Sharon Worcester

BOSTON – The novel oral sphingosine 1-phosphate 1 receptor modulator RPC1063 safely and effectively reduced the cumulative number of total gadolinium-enhancing lesions in relapsing multiple sclerosis patients in phase II of the randomized, double-blind, placebo-controlled RADIANCE study.

At weeks 12-24 after treatment initiation, 87 patients who received 0.5 mg of RPC1063 and 83 patients who received a 1-mg dose experienced a highly significant 86% reduction in the number of gadolinium-enhancing (GdE) lesions on brain MRI, compared with 88 patients who received placebo (cumulative number of total lesions, 1.5 for both RPC1063 doses vs. 11.1 with placebo), Dr. Amit Bar-Or of the Montreal Neurological Institute and Hospital at McGill University reported at the joint meeting of the European and Americas committees on Treatment and Research in Multiple Sclerosis.

RPC1063 patients also fared significantly better on all secondary endpoints. For example, the mean number of GdE lesions at week 24 was reduced by 91% and 94% in patients who received 0.5 and 1 mg of RPC1063, respectively, compared with the number of lesions in those who received placebo (mean of 0.3 and 0.2 lesions, respectively, vs. 3.2 lesions). In addition, the cumulative number of new or enlarging T2 lesions from weeks 12-24 was reduced by 84% and 91% in the groups, respectively (suggesting a dose response), compared with the number in those who received placebo (cumulative number, 0.8 and 0.5 vs. 9.0).

The annualized relapse rate was 0.35 and 0.24 in the 0.5- and 1-mg dose groups, compared with 0.5 in the placebo group, representing 31% and 53% decreases, respectively. Although the study was not powered to detect an effect on the annualized relapse rate, this finding also hinted at a dose-response.

Immunomodulation through the sphingosine 1-phosphate receptor family is a validated therapeutic approach for the treatment of relapsing MS – the approved oral drug fingolimod (Gilenya) is a sphingosine 1-phosphate receptor modulator with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5 – but RPC1063 has been tested previously only in healthy volunteers. The phase II results of the combined phase II/III RADIANCE trial suggest it is safe and effective in patients with MS, Dr. Bar-Or said.

Study subjects were adults aged 18-55 years (mean of 39 years) with MS as diagnosed by the revised McDonald criteria who exhibited a relapsing clinical course consistent with relapsing disease. The patients had a history of brain MRI lesions consistent with MS, a baseline Expanded Disability Status Scale (EDSS) score between 0 and 5.0 points, and either one documented relapse within the last year, or at least one documented relapse in the past 2 years plus at least one GdE lesion.

All patients underwent a 30-day screening period prior to randomization, followed by a 7-day titration period to either 0.5 mg or 1 mg of active treatment or placebo for 24 weeks. During a blinded safety extension phase, all those who received placebo were randomized to receive 0.5 or 1 mg of RPC1036.

The completion rate was similarly high across all three groups (97.7%, 98.8%, and 96.6%, respectively).

Patients in the 0.5-mg and 1-mg groups experienced approximately 50% and 60% reductions in absolute lymphocyte count at week 24, compared with placebo.

Treatment-emergent adverse events (TEAEs) during the first 24 weeks of the study occurred in 64%, 57%, and 59% of patients in the 0.5-mg, 1-mg, and placebo groups, respectively. The most common TEAEs were nasopharyngitis, headache, and urinary tract infection. Only three serious TEAEs occurred: optic neuritis, somatoform autonomic dysfunction, and uterine cervical squamous metaplasia. All were in the 0.5-mg treatment group but were deemed unrelated to RPC1063.

“There were no notable cardiac, pulmonary, ophthalmologic, infectious, or malignancy-related TEAEs. Three TEAEs of liver enzyme abnormalities greater than or equal to three times the upper limit of normal were documented, but all of these occurred with no signs or symptoms associated,” said Dr. Bar-Or, noting that two occurred in the 0.5-mg group, one occurred in the 1-mg treatment group, and all resolved with continued treatment.

The exclusion criteria of the trial nearly matched those of the label contraindications for fingolimod without “any overt attempt of extending the exclusion,” Dr. Bar-Or said during a press conference. He noted that the RADIANCE trial’s week-long titration process also helped to mitigate any potential adverse events.

Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity, with good overall tolerability and safety – including with respect to cardiac and hepatic safety results. The findings suggest a favorable risk-benefit profile in patients with relapsing MS, and they support the ongoing phase III portion of the RADIANCE trial, as well as a second phase III trial – SUNBEAM – which will compare RPC1063 and interferon beta-1a in relapsing MS, he concluded.

The trial was funded by Receptos. Dr. Bar-Or reported receiving financial support from Biogen Idec, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, MedImmune, Merck Serono, Novartis, Ono Pharmaceuticals, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience.

BOSTON – The novel oral sphingosine 1-phosphate 1 receptor modulator RPC1063 safely and effectively reduced the cumulative number of total gadolinium-enhancing lesions in relapsing multiple sclerosis patients in phase II of the randomized, double-blind, placebo-controlled RADIANCE study.

At weeks 12-24 after treatment initiation, 87 patients who received 0.5 mg of RPC1063 and 83 patients who received a 1-mg dose experienced a highly significant 86% reduction in the number of gadolinium-enhancing (GdE) lesions on brain MRI, compared with 88 patients who received placebo (cumulative number of total lesions, 1.5 for both RPC1063 doses vs. 11.1 with placebo), Dr. Amit Bar-Or of the Montreal Neurological Institute and Hospital at McGill University reported at the joint meeting of the European and Americas committees on Treatment and Research in Multiple Sclerosis.

RPC1063 patients also fared significantly better on all secondary endpoints. For example, the mean number of GdE lesions at week 24 was reduced by 91% and 94% in patients who received 0.5 and 1 mg of RPC1063, respectively, compared with the number of lesions in those who received placebo (mean of 0.3 and 0.2 lesions, respectively, vs. 3.2 lesions). In addition, the cumulative number of new or enlarging T2 lesions from weeks 12-24 was reduced by 84% and 91% in the groups, respectively (suggesting a dose response), compared with the number in those who received placebo (cumulative number, 0.8 and 0.5 vs. 9.0).

The annualized relapse rate was 0.35 and 0.24 in the 0.5- and 1-mg dose groups, compared with 0.5 in the placebo group, representing 31% and 53% decreases, respectively. Although the study was not powered to detect an effect on the annualized relapse rate, this finding also hinted at a dose-response.

Immunomodulation through the sphingosine 1-phosphate receptor family is a validated therapeutic approach for the treatment of relapsing MS – the approved oral drug fingolimod (Gilenya) is a sphingosine 1-phosphate receptor modulator with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5 – but RPC1063 has been tested previously only in healthy volunteers. The phase II results of the combined phase II/III RADIANCE trial suggest it is safe and effective in patients with MS, Dr. Bar-Or said.

Study subjects were adults aged 18-55 years (mean of 39 years) with MS as diagnosed by the revised McDonald criteria who exhibited a relapsing clinical course consistent with relapsing disease. The patients had a history of brain MRI lesions consistent with MS, a baseline Expanded Disability Status Scale (EDSS) score between 0 and 5.0 points, and either one documented relapse within the last year, or at least one documented relapse in the past 2 years plus at least one GdE lesion.

All patients underwent a 30-day screening period prior to randomization, followed by a 7-day titration period to either 0.5 mg or 1 mg of active treatment or placebo for 24 weeks. During a blinded safety extension phase, all those who received placebo were randomized to receive 0.5 or 1 mg of RPC1036.

The completion rate was similarly high across all three groups (97.7%, 98.8%, and 96.6%, respectively).

Patients in the 0.5-mg and 1-mg groups experienced approximately 50% and 60% reductions in absolute lymphocyte count at week 24, compared with placebo.

Treatment-emergent adverse events (TEAEs) during the first 24 weeks of the study occurred in 64%, 57%, and 59% of patients in the 0.5-mg, 1-mg, and placebo groups, respectively. The most common TEAEs were nasopharyngitis, headache, and urinary tract infection. Only three serious TEAEs occurred: optic neuritis, somatoform autonomic dysfunction, and uterine cervical squamous metaplasia. All were in the 0.5-mg treatment group but were deemed unrelated to RPC1063.

“There were no notable cardiac, pulmonary, ophthalmologic, infectious, or malignancy-related TEAEs. Three TEAEs of liver enzyme abnormalities greater than or equal to three times the upper limit of normal were documented, but all of these occurred with no signs or symptoms associated,” said Dr. Bar-Or, noting that two occurred in the 0.5-mg group, one occurred in the 1-mg treatment group, and all resolved with continued treatment.

The exclusion criteria of the trial nearly matched those of the label contraindications for fingolimod without “any overt attempt of extending the exclusion,” Dr. Bar-Or said during a press conference. He noted that the RADIANCE trial’s week-long titration process also helped to mitigate any potential adverse events.

Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity, with good overall tolerability and safety – including with respect to cardiac and hepatic safety results. The findings suggest a favorable risk-benefit profile in patients with relapsing MS, and they support the ongoing phase III portion of the RADIANCE trial, as well as a second phase III trial – SUNBEAM – which will compare RPC1063 and interferon beta-1a in relapsing MS, he concluded.

The trial was funded by Receptos. Dr. Bar-Or reported receiving financial support from Biogen Idec, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, MedImmune, Merck Serono, Novartis, Ono Pharmaceuticals, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience.

BOSTON – The novel oral sphingosine 1-phosphate 1 receptor modulator RPC1063 safely and effectively reduced the cumulative number of total gadolinium-enhancing lesions in relapsing multiple sclerosis patients in phase II of the randomized, double-blind, placebo-controlled RADIANCE study.

At weeks 12-24 after treatment initiation, 87 patients who received 0.5 mg of RPC1063 and 83 patients who received a 1-mg dose experienced a highly significant 86% reduction in the number of gadolinium-enhancing (GdE) lesions on brain MRI, compared with 88 patients who received placebo (cumulative number of total lesions, 1.5 for both RPC1063 doses vs. 11.1 with placebo), Dr. Amit Bar-Or of the Montreal Neurological Institute and Hospital at McGill University reported at the joint meeting of the European and Americas committees on Treatment and Research in Multiple Sclerosis.

RPC1063 patients also fared significantly better on all secondary endpoints. For example, the mean number of GdE lesions at week 24 was reduced by 91% and 94% in patients who received 0.5 and 1 mg of RPC1063, respectively, compared with the number of lesions in those who received placebo (mean of 0.3 and 0.2 lesions, respectively, vs. 3.2 lesions). In addition, the cumulative number of new or enlarging T2 lesions from weeks 12-24 was reduced by 84% and 91% in the groups, respectively (suggesting a dose response), compared with the number in those who received placebo (cumulative number, 0.8 and 0.5 vs. 9.0).

The annualized relapse rate was 0.35 and 0.24 in the 0.5- and 1-mg dose groups, compared with 0.5 in the placebo group, representing 31% and 53% decreases, respectively. Although the study was not powered to detect an effect on the annualized relapse rate, this finding also hinted at a dose-response.

Immunomodulation through the sphingosine 1-phosphate receptor family is a validated therapeutic approach for the treatment of relapsing MS – the approved oral drug fingolimod (Gilenya) is a sphingosine 1-phosphate receptor modulator with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5 – but RPC1063 has been tested previously only in healthy volunteers. The phase II results of the combined phase II/III RADIANCE trial suggest it is safe and effective in patients with MS, Dr. Bar-Or said.

Study subjects were adults aged 18-55 years (mean of 39 years) with MS as diagnosed by the revised McDonald criteria who exhibited a relapsing clinical course consistent with relapsing disease. The patients had a history of brain MRI lesions consistent with MS, a baseline Expanded Disability Status Scale (EDSS) score between 0 and 5.0 points, and either one documented relapse within the last year, or at least one documented relapse in the past 2 years plus at least one GdE lesion.

All patients underwent a 30-day screening period prior to randomization, followed by a 7-day titration period to either 0.5 mg or 1 mg of active treatment or placebo for 24 weeks. During a blinded safety extension phase, all those who received placebo were randomized to receive 0.5 or 1 mg of RPC1036.

The completion rate was similarly high across all three groups (97.7%, 98.8%, and 96.6%, respectively).

Patients in the 0.5-mg and 1-mg groups experienced approximately 50% and 60% reductions in absolute lymphocyte count at week 24, compared with placebo.

Treatment-emergent adverse events (TEAEs) during the first 24 weeks of the study occurred in 64%, 57%, and 59% of patients in the 0.5-mg, 1-mg, and placebo groups, respectively. The most common TEAEs were nasopharyngitis, headache, and urinary tract infection. Only three serious TEAEs occurred: optic neuritis, somatoform autonomic dysfunction, and uterine cervical squamous metaplasia. All were in the 0.5-mg treatment group but were deemed unrelated to RPC1063.

“There were no notable cardiac, pulmonary, ophthalmologic, infectious, or malignancy-related TEAEs. Three TEAEs of liver enzyme abnormalities greater than or equal to three times the upper limit of normal were documented, but all of these occurred with no signs or symptoms associated,” said Dr. Bar-Or, noting that two occurred in the 0.5-mg group, one occurred in the 1-mg treatment group, and all resolved with continued treatment.

The exclusion criteria of the trial nearly matched those of the label contraindications for fingolimod without “any overt attempt of extending the exclusion,” Dr. Bar-Or said during a press conference. He noted that the RADIANCE trial’s week-long titration process also helped to mitigate any potential adverse events.

Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity, with good overall tolerability and safety – including with respect to cardiac and hepatic safety results. The findings suggest a favorable risk-benefit profile in patients with relapsing MS, and they support the ongoing phase III portion of the RADIANCE trial, as well as a second phase III trial – SUNBEAM – which will compare RPC1063 and interferon beta-1a in relapsing MS, he concluded.

The trial was funded by Receptos. Dr. Bar-Or reported receiving financial support from Biogen Idec, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, MedImmune, Merck Serono, Novartis, Ono Pharmaceuticals, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience.

LAS VEGAS – A number of drugs are showing promise for the treatment of psoriatic arthritis, but broader improvements are needed with respect to treatment strategies, according to Dr. Iain McInnes.

Earlier diagnosis, appropriate therapies, and treating to target are among the topics he covered in a presentation on maximizing patient outcomes at the annual Perspectives in Rheumatic Diseases.

A recent study demonstrated that even a 6-month delay in the diagnosis of psoriatic arthritis is associated with worse long-term outcomes on several measures. In that study of 283 patients (Ann. Rheum. Dis. 2014 Feb. 13 [doi: 10.1136/annrheumdis-2013-204858]), the median lag time from disease onset to first rheumatological assessment was 1 year, with only 30% of patients being seen by a rheumatologist within 6 months.

Multiple stepwise regression analysis showed that late consulters had a greater risk of developing peripheral joint erosions (odds ratio, 4.25) and had worse Health Assessment Questionnaire scores (odds ratio, 2.2).

One finding that could help with earlier diagnosis is detection of early entheseal involvement, said Dr. McInnes, professor of medicine and director of the Institute of Infection, Immunity and Immunology at the University of Glasgow (Scotland).

Subclinical entheseal involvement appears to predict psoriatic arthritis in patients presenting with psoriasis, he said at the conference.

In one study, the mean Glasgow Ultrasound Enthesitis Scoring System (GUESS) score was 7.9 in patients with psoriasis, compared with 2.9 in controls, and in another study, thickness of the quadriceps tendon was a significant predictor of the development of psoriatic arthritis in those with psoriasis.

A key challenge in maximizing outcomes in psoriatic arthritis is that rheumatoid arthritis and psoriatic arthritis are typically treated as homogeneous for the purposes of drug development, but the two diseases have distinct clinical phenotypes and time course, tissue distribution, tissue cell/molecular features, genetic susceptibility, and probably impact of immune senescence.

In fact, while disease-modifying antirheumatic drugs are included in European League Against Rheumatsm (EULAR) treatment guidelines for psoriatic arthritis, the Methotrexate in Psoriatic Arthritis (MIPA) trial, a 6-month, double-blind, randomized, placebo-controlled trial of methotrexate, showed no benefit for key psoriatic arthritis endpoints at 3 and 6 months (Rheumatology 2012;51:1368-77).

Data on methotrexate combination therapy is limited, but existing clinical trials and registry data show no clear evidence of benefit. Methotrexate also has long-term toxicity issues.

In studies of patients who received anti–tumor necrosis factor therapy, 59%-69% of patients achieved 20% improvement (ACR 20 response), 37%-50% achieved 50% improvement (ACR 50 response), and up to 52% of patients achieved minimal disease activity at various time points. Also, radiographic progression was improved with anti-TNF therapy vs. placebo. However, TNF inhibitors lose efficacy over time in some patients, and are associated with an increased risk of infection.

Other disappointments or unmet needs in psoriatic arthritis are dichotomous skin and joint responses to biologics, lack of established predictors of response to biologics, lack of a cure, and difficulties in achieving sustained remission, Dr. McInnes said.

Future therapeutic options, including several drugs in development, include drugs that target cytokines and their receptors, such as ustekinumab, which targets IL-12/23; secukinumab and ixekizumab, which target IL-17; and brodalumab, which targets IL-17 receptor A. Other potential targets include IL-6 and the IL-6 receptor and IL-23 and the IL-23 receptor.

Studies of ustekinumab, for example, demonstrate beneficial effects on enthesitis, dactylitis, and modified van der Heijde-Sharp score.

Drugs that target intracellular signaling pathways are also being studied in psoriatic arthritis, including JAK family agents such as tofacitinib and phosphodiesterase inhibitors like apremilast.

As for strategies to improve outcomes, the Tight Control in Psoriatic Arthritis (TICOPA) study provided a rationale for treating to target. Current recommendations call for a target of remission or low disease activity.

The availability of highly effective biologics makes minimal level of disease activity a realistic treatment target, Dr. McInnes said.

The conference was held by Global Academy for Medical Education. Global Academy for Medical Education and this news organization are owned by Frontline Medical Communications.

Dr. McInnes reported receiving research/grant support from Pfizer, Bristol-Myers Squibb, AstraZeneca, and Novo Nordisk, and serving as a consultant to Novartis, Bristol-Myers Squibb, Pfizer, and Galapagos. He is a member of scientific advisory boards for AstraZeneca, Crescendo Bioscience, and Janssen Biotech.

LAS VEGAS – A number of drugs are showing promise for the treatment of psoriatic arthritis, but broader improvements are needed with respect to treatment strategies, according to Dr. Iain McInnes.

Earlier diagnosis, appropriate therapies, and treating to target are among the topics he covered in a presentation on maximizing patient outcomes at the annual Perspectives in Rheumatic Diseases.

A recent study demonstrated that even a 6-month delay in the diagnosis of psoriatic arthritis is associated with worse long-term outcomes on several measures. In that study of 283 patients (Ann. Rheum. Dis. 2014 Feb. 13 [doi: 10.1136/annrheumdis-2013-204858]), the median lag time from disease onset to first rheumatological assessment was 1 year, with only 30% of patients being seen by a rheumatologist within 6 months.

Multiple stepwise regression analysis showed that late consulters had a greater risk of developing peripheral joint erosions (odds ratio, 4.25) and had worse Health Assessment Questionnaire scores (odds ratio, 2.2).

One finding that could help with earlier diagnosis is detection of early entheseal involvement, said Dr. McInnes, professor of medicine and director of the Institute of Infection, Immunity and Immunology at the University of Glasgow (Scotland).

Subclinical entheseal involvement appears to predict psoriatic arthritis in patients presenting with psoriasis, he said at the conference.

In one study, the mean Glasgow Ultrasound Enthesitis Scoring System (GUESS) score was 7.9 in patients with psoriasis, compared with 2.9 in controls, and in another study, thickness of the quadriceps tendon was a significant predictor of the development of psoriatic arthritis in those with psoriasis.

A key challenge in maximizing outcomes in psoriatic arthritis is that rheumatoid arthritis and psoriatic arthritis are typically treated as homogeneous for the purposes of drug development, but the two diseases have distinct clinical phenotypes and time course, tissue distribution, tissue cell/molecular features, genetic susceptibility, and probably impact of immune senescence.

In fact, while disease-modifying antirheumatic drugs are included in European League Against Rheumatsm (EULAR) treatment guidelines for psoriatic arthritis, the Methotrexate in Psoriatic Arthritis (MIPA) trial, a 6-month, double-blind, randomized, placebo-controlled trial of methotrexate, showed no benefit for key psoriatic arthritis endpoints at 3 and 6 months (Rheumatology 2012;51:1368-77).

Data on methotrexate combination therapy is limited, but existing clinical trials and registry data show no clear evidence of benefit. Methotrexate also has long-term toxicity issues.

In studies of patients who received anti–tumor necrosis factor therapy, 59%-69% of patients achieved 20% improvement (ACR 20 response), 37%-50% achieved 50% improvement (ACR 50 response), and up to 52% of patients achieved minimal disease activity at various time points. Also, radiographic progression was improved with anti-TNF therapy vs. placebo. However, TNF inhibitors lose efficacy over time in some patients, and are associated with an increased risk of infection.

Other disappointments or unmet needs in psoriatic arthritis are dichotomous skin and joint responses to biologics, lack of established predictors of response to biologics, lack of a cure, and difficulties in achieving sustained remission, Dr. McInnes said.

Future therapeutic options, including several drugs in development, include drugs that target cytokines and their receptors, such as ustekinumab, which targets IL-12/23; secukinumab and ixekizumab, which target IL-17; and brodalumab, which targets IL-17 receptor A. Other potential targets include IL-6 and the IL-6 receptor and IL-23 and the IL-23 receptor.

Studies of ustekinumab, for example, demonstrate beneficial effects on enthesitis, dactylitis, and modified van der Heijde-Sharp score.

Drugs that target intracellular signaling pathways are also being studied in psoriatic arthritis, including JAK family agents such as tofacitinib and phosphodiesterase inhibitors like apremilast.

As for strategies to improve outcomes, the Tight Control in Psoriatic Arthritis (TICOPA) study provided a rationale for treating to target. Current recommendations call for a target of remission or low disease activity.

The availability of highly effective biologics makes minimal level of disease activity a realistic treatment target, Dr. McInnes said.

The conference was held by Global Academy for Medical Education. Global Academy for Medical Education and this news organization are owned by Frontline Medical Communications.

Dr. McInnes reported receiving research/grant support from Pfizer, Bristol-Myers Squibb, AstraZeneca, and Novo Nordisk, and serving as a consultant to Novartis, Bristol-Myers Squibb, Pfizer, and Galapagos. He is a member of scientific advisory boards for AstraZeneca, Crescendo Bioscience, and Janssen Biotech.

LAS VEGAS – A number of drugs are showing promise for the treatment of psoriatic arthritis, but broader improvements are needed with respect to treatment strategies, according to Dr. Iain McInnes.

Earlier diagnosis, appropriate therapies, and treating to target are among the topics he covered in a presentation on maximizing patient outcomes at the annual Perspectives in Rheumatic Diseases.

A recent study demonstrated that even a 6-month delay in the diagnosis of psoriatic arthritis is associated with worse long-term outcomes on several measures. In that study of 283 patients (Ann. Rheum. Dis. 2014 Feb. 13 [doi: 10.1136/annrheumdis-2013-204858]), the median lag time from disease onset to first rheumatological assessment was 1 year, with only 30% of patients being seen by a rheumatologist within 6 months.

Multiple stepwise regression analysis showed that late consulters had a greater risk of developing peripheral joint erosions (odds ratio, 4.25) and had worse Health Assessment Questionnaire scores (odds ratio, 2.2).

One finding that could help with earlier diagnosis is detection of early entheseal involvement, said Dr. McInnes, professor of medicine and director of the Institute of Infection, Immunity and Immunology at the University of Glasgow (Scotland).

Subclinical entheseal involvement appears to predict psoriatic arthritis in patients presenting with psoriasis, he said at the conference.

In one study, the mean Glasgow Ultrasound Enthesitis Scoring System (GUESS) score was 7.9 in patients with psoriasis, compared with 2.9 in controls, and in another study, thickness of the quadriceps tendon was a significant predictor of the development of psoriatic arthritis in those with psoriasis.

A key challenge in maximizing outcomes in psoriatic arthritis is that rheumatoid arthritis and psoriatic arthritis are typically treated as homogeneous for the purposes of drug development, but the two diseases have distinct clinical phenotypes and time course, tissue distribution, tissue cell/molecular features, genetic susceptibility, and probably impact of immune senescence.

In fact, while disease-modifying antirheumatic drugs are included in European League Against Rheumatsm (EULAR) treatment guidelines for psoriatic arthritis, the Methotrexate in Psoriatic Arthritis (MIPA) trial, a 6-month, double-blind, randomized, placebo-controlled trial of methotrexate, showed no benefit for key psoriatic arthritis endpoints at 3 and 6 months (Rheumatology 2012;51:1368-77).

Data on methotrexate combination therapy is limited, but existing clinical trials and registry data show no clear evidence of benefit. Methotrexate also has long-term toxicity issues.

In studies of patients who received anti–tumor necrosis factor therapy, 59%-69% of patients achieved 20% improvement (ACR 20 response), 37%-50% achieved 50% improvement (ACR 50 response), and up to 52% of patients achieved minimal disease activity at various time points. Also, radiographic progression was improved with anti-TNF therapy vs. placebo. However, TNF inhibitors lose efficacy over time in some patients, and are associated with an increased risk of infection.

Other disappointments or unmet needs in psoriatic arthritis are dichotomous skin and joint responses to biologics, lack of established predictors of response to biologics, lack of a cure, and difficulties in achieving sustained remission, Dr. McInnes said.

Future therapeutic options, including several drugs in development, include drugs that target cytokines and their receptors, such as ustekinumab, which targets IL-12/23; secukinumab and ixekizumab, which target IL-17; and brodalumab, which targets IL-17 receptor A. Other potential targets include IL-6 and the IL-6 receptor and IL-23 and the IL-23 receptor.

Studies of ustekinumab, for example, demonstrate beneficial effects on enthesitis, dactylitis, and modified van der Heijde-Sharp score.

Drugs that target intracellular signaling pathways are also being studied in psoriatic arthritis, including JAK family agents such as tofacitinib and phosphodiesterase inhibitors like apremilast.

As for strategies to improve outcomes, the Tight Control in Psoriatic Arthritis (TICOPA) study provided a rationale for treating to target. Current recommendations call for a target of remission or low disease activity.

The availability of highly effective biologics makes minimal level of disease activity a realistic treatment target, Dr. McInnes said.

The conference was held by Global Academy for Medical Education. Global Academy for Medical Education and this news organization are owned by Frontline Medical Communications.

Dr. McInnes reported receiving research/grant support from Pfizer, Bristol-Myers Squibb, AstraZeneca, and Novo Nordisk, and serving as a consultant to Novartis, Bristol-Myers Squibb, Pfizer, and Galapagos. He is a member of scientific advisory boards for AstraZeneca, Crescendo Bioscience, and Janssen Biotech.

LAS VEGAS - When bisphosphonates are used appropriately, the benefit with respect to fracture reduction outweighs the risk of an atypical femoral fracture, according to the American Society for Bone and Mineral Research task force.

The decision to prescribe bisphosphonates depends on several factors, including dual-energy x-ray absorptiometry (DXA) results and patient factors, and consideration for a drug holiday is warranted in each patient’s care, Dr. Marcy B. Bolster of the Harvard Medical School and director of the rheumatology fellowship training program at Massachusetts General Hospital, both in Boston, said at the annual Perspectives in Rheumatic Diseases conference.

The ASBMR task force concluded, based on a review of the available literature, that a causal relationship between bisphosphonates and atypical femoral fractures has not been established; atypical femoral fractures also occur in patients who have not received bisphosphonates, as well as in some patients taking denosumab, but the task force noted that there is some evidence from radiograph-based studies to suggest a strong relationship between bisphosphonate use and atypical femoral fractures. Studies suggest that longer duration of therapy may contribute to the risk of atypical femoral fractures, Dr. Bolster said.

For example, in a Swedish study involving nearly 13,000 women, 1,271 subtrochanteric fractures had occurred and 59 of these were deemed atypical. Bisphosphonates were used by 78% of the case patients, compared with 10% of 263 controls who had had subtrochanteric fractures that did not have the characteristics of the atypical femoral fractures. The odds ratio for an atypical fracture was 1.3/100 daily doses, and in those who used bisphosphonates for 2-2.9 years, the adjusted odds ratio for a fracture was 61.7.

Further, after drug discontinuation, the odds ratio decreased by 70% per year since last use.

The number needed to harm (one atypical femoral fracture) was 2,000 per year (N. Engl. J. Med 2011;364:1728-37).

Most atypical fractures associated with bisphosphonate use in that study occurred within 1 year of the last prescription, and the risk reduction after stopping was similar whether treatment duration was less than or more than 2 years. Also, there was no increased risk of atypical femoral fractures in patients taking glucocorticoids or proton pump inhibitors, and the atypical fracture risk in bisphosphonate users did not differ based on age younger or older than 85 years.

In a Kaiser Permanente study of more than 1.8 million patients aged 45 years or older, 142 had atypical femoral fractures. Most (137) were women, 28 experienced bilateral fractures, and 128 (90%) had bisphosphonate exposure ranging from 1 month to 13 years (mean, 5.5 years) prior to the fracture.

Age-adjusted incidence rates were 1.78/100,000 patient-years for those with up to 1.9 years of bisphosphonate use, and 113.1/100,000 patient-years in those with 8-9.9 years of use (J. Bone Miner. Res. 2012 [doi:10.1002/jbmr.1719]).

Increased rates of atypical femoral fractures occurred after 3-4 years of exposure – and more so with 6-10 years of exposure.

The findings beg the question of how long is long enough when it comes to bisphosphonate therapy for osteoporosis, Dr. Bolster said.

First, it is important to reassess the use of bisphosphonates for low bone mass. It has been well-established that patients with osteoporosis (a T score less than –2.5 or presence of a fragility fracture) warrant treatment. The National Osteoporosis Foundation guidelines have changed, however, for those with osteopenia, such that, previously, treatment was initiated in patients with osteopenia (a T score less than –2.0 or a T score less than –1.5 plus one risk factor), and it is now recommended that treatment decisions for patients with osteopenia incorporate the World Health Organization (WHO) FRAX tool to aid in determining which patients with osteopenia are at high risk for fracture. Treatment decisions are based on the presence of increased risk for fracture, she said.

Consider discontinuation of bisphosphonates in patients with osteopenia or in whom fracture risk is not determined to be increased, Dr. Bolster advised.

Given potential adverse effects, it is important to treat only those patients who are at increased risk for fracture. In those patients who warrant therapy, the duration of therapy and a drug holiday should also be considered because of the concern for potential risks associated with prolonged bisphosphonate therapy, she said.

If fracture risk is mild, treatment for about 5 years is warranted, and then bisphosphonates should be discontinued until bone mineral density decreases significantly (generally about 3-5 years) or until a fracture occurs.

For moderately increased fracture risk, published recommendations call for treating for 5-10 years, then discontinuing bisphosphonates for 2-3 years (or less if bone mineral density decreases or fracture occurs).

For high risk patients, published recommendations suggest treating for 10 years, then discontinuing treatment for 1-2 years (or less if bone mineral density decreases or fracture occurs). An alternate medication, such as teriparatide, if warranted, can be used in these patients during the bisphosphonate holiday, she said.

Findings from recent trials, including the Long-term Extension (FLEX) of the Fracture Intervention Trial (FIT), and the HORIZON trial suggest that 3-5 years of treatment may be sufficient unless there is a high risk for vertebral fracture, in which case treatment should potentially continue for up to 6-10 years.

“Consider avoiding the use of an antiresorptive agent during the drug holiday,” Dr. Bolster said, explaining that although it has yet to be determined, there is concern that the atypical femoral fractures may result from prolonged inhibition of bone turnover that occurs with antiresorptive therapy, so it may not make sense to add an antiresorptive agent during a bisphosphonate holiday.

This area, however, clearly warrants further study, she noted.

During 1-2 years of a drug holiday, fracture protection appears to persist, and the risk of atypical femoral fractures decreases rapidly, she added.

When deciding how long a drug holiday should last, consider the utility of bone turnover markers, she also suggested. Bone turnover marker use in treatment decision making, however, also warrants further investigation.

There is a lack of standardization with these markers, and they may be affected by other conditions and medication, but the International Osteoporosis Foundation endorses serum C-terminal telopeptide of type 1 collagen and serum procollagen type 1 N-terminal propeptide.

Using bone turnover makers along with a DXA scan may be helpful in determining the appropriate duration of a drug holiday, but more knowledge in this field is needed, Dr. Bolster said at the meeting held by Global Academy for Medical Education. Global Academy for Medical Education and this news organization are owned by Frontline Medical Communications.

In essence, the decision should be individualized based on age, compliance, treatment duration, risk factors, and risk of vertebral fractures, and these factors should be reassessed regularly, she said.

Dr. Bolster reported that she has worked on a clinical trial for Eli Lilly, received fellowship program grant support from Amgen and AbbVie in salary support for a first-year rheumatology fellow, has investments in Johnson and Johnson, has served on committees for American College of Rheumatology, American Board of Internal Medicine, and the International Society for Clinical Densitometry, and as a board member for ACR and Rheumatology Research Foundation.

LAS VEGAS - When bisphosphonates are used appropriately, the benefit with respect to fracture reduction outweighs the risk of an atypical femoral fracture, according to the American Society for Bone and Mineral Research task force.

The decision to prescribe bisphosphonates depends on several factors, including dual-energy x-ray absorptiometry (DXA) results and patient factors, and consideration for a drug holiday is warranted in each patient’s care, Dr. Marcy B. Bolster of the Harvard Medical School and director of the rheumatology fellowship training program at Massachusetts General Hospital, both in Boston, said at the annual Perspectives in Rheumatic Diseases conference.

The ASBMR task force concluded, based on a review of the available literature, that a causal relationship between bisphosphonates and atypical femoral fractures has not been established; atypical femoral fractures also occur in patients who have not received bisphosphonates, as well as in some patients taking denosumab, but the task force noted that there is some evidence from radiograph-based studies to suggest a strong relationship between bisphosphonate use and atypical femoral fractures. Studies suggest that longer duration of therapy may contribute to the risk of atypical femoral fractures, Dr. Bolster said.

For example, in a Swedish study involving nearly 13,000 women, 1,271 subtrochanteric fractures had occurred and 59 of these were deemed atypical. Bisphosphonates were used by 78% of the case patients, compared with 10% of 263 controls who had had subtrochanteric fractures that did not have the characteristics of the atypical femoral fractures. The odds ratio for an atypical fracture was 1.3/100 daily doses, and in those who used bisphosphonates for 2-2.9 years, the adjusted odds ratio for a fracture was 61.7.

Further, after drug discontinuation, the odds ratio decreased by 70% per year since last use.

The number needed to harm (one atypical femoral fracture) was 2,000 per year (N. Engl. J. Med 2011;364:1728-37).

Most atypical fractures associated with bisphosphonate use in that study occurred within 1 year of the last prescription, and the risk reduction after stopping was similar whether treatment duration was less than or more than 2 years. Also, there was no increased risk of atypical femoral fractures in patients taking glucocorticoids or proton pump inhibitors, and the atypical fracture risk in bisphosphonate users did not differ based on age younger or older than 85 years.

In a Kaiser Permanente study of more than 1.8 million patients aged 45 years or older, 142 had atypical femoral fractures. Most (137) were women, 28 experienced bilateral fractures, and 128 (90%) had bisphosphonate exposure ranging from 1 month to 13 years (mean, 5.5 years) prior to the fracture.

Age-adjusted incidence rates were 1.78/100,000 patient-years for those with up to 1.9 years of bisphosphonate use, and 113.1/100,000 patient-years in those with 8-9.9 years of use (J. Bone Miner. Res. 2012 [doi:10.1002/jbmr.1719]).

Increased rates of atypical femoral fractures occurred after 3-4 years of exposure – and more so with 6-10 years of exposure.

The findings beg the question of how long is long enough when it comes to bisphosphonate therapy for osteoporosis, Dr. Bolster said.

First, it is important to reassess the use of bisphosphonates for low bone mass. It has been well-established that patients with osteoporosis (a T score less than –2.5 or presence of a fragility fracture) warrant treatment. The National Osteoporosis Foundation guidelines have changed, however, for those with osteopenia, such that, previously, treatment was initiated in patients with osteopenia (a T score less than –2.0 or a T score less than –1.5 plus one risk factor), and it is now recommended that treatment decisions for patients with osteopenia incorporate the World Health Organization (WHO) FRAX tool to aid in determining which patients with osteopenia are at high risk for fracture. Treatment decisions are based on the presence of increased risk for fracture, she said.

Consider discontinuation of bisphosphonates in patients with osteopenia or in whom fracture risk is not determined to be increased, Dr. Bolster advised.

Given potential adverse effects, it is important to treat only those patients who are at increased risk for fracture. In those patients who warrant therapy, the duration of therapy and a drug holiday should also be considered because of the concern for potential risks associated with prolonged bisphosphonate therapy, she said.

If fracture risk is mild, treatment for about 5 years is warranted, and then bisphosphonates should be discontinued until bone mineral density decreases significantly (generally about 3-5 years) or until a fracture occurs.

For moderately increased fracture risk, published recommendations call for treating for 5-10 years, then discontinuing bisphosphonates for 2-3 years (or less if bone mineral density decreases or fracture occurs).

For high risk patients, published recommendations suggest treating for 10 years, then discontinuing treatment for 1-2 years (or less if bone mineral density decreases or fracture occurs). An alternate medication, such as teriparatide, if warranted, can be used in these patients during the bisphosphonate holiday, she said.

Findings from recent trials, including the Long-term Extension (FLEX) of the Fracture Intervention Trial (FIT), and the HORIZON trial suggest that 3-5 years of treatment may be sufficient unless there is a high risk for vertebral fracture, in which case treatment should potentially continue for up to 6-10 years.

“Consider avoiding the use of an antiresorptive agent during the drug holiday,” Dr. Bolster said, explaining that although it has yet to be determined, there is concern that the atypical femoral fractures may result from prolonged inhibition of bone turnover that occurs with antiresorptive therapy, so it may not make sense to add an antiresorptive agent during a bisphosphonate holiday.

This area, however, clearly warrants further study, she noted.

During 1-2 years of a drug holiday, fracture protection appears to persist, and the risk of atypical femoral fractures decreases rapidly, she added.

When deciding how long a drug holiday should last, consider the utility of bone turnover markers, she also suggested. Bone turnover marker use in treatment decision making, however, also warrants further investigation.

There is a lack of standardization with these markers, and they may be affected by other conditions and medication, but the International Osteoporosis Foundation endorses serum C-terminal telopeptide of type 1 collagen and serum procollagen type 1 N-terminal propeptide.

Using bone turnover makers along with a DXA scan may be helpful in determining the appropriate duration of a drug holiday, but more knowledge in this field is needed, Dr. Bolster said at the meeting held by Global Academy for Medical Education. Global Academy for Medical Education and this news organization are owned by Frontline Medical Communications.

In essence, the decision should be individualized based on age, compliance, treatment duration, risk factors, and risk of vertebral fractures, and these factors should be reassessed regularly, she said.

Dr. Bolster reported that she has worked on a clinical trial for Eli Lilly, received fellowship program grant support from Amgen and AbbVie in salary support for a first-year rheumatology fellow, has investments in Johnson and Johnson, has served on committees for American College of Rheumatology, American Board of Internal Medicine, and the International Society for Clinical Densitometry, and as a board member for ACR and Rheumatology Research Foundation.

LAS VEGAS - When bisphosphonates are used appropriately, the benefit with respect to fracture reduction outweighs the risk of an atypical femoral fracture, according to the American Society for Bone and Mineral Research task force.

The decision to prescribe bisphosphonates depends on several factors, including dual-energy x-ray absorptiometry (DXA) results and patient factors, and consideration for a drug holiday is warranted in each patient’s care, Dr. Marcy B. Bolster of the Harvard Medical School and director of the rheumatology fellowship training program at Massachusetts General Hospital, both in Boston, said at the annual Perspectives in Rheumatic Diseases conference.

The ASBMR task force concluded, based on a review of the available literature, that a causal relationship between bisphosphonates and atypical femoral fractures has not been established; atypical femoral fractures also occur in patients who have not received bisphosphonates, as well as in some patients taking denosumab, but the task force noted that there is some evidence from radiograph-based studies to suggest a strong relationship between bisphosphonate use and atypical femoral fractures. Studies suggest that longer duration of therapy may contribute to the risk of atypical femoral fractures, Dr. Bolster said.

For example, in a Swedish study involving nearly 13,000 women, 1,271 subtrochanteric fractures had occurred and 59 of these were deemed atypical. Bisphosphonates were used by 78% of the case patients, compared with 10% of 263 controls who had had subtrochanteric fractures that did not have the characteristics of the atypical femoral fractures. The odds ratio for an atypical fracture was 1.3/100 daily doses, and in those who used bisphosphonates for 2-2.9 years, the adjusted odds ratio for a fracture was 61.7.

Further, after drug discontinuation, the odds ratio decreased by 70% per year since last use.

The number needed to harm (one atypical femoral fracture) was 2,000 per year (N. Engl. J. Med 2011;364:1728-37).

Most atypical fractures associated with bisphosphonate use in that study occurred within 1 year of the last prescription, and the risk reduction after stopping was similar whether treatment duration was less than or more than 2 years. Also, there was no increased risk of atypical femoral fractures in patients taking glucocorticoids or proton pump inhibitors, and the atypical fracture risk in bisphosphonate users did not differ based on age younger or older than 85 years.

In a Kaiser Permanente study of more than 1.8 million patients aged 45 years or older, 142 had atypical femoral fractures. Most (137) were women, 28 experienced bilateral fractures, and 128 (90%) had bisphosphonate exposure ranging from 1 month to 13 years (mean, 5.5 years) prior to the fracture.

Age-adjusted incidence rates were 1.78/100,000 patient-years for those with up to 1.9 years of bisphosphonate use, and 113.1/100,000 patient-years in those with 8-9.9 years of use (J. Bone Miner. Res. 2012 [doi:10.1002/jbmr.1719]).

Increased rates of atypical femoral fractures occurred after 3-4 years of exposure – and more so with 6-10 years of exposure.

The findings beg the question of how long is long enough when it comes to bisphosphonate therapy for osteoporosis, Dr. Bolster said.

First, it is important to reassess the use of bisphosphonates for low bone mass. It has been well-established that patients with osteoporosis (a T score less than –2.5 or presence of a fragility fracture) warrant treatment. The National Osteoporosis Foundation guidelines have changed, however, for those with osteopenia, such that, previously, treatment was initiated in patients with osteopenia (a T score less than –2.0 or a T score less than –1.5 plus one risk factor), and it is now recommended that treatment decisions for patients with osteopenia incorporate the World Health Organization (WHO) FRAX tool to aid in determining which patients with osteopenia are at high risk for fracture. Treatment decisions are based on the presence of increased risk for fracture, she said.

Consider discontinuation of bisphosphonates in patients with osteopenia or in whom fracture risk is not determined to be increased, Dr. Bolster advised.

Given potential adverse effects, it is important to treat only those patients who are at increased risk for fracture. In those patients who warrant therapy, the duration of therapy and a drug holiday should also be considered because of the concern for potential risks associated with prolonged bisphosphonate therapy, she said.

If fracture risk is mild, treatment for about 5 years is warranted, and then bisphosphonates should be discontinued until bone mineral density decreases significantly (generally about 3-5 years) or until a fracture occurs.

For moderately increased fracture risk, published recommendations call for treating for 5-10 years, then discontinuing bisphosphonates for 2-3 years (or less if bone mineral density decreases or fracture occurs).

For high risk patients, published recommendations suggest treating for 10 years, then discontinuing treatment for 1-2 years (or less if bone mineral density decreases or fracture occurs). An alternate medication, such as teriparatide, if warranted, can be used in these patients during the bisphosphonate holiday, she said.

Findings from recent trials, including the Long-term Extension (FLEX) of the Fracture Intervention Trial (FIT), and the HORIZON trial suggest that 3-5 years of treatment may be sufficient unless there is a high risk for vertebral fracture, in which case treatment should potentially continue for up to 6-10 years.

“Consider avoiding the use of an antiresorptive agent during the drug holiday,” Dr. Bolster said, explaining that although it has yet to be determined, there is concern that the atypical femoral fractures may result from prolonged inhibition of bone turnover that occurs with antiresorptive therapy, so it may not make sense to add an antiresorptive agent during a bisphosphonate holiday.

This area, however, clearly warrants further study, she noted.

During 1-2 years of a drug holiday, fracture protection appears to persist, and the risk of atypical femoral fractures decreases rapidly, she added.

When deciding how long a drug holiday should last, consider the utility of bone turnover markers, she also suggested. Bone turnover marker use in treatment decision making, however, also warrants further investigation.

There is a lack of standardization with these markers, and they may be affected by other conditions and medication, but the International Osteoporosis Foundation endorses serum C-terminal telopeptide of type 1 collagen and serum procollagen type 1 N-terminal propeptide.

Using bone turnover makers along with a DXA scan may be helpful in determining the appropriate duration of a drug holiday, but more knowledge in this field is needed, Dr. Bolster said at the meeting held by Global Academy for Medical Education. Global Academy for Medical Education and this news organization are owned by Frontline Medical Communications.

In essence, the decision should be individualized based on age, compliance, treatment duration, risk factors, and risk of vertebral fractures, and these factors should be reassessed regularly, she said.

Dr. Bolster reported that she has worked on a clinical trial for Eli Lilly, received fellowship program grant support from Amgen and AbbVie in salary support for a first-year rheumatology fellow, has investments in Johnson and Johnson, has served on committees for American College of Rheumatology, American Board of Internal Medicine, and the International Society for Clinical Densitometry, and as a board member for ACR and Rheumatology Research Foundation.

BOSTON – Age and any exposure to disease-modifying therapy were among the factors identified as independent predictors of the likelihood of conversion from clinically isolated syndrome to clinically definite multiple sclerosis in patients in a large prospective cohort study.

The findings could have important implications for treatment initiation in patients at higher risk of conversion, Dr. Tim Spelman said at a joint meeting of the Americas and European committees for Treatment and Research in Multiple Sclerosis. The logical extension of these findings would be to develop a risk calculator that considers the values for the predictors identified in this study, and that helps in the identification of patients who may benefit from closer monitoring and early treatment intervention.

Of 3,296 patients with clinically isolated syndrome who were enrolled in the MSBase Incident Study (MSBASIS) subset of the MSBase global registry, 1,953 (59%) experienced a second attack, marking the conversion to clinically definite disease. Age was one factor found to be significantly associated with conversion; for every additional 5 years of age at the time of clinically isolated syndrome (CIS), the likelihood of relapse was reduced by 10% (hazard ratio, 0.90), Dr. Spelman said.

Relapse risk was also lower in patients with any exposure to disease-modifying therapy compared with those with no such exposure (hazard ratio, 0.57), and in those with increasing proportion of follow-up time on disease-modifying therapy (hazard ratio, 0.35), said Dr. Spelman of the University of Melbourne, Parkville, Australia.

Having at least 1 T1 gadolinium enhancing lesion on cerebral magnetic resonance imaging was associated with an increased risk of relapse, compared with having no such lesions (hazard ratio, 1.25), and having at least 1 infratentorial and at least 1 juxtacortical lesion on cerebral MRI were also associated with an increased risk of relapse, compared with having no such lesions (hazard ratios of 1.23 and 1.21, respectively).

Finally, the presence of oligoclonal bands on baseline cerebrospinal fluid examination was also associated with an increased risk of relapse (hazard ratio, 1.52). Baseline spinal MRI lesion frequency was co-linear with oligoclonal banding in the CSF, Dr. Spelman said.

Patients in the study were recruited from 50 clinics in 22 different countries, contributing a total of 5,379 patient years of data with more than 30,000 observation points.

Dr. Spelman reported receiving honoraria for consultancy and funding for travel from Biogen Idec.

BOSTON – Age and any exposure to disease-modifying therapy were among the factors identified as independent predictors of the likelihood of conversion from clinically isolated syndrome to clinically definite multiple sclerosis in patients in a large prospective cohort study.

The findings could have important implications for treatment initiation in patients at higher risk of conversion, Dr. Tim Spelman said at a joint meeting of the Americas and European committees for Treatment and Research in Multiple Sclerosis. The logical extension of these findings would be to develop a risk calculator that considers the values for the predictors identified in this study, and that helps in the identification of patients who may benefit from closer monitoring and early treatment intervention.

Of 3,296 patients with clinically isolated syndrome who were enrolled in the MSBase Incident Study (MSBASIS) subset of the MSBase global registry, 1,953 (59%) experienced a second attack, marking the conversion to clinically definite disease. Age was one factor found to be significantly associated with conversion; for every additional 5 years of age at the time of clinically isolated syndrome (CIS), the likelihood of relapse was reduced by 10% (hazard ratio, 0.90), Dr. Spelman said.

Relapse risk was also lower in patients with any exposure to disease-modifying therapy compared with those with no such exposure (hazard ratio, 0.57), and in those with increasing proportion of follow-up time on disease-modifying therapy (hazard ratio, 0.35), said Dr. Spelman of the University of Melbourne, Parkville, Australia.

Having at least 1 T1 gadolinium enhancing lesion on cerebral magnetic resonance imaging was associated with an increased risk of relapse, compared with having no such lesions (hazard ratio, 1.25), and having at least 1 infratentorial and at least 1 juxtacortical lesion on cerebral MRI were also associated with an increased risk of relapse, compared with having no such lesions (hazard ratios of 1.23 and 1.21, respectively).

Finally, the presence of oligoclonal bands on baseline cerebrospinal fluid examination was also associated with an increased risk of relapse (hazard ratio, 1.52). Baseline spinal MRI lesion frequency was co-linear with oligoclonal banding in the CSF, Dr. Spelman said.

Patients in the study were recruited from 50 clinics in 22 different countries, contributing a total of 5,379 patient years of data with more than 30,000 observation points.

Dr. Spelman reported receiving honoraria for consultancy and funding for travel from Biogen Idec.

BOSTON – Age and any exposure to disease-modifying therapy were among the factors identified as independent predictors of the likelihood of conversion from clinically isolated syndrome to clinically definite multiple sclerosis in patients in a large prospective cohort study.

The findings could have important implications for treatment initiation in patients at higher risk of conversion, Dr. Tim Spelman said at a joint meeting of the Americas and European committees for Treatment and Research in Multiple Sclerosis. The logical extension of these findings would be to develop a risk calculator that considers the values for the predictors identified in this study, and that helps in the identification of patients who may benefit from closer monitoring and early treatment intervention.

Of 3,296 patients with clinically isolated syndrome who were enrolled in the MSBase Incident Study (MSBASIS) subset of the MSBase global registry, 1,953 (59%) experienced a second attack, marking the conversion to clinically definite disease. Age was one factor found to be significantly associated with conversion; for every additional 5 years of age at the time of clinically isolated syndrome (CIS), the likelihood of relapse was reduced by 10% (hazard ratio, 0.90), Dr. Spelman said.

Relapse risk was also lower in patients with any exposure to disease-modifying therapy compared with those with no such exposure (hazard ratio, 0.57), and in those with increasing proportion of follow-up time on disease-modifying therapy (hazard ratio, 0.35), said Dr. Spelman of the University of Melbourne, Parkville, Australia.

Having at least 1 T1 gadolinium enhancing lesion on cerebral magnetic resonance imaging was associated with an increased risk of relapse, compared with having no such lesions (hazard ratio, 1.25), and having at least 1 infratentorial and at least 1 juxtacortical lesion on cerebral MRI were also associated with an increased risk of relapse, compared with having no such lesions (hazard ratios of 1.23 and 1.21, respectively).

Finally, the presence of oligoclonal bands on baseline cerebrospinal fluid examination was also associated with an increased risk of relapse (hazard ratio, 1.52). Baseline spinal MRI lesion frequency was co-linear with oligoclonal banding in the CSF, Dr. Spelman said.

Patients in the study were recruited from 50 clinics in 22 different countries, contributing a total of 5,379 patient years of data with more than 30,000 observation points.

Dr. Spelman reported receiving honoraria for consultancy and funding for travel from Biogen Idec.

BOSTON – The efficacy of alemtuzumab was maintained at 4-year follow-up in patients who had active relapsing-remitting multiple sclerosis and relapsed on prior therapy, according to findings from the extension phase of the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS II) study.

Response was maintained even though most of the 393 patients in the extension study had not received either alemtuzumab or any other disease modifying therapy during the 3 years after they received two courses of alemtuzumab as part of the core CARE-MS II study – a phase 3, randomized comparison of alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), Dr. Hans-Peter Hartung of Heinrich-Heine University, Dusseldorf, Germany and his colleagues reported in a poster at the joint Americas and European committees on Treatment and Research in MS conference.

In the core CARE-MS II trial, annual treatment with alemtuzumab – a humanized anti-CD52 monoclonal antibody – reduced the annualized relapse rate by 49% (from 0.52 to 0.26), and reduced the rate of sustained accumulation of disability by 42%, compared with SC IFNB-1a (Rebif) at 2 years. Alemtuzumab is not approved in the United States for MS, although it is approved for MS in more than 30 other countries. Alemtuzumab was withdrawn from the market by Genzyme in the form of brand name Campath, indicated for a type of leukemia, when it was being developed for MS.

In 393 patients who were in the alemtuzumab 12-mg arm of the core study and enrolled in the extension study (93% of the population), the annualized relapse rate was 0.22 at 3 years, and 0.23 at 4 years (mean of 0.24 for years 0-4). Disability, as assessed by change in the Expanded Disability Status Scale score, remained stable or improved from baseline; 69%, 66%, and 67% of patients improved or remained stable from years 0-3, 0-4, and 3-4, respectively, the researchers reported.
“At year 4, 71% and 76% of alemtuzumab-treated patients were sustained accumulation of disability-free by 3- and 6-month sustained disability criteria, respectively,” they wrote.

Over the 4 years of the extension study, 68% of the patients received only the initial two annual courses of alemtuzumab; 24% received one additional course, 7% received two additional courses, and 5% received another disease-modifying therapy.

In 146 patients who were in the SC IFNB-1a 44 mcg arm of the core study and enrolled in the extension study (83%), 143 crossed over to alemtuzumab, and 131 of them received 2 courses. The annualized relapse rate in those who received alemtuzumab decreased by 71% at 4 years (from 0.52 to 0.15), and the Expanded Disability Status Scale scores at 2 years either remained stable or improved in 69% of patients.

“Two years after switching to alemtuzumab, the proportion of patients experiencing 3-month sustained accumulation of disability or 6-month sustained accumulation of disability were 15% and 11%, respectively, compared with 23% and 21% during the 2 years of SC IFNB-1a in CARE-MS II,” the researchers reported.

No unexpected adverse events occurred in either group during the extension study, and the safety profile among those who switched from SC IFNB-1a was similar to that in patients who received alemtuzumab for all 4 years.

“These findings augment previously reported data in support of the durable efficacy and positive benefit-risk profile for alemtuzumab in relapsing-remitting multiple sclerosis patients who relapsed on prior therapy,” the investigators concluded.

BOSTON – The efficacy of alemtuzumab was maintained at 4-year follow-up in patients who had active relapsing-remitting multiple sclerosis and relapsed on prior therapy, according to findings from the extension phase of the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS II) study.

Response was maintained even though most of the 393 patients in the extension study had not received either alemtuzumab or any other disease modifying therapy during the 3 years after they received two courses of alemtuzumab as part of the core CARE-MS II study – a phase 3, randomized comparison of alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), Dr. Hans-Peter Hartung of Heinrich-Heine University, Dusseldorf, Germany and his colleagues reported in a poster at the joint Americas and European committees on Treatment and Research in MS conference.

In the core CARE-MS II trial, annual treatment with alemtuzumab – a humanized anti-CD52 monoclonal antibody – reduced the annualized relapse rate by 49% (from 0.52 to 0.26), and reduced the rate of sustained accumulation of disability by 42%, compared with SC IFNB-1a (Rebif) at 2 years. Alemtuzumab is not approved in the United States for MS, although it is approved for MS in more than 30 other countries. Alemtuzumab was withdrawn from the market by Genzyme in the form of brand name Campath, indicated for a type of leukemia, when it was being developed for MS.

In 393 patients who were in the alemtuzumab 12-mg arm of the core study and enrolled in the extension study (93% of the population), the annualized relapse rate was 0.22 at 3 years, and 0.23 at 4 years (mean of 0.24 for years 0-4). Disability, as assessed by change in the Expanded Disability Status Scale score, remained stable or improved from baseline; 69%, 66%, and 67% of patients improved or remained stable from years 0-3, 0-4, and 3-4, respectively, the researchers reported.
“At year 4, 71% and 76% of alemtuzumab-treated patients were sustained accumulation of disability-free by 3- and 6-month sustained disability criteria, respectively,” they wrote.

Over the 4 years of the extension study, 68% of the patients received only the initial two annual courses of alemtuzumab; 24% received one additional course, 7% received two additional courses, and 5% received another disease-modifying therapy.

In 146 patients who were in the SC IFNB-1a 44 mcg arm of the core study and enrolled in the extension study (83%), 143 crossed over to alemtuzumab, and 131 of them received 2 courses. The annualized relapse rate in those who received alemtuzumab decreased by 71% at 4 years (from 0.52 to 0.15), and the Expanded Disability Status Scale scores at 2 years either remained stable or improved in 69% of patients.

“Two years after switching to alemtuzumab, the proportion of patients experiencing 3-month sustained accumulation of disability or 6-month sustained accumulation of disability were 15% and 11%, respectively, compared with 23% and 21% during the 2 years of SC IFNB-1a in CARE-MS II,” the researchers reported.

No unexpected adverse events occurred in either group during the extension study, and the safety profile among those who switched from SC IFNB-1a was similar to that in patients who received alemtuzumab for all 4 years.

“These findings augment previously reported data in support of the durable efficacy and positive benefit-risk profile for alemtuzumab in relapsing-remitting multiple sclerosis patients who relapsed on prior therapy,” the investigators concluded.

BOSTON – The efficacy of alemtuzumab was maintained at 4-year follow-up in patients who had active relapsing-remitting multiple sclerosis and relapsed on prior therapy, according to findings from the extension phase of the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS II) study.

Response was maintained even though most of the 393 patients in the extension study had not received either alemtuzumab or any other disease modifying therapy during the 3 years after they received two courses of alemtuzumab as part of the core CARE-MS II study – a phase 3, randomized comparison of alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), Dr. Hans-Peter Hartung of Heinrich-Heine University, Dusseldorf, Germany and his colleagues reported in a poster at the joint Americas and European committees on Treatment and Research in MS conference.

In the core CARE-MS II trial, annual treatment with alemtuzumab – a humanized anti-CD52 monoclonal antibody – reduced the annualized relapse rate by 49% (from 0.52 to 0.26), and reduced the rate of sustained accumulation of disability by 42%, compared with SC IFNB-1a (Rebif) at 2 years. Alemtuzumab is not approved in the United States for MS, although it is approved for MS in more than 30 other countries. Alemtuzumab was withdrawn from the market by Genzyme in the form of brand name Campath, indicated for a type of leukemia, when it was being developed for MS.

In 393 patients who were in the alemtuzumab 12-mg arm of the core study and enrolled in the extension study (93% of the population), the annualized relapse rate was 0.22 at 3 years, and 0.23 at 4 years (mean of 0.24 for years 0-4). Disability, as assessed by change in the Expanded Disability Status Scale score, remained stable or improved from baseline; 69%, 66%, and 67% of patients improved or remained stable from years 0-3, 0-4, and 3-4, respectively, the researchers reported.
“At year 4, 71% and 76% of alemtuzumab-treated patients were sustained accumulation of disability-free by 3- and 6-month sustained disability criteria, respectively,” they wrote.

Over the 4 years of the extension study, 68% of the patients received only the initial two annual courses of alemtuzumab; 24% received one additional course, 7% received two additional courses, and 5% received another disease-modifying therapy.

In 146 patients who were in the SC IFNB-1a 44 mcg arm of the core study and enrolled in the extension study (83%), 143 crossed over to alemtuzumab, and 131 of them received 2 courses. The annualized relapse rate in those who received alemtuzumab decreased by 71% at 4 years (from 0.52 to 0.15), and the Expanded Disability Status Scale scores at 2 years either remained stable or improved in 69% of patients.

“Two years after switching to alemtuzumab, the proportion of patients experiencing 3-month sustained accumulation of disability or 6-month sustained accumulation of disability were 15% and 11%, respectively, compared with 23% and 21% during the 2 years of SC IFNB-1a in CARE-MS II,” the researchers reported.

No unexpected adverse events occurred in either group during the extension study, and the safety profile among those who switched from SC IFNB-1a was similar to that in patients who received alemtuzumab for all 4 years.

“These findings augment previously reported data in support of the durable efficacy and positive benefit-risk profile for alemtuzumab in relapsing-remitting multiple sclerosis patients who relapsed on prior therapy,” the investigators concluded.

BOSTON – Autonomic symptom burden in patients with multiple sclerosis is associated with fatigue severity and quality of life, according to findings from a study of 100 patients.

Autonomic symptoms occur between attacks, can affect multiple organ systems, and have been well described in the literature as affecting up to 80% of patients, but are primarily attributed to chronic, long-term, long-phase duration of multiple sclerosis (MS) and progressive disease. The current findings show that autonomic symptoms are present during early disease stages and at low levels of disability, as well.

“We recognize the visceral symptoms the best, and we perhaps do the best job of identifying and treating these, but cardiovascular dysfunction is also described, and can be subclinical and less obvious to recognize in a symptomatic treatment setting,” Dr. Melissa M. Cortez said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

In fact, in this study the association between autonomic symptom burden and FSS scores were strongest when looking at orthostatic intolerance – one of five domains in the COMPASS-31 scale, a recently published, shortened version of the Autonomic Symptom Profile, said Dr. Cortez of the University of Utah, Salt Lake City.

“The findings raise the question of whether perhaps some of these symptoms are simply reflective of non‑disease-specific factors, or whether they actually are, in fact, reflecting aspects of disease burden that we’re not capturing well with established disease measures,” she said.

The 100 consecutive patients in the study had a mean age of 48 years and mean disease duration of 14.7 years. Their mean score on the COMPASS-31 scale was 27 out of a possible 100, and the mean Fatigue Severity Scale (FSS) score was 5 out of 7. Composite scores for the MS Quality of Life-54 (MSQOL-54) questionnaire were 58 out of 100 for physical health, and 65 out of 100 for mental health.

Significant correlations were found between COMPASS-31 and the MSQOL-54 composites (physical, r = ‑0.60; mental, r = ‑0.54), and the FSS (r = 0.51), Dr. Cortez reported.

COMPASS-31 score was not significantly associated with disease severity as measured by the Expanded Disability Status Scale, or with disease duration, said Dr. Cortez, who completed the study during her time as a fellow at the Mayo Clinic Arizona in Scottsdale, Ariz.

“The relationships persisted after adjustment for marital status, fatigue-causing medications, and depression,” Dr. Cortez noted.

Most (78%) of the patients in the study were women, and 84% had relapsing-remitting MS.

The finding of an association between autonomic symptom burden and increased fatigue severity, particularly in the orthostatic intolerance domain, highlights a clinical opportunity to assess and treat autonomic symptom burden. They also reveal a need to look more closely at whether autonomic function explains a portion of MS-related fatigue, she said.

“I think we need to do better at identifying what physiologic as well as functional measures can define both fatigue and autonomic dysfunction that would be relevant to this population. What I’d like to do next is think about whether or not treatments targeted at addressing this measurable autonomic dysfunction could then, in fact, alter MS-related fatigue, for example.”

Dr. Cortez reported having no disclosures.

BOSTON – Autonomic symptom burden in patients with multiple sclerosis is associated with fatigue severity and quality of life, according to findings from a study of 100 patients.

Autonomic symptoms occur between attacks, can affect multiple organ systems, and have been well described in the literature as affecting up to 80% of patients, but are primarily attributed to chronic, long-term, long-phase duration of multiple sclerosis (MS) and progressive disease. The current findings show that autonomic symptoms are present during early disease stages and at low levels of disability, as well.

“We recognize the visceral symptoms the best, and we perhaps do the best job of identifying and treating these, but cardiovascular dysfunction is also described, and can be subclinical and less obvious to recognize in a symptomatic treatment setting,” Dr. Melissa M. Cortez said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

In fact, in this study the association between autonomic symptom burden and FSS scores were strongest when looking at orthostatic intolerance – one of five domains in the COMPASS-31 scale, a recently published, shortened version of the Autonomic Symptom Profile, said Dr. Cortez of the University of Utah, Salt Lake City.

“The findings raise the question of whether perhaps some of these symptoms are simply reflective of non‑disease-specific factors, or whether they actually are, in fact, reflecting aspects of disease burden that we’re not capturing well with established disease measures,” she said.

The 100 consecutive patients in the study had a mean age of 48 years and mean disease duration of 14.7 years. Their mean score on the COMPASS-31 scale was 27 out of a possible 100, and the mean Fatigue Severity Scale (FSS) score was 5 out of 7. Composite scores for the MS Quality of Life-54 (MSQOL-54) questionnaire were 58 out of 100 for physical health, and 65 out of 100 for mental health.

Significant correlations were found between COMPASS-31 and the MSQOL-54 composites (physical, r = ‑0.60; mental, r = ‑0.54), and the FSS (r = 0.51), Dr. Cortez reported.

COMPASS-31 score was not significantly associated with disease severity as measured by the Expanded Disability Status Scale, or with disease duration, said Dr. Cortez, who completed the study during her time as a fellow at the Mayo Clinic Arizona in Scottsdale, Ariz.

“The relationships persisted after adjustment for marital status, fatigue-causing medications, and depression,” Dr. Cortez noted.

Most (78%) of the patients in the study were women, and 84% had relapsing-remitting MS.

The finding of an association between autonomic symptom burden and increased fatigue severity, particularly in the orthostatic intolerance domain, highlights a clinical opportunity to assess and treat autonomic symptom burden. They also reveal a need to look more closely at whether autonomic function explains a portion of MS-related fatigue, she said.

“I think we need to do better at identifying what physiologic as well as functional measures can define both fatigue and autonomic dysfunction that would be relevant to this population. What I’d like to do next is think about whether or not treatments targeted at addressing this measurable autonomic dysfunction could then, in fact, alter MS-related fatigue, for example.”

Dr. Cortez reported having no disclosures.

BOSTON – Autonomic symptom burden in patients with multiple sclerosis is associated with fatigue severity and quality of life, according to findings from a study of 100 patients.

Autonomic symptoms occur between attacks, can affect multiple organ systems, and have been well described in the literature as affecting up to 80% of patients, but are primarily attributed to chronic, long-term, long-phase duration of multiple sclerosis (MS) and progressive disease. The current findings show that autonomic symptoms are present during early disease stages and at low levels of disability, as well.

“We recognize the visceral symptoms the best, and we perhaps do the best job of identifying and treating these, but cardiovascular dysfunction is also described, and can be subclinical and less obvious to recognize in a symptomatic treatment setting,” Dr. Melissa M. Cortez said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

In fact, in this study the association between autonomic symptom burden and FSS scores were strongest when looking at orthostatic intolerance – one of five domains in the COMPASS-31 scale, a recently published, shortened version of the Autonomic Symptom Profile, said Dr. Cortez of the University of Utah, Salt Lake City.

“The findings raise the question of whether perhaps some of these symptoms are simply reflective of non‑disease-specific factors, or whether they actually are, in fact, reflecting aspects of disease burden that we’re not capturing well with established disease measures,” she said.

The 100 consecutive patients in the study had a mean age of 48 years and mean disease duration of 14.7 years. Their mean score on the COMPASS-31 scale was 27 out of a possible 100, and the mean Fatigue Severity Scale (FSS) score was 5 out of 7. Composite scores for the MS Quality of Life-54 (MSQOL-54) questionnaire were 58 out of 100 for physical health, and 65 out of 100 for mental health.

Significant correlations were found between COMPASS-31 and the MSQOL-54 composites (physical, r = ‑0.60; mental, r = ‑0.54), and the FSS (r = 0.51), Dr. Cortez reported.

COMPASS-31 score was not significantly associated with disease severity as measured by the Expanded Disability Status Scale, or with disease duration, said Dr. Cortez, who completed the study during her time as a fellow at the Mayo Clinic Arizona in Scottsdale, Ariz.

“The relationships persisted after adjustment for marital status, fatigue-causing medications, and depression,” Dr. Cortez noted.

Most (78%) of the patients in the study were women, and 84% had relapsing-remitting MS.

The finding of an association between autonomic symptom burden and increased fatigue severity, particularly in the orthostatic intolerance domain, highlights a clinical opportunity to assess and treat autonomic symptom burden. They also reveal a need to look more closely at whether autonomic function explains a portion of MS-related fatigue, she said.

“I think we need to do better at identifying what physiologic as well as functional measures can define both fatigue and autonomic dysfunction that would be relevant to this population. What I’d like to do next is think about whether or not treatments targeted at addressing this measurable autonomic dysfunction could then, in fact, alter MS-related fatigue, for example.”

Dr. Cortez reported having no disclosures.

BOSTON – Retinal changes over time mirror global central nervous system processes in patients with multiple sclerosis, according to findings from a longitudinal study comparing optical coherence tomography and magnetic resonance imaging findings.

The results validate optical coherence tomography (OCT) measures for both clinical monitoring of patients, and as an outcome measure in clinical trials, and could have implications that reach beyond MS, Dr. Shiv Saidha said at the joint meeting of the European and Americas committees for Treatment and Research in Multiple Sclerosis.

Courtesy National Eye Institute

In 107 multiple sclerosis (MS) patients with a mean age of 44 years and median disease duration of 10 years who underwent biannual high-definition spectral-domain OCT with automated intraretinal segmentation for a mean of 46 months, and baseline and annual 3T magnetic resonance imaging including substructure volumetrics for a mean of 39 months, a significant association was seen over time between the rate of ganglion cell layer plus inner plexiform layer (GCIP) atrophy and the rate of whole brain atrophy (r = 0.45). The association was mainly driven by the relationship between GCIP thinning and cortical gray matter atrophy (r = 0.37), said Dr. Saidha of Johns Hopkins University, Baltimore.

"These results remained significant after correction for multiple comparisons, and they were verified by a number of additional statistical techniques," he said.

Adjustment was made for age, gender, MS subtype, disease duration, and history of optic neuritis.

With respect to subtype analyses, there also was a significant relationship between the rate of GCIP thinning and lesion accumulation (r = 0.30), and between the rate of inner nuclear layer (INL) atrophy and lesion accumulation (r = 0.28), in patients with relapsing-remitting MS. Thus, GCIP atrophy also mirrors lesion accumulation as well as brain atrophy (but to a lesser degree), and INL solely mirrors lesion accumulation and could also provide information regarding global inflammation, he said.

Additionally, the association between GCIP thinning and whole brain atrophy rate was stronger in patients with primary progressive MS (r = 0.54) – and particularly so in secondary progressive MS (r = 0.73) – than in those with relapsing-remitting MS (r = 0.33).

Optic neuritis in this study appeared to be relevant, he said, noting that with each of three sequential refinements for optic neuritis history (one model included all eyes with optic neuritis, one excluded all eyes with optic neuritis, and a third excluded all patients with any history of optic neuritis), a stepwise increase in the correlation between the rate of GCIP thinning and whole brain atrophy was seen.

"We did not observe a similar effect in secondary progressive MS. One possibility for this is that immediately following an optic neuritis event, you get this rapid disproportionate localized tissue injury which is sensitively captured with OCT, and the rate of brain change remains unchanged at that point. Then, as time goes on, the two rates (the rate of change in retinal and brain measures) may become realigned again in the future," he said.

The findings of this study are notable, because optic neuropathy is "virtually ubiquitous" as part of the MS disease process, with postmortem studies showing that up to 99% of patients have demyelinating plaques within their optic nerves at the time of death.

"The hypothesis is that demyelination within the optic nerve and/or transection of axons related to acute inflammation result in retrograde degeneration of the constituent fibers of the optic nerve," Dr. Saidha said, explaining that these fibers are derived from the innermost layer of the retina (the retinal fiber layer), that the axons are derived from the ganglion cell neurons from the ganglion cell layer, and that therefore, optical neuropathy results in atrophy of both the retinal nerve fiber and ganglion cell layers.

The majority of available studies looking at the relationship between OCT and brain substructure metrics have been cross-sectional, so a critically unanswered question is whether OCT really has utility in terms of tracking patients longitudinally.

"In other words, does atrophy or change within specific retinal layers parallel global concomitant neurodegeneration, which is really the principal correlate of disability in MS," he said, adding that the ways in which these relationships might vary by MS subtype has been "virtually unexplored."

Also, a history of optic neuritis has been shown on a cross-sectional level to potentially blunt or mask relationships between OCT measures and MRI, perhaps related to excessive localized tissue injury immediately following the optic neuritis; this raised the question of whether a history of optic neuritis is relevant to the interpretation of OCT measures over time for tracking patients.

"The results of this study suggest that GCIP atrophy ... really does mirror what’s happening globally as part of the MS disease process," he said, noting that it is among the first studies to show that over time, OCT probably does have utility in terms of tracking patients and providing information about both subclinical and clinical aspects of the disease process.

"This really cements and poises OCT as a potentially useful outcome measure in trials of putative neuroprotectants," he said, concluding that the results have far-reaching implications for the field of neurodegeneration in general, and that they could have profound implications if they are replicated in pure neurodegenerative disorders such as dementias.

Dr. Saidha reported that he has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors, Educational Grant Support from Novartis and Teva Neurosciences, and speaking honoraria from the National Association of Managed Care Physicians.

BOSTON – Retinal changes over time mirror global central nervous system processes in patients with multiple sclerosis, according to findings from a longitudinal study comparing optical coherence tomography and magnetic resonance imaging findings.

The results validate optical coherence tomography (OCT) measures for both clinical monitoring of patients, and as an outcome measure in clinical trials, and could have implications that reach beyond MS, Dr. Shiv Saidha said at the joint meeting of the European and Americas committees for Treatment and Research in Multiple Sclerosis.

Courtesy National Eye Institute

In 107 multiple sclerosis (MS) patients with a mean age of 44 years and median disease duration of 10 years who underwent biannual high-definition spectral-domain OCT with automated intraretinal segmentation for a mean of 46 months, and baseline and annual 3T magnetic resonance imaging including substructure volumetrics for a mean of 39 months, a significant association was seen over time between the rate of ganglion cell layer plus inner plexiform layer (GCIP) atrophy and the rate of whole brain atrophy (r = 0.45). The association was mainly driven by the relationship between GCIP thinning and cortical gray matter atrophy (r = 0.37), said Dr. Saidha of Johns Hopkins University, Baltimore.

"These results remained significant after correction for multiple comparisons, and they were verified by a number of additional statistical techniques," he said.

Adjustment was made for age, gender, MS subtype, disease duration, and history of optic neuritis.

With respect to subtype analyses, there also was a significant relationship between the rate of GCIP thinning and lesion accumulation (r = 0.30), and between the rate of inner nuclear layer (INL) atrophy and lesion accumulation (r = 0.28), in patients with relapsing-remitting MS. Thus, GCIP atrophy also mirrors lesion accumulation as well as brain atrophy (but to a lesser degree), and INL solely mirrors lesion accumulation and could also provide information regarding global inflammation, he said.

Additionally, the association between GCIP thinning and whole brain atrophy rate was stronger in patients with primary progressive MS (r = 0.54) – and particularly so in secondary progressive MS (r = 0.73) – than in those with relapsing-remitting MS (r = 0.33).

Optic neuritis in this study appeared to be relevant, he said, noting that with each of three sequential refinements for optic neuritis history (one model included all eyes with optic neuritis, one excluded all eyes with optic neuritis, and a third excluded all patients with any history of optic neuritis), a stepwise increase in the correlation between the rate of GCIP thinning and whole brain atrophy was seen.

"We did not observe a similar effect in secondary progressive MS. One possibility for this is that immediately following an optic neuritis event, you get this rapid disproportionate localized tissue injury which is sensitively captured with OCT, and the rate of brain change remains unchanged at that point. Then, as time goes on, the two rates (the rate of change in retinal and brain measures) may become realigned again in the future," he said.

The findings of this study are notable, because optic neuropathy is "virtually ubiquitous" as part of the MS disease process, with postmortem studies showing that up to 99% of patients have demyelinating plaques within their optic nerves at the time of death.

"The hypothesis is that demyelination within the optic nerve and/or transection of axons related to acute inflammation result in retrograde degeneration of the constituent fibers of the optic nerve," Dr. Saidha said, explaining that these fibers are derived from the innermost layer of the retina (the retinal fiber layer), that the axons are derived from the ganglion cell neurons from the ganglion cell layer, and that therefore, optical neuropathy results in atrophy of both the retinal nerve fiber and ganglion cell layers.

The majority of available studies looking at the relationship between OCT and brain substructure metrics have been cross-sectional, so a critically unanswered question is whether OCT really has utility in terms of tracking patients longitudinally.

"In other words, does atrophy or change within specific retinal layers parallel global concomitant neurodegeneration, which is really the principal correlate of disability in MS," he said, adding that the ways in which these relationships might vary by MS subtype has been "virtually unexplored."

Also, a history of optic neuritis has been shown on a cross-sectional level to potentially blunt or mask relationships between OCT measures and MRI, perhaps related to excessive localized tissue injury immediately following the optic neuritis; this raised the question of whether a history of optic neuritis is relevant to the interpretation of OCT measures over time for tracking patients.

"The results of this study suggest that GCIP atrophy ... really does mirror what’s happening globally as part of the MS disease process," he said, noting that it is among the first studies to show that over time, OCT probably does have utility in terms of tracking patients and providing information about both subclinical and clinical aspects of the disease process.

"This really cements and poises OCT as a potentially useful outcome measure in trials of putative neuroprotectants," he said, concluding that the results have far-reaching implications for the field of neurodegeneration in general, and that they could have profound implications if they are replicated in pure neurodegenerative disorders such as dementias.

Dr. Saidha reported that he has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors, Educational Grant Support from Novartis and Teva Neurosciences, and speaking honoraria from the National Association of Managed Care Physicians.

BOSTON – Retinal changes over time mirror global central nervous system processes in patients with multiple sclerosis, according to findings from a longitudinal study comparing optical coherence tomography and magnetic resonance imaging findings.

The results validate optical coherence tomography (OCT) measures for both clinical monitoring of patients, and as an outcome measure in clinical trials, and could have implications that reach beyond MS, Dr. Shiv Saidha said at the joint meeting of the European and Americas committees for Treatment and Research in Multiple Sclerosis.

Courtesy National Eye Institute

In 107 multiple sclerosis (MS) patients with a mean age of 44 years and median disease duration of 10 years who underwent biannual high-definition spectral-domain OCT with automated intraretinal segmentation for a mean of 46 months, and baseline and annual 3T magnetic resonance imaging including substructure volumetrics for a mean of 39 months, a significant association was seen over time between the rate of ganglion cell layer plus inner plexiform layer (GCIP) atrophy and the rate of whole brain atrophy (r = 0.45). The association was mainly driven by the relationship between GCIP thinning and cortical gray matter atrophy (r = 0.37), said Dr. Saidha of Johns Hopkins University, Baltimore.

"These results remained significant after correction for multiple comparisons, and they were verified by a number of additional statistical techniques," he said.

Adjustment was made for age, gender, MS subtype, disease duration, and history of optic neuritis.

With respect to subtype analyses, there also was a significant relationship between the rate of GCIP thinning and lesion accumulation (r = 0.30), and between the rate of inner nuclear layer (INL) atrophy and lesion accumulation (r = 0.28), in patients with relapsing-remitting MS. Thus, GCIP atrophy also mirrors lesion accumulation as well as brain atrophy (but to a lesser degree), and INL solely mirrors lesion accumulation and could also provide information regarding global inflammation, he said.

Additionally, the association between GCIP thinning and whole brain atrophy rate was stronger in patients with primary progressive MS (r = 0.54) – and particularly so in secondary progressive MS (r = 0.73) – than in those with relapsing-remitting MS (r = 0.33).

Optic neuritis in this study appeared to be relevant, he said, noting that with each of three sequential refinements for optic neuritis history (one model included all eyes with optic neuritis, one excluded all eyes with optic neuritis, and a third excluded all patients with any history of optic neuritis), a stepwise increase in the correlation between the rate of GCIP thinning and whole brain atrophy was seen.

"We did not observe a similar effect in secondary progressive MS. One possibility for this is that immediately following an optic neuritis event, you get this rapid disproportionate localized tissue injury which is sensitively captured with OCT, and the rate of brain change remains unchanged at that point. Then, as time goes on, the two rates (the rate of change in retinal and brain measures) may become realigned again in the future," he said.

The findings of this study are notable, because optic neuropathy is "virtually ubiquitous" as part of the MS disease process, with postmortem studies showing that up to 99% of patients have demyelinating plaques within their optic nerves at the time of death.

"The hypothesis is that demyelination within the optic nerve and/or transection of axons related to acute inflammation result in retrograde degeneration of the constituent fibers of the optic nerve," Dr. Saidha said, explaining that these fibers are derived from the innermost layer of the retina (the retinal fiber layer), that the axons are derived from the ganglion cell neurons from the ganglion cell layer, and that therefore, optical neuropathy results in atrophy of both the retinal nerve fiber and ganglion cell layers.

The majority of available studies looking at the relationship between OCT and brain substructure metrics have been cross-sectional, so a critically unanswered question is whether OCT really has utility in terms of tracking patients longitudinally.

"In other words, does atrophy or change within specific retinal layers parallel global concomitant neurodegeneration, which is really the principal correlate of disability in MS," he said, adding that the ways in which these relationships might vary by MS subtype has been "virtually unexplored."

Also, a history of optic neuritis has been shown on a cross-sectional level to potentially blunt or mask relationships between OCT measures and MRI, perhaps related to excessive localized tissue injury immediately following the optic neuritis; this raised the question of whether a history of optic neuritis is relevant to the interpretation of OCT measures over time for tracking patients.

"The results of this study suggest that GCIP atrophy ... really does mirror what’s happening globally as part of the MS disease process," he said, noting that it is among the first studies to show that over time, OCT probably does have utility in terms of tracking patients and providing information about both subclinical and clinical aspects of the disease process.

"This really cements and poises OCT as a potentially useful outcome measure in trials of putative neuroprotectants," he said, concluding that the results have far-reaching implications for the field of neurodegeneration in general, and that they could have profound implications if they are replicated in pure neurodegenerative disorders such as dementias.

Dr. Saidha reported that he has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors, Educational Grant Support from Novartis and Teva Neurosciences, and speaking honoraria from the National Association of Managed Care Physicians.

LAKE BUENA VISTA, FLA. – Nearly 44% of incompletely vaccinated inpatients with influenza had a missed opportunity for vaccination, according to a chart review at Children’s Hospital Colorado.

Among 197 such children admitted with confirmed influenza in 2010-2014, 86 (44%) had a total of 507 medical visits during which influenza vaccine was available, Dr. Suchitra Rao of the University of Colorado, Denver, reported in a poster at the Pediatric Hospital Medicine 2014 meeting.

© Sean Locke/iStockphoto.com

The majority of patients with missed opportunity visits were considered high risk for severe complications from influenza from factors such as age younger than 2 years, immunosuppression, pregnancy, or an underlying chronic pulmonary, cardiovascular, renal, hepatic, neurological, hematologic, or metabolic disorder, Dr. Rao reported.

The bulk of missed opportunity visits occurred during September, October, and November (20%-23% each month) prior to onset of the influenza season, with declining percentages taking place between December and April. Most of the visits (45%) occurred at specialty clinics, followed by the emergency department or urgent care setting (22%).

"Subspecialty outpatient visits provide an excellent opportunity for influenza vaccination because they target high-risk patients and they represent the highest proportion of missed opportunities for vaccination," Dr. Rao and her colleagues wrote. Future analyses will explore independent risk factors for missed opportunities, and identify differences in visit characteristic for high vs. low risk groups, they noted.

The Pediatric Hospital Medicine 2014 meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, the AAP Section on Hospital Medicine, and the Academic Pediatric Association.

The authors reported having no relevant financial disclosures.

LAKE BUENA VISTA, FLA. – Nearly 44% of incompletely vaccinated inpatients with influenza had a missed opportunity for vaccination, according to a chart review at Children’s Hospital Colorado.

Among 197 such children admitted with confirmed influenza in 2010-2014, 86 (44%) had a total of 507 medical visits during which influenza vaccine was available, Dr. Suchitra Rao of the University of Colorado, Denver, reported in a poster at the Pediatric Hospital Medicine 2014 meeting.

© Sean Locke/iStockphoto.com

The majority of patients with missed opportunity visits were considered high risk for severe complications from influenza from factors such as age younger than 2 years, immunosuppression, pregnancy, or an underlying chronic pulmonary, cardiovascular, renal, hepatic, neurological, hematologic, or metabolic disorder, Dr. Rao reported.

The bulk of missed opportunity visits occurred during September, October, and November (20%-23% each month) prior to onset of the influenza season, with declining percentages taking place between December and April. Most of the visits (45%) occurred at specialty clinics, followed by the emergency department or urgent care setting (22%).

"Subspecialty outpatient visits provide an excellent opportunity for influenza vaccination because they target high-risk patients and they represent the highest proportion of missed opportunities for vaccination," Dr. Rao and her colleagues wrote. Future analyses will explore independent risk factors for missed opportunities, and identify differences in visit characteristic for high vs. low risk groups, they noted.

The Pediatric Hospital Medicine 2014 meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, the AAP Section on Hospital Medicine, and the Academic Pediatric Association.

The authors reported having no relevant financial disclosures.

LAKE BUENA VISTA, FLA. – Nearly 44% of incompletely vaccinated inpatients with influenza had a missed opportunity for vaccination, according to a chart review at Children’s Hospital Colorado.

Among 197 such children admitted with confirmed influenza in 2010-2014, 86 (44%) had a total of 507 medical visits during which influenza vaccine was available, Dr. Suchitra Rao of the University of Colorado, Denver, reported in a poster at the Pediatric Hospital Medicine 2014 meeting.

© Sean Locke/iStockphoto.com

The majority of patients with missed opportunity visits were considered high risk for severe complications from influenza from factors such as age younger than 2 years, immunosuppression, pregnancy, or an underlying chronic pulmonary, cardiovascular, renal, hepatic, neurological, hematologic, or metabolic disorder, Dr. Rao reported.

The bulk of missed opportunity visits occurred during September, October, and November (20%-23% each month) prior to onset of the influenza season, with declining percentages taking place between December and April. Most of the visits (45%) occurred at specialty clinics, followed by the emergency department or urgent care setting (22%).

"Subspecialty outpatient visits provide an excellent opportunity for influenza vaccination because they target high-risk patients and they represent the highest proportion of missed opportunities for vaccination," Dr. Rao and her colleagues wrote. Future analyses will explore independent risk factors for missed opportunities, and identify differences in visit characteristic for high vs. low risk groups, they noted.

The Pediatric Hospital Medicine 2014 meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, the AAP Section on Hospital Medicine, and the Academic Pediatric Association.

The authors reported having no relevant financial disclosures.

Intra-abdominal vagal nerve blockade to treat morbid obesity didn’t meet prespecified efficacy objectives in the randomized, double-blind ReCharge study, but treated patients did experience significantly greater weight loss than did those who underwent a sham procedure.

Mean excess weight loss was 24.4% (9.2% of initial body weight loss) in 162 patients who had a body mass index of 40-45 kg/m² or 35-40 kg/m² plus one or more obesity-related conditions, who underwent vagal nerve block therapy, compared with 15.9% (6% of initial body weight loss) in 77 patients in the sham group, for a mean between-group difference of 8.5 percentage points.

The difference was statistically significant, but it was less than the prespecified 10-point superiority margin, Dr. Sayeed Ikramuddin of the University of Minnesota, Minneapolis, and colleagues reported online Sept. 2 in JAMA.

At 12 months, 20% or more excess weight loss was achieved by 52% of patients in the vagal nerve block group, compared with 32% of patients in the sham procedure group. A total of 25% or more excess weight loss was achieved by 38% and 23% of patients in the groups, respectively, the investigators said (JAMA 2014;312:915-22).

Patients in the treatment group experienced more heartburn and dyspepsia, abdominal and other nonspecific pain, dysphagia, nausea, and eructation or belching than those in the control group. But these side effects were generally mild or moderate in severity. Serious adverse events associated with vagal nerve blockade occurred in 3.7% of treatment group patients, which was well below the 15% upper threshold for safety in the trial.

Additional study is needed to compare vagal nerve block with other obesity treatments, and to assess long-term durability and safety of the procedure, the investigators concluded.

This study was supported by EnteroMedics, which makes the vagal nerve blockade device used in the study. Dr. Ikramudden reported serving on the advisory board for Novo Nordisk and Medica, serving as a consultant for Metamodix and on an expert panel for OptumHealth, and receiving grant support from USGI Medical, ReShape Medical, and Covidien.

Intra-abdominal vagal nerve blockade to treat morbid obesity didn’t meet prespecified efficacy objectives in the randomized, double-blind ReCharge study, but treated patients did experience significantly greater weight loss than did those who underwent a sham procedure.

Mean excess weight loss was 24.4% (9.2% of initial body weight loss) in 162 patients who had a body mass index of 40-45 kg/m² or 35-40 kg/m² plus one or more obesity-related conditions, who underwent vagal nerve block therapy, compared with 15.9% (6% of initial body weight loss) in 77 patients in the sham group, for a mean between-group difference of 8.5 percentage points.

The difference was statistically significant, but it was less than the prespecified 10-point superiority margin, Dr. Sayeed Ikramuddin of the University of Minnesota, Minneapolis, and colleagues reported online Sept. 2 in JAMA.

At 12 months, 20% or more excess weight loss was achieved by 52% of patients in the vagal nerve block group, compared with 32% of patients in the sham procedure group. A total of 25% or more excess weight loss was achieved by 38% and 23% of patients in the groups, respectively, the investigators said (JAMA 2014;312:915-22).

Patients in the treatment group experienced more heartburn and dyspepsia, abdominal and other nonspecific pain, dysphagia, nausea, and eructation or belching than those in the control group. But these side effects were generally mild or moderate in severity. Serious adverse events associated with vagal nerve blockade occurred in 3.7% of treatment group patients, which was well below the 15% upper threshold for safety in the trial.

Additional study is needed to compare vagal nerve block with other obesity treatments, and to assess long-term durability and safety of the procedure, the investigators concluded.

This study was supported by EnteroMedics, which makes the vagal nerve blockade device used in the study. Dr. Ikramudden reported serving on the advisory board for Novo Nordisk and Medica, serving as a consultant for Metamodix and on an expert panel for OptumHealth, and receiving grant support from USGI Medical, ReShape Medical, and Covidien.

Intra-abdominal vagal nerve blockade to treat morbid obesity didn’t meet prespecified efficacy objectives in the randomized, double-blind ReCharge study, but treated patients did experience significantly greater weight loss than did those who underwent a sham procedure.

Mean excess weight loss was 24.4% (9.2% of initial body weight loss) in 162 patients who had a body mass index of 40-45 kg/m² or 35-40 kg/m² plus one or more obesity-related conditions, who underwent vagal nerve block therapy, compared with 15.9% (6% of initial body weight loss) in 77 patients in the sham group, for a mean between-group difference of 8.5 percentage points.

The difference was statistically significant, but it was less than the prespecified 10-point superiority margin, Dr. Sayeed Ikramuddin of the University of Minnesota, Minneapolis, and colleagues reported online Sept. 2 in JAMA.

At 12 months, 20% or more excess weight loss was achieved by 52% of patients in the vagal nerve block group, compared with 32% of patients in the sham procedure group. A total of 25% or more excess weight loss was achieved by 38% and 23% of patients in the groups, respectively, the investigators said (JAMA 2014;312:915-22).

Patients in the treatment group experienced more heartburn and dyspepsia, abdominal and other nonspecific pain, dysphagia, nausea, and eructation or belching than those in the control group. But these side effects were generally mild or moderate in severity. Serious adverse events associated with vagal nerve blockade occurred in 3.7% of treatment group patients, which was well below the 15% upper threshold for safety in the trial.

Additional study is needed to compare vagal nerve block with other obesity treatments, and to assess long-term durability and safety of the procedure, the investigators concluded.

This study was supported by EnteroMedics, which makes the vagal nerve blockade device used in the study. Dr. Ikramudden reported serving on the advisory board for Novo Nordisk and Medica, serving as a consultant for Metamodix and on an expert panel for OptumHealth, and receiving grant support from USGI Medical, ReShape Medical, and Covidien.