with online self-management programming," Dr. Shigaki and her colleagues cautioned. But that could change as Medicare shifts its thinking on reimbursement for behavioral and psychosocial approaches that reduce the overall costs of chronic illness.

The study was funded by a grant from the National Institute on Disability and Rehabilitation Research of the Department of Education. One of the authors reported receiving honoraria from the Association of Rheumatology Health Professionals.

[email protected]

Using an online self-help tool for 10 weeks improved rheumatoid arthritis patients’ quality of life up to 9 months after the intervention, according to a small, randomized trial.

However, patients didn’t see improvements in health status or pain and other symptoms beyond those of patients who were randomized to a waiting list and didn’t receive the intervention, according to Cheryl L. Shigaki, Ph.D., of the department of health psychology at the University of Missouri, Columbia, and her colleagues (Arthritis Care Res. 2013;65:1573-81).

The only previous study of an online self-management intervention involved patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia, and those with RA showed sustained improvement in self-reported global health and activity limitation at 12 months after beginning the program (Arthritis Rheum. 2008;59:1009-17).

The self-management tool included content delivered via a visual slideshow, as well as access to the online site RAHelp.org, which provided peer support through social networking applications. Patients in the intervention group also had weekly phone calls with a counselor trained in cognitive-behavioral group interventions.

The mean age of the 106 patients who underwent the intervention (54 patients) or went on a wait list (52 patients) was 49 and 50 years, respectively, and 98 of the 106 patients were women. A total of 86% had attended graduate school or at least some college, and 94% of the 106 patients were white.

Immediately after the 10-week intervention period, participants in the treatment group had significantly better scores on the Arthritis Self-Efficacy Scale than did those in the wait-list group (83.9 vs. 68.5, respectively), and that difference was maintained 9 months after the intervention (84.1 vs. 68.6). The effect size associated with the intervention at both time points was large, at 0.92.

The intervention had significantly greater positive effect on quality of life than did being on the waiting list, Dr. Shigaki and her colleagues noted, and had a moderate effect size on Quality of Life Scale scores that was retained from immediately after the intervention (88.4 vs. 84.9) through 9 months later (88.0 vs. 83.1).

The investigators acknowledged that it’s difficult to determine how much of the intervention’s impact was attributable to the online materials and peer support, and how much was because of the phone calls with counselors. However, given the public’s increasing comfort with online communications since the trial began in 2003, they said, "we expect that a future version of RAHelp could be conducted safely and effectively without scheduled phone contacts, and that most, if not all, interactions could be conducted online."

The investigators cautioned that the participants were not blinded to the intervention and may have benefited from an attention effect. The participants also were early adopters of Internet tools and services, and they had a high level of education and income. Thus, their results may not be generalizable to a broader population. But they may represent people "who accept and are comfortable with, or even perhaps prefer, receiving health care services online."

The program could be scaled up by "significantly reducing the amount of clinician phone contact time without introducing untoward risk or consumer rejection," the researchers added.

Reimbursement could be a barrier to expanding similar programs, however. "At this time, there is no clear and consistent way to recoup costs associated with online self-management programming," Dr. Shigaki and her colleagues cautioned. But that could change as Medicare shifts its thinking on reimbursement for behavioral and psychosocial approaches that reduce the overall costs of chronic illness.

The study was funded by a grant from the National Institute on Disability and Rehabilitation Research of the Department of Education. One of the authors reported receiving honoraria from the Association of Rheumatology Health Professionals.

[email protected]

Using an online self-help tool for 10 weeks improved rheumatoid arthritis patients’ quality of life up to 9 months after the intervention, according to a small, randomized trial.

However, patients didn’t see improvements in health status or pain and other symptoms beyond those of patients who were randomized to a waiting list and didn’t receive the intervention, according to Cheryl L. Shigaki, Ph.D., of the department of health psychology at the University of Missouri, Columbia, and her colleagues (Arthritis Care Res. 2013;65:1573-81).

The only previous study of an online self-management intervention involved patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia, and those with RA showed sustained improvement in self-reported global health and activity limitation at 12 months after beginning the program (Arthritis Rheum. 2008;59:1009-17).

The self-management tool included content delivered via a visual slideshow, as well as access to the online site RAHelp.org, which provided peer support through social networking applications. Patients in the intervention group also had weekly phone calls with a counselor trained in cognitive-behavioral group interventions.

The mean age of the 106 patients who underwent the intervention (54 patients) or went on a wait list (52 patients) was 49 and 50 years, respectively, and 98 of the 106 patients were women. A total of 86% had attended graduate school or at least some college, and 94% of the 106 patients were white.

Immediately after the 10-week intervention period, participants in the treatment group had significantly better scores on the Arthritis Self-Efficacy Scale than did those in the wait-list group (83.9 vs. 68.5, respectively), and that difference was maintained 9 months after the intervention (84.1 vs. 68.6). The effect size associated with the intervention at both time points was large, at 0.92.

The intervention had significantly greater positive effect on quality of life than did being on the waiting list, Dr. Shigaki and her colleagues noted, and had a moderate effect size on Quality of Life Scale scores that was retained from immediately after the intervention (88.4 vs. 84.9) through 9 months later (88.0 vs. 83.1).

The investigators acknowledged that it’s difficult to determine how much of the intervention’s impact was attributable to the online materials and peer support, and how much was because of the phone calls with counselors. However, given the public’s increasing comfort with online communications since the trial began in 2003, they said, "we expect that a future version of RAHelp could be conducted safely and effectively without scheduled phone contacts, and that most, if not all, interactions could be conducted online."

The investigators cautioned that the participants were not blinded to the intervention and may have benefited from an attention effect. The participants also were early adopters of Internet tools and services, and they had a high level of education and income. Thus, their results may not be generalizable to a broader population. But they may represent people "who accept and are comfortable with, or even perhaps prefer, receiving health care services online."

The program could be scaled up by "significantly reducing the amount of clinician phone contact time without introducing untoward risk or consumer rejection," the researchers added.

Reimbursement could be a barrier to expanding similar programs, however. "At this time, there is no clear and consistent way to recoup costs associated with online self-management programming," Dr. Shigaki and her colleagues cautioned. But that could change as Medicare shifts its thinking on reimbursement for behavioral and psychosocial approaches that reduce the overall costs of chronic illness.

The study was funded by a grant from the National Institute on Disability and Rehabilitation Research of the Department of Education. One of the authors reported receiving honoraria from the Association of Rheumatology Health Professionals.

[email protected]

Using an online self-help tool for 10 weeks improved rheumatoid arthritis patients’ quality of life up to 9 months after the intervention, according to a small, randomized trial.

However, patients didn’t see improvements in health status or pain and other symptoms beyond those of patients who were randomized to a waiting list and didn’t receive the intervention, according to Cheryl L. Shigaki, Ph.D., of the department of health psychology at the University of Missouri, Columbia, and her colleagues (Arthritis Care Res. 2013;65:1573-81).

The only previous study of an online self-management intervention involved patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia, and those with RA showed sustained improvement in self-reported global health and activity limitation at 12 months after beginning the program (Arthritis Rheum. 2008;59:1009-17).

The self-management tool included content delivered via a visual slideshow, as well as access to the online site RAHelp.org, which provided peer support through social networking applications. Patients in the intervention group also had weekly phone calls with a counselor trained in cognitive-behavioral group interventions.

The mean age of the 106 patients who underwent the intervention (54 patients) or went on a wait list (52 patients) was 49 and 50 years, respectively, and 98 of the 106 patients were women. A total of 86% had attended graduate school or at least some college, and 94% of the 106 patients were white.

Immediately after the 10-week intervention period, participants in the treatment group had significantly better scores on the Arthritis Self-Efficacy Scale than did those in the wait-list group (83.9 vs. 68.5, respectively), and that difference was maintained 9 months after the intervention (84.1 vs. 68.6). The effect size associated with the intervention at both time points was large, at 0.92.

The intervention had significantly greater positive effect on quality of life than did being on the waiting list, Dr. Shigaki and her colleagues noted, and had a moderate effect size on Quality of Life Scale scores that was retained from immediately after the intervention (88.4 vs. 84.9) through 9 months later (88.0 vs. 83.1).

The investigators acknowledged that it’s difficult to determine how much of the intervention’s impact was attributable to the online materials and peer support, and how much was because of the phone calls with counselors. However, given the public’s increasing comfort with online communications since the trial began in 2003, they said, "we expect that a future version of RAHelp could be conducted safely and effectively without scheduled phone contacts, and that most, if not all, interactions could be conducted online."

The investigators cautioned that the participants were not blinded to the intervention and may have benefited from an attention effect. The participants also were early adopters of Internet tools and services, and they had a high level of education and income. Thus, their results may not be generalizable to a broader population. But they may represent people "who accept and are comfortable with, or even perhaps prefer, receiving health care services online."

The program could be scaled up by "significantly reducing the amount of clinician phone contact time without introducing untoward risk or consumer rejection," the researchers added.

Reimbursement could be a barrier to expanding similar programs, however. "At this time, there is no clear and consistent way to recoup costs associated with online self-management programming," Dr. Shigaki and her colleagues cautioned. But that could change as Medicare shifts its thinking on reimbursement for behavioral and psychosocial approaches that reduce the overall costs of chronic illness.

The study was funded by a grant from the National Institute on Disability and Rehabilitation Research of the Department of Education. One of the authors reported receiving honoraria from the Association of Rheumatology Health Professionals.

[email protected]

Using an online self-help tool for 10 weeks improved rheumatoid arthritis patients’ quality of life up to 9 months after the intervention, according to a small, randomized trial.

However, patients didn’t see improvements in health status or pain and other symptoms beyond those of patients who were randomized to a waiting list and didn’t receive the intervention, according to Cheryl L. Shigaki, Ph.D., of the department of health psychology at the University of Missouri, Columbia, and her colleagues (Arthritis Care Res. 2013;65:1573-81).

The only previous study of an online self-management intervention involved patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia, and those with RA showed sustained improvement in self-reported global health and activity limitation at 12 months after beginning the program (Arthritis Rheum. 2008;59:1009-17).

The self-management tool included content delivered via a visual slideshow, as well as access to the online site RAHelp.org, which provided peer support through social networking applications. Patients in the intervention group also had weekly phone calls with a counselor trained in cognitive-behavioral group interventions.

The mean age of the 106 patients who underwent the intervention (54 patients) or went on a wait list (52 patients) was 49 and 50 years, respectively, and 98 of the 106 patients were women. A total of 86% had attended graduate school or at least some college, and 94% of the 106 patients were white.

Immediately after the 10-week intervention period, participants in the treatment group had significantly better scores on the Arthritis Self-Efficacy Scale than did those in the wait-list group (83.9 vs. 68.5, respectively), and that difference was maintained 9 months after the intervention (84.1 vs. 68.6). The effect size associated with the intervention at both time points was large, at 0.92.

The intervention had significantly greater positive effect on quality of life than did being on the waiting list, Dr. Shigaki and her colleagues noted, and had a moderate effect size on Quality of Life Scale scores that was retained from immediately after the intervention (88.4 vs. 84.9) through 9 months later (88.0 vs. 83.1).

The investigators acknowledged that it’s difficult to determine how much of the intervention’s impact was attributable to the online materials and peer support, and how much was because of the phone calls with counselors. However, given the public’s increasing comfort with online communications since the trial began in 2003, they said, "we expect that a future version of RAHelp could be conducted safely and effectively without scheduled phone contacts, and that most, if not all, interactions could be conducted online."

The investigators cautioned that the participants were not blinded to the intervention and may have benefited from an attention effect. The participants also were early adopters of Internet tools and services, and they had a high level of education and income. Thus, their results may not be generalizable to a broader population. But they may represent people "who accept and are comfortable with, or even perhaps prefer, receiving health care services online."

The program could be scaled up by "significantly reducing the amount of clinician phone contact time without introducing untoward risk or consumer rejection," the researchers added.

Reimbursement could be a barrier to expanding similar programs, however. "At this time, there is no clear and consistent way to recoup costs associated with online self-management programming," Dr. Shigaki and her colleagues cautioned. But that could change as Medicare shifts its thinking on reimbursement for behavioral and psychosocial approaches that reduce the overall costs of chronic illness.

The study was funded by a grant from the National Institute on Disability and Rehabilitation Research of the Department of Education. One of the authors reported receiving honoraria from the Association of Rheumatology Health Professionals.

[email protected]

Postictal generalized EEG suppression occurs more often in adults than in children and might be related to why adults have a higher rate of sudden unexpected death in epilepsy than that of children, according to results from a prospective study.

Cardiopulmonary abnormalities involving ictal apnea and bradycardia happened more frequently in children, whereas ictal tachycardia occurred more often among adults. However, there was no difference in desaturation or ictal bradypnea or tachypnea in children versus adults, reported Dr. Milena Pavlova of the division of epilepsy, neurophysiology, and sleep at Brigham and Women’s Hospital, Boston, and her colleagues.

"The evolution of ictal cardiorespiratory abnormalities [had] not been systematically studied for age-related findings," the researchers noted. "There is some evidence in adults that postictal generalized EEG suppression (PGES) may potentially be a risk marker for SUDEP [sudden unexpected death in epilepsy] and that age related maturation of brain may be involved in the manifestation of PGES, but not many studies have looked into the possible effect of this age-related brain maturation on PGES," they wrote (Epilepsy Behav. 2013 Oct. 17 [doi:10.1016/j.yebeh.2013.09.026]).

"The evolution of ictal cardiorespiratory abnormalities [had] not been systematically studied for age-related findings..."

The study involved 26 children with a mean age of 10.6 years (range of 2-20 years) and 22 adults with a mean age of 37 years (range of 22-62 years) who had been admitted to the long-term monitoring units at two hospitals for the evaluation of seizures. They underwent standard continuous video-EEG monitoring as well as electrocardiography, respiratory inductance plethysmography (RIP), and finger pulse oximetry. The investigators recorded 101 seizures in children (mean of 3.9) and 55 in adults (mean of 2.55).

After one or more seizures, 13 of 22 (59%) adults had PGES, compared with only 1 of 26 (4%) children. This was a significant difference with an odds ratio of 0.20. Furthermore, PGES occurred in 6 (6%) of the seizures recorded in children, compared with 13 (24%) in adults.

"The fact that PGES was more frequent in adults than in children and the fact that age had no correlation with PGES in adults lead us to hypothesize that age may play a role in the occurrence of PGES only up to a point where the brain is mature enough to exhibit PGES. Once the brain is mature enough to be capable of manifesting PGES, further increase in age may not have any additional effect. These findings further support the idea of a less mature ‘controlling network’ in the developing brain being less capable of exhibiting PGES," the investigators wrote.

Children had more than three times greater odds of developing ictal central apnea (odds ratio = 3.36) than those of adults (39 of 78 [50%] seizures in children with good RIP data vs. 17 of 55 [31%] in adults). None of the apnea events recorded in either children or adults were obstructive in nature.

Ictal bradycardia was nearly five times more likely to occur in children than in adults (15 of 63 [24%] vs. 4 of 55 [7%], respectively). In comparison, ictal tachycardia was 60% less likely to occur among children than in adults (31 of 63 [49%] vs. 35 of 55 [64%], respectively; OR = 0.40).

The rates of other cardiopulmonary abnormalities (ictal bradypnea and tachypnea, ictal and postictal bradycardia and tachycardia) did not differ significantly between children and adults.

The adult and pediatric cohorts had similar characteristics for patient (gender, body mass index, antiepileptic drug usage, MRI lesions) and seizure variables (seizure type, duration, localization, lateralization, secondary-generalization, body-position, sleep-wake state). However, seizures in children more often involved the frontal lobe (47 of 101, 47%) compared with adults (11 of 55, 20%), whereas temporal lobe seizures were nearly five times more likely to occur in adults (37 of 55, 67%) than in children (29 of 101, 29%).

The study was funded by a grant from the Harvard Catalyst. One author reported serving as a consultant for Digitrace and Best Doctors. No other authors had conflicts of interest to report.

[email protected]

Postictal generalized EEG suppression occurs more often in adults than in children and might be related to why adults have a higher rate of sudden unexpected death in epilepsy than that of children, according to results from a prospective study.

Cardiopulmonary abnormalities involving ictal apnea and bradycardia happened more frequently in children, whereas ictal tachycardia occurred more often among adults. However, there was no difference in desaturation or ictal bradypnea or tachypnea in children versus adults, reported Dr. Milena Pavlova of the division of epilepsy, neurophysiology, and sleep at Brigham and Women’s Hospital, Boston, and her colleagues.

"The evolution of ictal cardiorespiratory abnormalities [had] not been systematically studied for age-related findings," the researchers noted. "There is some evidence in adults that postictal generalized EEG suppression (PGES) may potentially be a risk marker for SUDEP [sudden unexpected death in epilepsy] and that age related maturation of brain may be involved in the manifestation of PGES, but not many studies have looked into the possible effect of this age-related brain maturation on PGES," they wrote (Epilepsy Behav. 2013 Oct. 17 [doi:10.1016/j.yebeh.2013.09.026]).

"The evolution of ictal cardiorespiratory abnormalities [had] not been systematically studied for age-related findings..."

The study involved 26 children with a mean age of 10.6 years (range of 2-20 years) and 22 adults with a mean age of 37 years (range of 22-62 years) who had been admitted to the long-term monitoring units at two hospitals for the evaluation of seizures. They underwent standard continuous video-EEG monitoring as well as electrocardiography, respiratory inductance plethysmography (RIP), and finger pulse oximetry. The investigators recorded 101 seizures in children (mean of 3.9) and 55 in adults (mean of 2.55).

After one or more seizures, 13 of 22 (59%) adults had PGES, compared with only 1 of 26 (4%) children. This was a significant difference with an odds ratio of 0.20. Furthermore, PGES occurred in 6 (6%) of the seizures recorded in children, compared with 13 (24%) in adults.

"The fact that PGES was more frequent in adults than in children and the fact that age had no correlation with PGES in adults lead us to hypothesize that age may play a role in the occurrence of PGES only up to a point where the brain is mature enough to exhibit PGES. Once the brain is mature enough to be capable of manifesting PGES, further increase in age may not have any additional effect. These findings further support the idea of a less mature ‘controlling network’ in the developing brain being less capable of exhibiting PGES," the investigators wrote.

Children had more than three times greater odds of developing ictal central apnea (odds ratio = 3.36) than those of adults (39 of 78 [50%] seizures in children with good RIP data vs. 17 of 55 [31%] in adults). None of the apnea events recorded in either children or adults were obstructive in nature.

Ictal bradycardia was nearly five times more likely to occur in children than in adults (15 of 63 [24%] vs. 4 of 55 [7%], respectively). In comparison, ictal tachycardia was 60% less likely to occur among children than in adults (31 of 63 [49%] vs. 35 of 55 [64%], respectively; OR = 0.40).

The rates of other cardiopulmonary abnormalities (ictal bradypnea and tachypnea, ictal and postictal bradycardia and tachycardia) did not differ significantly between children and adults.

The adult and pediatric cohorts had similar characteristics for patient (gender, body mass index, antiepileptic drug usage, MRI lesions) and seizure variables (seizure type, duration, localization, lateralization, secondary-generalization, body-position, sleep-wake state). However, seizures in children more often involved the frontal lobe (47 of 101, 47%) compared with adults (11 of 55, 20%), whereas temporal lobe seizures were nearly five times more likely to occur in adults (37 of 55, 67%) than in children (29 of 101, 29%).

The study was funded by a grant from the Harvard Catalyst. One author reported serving as a consultant for Digitrace and Best Doctors. No other authors had conflicts of interest to report.

[email protected]

Postictal generalized EEG suppression occurs more often in adults than in children and might be related to why adults have a higher rate of sudden unexpected death in epilepsy than that of children, according to results from a prospective study.

Cardiopulmonary abnormalities involving ictal apnea and bradycardia happened more frequently in children, whereas ictal tachycardia occurred more often among adults. However, there was no difference in desaturation or ictal bradypnea or tachypnea in children versus adults, reported Dr. Milena Pavlova of the division of epilepsy, neurophysiology, and sleep at Brigham and Women’s Hospital, Boston, and her colleagues.

"The evolution of ictal cardiorespiratory abnormalities [had] not been systematically studied for age-related findings," the researchers noted. "There is some evidence in adults that postictal generalized EEG suppression (PGES) may potentially be a risk marker for SUDEP [sudden unexpected death in epilepsy] and that age related maturation of brain may be involved in the manifestation of PGES, but not many studies have looked into the possible effect of this age-related brain maturation on PGES," they wrote (Epilepsy Behav. 2013 Oct. 17 [doi:10.1016/j.yebeh.2013.09.026]).

"The evolution of ictal cardiorespiratory abnormalities [had] not been systematically studied for age-related findings..."

The study involved 26 children with a mean age of 10.6 years (range of 2-20 years) and 22 adults with a mean age of 37 years (range of 22-62 years) who had been admitted to the long-term monitoring units at two hospitals for the evaluation of seizures. They underwent standard continuous video-EEG monitoring as well as electrocardiography, respiratory inductance plethysmography (RIP), and finger pulse oximetry. The investigators recorded 101 seizures in children (mean of 3.9) and 55 in adults (mean of 2.55).

After one or more seizures, 13 of 22 (59%) adults had PGES, compared with only 1 of 26 (4%) children. This was a significant difference with an odds ratio of 0.20. Furthermore, PGES occurred in 6 (6%) of the seizures recorded in children, compared with 13 (24%) in adults.

"The fact that PGES was more frequent in adults than in children and the fact that age had no correlation with PGES in adults lead us to hypothesize that age may play a role in the occurrence of PGES only up to a point where the brain is mature enough to exhibit PGES. Once the brain is mature enough to be capable of manifesting PGES, further increase in age may not have any additional effect. These findings further support the idea of a less mature ‘controlling network’ in the developing brain being less capable of exhibiting PGES," the investigators wrote.

Children had more than three times greater odds of developing ictal central apnea (odds ratio = 3.36) than those of adults (39 of 78 [50%] seizures in children with good RIP data vs. 17 of 55 [31%] in adults). None of the apnea events recorded in either children or adults were obstructive in nature.

Ictal bradycardia was nearly five times more likely to occur in children than in adults (15 of 63 [24%] vs. 4 of 55 [7%], respectively). In comparison, ictal tachycardia was 60% less likely to occur among children than in adults (31 of 63 [49%] vs. 35 of 55 [64%], respectively; OR = 0.40).

The rates of other cardiopulmonary abnormalities (ictal bradypnea and tachypnea, ictal and postictal bradycardia and tachycardia) did not differ significantly between children and adults.

The adult and pediatric cohorts had similar characteristics for patient (gender, body mass index, antiepileptic drug usage, MRI lesions) and seizure variables (seizure type, duration, localization, lateralization, secondary-generalization, body-position, sleep-wake state). However, seizures in children more often involved the frontal lobe (47 of 101, 47%) compared with adults (11 of 55, 20%), whereas temporal lobe seizures were nearly five times more likely to occur in adults (37 of 55, 67%) than in children (29 of 101, 29%).

The study was funded by a grant from the Harvard Catalyst. One author reported serving as a consultant for Digitrace and Best Doctors. No other authors had conflicts of interest to report.

[email protected]

The investigational biosimilar drug CT-P13 proved to have equivalent efficacy and safety comparable to that of infliximab, the tumor necrosis factor–alpha inhibitor that it is manufactured to mimic.

The findings are based on data from a randomized, double-blind, multicenter trial of 606 patients with active rheumatoid arthritis who had inadequate response to methotrexate alone.

Dr. Dae Hyun Yoo of Hanyang University Hospital for Rheumatic Diseases in Seoul, South Korea, reported no difference in the percentage of patients who met American College of Rheumatology 20% improvement criteria (ACR20) at 30 weeks (60.9% for CT-P13 vs. 58.6% for infliximab), which was the primary outcome of the study. The 95% confidence intervals for CT-P13 (–6%-10%) and infliximab (–4%-12%) were within the prespecified range of plus or minus 15% for equivalency (Ann. Rheum. Dis. 2013;72:1613-20).

The overall number of patients who reported treatment-emergent adverse events was virtually the same in patients who took CT-P13 (181) or infliximab (183). The adverse events that were deemed to be related to the study medications also occurred in a similar number of CT-P13 (106) and infliximab (108) patients. Most of these were mild to moderate in intensity. The trial’s safety objective was to determine whether CT-P13 had safety that was comparable, not equivalent, to that of infliximab.

Biosimilar drugs are meant to be "highly similar, but not identical and not ‘bioidentical,’ to approved ‘reference agents,’ " the authors wrote. CT-P13 is an immunoglobulin G1 chimeric human-murine monoclonal antibody to tumor necrosis factor–alpha (TNF-alpha) that has an amino acid sequence identical to that of infliximab. It is produced in the same type of cell line as the one used to produce infliximab.

In this study, known as PLANETRA (Program evaLuating the Autoimmune Disease iNvEstigational Drug cT-p13 in RA Patients), the investigators enrolled patients according to the same criteria as those used in several other clinical trials with infliximab, including the ATTRACT study for which infliximab was approved for the treatment of RA. The results obtained with CT-P13 were similar to those of other RA trials with infliximab that had the same enrollment criteria. The trial was conducted at 100 centers in 19 countries in Europe, Asia, Latin America, and the Middle East.

Patients in the trial met the revised 1987 ACR classification criteria for at least 1 year prior to screening, and were required to have at least six swollen and at least six tender joints and at least two of the following: morning stiffness lasting 45 or more minutes; serum C-reactive protein (CRP) level greater than 2.0 mg/dL; and an erythrocyte sedimentation rate of greater than 28 mm/hour. They needed to meet those criteria despite taking methotrexate for at least 3 months on a stable dose of 12.5-25 mg/week for 4 or more weeks prior to screening. Patients were permitted to receive an equivalent of 10 mg prednisolone or less per day and NSAIDs, if they had received a stable dose for at least 4 weeks prior to screening.

Approximately 82% of the patients were female, and the median age of patients was 50 years at baseline. The patients received either study drug at a dose of 3 mg/kg infused over a 2-hour period at weeks 0, 2, and 6, and then every 8 weeks to week 30. The patients also received an antihistamine 30-60 minutes before the infusion, at the investigator’s discretion. Weekly methotrexate doses ranged from 12.5 mg to 25 mg. Patients also received 5 mg/week or more of folic acid.

Because the higher overall CRP level at baseline of the patients in the ATTRACT study could indicate that the PLANETRA cohort had less severe disease (3.1 mg/dL vs./ 1.9 mg/dL), Dr. Yoo and his associates conducted a post hoc sensitivity analysis of patients with baseline CRP greater than 2 mg/dL or 2 mg/dL or less. The results showed no difference in treatment response based on baseline CRP level.

The approximate 7.5% rate of infusion reactions noted in both in the CT-P13 and infliximab arms of the trial was lower than the 20% noted in the product label for infliximab, and antidrug antibody status did not appear to affect their incidence or response to the study drugs.

"Assessment of efficacy and safety of CT-P13 in patients with RA for up to 1 year is ongoing, and the positive results of this study provide a rationale for future studies of CT-P13 in the treatment of other TNF-mediated inflammatory diseases," the investigators wrote.

The study was sponsored by Celltrion. Many of the authors received research grants and/or consultancy fees and logistics support from the company. One author is a full-time employee of Celltrion, and another author declared receiving payment for lectures from the company.

[email protected]

The investigational biosimilar drug CT-P13 proved to have equivalent efficacy and safety comparable to that of infliximab, the tumor necrosis factor–alpha inhibitor that it is manufactured to mimic.

The findings are based on data from a randomized, double-blind, multicenter trial of 606 patients with active rheumatoid arthritis who had inadequate response to methotrexate alone.

Dr. Dae Hyun Yoo of Hanyang University Hospital for Rheumatic Diseases in Seoul, South Korea, reported no difference in the percentage of patients who met American College of Rheumatology 20% improvement criteria (ACR20) at 30 weeks (60.9% for CT-P13 vs. 58.6% for infliximab), which was the primary outcome of the study. The 95% confidence intervals for CT-P13 (–6%-10%) and infliximab (–4%-12%) were within the prespecified range of plus or minus 15% for equivalency (Ann. Rheum. Dis. 2013;72:1613-20).

The overall number of patients who reported treatment-emergent adverse events was virtually the same in patients who took CT-P13 (181) or infliximab (183). The adverse events that were deemed to be related to the study medications also occurred in a similar number of CT-P13 (106) and infliximab (108) patients. Most of these were mild to moderate in intensity. The trial’s safety objective was to determine whether CT-P13 had safety that was comparable, not equivalent, to that of infliximab.

Biosimilar drugs are meant to be "highly similar, but not identical and not ‘bioidentical,’ to approved ‘reference agents,’ " the authors wrote. CT-P13 is an immunoglobulin G1 chimeric human-murine monoclonal antibody to tumor necrosis factor–alpha (TNF-alpha) that has an amino acid sequence identical to that of infliximab. It is produced in the same type of cell line as the one used to produce infliximab.

In this study, known as PLANETRA (Program evaLuating the Autoimmune Disease iNvEstigational Drug cT-p13 in RA Patients), the investigators enrolled patients according to the same criteria as those used in several other clinical trials with infliximab, including the ATTRACT study for which infliximab was approved for the treatment of RA. The results obtained with CT-P13 were similar to those of other RA trials with infliximab that had the same enrollment criteria. The trial was conducted at 100 centers in 19 countries in Europe, Asia, Latin America, and the Middle East.

Patients in the trial met the revised 1987 ACR classification criteria for at least 1 year prior to screening, and were required to have at least six swollen and at least six tender joints and at least two of the following: morning stiffness lasting 45 or more minutes; serum C-reactive protein (CRP) level greater than 2.0 mg/dL; and an erythrocyte sedimentation rate of greater than 28 mm/hour. They needed to meet those criteria despite taking methotrexate for at least 3 months on a stable dose of 12.5-25 mg/week for 4 or more weeks prior to screening. Patients were permitted to receive an equivalent of 10 mg prednisolone or less per day and NSAIDs, if they had received a stable dose for at least 4 weeks prior to screening.

Approximately 82% of the patients were female, and the median age of patients was 50 years at baseline. The patients received either study drug at a dose of 3 mg/kg infused over a 2-hour period at weeks 0, 2, and 6, and then every 8 weeks to week 30. The patients also received an antihistamine 30-60 minutes before the infusion, at the investigator’s discretion. Weekly methotrexate doses ranged from 12.5 mg to 25 mg. Patients also received 5 mg/week or more of folic acid.

Because the higher overall CRP level at baseline of the patients in the ATTRACT study could indicate that the PLANETRA cohort had less severe disease (3.1 mg/dL vs./ 1.9 mg/dL), Dr. Yoo and his associates conducted a post hoc sensitivity analysis of patients with baseline CRP greater than 2 mg/dL or 2 mg/dL or less. The results showed no difference in treatment response based on baseline CRP level.

The approximate 7.5% rate of infusion reactions noted in both in the CT-P13 and infliximab arms of the trial was lower than the 20% noted in the product label for infliximab, and antidrug antibody status did not appear to affect their incidence or response to the study drugs.

"Assessment of efficacy and safety of CT-P13 in patients with RA for up to 1 year is ongoing, and the positive results of this study provide a rationale for future studies of CT-P13 in the treatment of other TNF-mediated inflammatory diseases," the investigators wrote.

The study was sponsored by Celltrion. Many of the authors received research grants and/or consultancy fees and logistics support from the company. One author is a full-time employee of Celltrion, and another author declared receiving payment for lectures from the company.

[email protected]

The investigational biosimilar drug CT-P13 proved to have equivalent efficacy and safety comparable to that of infliximab, the tumor necrosis factor–alpha inhibitor that it is manufactured to mimic.

The findings are based on data from a randomized, double-blind, multicenter trial of 606 patients with active rheumatoid arthritis who had inadequate response to methotrexate alone.

Dr. Dae Hyun Yoo of Hanyang University Hospital for Rheumatic Diseases in Seoul, South Korea, reported no difference in the percentage of patients who met American College of Rheumatology 20% improvement criteria (ACR20) at 30 weeks (60.9% for CT-P13 vs. 58.6% for infliximab), which was the primary outcome of the study. The 95% confidence intervals for CT-P13 (–6%-10%) and infliximab (–4%-12%) were within the prespecified range of plus or minus 15% for equivalency (Ann. Rheum. Dis. 2013;72:1613-20).

The overall number of patients who reported treatment-emergent adverse events was virtually the same in patients who took CT-P13 (181) or infliximab (183). The adverse events that were deemed to be related to the study medications also occurred in a similar number of CT-P13 (106) and infliximab (108) patients. Most of these were mild to moderate in intensity. The trial’s safety objective was to determine whether CT-P13 had safety that was comparable, not equivalent, to that of infliximab.

Biosimilar drugs are meant to be "highly similar, but not identical and not ‘bioidentical,’ to approved ‘reference agents,’ " the authors wrote. CT-P13 is an immunoglobulin G1 chimeric human-murine monoclonal antibody to tumor necrosis factor–alpha (TNF-alpha) that has an amino acid sequence identical to that of infliximab. It is produced in the same type of cell line as the one used to produce infliximab.

In this study, known as PLANETRA (Program evaLuating the Autoimmune Disease iNvEstigational Drug cT-p13 in RA Patients), the investigators enrolled patients according to the same criteria as those used in several other clinical trials with infliximab, including the ATTRACT study for which infliximab was approved for the treatment of RA. The results obtained with CT-P13 were similar to those of other RA trials with infliximab that had the same enrollment criteria. The trial was conducted at 100 centers in 19 countries in Europe, Asia, Latin America, and the Middle East.

Patients in the trial met the revised 1987 ACR classification criteria for at least 1 year prior to screening, and were required to have at least six swollen and at least six tender joints and at least two of the following: morning stiffness lasting 45 or more minutes; serum C-reactive protein (CRP) level greater than 2.0 mg/dL; and an erythrocyte sedimentation rate of greater than 28 mm/hour. They needed to meet those criteria despite taking methotrexate for at least 3 months on a stable dose of 12.5-25 mg/week for 4 or more weeks prior to screening. Patients were permitted to receive an equivalent of 10 mg prednisolone or less per day and NSAIDs, if they had received a stable dose for at least 4 weeks prior to screening.

Approximately 82% of the patients were female, and the median age of patients was 50 years at baseline. The patients received either study drug at a dose of 3 mg/kg infused over a 2-hour period at weeks 0, 2, and 6, and then every 8 weeks to week 30. The patients also received an antihistamine 30-60 minutes before the infusion, at the investigator’s discretion. Weekly methotrexate doses ranged from 12.5 mg to 25 mg. Patients also received 5 mg/week or more of folic acid.

Because the higher overall CRP level at baseline of the patients in the ATTRACT study could indicate that the PLANETRA cohort had less severe disease (3.1 mg/dL vs./ 1.9 mg/dL), Dr. Yoo and his associates conducted a post hoc sensitivity analysis of patients with baseline CRP greater than 2 mg/dL or 2 mg/dL or less. The results showed no difference in treatment response based on baseline CRP level.

The approximate 7.5% rate of infusion reactions noted in both in the CT-P13 and infliximab arms of the trial was lower than the 20% noted in the product label for infliximab, and antidrug antibody status did not appear to affect their incidence or response to the study drugs.

"Assessment of efficacy and safety of CT-P13 in patients with RA for up to 1 year is ongoing, and the positive results of this study provide a rationale for future studies of CT-P13 in the treatment of other TNF-mediated inflammatory diseases," the investigators wrote.

The study was sponsored by Celltrion. Many of the authors received research grants and/or consultancy fees and logistics support from the company. One author is a full-time employee of Celltrion, and another author declared receiving payment for lectures from the company.

[email protected]

Longitudinal loss of bone mineral density from the femoral neck was associated with prevalent knee osteoarthritis in an observational cohort study, lending support to the notion that osteoporosis treatments are worth further investigation for the prevention of osteoarthritis progression.

The study, led by Dr. Ji Y. Lee of the division of rheumatology at Tufts Medical Center, Boston, builds on previous research that loss of bone mineral density (BMD) is associated with the progression of radiographic joint space narrowing. The current study is the first to examine the relationship between BMD and knee osteoarthritis (OA) progression as measured by cartilage volume and thickness on MRI, providing a more sensitive measure of changes in knee cartilage (Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37926]).

The study contrasts with previous research, which has shown a positive relationship between BMD and incident or prevalent radiographically measured knee OA. Other past studies have found no relationship between BMD and radiographic progression of OA or a paradoxical opposite relationship in which low BMD predicted radiographic progression, according to Dr. Lee and associates.

Because previous studies included patients who already had OA, there may have been selection bias (collider confounding) in which the variables of interest – BMD and cartilage volume and thickness – were affected by the same factors. Dr. Lee and colleagues hoped to avoid this selection bias by studying the effect of risk factors that change after disease onset – in this case, change in BMD.

The investigators analyzed a cohort of 127 patients with prevalent knee OA, defined as a Kellgren-Lawrence grade of 2 or more. The patients had at least two MRI scans over a 2-year period, but most had three scans: at baseline and at 1 and 2 years. The patients (41% men) had a mean age of 63 years and mean body mass index (BMI) of 30 kg/m². Baseline BMD averaged across two femoral neck measurements was 0.95 g/cm².

In multivariate linear regression models – adjusted for baseline values of age, gender, BMI, alignment status, and vitamin D treatment – BMD loss of 0.1 g/cm² was associated with a 1.25% per year loss of cartilage volume. For patients who lost BMD at a rate considered to be significant (calculated by the investigators to be a loss of at least 4.7% from baseline), cartilage volume loss was 1.02% per year greater than for patients without BMD loss.

The models also showed that a BMD loss of 0.1 g/cm² was associated with a significant loss of cartilage thickness at the tibia (0.028 mm/year). Those who lost at least 4.7% of BMD lost a mean of 0.021 mm in tibial cartilage thickness per year, compared with those who did not lose BMD, the investigators reported.

Baseline BMD, however, was not significantly associated with any cartilage outcomes in the study.

The biological mechanisms conjectured to link systemic BMD to cartilage loss in knee OA include the possibility that "BMD health might provide an environment that supports optimal subchondral bone turnover and remodeling in response to OA stressors, thus favoring joint stabilization" and the beneficial effect that optimal bone health might have on cartilage health via "humoral mechanisms," Dr. Lee and colleagues wrote. "Systemic BMD could also be a marker for a range of covariates that mediate or confound the relationship, such as systemic inflammation, circulating growth factors or hormones, physical activity, or frailty."

The original trial from which the observational cohort was derived, the Randomized Controlled Trial of Vitamin D for Knee OA, was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. None of the authors had financial disclosures to report.

Longitudinal loss of bone mineral density from the femoral neck was associated with prevalent knee osteoarthritis in an observational cohort study, lending support to the notion that osteoporosis treatments are worth further investigation for the prevention of osteoarthritis progression.

The study, led by Dr. Ji Y. Lee of the division of rheumatology at Tufts Medical Center, Boston, builds on previous research that loss of bone mineral density (BMD) is associated with the progression of radiographic joint space narrowing. The current study is the first to examine the relationship between BMD and knee osteoarthritis (OA) progression as measured by cartilage volume and thickness on MRI, providing a more sensitive measure of changes in knee cartilage (Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37926]).

The study contrasts with previous research, which has shown a positive relationship between BMD and incident or prevalent radiographically measured knee OA. Other past studies have found no relationship between BMD and radiographic progression of OA or a paradoxical opposite relationship in which low BMD predicted radiographic progression, according to Dr. Lee and associates.

Because previous studies included patients who already had OA, there may have been selection bias (collider confounding) in which the variables of interest – BMD and cartilage volume and thickness – were affected by the same factors. Dr. Lee and colleagues hoped to avoid this selection bias by studying the effect of risk factors that change after disease onset – in this case, change in BMD.

The investigators analyzed a cohort of 127 patients with prevalent knee OA, defined as a Kellgren-Lawrence grade of 2 or more. The patients had at least two MRI scans over a 2-year period, but most had three scans: at baseline and at 1 and 2 years. The patients (41% men) had a mean age of 63 years and mean body mass index (BMI) of 30 kg/m². Baseline BMD averaged across two femoral neck measurements was 0.95 g/cm².

In multivariate linear regression models – adjusted for baseline values of age, gender, BMI, alignment status, and vitamin D treatment – BMD loss of 0.1 g/cm² was associated with a 1.25% per year loss of cartilage volume. For patients who lost BMD at a rate considered to be significant (calculated by the investigators to be a loss of at least 4.7% from baseline), cartilage volume loss was 1.02% per year greater than for patients without BMD loss.

The models also showed that a BMD loss of 0.1 g/cm² was associated with a significant loss of cartilage thickness at the tibia (0.028 mm/year). Those who lost at least 4.7% of BMD lost a mean of 0.021 mm in tibial cartilage thickness per year, compared with those who did not lose BMD, the investigators reported.

Baseline BMD, however, was not significantly associated with any cartilage outcomes in the study.

The biological mechanisms conjectured to link systemic BMD to cartilage loss in knee OA include the possibility that "BMD health might provide an environment that supports optimal subchondral bone turnover and remodeling in response to OA stressors, thus favoring joint stabilization" and the beneficial effect that optimal bone health might have on cartilage health via "humoral mechanisms," Dr. Lee and colleagues wrote. "Systemic BMD could also be a marker for a range of covariates that mediate or confound the relationship, such as systemic inflammation, circulating growth factors or hormones, physical activity, or frailty."

The original trial from which the observational cohort was derived, the Randomized Controlled Trial of Vitamin D for Knee OA, was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. None of the authors had financial disclosures to report.

Longitudinal loss of bone mineral density from the femoral neck was associated with prevalent knee osteoarthritis in an observational cohort study, lending support to the notion that osteoporosis treatments are worth further investigation for the prevention of osteoarthritis progression.

The study, led by Dr. Ji Y. Lee of the division of rheumatology at Tufts Medical Center, Boston, builds on previous research that loss of bone mineral density (BMD) is associated with the progression of radiographic joint space narrowing. The current study is the first to examine the relationship between BMD and knee osteoarthritis (OA) progression as measured by cartilage volume and thickness on MRI, providing a more sensitive measure of changes in knee cartilage (Arthritis Rheum. 2013 March 12 [doi:10.1002/art.37926]).

The study contrasts with previous research, which has shown a positive relationship between BMD and incident or prevalent radiographically measured knee OA. Other past studies have found no relationship between BMD and radiographic progression of OA or a paradoxical opposite relationship in which low BMD predicted radiographic progression, according to Dr. Lee and associates.

Because previous studies included patients who already had OA, there may have been selection bias (collider confounding) in which the variables of interest – BMD and cartilage volume and thickness – were affected by the same factors. Dr. Lee and colleagues hoped to avoid this selection bias by studying the effect of risk factors that change after disease onset – in this case, change in BMD.

The investigators analyzed a cohort of 127 patients with prevalent knee OA, defined as a Kellgren-Lawrence grade of 2 or more. The patients had at least two MRI scans over a 2-year period, but most had three scans: at baseline and at 1 and 2 years. The patients (41% men) had a mean age of 63 years and mean body mass index (BMI) of 30 kg/m². Baseline BMD averaged across two femoral neck measurements was 0.95 g/cm².

In multivariate linear regression models – adjusted for baseline values of age, gender, BMI, alignment status, and vitamin D treatment – BMD loss of 0.1 g/cm² was associated with a 1.25% per year loss of cartilage volume. For patients who lost BMD at a rate considered to be significant (calculated by the investigators to be a loss of at least 4.7% from baseline), cartilage volume loss was 1.02% per year greater than for patients without BMD loss.

The models also showed that a BMD loss of 0.1 g/cm² was associated with a significant loss of cartilage thickness at the tibia (0.028 mm/year). Those who lost at least 4.7% of BMD lost a mean of 0.021 mm in tibial cartilage thickness per year, compared with those who did not lose BMD, the investigators reported.

Baseline BMD, however, was not significantly associated with any cartilage outcomes in the study.

The biological mechanisms conjectured to link systemic BMD to cartilage loss in knee OA include the possibility that "BMD health might provide an environment that supports optimal subchondral bone turnover and remodeling in response to OA stressors, thus favoring joint stabilization" and the beneficial effect that optimal bone health might have on cartilage health via "humoral mechanisms," Dr. Lee and colleagues wrote. "Systemic BMD could also be a marker for a range of covariates that mediate or confound the relationship, such as systemic inflammation, circulating growth factors or hormones, physical activity, or frailty."

The original trial from which the observational cohort was derived, the Randomized Controlled Trial of Vitamin D for Knee OA, was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. None of the authors had financial disclosures to report.