Sara Freeman

VIENNA – The beneficial effects of aflibercept on diabetic eye disease are independent of how well blood glucose is being controlled at the start of treatment, according to a post hoc analysis of two randomized, phase III studies.

Intravitreal injection of 2 mg of aflibercept every month or every other month had similar effects on the primary endpoint of best-corrected visual acuity (BCVA) in more than 800 subjects with diabetic macular edema (DME) with central involvement. BCVA was assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.

The mean change in BCVA from baseline to 1-year follow-up was increased by around 11 letters with aflibercept treatment regardless of which quartile of hemoglobin A_1c patients fit into at study entry. In contrast, patients treated with laser therapy appeared to have lessening benefit from treatment as baseline HbA_1c increased, with an improvement of 4.1 letters in the first to –0.3 letters in the fourth HbA1c quartiles.

Aflibercept-treated patients also experienced a significant decrease in central retinal thickness (CRT) compared with laser therapy. The mean change in CRT from baseline to 1 year was –201 micrometers in aflibercept-treated patients with a baseline HbA_1c of between 4.5% and less than 6.5% (quartile 1), and –195, –196, and –188 micrometers in patients with HbA1c levels of 6.7% to less than 7.4% (quartile 2), 7.4% to less than 8.6% (quartile 3), and 8.6% to 14.7% (quartile 4). Corresponding values for laser therapy were –102, –83, –69, and –43 micometers.

“The findings show that improvements achieved with intravitreal aflibercept over laser in anatomical and functional outcomes – best-corrected visual acuity and central retinal thickness – were robust and similar in patients even with variable systemic disease control at baseline,” said Dr. Oliver Zeitz of Bayer HealthCare, which sponsored the study and markets aflibercept (Eylea) in conjunction with Regeneron Pharmaceuticals.

“Furthermore, we could see in these trials, in the overall population, we could observe improvement in diabetic retinopathy severity scale, which may indicate that aflibercept is not only efficacious on treating DME but also has a potentially beneficial effect on the underlying diabetic retinopathy,” Dr. Zeitz added when presenting the findings at the annual meeting of the European Association for the Study of Diabetes.

VIVID-DME and VISTA-DME are two similarly designed, ongoing studies that are evaluating the efficacy and safety of intravitreal aflibercept injection for the treatment of DME versus laser photocoagulation. A total of 872 patients were randomized in both trials to receive aflibercept 2 mg every 4 or 8 weeks plus a sham laser treatment, or to macular laser photocoagulation plus sham intravitreal therapy.

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor especially formulated for injection into the eye. The rationale for using the drug is that it helps stop the growth of new blood vessels that will obscure visions if left unchecked. It also decreases vascular permeability in the eye by blocking VEGF-A and placental growth factor.

Intravitreal aflibercept is approved in the United States and the European Union and several other countries for the management of wet age-related macular degeneration and for macular edema after central retinal vein occlusion. The drug has also just received FDA approval for the treatment of DME, according to a Regeneron statement.

Safety is, of course, an important consideration, Dr. Zeitz said, adding that there was a similar overall incidence of ocular and nonocular adverse events. There was also no difference in ocular serious adverse events, including arterial thromboembolic events as defined by the Anti-Platelet Trialists’ Collaboration. There were no cases of endophthalmitis reported.

Dr. Zeitz and his coauthors are employees of Bayer HealthCare, which sponsored the VISTA- and VIVID-DME studies.

VIENNA – The beneficial effects of aflibercept on diabetic eye disease are independent of how well blood glucose is being controlled at the start of treatment, according to a post hoc analysis of two randomized, phase III studies.

Intravitreal injection of 2 mg of aflibercept every month or every other month had similar effects on the primary endpoint of best-corrected visual acuity (BCVA) in more than 800 subjects with diabetic macular edema (DME) with central involvement. BCVA was assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.

The mean change in BCVA from baseline to 1-year follow-up was increased by around 11 letters with aflibercept treatment regardless of which quartile of hemoglobin A_1c patients fit into at study entry. In contrast, patients treated with laser therapy appeared to have lessening benefit from treatment as baseline HbA_1c increased, with an improvement of 4.1 letters in the first to –0.3 letters in the fourth HbA1c quartiles.

Aflibercept-treated patients also experienced a significant decrease in central retinal thickness (CRT) compared with laser therapy. The mean change in CRT from baseline to 1 year was –201 micrometers in aflibercept-treated patients with a baseline HbA_1c of between 4.5% and less than 6.5% (quartile 1), and –195, –196, and –188 micrometers in patients with HbA1c levels of 6.7% to less than 7.4% (quartile 2), 7.4% to less than 8.6% (quartile 3), and 8.6% to 14.7% (quartile 4). Corresponding values for laser therapy were –102, –83, –69, and –43 micometers.

“The findings show that improvements achieved with intravitreal aflibercept over laser in anatomical and functional outcomes – best-corrected visual acuity and central retinal thickness – were robust and similar in patients even with variable systemic disease control at baseline,” said Dr. Oliver Zeitz of Bayer HealthCare, which sponsored the study and markets aflibercept (Eylea) in conjunction with Regeneron Pharmaceuticals.

“Furthermore, we could see in these trials, in the overall population, we could observe improvement in diabetic retinopathy severity scale, which may indicate that aflibercept is not only efficacious on treating DME but also has a potentially beneficial effect on the underlying diabetic retinopathy,” Dr. Zeitz added when presenting the findings at the annual meeting of the European Association for the Study of Diabetes.

VIVID-DME and VISTA-DME are two similarly designed, ongoing studies that are evaluating the efficacy and safety of intravitreal aflibercept injection for the treatment of DME versus laser photocoagulation. A total of 872 patients were randomized in both trials to receive aflibercept 2 mg every 4 or 8 weeks plus a sham laser treatment, or to macular laser photocoagulation plus sham intravitreal therapy.

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor especially formulated for injection into the eye. The rationale for using the drug is that it helps stop the growth of new blood vessels that will obscure visions if left unchecked. It also decreases vascular permeability in the eye by blocking VEGF-A and placental growth factor.

Intravitreal aflibercept is approved in the United States and the European Union and several other countries for the management of wet age-related macular degeneration and for macular edema after central retinal vein occlusion. The drug has also just received FDA approval for the treatment of DME, according to a Regeneron statement.

Safety is, of course, an important consideration, Dr. Zeitz said, adding that there was a similar overall incidence of ocular and nonocular adverse events. There was also no difference in ocular serious adverse events, including arterial thromboembolic events as defined by the Anti-Platelet Trialists’ Collaboration. There were no cases of endophthalmitis reported.

Dr. Zeitz and his coauthors are employees of Bayer HealthCare, which sponsored the VISTA- and VIVID-DME studies.

VIENNA – The beneficial effects of aflibercept on diabetic eye disease are independent of how well blood glucose is being controlled at the start of treatment, according to a post hoc analysis of two randomized, phase III studies.

Intravitreal injection of 2 mg of aflibercept every month or every other month had similar effects on the primary endpoint of best-corrected visual acuity (BCVA) in more than 800 subjects with diabetic macular edema (DME) with central involvement. BCVA was assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.

The mean change in BCVA from baseline to 1-year follow-up was increased by around 11 letters with aflibercept treatment regardless of which quartile of hemoglobin A_1c patients fit into at study entry. In contrast, patients treated with laser therapy appeared to have lessening benefit from treatment as baseline HbA_1c increased, with an improvement of 4.1 letters in the first to –0.3 letters in the fourth HbA1c quartiles.

Aflibercept-treated patients also experienced a significant decrease in central retinal thickness (CRT) compared with laser therapy. The mean change in CRT from baseline to 1 year was –201 micrometers in aflibercept-treated patients with a baseline HbA_1c of between 4.5% and less than 6.5% (quartile 1), and –195, –196, and –188 micrometers in patients with HbA1c levels of 6.7% to less than 7.4% (quartile 2), 7.4% to less than 8.6% (quartile 3), and 8.6% to 14.7% (quartile 4). Corresponding values for laser therapy were –102, –83, –69, and –43 micometers.

“The findings show that improvements achieved with intravitreal aflibercept over laser in anatomical and functional outcomes – best-corrected visual acuity and central retinal thickness – were robust and similar in patients even with variable systemic disease control at baseline,” said Dr. Oliver Zeitz of Bayer HealthCare, which sponsored the study and markets aflibercept (Eylea) in conjunction with Regeneron Pharmaceuticals.

“Furthermore, we could see in these trials, in the overall population, we could observe improvement in diabetic retinopathy severity scale, which may indicate that aflibercept is not only efficacious on treating DME but also has a potentially beneficial effect on the underlying diabetic retinopathy,” Dr. Zeitz added when presenting the findings at the annual meeting of the European Association for the Study of Diabetes.

VIVID-DME and VISTA-DME are two similarly designed, ongoing studies that are evaluating the efficacy and safety of intravitreal aflibercept injection for the treatment of DME versus laser photocoagulation. A total of 872 patients were randomized in both trials to receive aflibercept 2 mg every 4 or 8 weeks plus a sham laser treatment, or to macular laser photocoagulation plus sham intravitreal therapy.

Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor especially formulated for injection into the eye. The rationale for using the drug is that it helps stop the growth of new blood vessels that will obscure visions if left unchecked. It also decreases vascular permeability in the eye by blocking VEGF-A and placental growth factor.

Intravitreal aflibercept is approved in the United States and the European Union and several other countries for the management of wet age-related macular degeneration and for macular edema after central retinal vein occlusion. The drug has also just received FDA approval for the treatment of DME, according to a Regeneron statement.

Safety is, of course, an important consideration, Dr. Zeitz said, adding that there was a similar overall incidence of ocular and nonocular adverse events. There was also no difference in ocular serious adverse events, including arterial thromboembolic events as defined by the Anti-Platelet Trialists’ Collaboration. There were no cases of endophthalmitis reported.

Dr. Zeitz and his coauthors are employees of Bayer HealthCare, which sponsored the VISTA- and VIVID-DME studies.

VIENNA – There is no increased risk for myocardial infarction or other vascular events from prolonged use of insulin in people with pre- or type 2 diabetes who are already at high risk for cardiovascular disease, according to additional follow-up data from the ORIGIN study.

The ORIGINALE (Origin and Legacy Effects) study provides an additional 2.5 years of observational follow-up of more than 8,000 of the 12,000-plus individuals who participated in the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) study.

© iStock/ThinkStockPhotos

The results of the ORIGIN trial were that 6.2 years of treatment with insulin glargine (Sanofi’s Lantus) had a neutral effect on cardiovascular events and other serious health outcomes such as cancer, and possibly slowed diabetes progression (N. Engl. J. Med. 2012;367:319-28). In addition, omega-3 fatty acid supplementation was found to offer no benefit over placebo.

The results of the ORIGINALE study continue to support these findings, Dr. Hertzel C. Gerstein reported at the annual meeting of the European Society for the Study of Diabetes.

The key conclusion of ORIGIN and ORIGINALE with regard to insulin use is that “targeting a normal fasting plasma glucose with basal insulin glargine for more than 6 years improves metabolic status and has a neutral effect on serious health outcomes,” Dr. Gerstein of McMaster University, Hamilton, Ont., observed.

Two coprimary composite cardiovascular outcomes were assessed, neither of which showed any advantage or disadvantage of using insulin glargine versus standard care.

The hazard ratio for the first coprimary outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in ORIGINALE was 1.01, and the HR for the second coprimary endpoint of any cardiovascular event, a revascularization procedure, or hospitalization for heart failure was 1.03.

There was also a “neutral effect” on the individual components of these composite endpoints, with HRs of 1.02, 1.05, 1.00, 0.90, and 1.04 for myocardial infarction, stroke, cardiovascular death, heart failure hospitalization, and revascularization, respectively.

Median hemoglobin A_1c values at the end of ORIGIN and at the end of ORIGINALE were 6.3% and 6.6%, respectively, in the 2,351 patients treated with insulin glargine, and 6.52% and 6.70% in the 3,267 patients in the standard-care arm.

Likewise, analysis showed a neutral effect on cancer incidence and cancer death between the insulin and standard-care groups.

There was a trend toward fewer new cases of diabetes among insulin-treated patients than in the standard-care group (37.7% vs. 41.7%; P = .12), with fewer new and possible diabetes cases if insulin was received (41.2% vs. 47.7%; P = .014). The latter included patients who could not be confirmed as having diabetes by adjudication criteria.

In an interview, Dr. Gerstein commented that the findings are reassuring for people at high cardiovascular risk with impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes who are in need of insulin therapy.

“Insulin is a safe and effective drug, we can use it to lower patients’ glucose levels, and it’s not going to do anything else,” he said. “We have to make sure we use it correctly to avoid hypoglycemia, but there are no hidden perils, at least based on what we know now, and close to 10 years of follow-up.”

Regarding the value of omega-3 fatty acid supplementation, also studied in ORIGIN, the results of ORIGINALE showed no effect on any outcome. “All of the evidence around the world shows that if you take an omega-3 fatty acid capsule, you have no difference in your health outcomes than if you do not,” he said. “All you do is create expensive urine. You do not do anything else with respect to your health.”

Sanofi provided funding for the study, which was coordinated by the Population Health Research Institute in Hamilton. Dr. Gerstein has received research support and adviser fees from Sanofi, Novartis, and other companies.

VIENNA – There is no increased risk for myocardial infarction or other vascular events from prolonged use of insulin in people with pre- or type 2 diabetes who are already at high risk for cardiovascular disease, according to additional follow-up data from the ORIGIN study.

The ORIGINALE (Origin and Legacy Effects) study provides an additional 2.5 years of observational follow-up of more than 8,000 of the 12,000-plus individuals who participated in the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) study.

© iStock/ThinkStockPhotos

The results of the ORIGIN trial were that 6.2 years of treatment with insulin glargine (Sanofi’s Lantus) had a neutral effect on cardiovascular events and other serious health outcomes such as cancer, and possibly slowed diabetes progression (N. Engl. J. Med. 2012;367:319-28). In addition, omega-3 fatty acid supplementation was found to offer no benefit over placebo.

The results of the ORIGINALE study continue to support these findings, Dr. Hertzel C. Gerstein reported at the annual meeting of the European Society for the Study of Diabetes.

The key conclusion of ORIGIN and ORIGINALE with regard to insulin use is that “targeting a normal fasting plasma glucose with basal insulin glargine for more than 6 years improves metabolic status and has a neutral effect on serious health outcomes,” Dr. Gerstein of McMaster University, Hamilton, Ont., observed.

Two coprimary composite cardiovascular outcomes were assessed, neither of which showed any advantage or disadvantage of using insulin glargine versus standard care.

The hazard ratio for the first coprimary outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in ORIGINALE was 1.01, and the HR for the second coprimary endpoint of any cardiovascular event, a revascularization procedure, or hospitalization for heart failure was 1.03.

There was also a “neutral effect” on the individual components of these composite endpoints, with HRs of 1.02, 1.05, 1.00, 0.90, and 1.04 for myocardial infarction, stroke, cardiovascular death, heart failure hospitalization, and revascularization, respectively.

Median hemoglobin A_1c values at the end of ORIGIN and at the end of ORIGINALE were 6.3% and 6.6%, respectively, in the 2,351 patients treated with insulin glargine, and 6.52% and 6.70% in the 3,267 patients in the standard-care arm.

Likewise, analysis showed a neutral effect on cancer incidence and cancer death between the insulin and standard-care groups.

There was a trend toward fewer new cases of diabetes among insulin-treated patients than in the standard-care group (37.7% vs. 41.7%; P = .12), with fewer new and possible diabetes cases if insulin was received (41.2% vs. 47.7%; P = .014). The latter included patients who could not be confirmed as having diabetes by adjudication criteria.

In an interview, Dr. Gerstein commented that the findings are reassuring for people at high cardiovascular risk with impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes who are in need of insulin therapy.

“Insulin is a safe and effective drug, we can use it to lower patients’ glucose levels, and it’s not going to do anything else,” he said. “We have to make sure we use it correctly to avoid hypoglycemia, but there are no hidden perils, at least based on what we know now, and close to 10 years of follow-up.”

Regarding the value of omega-3 fatty acid supplementation, also studied in ORIGIN, the results of ORIGINALE showed no effect on any outcome. “All of the evidence around the world shows that if you take an omega-3 fatty acid capsule, you have no difference in your health outcomes than if you do not,” he said. “All you do is create expensive urine. You do not do anything else with respect to your health.”

Sanofi provided funding for the study, which was coordinated by the Population Health Research Institute in Hamilton. Dr. Gerstein has received research support and adviser fees from Sanofi, Novartis, and other companies.

VIENNA – There is no increased risk for myocardial infarction or other vascular events from prolonged use of insulin in people with pre- or type 2 diabetes who are already at high risk for cardiovascular disease, according to additional follow-up data from the ORIGIN study.

The ORIGINALE (Origin and Legacy Effects) study provides an additional 2.5 years of observational follow-up of more than 8,000 of the 12,000-plus individuals who participated in the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) study.

© iStock/ThinkStockPhotos

The results of the ORIGIN trial were that 6.2 years of treatment with insulin glargine (Sanofi’s Lantus) had a neutral effect on cardiovascular events and other serious health outcomes such as cancer, and possibly slowed diabetes progression (N. Engl. J. Med. 2012;367:319-28). In addition, omega-3 fatty acid supplementation was found to offer no benefit over placebo.

The results of the ORIGINALE study continue to support these findings, Dr. Hertzel C. Gerstein reported at the annual meeting of the European Society for the Study of Diabetes.

The key conclusion of ORIGIN and ORIGINALE with regard to insulin use is that “targeting a normal fasting plasma glucose with basal insulin glargine for more than 6 years improves metabolic status and has a neutral effect on serious health outcomes,” Dr. Gerstein of McMaster University, Hamilton, Ont., observed.

Two coprimary composite cardiovascular outcomes were assessed, neither of which showed any advantage or disadvantage of using insulin glargine versus standard care.

The hazard ratio for the first coprimary outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in ORIGINALE was 1.01, and the HR for the second coprimary endpoint of any cardiovascular event, a revascularization procedure, or hospitalization for heart failure was 1.03.

There was also a “neutral effect” on the individual components of these composite endpoints, with HRs of 1.02, 1.05, 1.00, 0.90, and 1.04 for myocardial infarction, stroke, cardiovascular death, heart failure hospitalization, and revascularization, respectively.

Median hemoglobin A_1c values at the end of ORIGIN and at the end of ORIGINALE were 6.3% and 6.6%, respectively, in the 2,351 patients treated with insulin glargine, and 6.52% and 6.70% in the 3,267 patients in the standard-care arm.

Likewise, analysis showed a neutral effect on cancer incidence and cancer death between the insulin and standard-care groups.

There was a trend toward fewer new cases of diabetes among insulin-treated patients than in the standard-care group (37.7% vs. 41.7%; P = .12), with fewer new and possible diabetes cases if insulin was received (41.2% vs. 47.7%; P = .014). The latter included patients who could not be confirmed as having diabetes by adjudication criteria.

In an interview, Dr. Gerstein commented that the findings are reassuring for people at high cardiovascular risk with impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes who are in need of insulin therapy.

“Insulin is a safe and effective drug, we can use it to lower patients’ glucose levels, and it’s not going to do anything else,” he said. “We have to make sure we use it correctly to avoid hypoglycemia, but there are no hidden perils, at least based on what we know now, and close to 10 years of follow-up.”

Regarding the value of omega-3 fatty acid supplementation, also studied in ORIGIN, the results of ORIGINALE showed no effect on any outcome. “All of the evidence around the world shows that if you take an omega-3 fatty acid capsule, you have no difference in your health outcomes than if you do not,” he said. “All you do is create expensive urine. You do not do anything else with respect to your health.”

Sanofi provided funding for the study, which was coordinated by the Population Health Research Institute in Hamilton. Dr. Gerstein has received research support and adviser fees from Sanofi, Novartis, and other companies.

VIENNA – A novel fixed-dose insulin analogue combination reduced blood glucose levels to a similar degree as a control basal-bolus regimen in patients with type 2 diabetes but just failed to show noninferiority for the primary endpoint in a phase IIIb randomized trial.

The percentage change in hemoglobin A_1c from baseline to week 26 was –1.3% for IDegAsp (Ryzodeg, Novo Nordisk) and –1.5% for the basal-bolus regimen used as the comparator.

IDegAsp is a soluble combination of 70% insulin degludec (Tresiba, Novo Nordisk) and 30% insulin aspart (NovoLog, Novo Nordisk). Unlike other fixed-dose insulins, IDeg and IAsp exist separately in a coformulation.

Although noninferiority was not demonstrated for glycemic control, there was a significant benefit in terms of a lower dose of insulin used (1.11 vs. 1.34 U) and less weight gain, of about 1 kg, with IDegAsp than with the basal-bolus approach. There were also numerically lower rates of confirmed (rate ratio, 0.81) and nocturnal hypoglycemia (RR, 0.80). Both regimens were well tolerated.

“If we are very, very, strict, and as we did not reach noninferiority, we can’t really say anything about anything else,” study investigator Dr. John Cooper of Stavanger (Norway) University Hospital conceded in an interview at the annual meeting of the European Association for the Study of Diabetes. He added, however, “common sense says that it is very close and it looks like it is a useful insulin.”

Patients with type 2 diabetes of at least 6 months duration and who had an HbA_1c of 7%-10% despite being treated with basal insulin with or without oral antidiabetic drugs for at least 3 months were eligible for inclusion in the study.

In all, 274 patients were included, with 138 randomized to twice-daily treatment with IDegAsp and 136 to IDeg once daily plus IAsp two to four times a day. The mean age of the participants was 60 years, the mean HbA_1c at baseline was 8.3%, and the average duration of diabetes was 13 years. The majority (63%) of patients had been treated with insulin glargine prior to study entry.

“IDegAsp twice daily may represent a simple alternative to basal-bolus treatment in patients who require intensification of basal insulin regimens, especially when adherence to more complex regimens is challenging,” Dr. Cooper said at the conclusion of his presentation.

He noted during the discussion that quality of life had been assessed using the Short-Form 36 at the start and end of the trial, and while there were no differences between the regimens in terms of the physical scores, there was a benefit seen in the mental component with IDegAsp that was driven mainly by improvements in social functioning.

“I’ve mainly used basal plus meal-time insulin doses in type 2 diabetes patients, but I might reconsider using the combination, but that’s more on the basis that I know it gives less hypoglycemia, compared with the older, premixed insulins,” Dr. Cooper commented in the postpresentation interview.

The novel insulin formulation could also offer patients who need treatment intensification a more convenient approach to their insulin therapy, he said, rather than having to inject long-acting insulin once daily and short-acting insulin up to four times a day. With IDegAsp, patients could inject just twice a day at major meal times. “This will certainly be a useful addition for some patients,” Dr. Cooper suggested.

To date, IDegAsp has been approved for use in several European, Asian, and South American countries. The Food and Drug Administration, however, has requested additional cardiovascular outcomes data to be obtained before giving market authorization for its use.

The study was funded by Novo Nordisk. Dr. Cooper has received research support and speaker fees from Novo Nordisk, Sanofi, Eli Lilly and Company, Merck, and AstraZeneca, and is a member of a speakers bureau for Novartis.

VIENNA – A novel fixed-dose insulin analogue combination reduced blood glucose levels to a similar degree as a control basal-bolus regimen in patients with type 2 diabetes but just failed to show noninferiority for the primary endpoint in a phase IIIb randomized trial.

The percentage change in hemoglobin A_1c from baseline to week 26 was –1.3% for IDegAsp (Ryzodeg, Novo Nordisk) and –1.5% for the basal-bolus regimen used as the comparator.

IDegAsp is a soluble combination of 70% insulin degludec (Tresiba, Novo Nordisk) and 30% insulin aspart (NovoLog, Novo Nordisk). Unlike other fixed-dose insulins, IDeg and IAsp exist separately in a coformulation.

Although noninferiority was not demonstrated for glycemic control, there was a significant benefit in terms of a lower dose of insulin used (1.11 vs. 1.34 U) and less weight gain, of about 1 kg, with IDegAsp than with the basal-bolus approach. There were also numerically lower rates of confirmed (rate ratio, 0.81) and nocturnal hypoglycemia (RR, 0.80). Both regimens were well tolerated.

“If we are very, very, strict, and as we did not reach noninferiority, we can’t really say anything about anything else,” study investigator Dr. John Cooper of Stavanger (Norway) University Hospital conceded in an interview at the annual meeting of the European Association for the Study of Diabetes. He added, however, “common sense says that it is very close and it looks like it is a useful insulin.”

Patients with type 2 diabetes of at least 6 months duration and who had an HbA_1c of 7%-10% despite being treated with basal insulin with or without oral antidiabetic drugs for at least 3 months were eligible for inclusion in the study.

In all, 274 patients were included, with 138 randomized to twice-daily treatment with IDegAsp and 136 to IDeg once daily plus IAsp two to four times a day. The mean age of the participants was 60 years, the mean HbA_1c at baseline was 8.3%, and the average duration of diabetes was 13 years. The majority (63%) of patients had been treated with insulin glargine prior to study entry.

“IDegAsp twice daily may represent a simple alternative to basal-bolus treatment in patients who require intensification of basal insulin regimens, especially when adherence to more complex regimens is challenging,” Dr. Cooper said at the conclusion of his presentation.

He noted during the discussion that quality of life had been assessed using the Short-Form 36 at the start and end of the trial, and while there were no differences between the regimens in terms of the physical scores, there was a benefit seen in the mental component with IDegAsp that was driven mainly by improvements in social functioning.

“I’ve mainly used basal plus meal-time insulin doses in type 2 diabetes patients, but I might reconsider using the combination, but that’s more on the basis that I know it gives less hypoglycemia, compared with the older, premixed insulins,” Dr. Cooper commented in the postpresentation interview.

The novel insulin formulation could also offer patients who need treatment intensification a more convenient approach to their insulin therapy, he said, rather than having to inject long-acting insulin once daily and short-acting insulin up to four times a day. With IDegAsp, patients could inject just twice a day at major meal times. “This will certainly be a useful addition for some patients,” Dr. Cooper suggested.

To date, IDegAsp has been approved for use in several European, Asian, and South American countries. The Food and Drug Administration, however, has requested additional cardiovascular outcomes data to be obtained before giving market authorization for its use.

The study was funded by Novo Nordisk. Dr. Cooper has received research support and speaker fees from Novo Nordisk, Sanofi, Eli Lilly and Company, Merck, and AstraZeneca, and is a member of a speakers bureau for Novartis.

VIENNA – A novel fixed-dose insulin analogue combination reduced blood glucose levels to a similar degree as a control basal-bolus regimen in patients with type 2 diabetes but just failed to show noninferiority for the primary endpoint in a phase IIIb randomized trial.

The percentage change in hemoglobin A_1c from baseline to week 26 was –1.3% for IDegAsp (Ryzodeg, Novo Nordisk) and –1.5% for the basal-bolus regimen used as the comparator.

IDegAsp is a soluble combination of 70% insulin degludec (Tresiba, Novo Nordisk) and 30% insulin aspart (NovoLog, Novo Nordisk). Unlike other fixed-dose insulins, IDeg and IAsp exist separately in a coformulation.

Although noninferiority was not demonstrated for glycemic control, there was a significant benefit in terms of a lower dose of insulin used (1.11 vs. 1.34 U) and less weight gain, of about 1 kg, with IDegAsp than with the basal-bolus approach. There were also numerically lower rates of confirmed (rate ratio, 0.81) and nocturnal hypoglycemia (RR, 0.80). Both regimens were well tolerated.

“If we are very, very, strict, and as we did not reach noninferiority, we can’t really say anything about anything else,” study investigator Dr. John Cooper of Stavanger (Norway) University Hospital conceded in an interview at the annual meeting of the European Association for the Study of Diabetes. He added, however, “common sense says that it is very close and it looks like it is a useful insulin.”

Patients with type 2 diabetes of at least 6 months duration and who had an HbA_1c of 7%-10% despite being treated with basal insulin with or without oral antidiabetic drugs for at least 3 months were eligible for inclusion in the study.

In all, 274 patients were included, with 138 randomized to twice-daily treatment with IDegAsp and 136 to IDeg once daily plus IAsp two to four times a day. The mean age of the participants was 60 years, the mean HbA_1c at baseline was 8.3%, and the average duration of diabetes was 13 years. The majority (63%) of patients had been treated with insulin glargine prior to study entry.

“IDegAsp twice daily may represent a simple alternative to basal-bolus treatment in patients who require intensification of basal insulin regimens, especially when adherence to more complex regimens is challenging,” Dr. Cooper said at the conclusion of his presentation.

He noted during the discussion that quality of life had been assessed using the Short-Form 36 at the start and end of the trial, and while there were no differences between the regimens in terms of the physical scores, there was a benefit seen in the mental component with IDegAsp that was driven mainly by improvements in social functioning.

“I’ve mainly used basal plus meal-time insulin doses in type 2 diabetes patients, but I might reconsider using the combination, but that’s more on the basis that I know it gives less hypoglycemia, compared with the older, premixed insulins,” Dr. Cooper commented in the postpresentation interview.

The novel insulin formulation could also offer patients who need treatment intensification a more convenient approach to their insulin therapy, he said, rather than having to inject long-acting insulin once daily and short-acting insulin up to four times a day. With IDegAsp, patients could inject just twice a day at major meal times. “This will certainly be a useful addition for some patients,” Dr. Cooper suggested.

To date, IDegAsp has been approved for use in several European, Asian, and South American countries. The Food and Drug Administration, however, has requested additional cardiovascular outcomes data to be obtained before giving market authorization for its use.

The study was funded by Novo Nordisk. Dr. Cooper has received research support and speaker fees from Novo Nordisk, Sanofi, Eli Lilly and Company, Merck, and AstraZeneca, and is a member of a speakers bureau for Novartis.

VIENNA – A web-based program halved the number of driving incidents experienced by patients with type 1 diabetes deemed at high risk for motoring accidents in a randomized trial.

The annual rate of driving mishaps was around 6 for diabetic drivers identified as being at high risk of future “driving mishaps” and who were randomized to the novel Internet intervention in addition to their routine care, compared with 3 for those at high risk who received usual care.

“Driving mishaps included collisions and moving vehicle violations,” said study investigator Daniel Cox, Ph.D., at the annual meeting of the European Association for the Study of Diabetes.

©Michael Shake/Fotolia.com

Dr. Cox, a clinical psychologist at the University of Virginia, Charlottesville, added that driving mishaps also included any event that could lead to a collision, such as severe hypoglycemia, someone else having to take control of the car, automatic driving, unintentionally stopping driving, and losing control of the vehicle but not actually hitting anything.

Participants were identified as being at high risk of future diabetes-related driving incidents using the 11-item Risk Assessment for Diabetic Drivers (RADD) questionnaire, which was developed by the investigators on the basis of responses from 500 individuals to questions on driving exposure, diabetes control, and the frequency of driving mishaps over the course of a year.

Peripheral neuropathy in the lower limbs was the most potent predictor of future driving mishaps, while hypoglycemia unawareness did not really rank, Dr. Cox observed, adding that RADD had 61% sensitivity and 75% specificity to differentiate diabetic drivers at high and low risk of a future driving mishap.

The study involved screening more than 1,700 drivers with type 1 diabetes who had registered with DiabetesDriving.com. Of these, 122 were identified via RADD as being at low risk of future driving mishaps and were included as a control group, while 379 were identified as being at high risk and were randomized to one of three groups: The first group continued to receive routine care, the second received the intervention in addition to routine care, and the third received the Internet intervention, routine care, and motivational interviewing conducted by telephone before and after using the web-based program.

At baseline, all participants underwent psychometric testing, and then they completed the intervention over a 2-month period. They were then asked to complete monthly online diaries to document any driving mishaps that may have occurred.

DiabetesDriving.com is an interactive, Internet intervention based on active learning. There are five sections to the program. The first provides participants with an overview on how to use a simple diabetes ‘tool kit’, which consists of a series of items contained in a plastic bag to keep in the car. Items in the kit include a key chain with a traffic light system giving guidance on blood glucose levels and whether it is safe to drive or not, a predrive checklist, a glucose meter, a fast-acting dextrose preparation, long-acting carbohydrates in the form of cheese crackers, and a car sticker to alert authorities in the event of a driving mishap.

Other sections of the program cover general issues on diabetes and driving, and how to detect, prevent, and manage extreme blood glucose levels while driving. The final section focuses on how safer driving habits can be sustained in the long term.

Results showed that RADD could be used to distinguish patients with type 1 diabetes at low and high risk of driving mishaps, with the latter having 258% more driving incidents than the former, a statistically significant difference. The basic demographics (i.e., age and gender) and the use of continuous glucose monitoring devices were similar between high- and low-risk patients.

There were 53% fewer driving mishaps among the high-risk diabetic drivers who underwent the intervention, compared with those who did not, Dr. Cox reported. “Motivational interviewing did not significantly influence the outcome,” he reported, and so the additional costs of this cannot be justified in this setting.

Interestingly, it did not seem to matter if drivers completed the whole program or just some of the sections. That said, completing the first section of the program was the most important element overall.

Drivers at high risk for driving mishaps can reduce future mishaps by using DiabetesDriving.com, Dr. Cox concluded. There is now a need to improve RADD’s sensitivity and specificity and to optimize the intervention, he added, which would help with the wider dissemination and use of the program in the diabetes community.

The National Institutes of Health funded the study, and Lifescan, Abbott, and Dex4 provided supplies, including glucose monitors and a fast-acting glucose. Dr. Cox and his coinvestigators had no conflicts of interest.

VIENNA – A web-based program halved the number of driving incidents experienced by patients with type 1 diabetes deemed at high risk for motoring accidents in a randomized trial.

The annual rate of driving mishaps was around 6 for diabetic drivers identified as being at high risk of future “driving mishaps” and who were randomized to the novel Internet intervention in addition to their routine care, compared with 3 for those at high risk who received usual care.

“Driving mishaps included collisions and moving vehicle violations,” said study investigator Daniel Cox, Ph.D., at the annual meeting of the European Association for the Study of Diabetes.

©Michael Shake/Fotolia.com

Dr. Cox, a clinical psychologist at the University of Virginia, Charlottesville, added that driving mishaps also included any event that could lead to a collision, such as severe hypoglycemia, someone else having to take control of the car, automatic driving, unintentionally stopping driving, and losing control of the vehicle but not actually hitting anything.

Participants were identified as being at high risk of future diabetes-related driving incidents using the 11-item Risk Assessment for Diabetic Drivers (RADD) questionnaire, which was developed by the investigators on the basis of responses from 500 individuals to questions on driving exposure, diabetes control, and the frequency of driving mishaps over the course of a year.

Peripheral neuropathy in the lower limbs was the most potent predictor of future driving mishaps, while hypoglycemia unawareness did not really rank, Dr. Cox observed, adding that RADD had 61% sensitivity and 75% specificity to differentiate diabetic drivers at high and low risk of a future driving mishap.

The study involved screening more than 1,700 drivers with type 1 diabetes who had registered with DiabetesDriving.com. Of these, 122 were identified via RADD as being at low risk of future driving mishaps and were included as a control group, while 379 were identified as being at high risk and were randomized to one of three groups: The first group continued to receive routine care, the second received the intervention in addition to routine care, and the third received the Internet intervention, routine care, and motivational interviewing conducted by telephone before and after using the web-based program.

At baseline, all participants underwent psychometric testing, and then they completed the intervention over a 2-month period. They were then asked to complete monthly online diaries to document any driving mishaps that may have occurred.

DiabetesDriving.com is an interactive, Internet intervention based on active learning. There are five sections to the program. The first provides participants with an overview on how to use a simple diabetes ‘tool kit’, which consists of a series of items contained in a plastic bag to keep in the car. Items in the kit include a key chain with a traffic light system giving guidance on blood glucose levels and whether it is safe to drive or not, a predrive checklist, a glucose meter, a fast-acting dextrose preparation, long-acting carbohydrates in the form of cheese crackers, and a car sticker to alert authorities in the event of a driving mishap.

Other sections of the program cover general issues on diabetes and driving, and how to detect, prevent, and manage extreme blood glucose levels while driving. The final section focuses on how safer driving habits can be sustained in the long term.

Results showed that RADD could be used to distinguish patients with type 1 diabetes at low and high risk of driving mishaps, with the latter having 258% more driving incidents than the former, a statistically significant difference. The basic demographics (i.e., age and gender) and the use of continuous glucose monitoring devices were similar between high- and low-risk patients.

There were 53% fewer driving mishaps among the high-risk diabetic drivers who underwent the intervention, compared with those who did not, Dr. Cox reported. “Motivational interviewing did not significantly influence the outcome,” he reported, and so the additional costs of this cannot be justified in this setting.

Interestingly, it did not seem to matter if drivers completed the whole program or just some of the sections. That said, completing the first section of the program was the most important element overall.

Drivers at high risk for driving mishaps can reduce future mishaps by using DiabetesDriving.com, Dr. Cox concluded. There is now a need to improve RADD’s sensitivity and specificity and to optimize the intervention, he added, which would help with the wider dissemination and use of the program in the diabetes community.

The National Institutes of Health funded the study, and Lifescan, Abbott, and Dex4 provided supplies, including glucose monitors and a fast-acting glucose. Dr. Cox and his coinvestigators had no conflicts of interest.

VIENNA – A web-based program halved the number of driving incidents experienced by patients with type 1 diabetes deemed at high risk for motoring accidents in a randomized trial.

The annual rate of driving mishaps was around 6 for diabetic drivers identified as being at high risk of future “driving mishaps” and who were randomized to the novel Internet intervention in addition to their routine care, compared with 3 for those at high risk who received usual care.

“Driving mishaps included collisions and moving vehicle violations,” said study investigator Daniel Cox, Ph.D., at the annual meeting of the European Association for the Study of Diabetes.

©Michael Shake/Fotolia.com

Dr. Cox, a clinical psychologist at the University of Virginia, Charlottesville, added that driving mishaps also included any event that could lead to a collision, such as severe hypoglycemia, someone else having to take control of the car, automatic driving, unintentionally stopping driving, and losing control of the vehicle but not actually hitting anything.

Participants were identified as being at high risk of future diabetes-related driving incidents using the 11-item Risk Assessment for Diabetic Drivers (RADD) questionnaire, which was developed by the investigators on the basis of responses from 500 individuals to questions on driving exposure, diabetes control, and the frequency of driving mishaps over the course of a year.

Peripheral neuropathy in the lower limbs was the most potent predictor of future driving mishaps, while hypoglycemia unawareness did not really rank, Dr. Cox observed, adding that RADD had 61% sensitivity and 75% specificity to differentiate diabetic drivers at high and low risk of a future driving mishap.

The study involved screening more than 1,700 drivers with type 1 diabetes who had registered with DiabetesDriving.com. Of these, 122 were identified via RADD as being at low risk of future driving mishaps and were included as a control group, while 379 were identified as being at high risk and were randomized to one of three groups: The first group continued to receive routine care, the second received the intervention in addition to routine care, and the third received the Internet intervention, routine care, and motivational interviewing conducted by telephone before and after using the web-based program.

At baseline, all participants underwent psychometric testing, and then they completed the intervention over a 2-month period. They were then asked to complete monthly online diaries to document any driving mishaps that may have occurred.

DiabetesDriving.com is an interactive, Internet intervention based on active learning. There are five sections to the program. The first provides participants with an overview on how to use a simple diabetes ‘tool kit’, which consists of a series of items contained in a plastic bag to keep in the car. Items in the kit include a key chain with a traffic light system giving guidance on blood glucose levels and whether it is safe to drive or not, a predrive checklist, a glucose meter, a fast-acting dextrose preparation, long-acting carbohydrates in the form of cheese crackers, and a car sticker to alert authorities in the event of a driving mishap.

Other sections of the program cover general issues on diabetes and driving, and how to detect, prevent, and manage extreme blood glucose levels while driving. The final section focuses on how safer driving habits can be sustained in the long term.

Results showed that RADD could be used to distinguish patients with type 1 diabetes at low and high risk of driving mishaps, with the latter having 258% more driving incidents than the former, a statistically significant difference. The basic demographics (i.e., age and gender) and the use of continuous glucose monitoring devices were similar between high- and low-risk patients.

There were 53% fewer driving mishaps among the high-risk diabetic drivers who underwent the intervention, compared with those who did not, Dr. Cox reported. “Motivational interviewing did not significantly influence the outcome,” he reported, and so the additional costs of this cannot be justified in this setting.

Interestingly, it did not seem to matter if drivers completed the whole program or just some of the sections. That said, completing the first section of the program was the most important element overall.

Drivers at high risk for driving mishaps can reduce future mishaps by using DiabetesDriving.com, Dr. Cox concluded. There is now a need to improve RADD’s sensitivity and specificity and to optimize the intervention, he added, which would help with the wider dissemination and use of the program in the diabetes community.

The National Institutes of Health funded the study, and Lifescan, Abbott, and Dex4 provided supplies, including glucose monitors and a fast-acting glucose. Dr. Cox and his coinvestigators had no conflicts of interest.

LIVERPOOL, ENGLAND – Invasive temporal arterial biopsy could be replaced by cranial Doppler ultrasound for the diagnosis of giant cell arteritis, according to research presented at the British Society for Rheumatology annual conference.

Cranial Doppler ultrasound (CDUS) more accurately diagnosed giant cell arteritis (GCA) compared with a clinical diagnosis at 3 months, with 81% sensitivity and 98% specificity. Temporal arterial biopsy was associated with a sensitivity of 53%, although it was 100% specific.

The noninvasive test also had high positive and negative predictive values of 97% and 88%, respectively, compared with 100% and just 47% for temporary artery biopsy.

GCA is one of the most common types of vasculitis and is characterized by inflammation of the medium and large arteries, usually in the head and neck. Permanent vision loss and ischemic stroke are some of the more serious symptoms of GCA, which is also linked to the development of polymyalgia rheumatica in around 50% of cases. The latter can manifest around the same time as those of GCA or develop shortly after.

"The inflammation in the temporal artery, or indeed in any large vessel affected by GCA is segmental in nature," said researcher Adam Croft, MRCP, Ph.D., of the Queen Elizabeth Hospital, Birmingham, England.

"So of course that means that if you stick a biopsy needle in randomly, as happens in temporal artery biopsy, then there is a good chance that you’ll end up with normal histology even in an affected artery." Furthermore, it is important to bear in mind that some of the characteristics of the inflammation seen in GCA have been observed in other vasculitic conditions, the researcher said.

Catching the inflammation early and treating with high-dose steroids can be "sight saving," but until now it has been difficult to determine if all patients with suspected GCA really need such treatment, and there is a high chance of over diagnosis and treatment.

Dr. Croft and colleagues conducted a retrospective study of 87 individuals with suspected GCA who underwent CDUS between January 2005 and July 2013. The aim was to see if CDUS could improve upon temporal arterial biopsy when compared with the standard of a clinical diagnosis at 3 months defined using American College of Rheumatology (ACR) criteria for GCA.

At the 3-month follow-up, 36 patients had a clinical diagnosis of GCA and 51 did not. All patients had undergone CDUS and of these, 30 (34%) had a halo sign present. The halo sign is a characteristic imaging feature used to detect GCA on ultrasound, but may be present in healthy individuals and in those with other inflammatory vascular disorders.

Temporal artery biopsy was performed in just over a quarter of all study subjects, 13 (43%) of whom had a halo sign present and 11 (19%) who did not. Biopsies were positive in 7 (54%) of individuals with a halo sign present and in one (9%) of those without the sign.

Dr. Croft observed that CDUS was the strongest predictor for a diagnosis of GCA at 3 months, whereas clinical symptoms using the ACR criteria were insufficiently specific to accurately rule in or rule out a diagnosis.

CDUS may be particularly useful in patients at either end of the clinical spectrum, he added; that is where the pretest clinical probability is very high or very low, and perhaps biopsy can be avoided in these patients.

Data on the discontinuation of steroids following a negative CDUS result in the study were compared with historical findings on steroid withdrawal in patients who had a negative biopsy. Significantly more (87% vs. 22%, P less than .01) patients with a negative ultrasound than biopsy stopped this treatment as a result, "suggesting that the clinician confidence in a negative ultrasound result is much greater, and they were more actively discontinuing steroids in these patients," said Dr. Croft.

For ultrasound to take the place of biopsy, however, he noted that an experienced ultrasonographer would be needed be able to identify the often subtle GCA changes, and that there was a short time frame when ultrasound would be accurate.

"The sensitivity rapidly falls after 4-5 days," the researcher noted, due to the use of steroids. "So you have to have the infrastructure to get these scans done early."

Dr. Croft had no conflicts of interest.

LIVERPOOL, ENGLAND – Invasive temporal arterial biopsy could be replaced by cranial Doppler ultrasound for the diagnosis of giant cell arteritis, according to research presented at the British Society for Rheumatology annual conference.

Cranial Doppler ultrasound (CDUS) more accurately diagnosed giant cell arteritis (GCA) compared with a clinical diagnosis at 3 months, with 81% sensitivity and 98% specificity. Temporal arterial biopsy was associated with a sensitivity of 53%, although it was 100% specific.

The noninvasive test also had high positive and negative predictive values of 97% and 88%, respectively, compared with 100% and just 47% for temporary artery biopsy.

GCA is one of the most common types of vasculitis and is characterized by inflammation of the medium and large arteries, usually in the head and neck. Permanent vision loss and ischemic stroke are some of the more serious symptoms of GCA, which is also linked to the development of polymyalgia rheumatica in around 50% of cases. The latter can manifest around the same time as those of GCA or develop shortly after.

"The inflammation in the temporal artery, or indeed in any large vessel affected by GCA is segmental in nature," said researcher Adam Croft, MRCP, Ph.D., of the Queen Elizabeth Hospital, Birmingham, England.

"So of course that means that if you stick a biopsy needle in randomly, as happens in temporal artery biopsy, then there is a good chance that you’ll end up with normal histology even in an affected artery." Furthermore, it is important to bear in mind that some of the characteristics of the inflammation seen in GCA have been observed in other vasculitic conditions, the researcher said.

Catching the inflammation early and treating with high-dose steroids can be "sight saving," but until now it has been difficult to determine if all patients with suspected GCA really need such treatment, and there is a high chance of over diagnosis and treatment.

Dr. Croft and colleagues conducted a retrospective study of 87 individuals with suspected GCA who underwent CDUS between January 2005 and July 2013. The aim was to see if CDUS could improve upon temporal arterial biopsy when compared with the standard of a clinical diagnosis at 3 months defined using American College of Rheumatology (ACR) criteria for GCA.

At the 3-month follow-up, 36 patients had a clinical diagnosis of GCA and 51 did not. All patients had undergone CDUS and of these, 30 (34%) had a halo sign present. The halo sign is a characteristic imaging feature used to detect GCA on ultrasound, but may be present in healthy individuals and in those with other inflammatory vascular disorders.

Temporal artery biopsy was performed in just over a quarter of all study subjects, 13 (43%) of whom had a halo sign present and 11 (19%) who did not. Biopsies were positive in 7 (54%) of individuals with a halo sign present and in one (9%) of those without the sign.

Dr. Croft observed that CDUS was the strongest predictor for a diagnosis of GCA at 3 months, whereas clinical symptoms using the ACR criteria were insufficiently specific to accurately rule in or rule out a diagnosis.

CDUS may be particularly useful in patients at either end of the clinical spectrum, he added; that is where the pretest clinical probability is very high or very low, and perhaps biopsy can be avoided in these patients.

Data on the discontinuation of steroids following a negative CDUS result in the study were compared with historical findings on steroid withdrawal in patients who had a negative biopsy. Significantly more (87% vs. 22%, P less than .01) patients with a negative ultrasound than biopsy stopped this treatment as a result, "suggesting that the clinician confidence in a negative ultrasound result is much greater, and they were more actively discontinuing steroids in these patients," said Dr. Croft.

For ultrasound to take the place of biopsy, however, he noted that an experienced ultrasonographer would be needed be able to identify the often subtle GCA changes, and that there was a short time frame when ultrasound would be accurate.

"The sensitivity rapidly falls after 4-5 days," the researcher noted, due to the use of steroids. "So you have to have the infrastructure to get these scans done early."

Dr. Croft had no conflicts of interest.

LIVERPOOL, ENGLAND – Invasive temporal arterial biopsy could be replaced by cranial Doppler ultrasound for the diagnosis of giant cell arteritis, according to research presented at the British Society for Rheumatology annual conference.

Cranial Doppler ultrasound (CDUS) more accurately diagnosed giant cell arteritis (GCA) compared with a clinical diagnosis at 3 months, with 81% sensitivity and 98% specificity. Temporal arterial biopsy was associated with a sensitivity of 53%, although it was 100% specific.

The noninvasive test also had high positive and negative predictive values of 97% and 88%, respectively, compared with 100% and just 47% for temporary artery biopsy.

GCA is one of the most common types of vasculitis and is characterized by inflammation of the medium and large arteries, usually in the head and neck. Permanent vision loss and ischemic stroke are some of the more serious symptoms of GCA, which is also linked to the development of polymyalgia rheumatica in around 50% of cases. The latter can manifest around the same time as those of GCA or develop shortly after.

"The inflammation in the temporal artery, or indeed in any large vessel affected by GCA is segmental in nature," said researcher Adam Croft, MRCP, Ph.D., of the Queen Elizabeth Hospital, Birmingham, England.

"So of course that means that if you stick a biopsy needle in randomly, as happens in temporal artery biopsy, then there is a good chance that you’ll end up with normal histology even in an affected artery." Furthermore, it is important to bear in mind that some of the characteristics of the inflammation seen in GCA have been observed in other vasculitic conditions, the researcher said.

Catching the inflammation early and treating with high-dose steroids can be "sight saving," but until now it has been difficult to determine if all patients with suspected GCA really need such treatment, and there is a high chance of over diagnosis and treatment.

Dr. Croft and colleagues conducted a retrospective study of 87 individuals with suspected GCA who underwent CDUS between January 2005 and July 2013. The aim was to see if CDUS could improve upon temporal arterial biopsy when compared with the standard of a clinical diagnosis at 3 months defined using American College of Rheumatology (ACR) criteria for GCA.

At the 3-month follow-up, 36 patients had a clinical diagnosis of GCA and 51 did not. All patients had undergone CDUS and of these, 30 (34%) had a halo sign present. The halo sign is a characteristic imaging feature used to detect GCA on ultrasound, but may be present in healthy individuals and in those with other inflammatory vascular disorders.

Temporal artery biopsy was performed in just over a quarter of all study subjects, 13 (43%) of whom had a halo sign present and 11 (19%) who did not. Biopsies were positive in 7 (54%) of individuals with a halo sign present and in one (9%) of those without the sign.

Dr. Croft observed that CDUS was the strongest predictor for a diagnosis of GCA at 3 months, whereas clinical symptoms using the ACR criteria were insufficiently specific to accurately rule in or rule out a diagnosis.

CDUS may be particularly useful in patients at either end of the clinical spectrum, he added; that is where the pretest clinical probability is very high or very low, and perhaps biopsy can be avoided in these patients.

Data on the discontinuation of steroids following a negative CDUS result in the study were compared with historical findings on steroid withdrawal in patients who had a negative biopsy. Significantly more (87% vs. 22%, P less than .01) patients with a negative ultrasound than biopsy stopped this treatment as a result, "suggesting that the clinician confidence in a negative ultrasound result is much greater, and they were more actively discontinuing steroids in these patients," said Dr. Croft.

For ultrasound to take the place of biopsy, however, he noted that an experienced ultrasonographer would be needed be able to identify the often subtle GCA changes, and that there was a short time frame when ultrasound would be accurate.

"The sensitivity rapidly falls after 4-5 days," the researcher noted, due to the use of steroids. "So you have to have the infrastructure to get these scans done early."

Dr. Croft had no conflicts of interest.

LIVERPOOL, ENGLAND – Hydroxychloroquine was not associated with any adverse long-term complications in the children of women with systemic lupus erythematosus who used the drug during pregnancy or while breastfeeding in a multicenter, cross-sectional survey.

In fact the research, recently reported at the British Society for Rheumatology annual conference, showed that the disease-modifying antirheumatic drug (DMARD) reduced exposed children’s risk of admission to hospital for infection (14% vs. 24.8% for nonexposed children; P = .03) and the need for outpatient visits (12.6% vs. 23.1%; P = .0.03).

There was no significant increased risk for congenital anomalies (2.1% vs. 2.2%), including congenital heart block (2.0% vs. 2.9%), or developmental problems such as attention-deficit hyperactivity disorder (0% vs. 2.9% for ADHD). Mothers who used the DMARD were also no more at risk of developing eclampsia during their pregnancy than those who did not (11% vs. 9%; P = .75).

©Jupiterimages/thinkstockphotos.com

"Hydroxychloroquine should be continued during pregnancy and breastfeeding," advised study investigator Dr. Mary Gayed of the department of rheumatology at the University of Birmingham (England).

Dr. Gayed, who presented the study findings on behalf of the British Isles Lupus Assessment Group (BILAG), said that these were hopefully reassuring findings. "We know that immunosuppressive agents, including hydroxychloroquine, are used in SLE [systemic lupus erythematosus] during pregnancy to prevent disease flare and to ensure optimum outcomes for both mother and child," she said, explaining the rationale behind the research, "but there are few published data regarding the long-term outcome of these children."

Randomized, controlled study data have shown that women who continue treatment with hydroxychloroquine during their pregnancy exhibit no disease activity and require only low doses of steroids by the end of their pregnancy, Dr. Gayed observed. This has been corroborated by other studies that have shown that discontinuing the DMARD leads to higher disease activity and the need for higher steroid doses.

Lack of good disease control during pregnancy is linked to maternal complications such as high blood pressure, proteinuria, thrombocytopenia, and secondary antiphospholipid syndrome. "We also know that women who have active lupus during pregnancy have a reduced rate of live births, earlier deliveries, increased pregnancy losses, and increased small-for-gestational-age babies, which makes it key to control disease activity throughout pregnancy," said Dr. Gayed.

Dr. Gayed and associates have previously reported their findings on the long-term out comes of all DMARDs used to treat SLE in pregnancy and will release further data from their survey on the safety of azathioprine at the upcoming European League Against Rheumatism Congress next month in Paris. The current research question was to look at their data specifically with regard to hydroxychloroquine and how this affected maternal, neonatal, and childhood outcomes.

Their retrospective survey involved 200 women with SLE, defined using American College of Rheumatology criteria, who gave birth to a total of 287 children. Of these, 118 women used the DMARD during their pregnancy or while breastfeeding, with 149 children exposed to hydroxychloroquine during the neonatal or postnatal periods. The majority of women (n = 76) used the drug during pregnancy and breastfeeding, 42 during pregnancy only, and 4 only while they were breastfeeding. There were 102 women who did not use the drug during pregnancy or breastfeeding and who gave birth to 138 nonexposed children.

At the birth of their children, the mean age of mothers was 32 years, and they had a mean disease duration of 7.5 years overall, with a mean maternal disease duration of 6.5 years versus 8.6 years comparing the hydroxychloroquine-exposed with the nonexposed children. The majority (66%) of the women were white, 15% were South Asian, 10% Afro-Caribbean, 1% Chinese, 1% Hispanic, and the remainder of other or unstated ethnicity. There was no significant difference in the use of azathioprine, aspirin, or heparin, but mothers who used hydroxychloroquine were significantly more likely to use steroids than women who did not use the DMARD (66% vs. 51%; P = .02).

The median gestational age at delivery was 38 weeks in both hydroxychloroquine-exposed and nonexposed children. There was no statistical difference in birth weight between the groups, which was a mean of 2.8 kg in both exposed and nonexposed children. The median age of children exposed to hydroxychloroquine at enrollment was 2.1 years versus 4.6 years for nonexposed children.

The findings are limited by the fact that these are self-reported data, and it was not always possible to check medical records, Dr. Gayed said. Data on disease activity and prednisolone dose were also not available. That said, "this U.K. cross-sectional survey highlights that hydroxychloroquine is compatible with pregnancy," Dr. Gayed concluded.

Dr. Gayed and coauthors reported no conflicts of interest.

LIVERPOOL, ENGLAND – Hydroxychloroquine was not associated with any adverse long-term complications in the children of women with systemic lupus erythematosus who used the drug during pregnancy or while breastfeeding in a multicenter, cross-sectional survey.

In fact the research, recently reported at the British Society for Rheumatology annual conference, showed that the disease-modifying antirheumatic drug (DMARD) reduced exposed children’s risk of admission to hospital for infection (14% vs. 24.8% for nonexposed children; P = .03) and the need for outpatient visits (12.6% vs. 23.1%; P = .0.03).

There was no significant increased risk for congenital anomalies (2.1% vs. 2.2%), including congenital heart block (2.0% vs. 2.9%), or developmental problems such as attention-deficit hyperactivity disorder (0% vs. 2.9% for ADHD). Mothers who used the DMARD were also no more at risk of developing eclampsia during their pregnancy than those who did not (11% vs. 9%; P = .75).

©Jupiterimages/thinkstockphotos.com

"Hydroxychloroquine should be continued during pregnancy and breastfeeding," advised study investigator Dr. Mary Gayed of the department of rheumatology at the University of Birmingham (England).

Dr. Gayed, who presented the study findings on behalf of the British Isles Lupus Assessment Group (BILAG), said that these were hopefully reassuring findings. "We know that immunosuppressive agents, including hydroxychloroquine, are used in SLE [systemic lupus erythematosus] during pregnancy to prevent disease flare and to ensure optimum outcomes for both mother and child," she said, explaining the rationale behind the research, "but there are few published data regarding the long-term outcome of these children."

Randomized, controlled study data have shown that women who continue treatment with hydroxychloroquine during their pregnancy exhibit no disease activity and require only low doses of steroids by the end of their pregnancy, Dr. Gayed observed. This has been corroborated by other studies that have shown that discontinuing the DMARD leads to higher disease activity and the need for higher steroid doses.

Lack of good disease control during pregnancy is linked to maternal complications such as high blood pressure, proteinuria, thrombocytopenia, and secondary antiphospholipid syndrome. "We also know that women who have active lupus during pregnancy have a reduced rate of live births, earlier deliveries, increased pregnancy losses, and increased small-for-gestational-age babies, which makes it key to control disease activity throughout pregnancy," said Dr. Gayed.

Dr. Gayed and associates have previously reported their findings on the long-term out comes of all DMARDs used to treat SLE in pregnancy and will release further data from their survey on the safety of azathioprine at the upcoming European League Against Rheumatism Congress next month in Paris. The current research question was to look at their data specifically with regard to hydroxychloroquine and how this affected maternal, neonatal, and childhood outcomes.

Their retrospective survey involved 200 women with SLE, defined using American College of Rheumatology criteria, who gave birth to a total of 287 children. Of these, 118 women used the DMARD during their pregnancy or while breastfeeding, with 149 children exposed to hydroxychloroquine during the neonatal or postnatal periods. The majority of women (n = 76) used the drug during pregnancy and breastfeeding, 42 during pregnancy only, and 4 only while they were breastfeeding. There were 102 women who did not use the drug during pregnancy or breastfeeding and who gave birth to 138 nonexposed children.

At the birth of their children, the mean age of mothers was 32 years, and they had a mean disease duration of 7.5 years overall, with a mean maternal disease duration of 6.5 years versus 8.6 years comparing the hydroxychloroquine-exposed with the nonexposed children. The majority (66%) of the women were white, 15% were South Asian, 10% Afro-Caribbean, 1% Chinese, 1% Hispanic, and the remainder of other or unstated ethnicity. There was no significant difference in the use of azathioprine, aspirin, or heparin, but mothers who used hydroxychloroquine were significantly more likely to use steroids than women who did not use the DMARD (66% vs. 51%; P = .02).

The median gestational age at delivery was 38 weeks in both hydroxychloroquine-exposed and nonexposed children. There was no statistical difference in birth weight between the groups, which was a mean of 2.8 kg in both exposed and nonexposed children. The median age of children exposed to hydroxychloroquine at enrollment was 2.1 years versus 4.6 years for nonexposed children.

The findings are limited by the fact that these are self-reported data, and it was not always possible to check medical records, Dr. Gayed said. Data on disease activity and prednisolone dose were also not available. That said, "this U.K. cross-sectional survey highlights that hydroxychloroquine is compatible with pregnancy," Dr. Gayed concluded.

Dr. Gayed and coauthors reported no conflicts of interest.

LIVERPOOL, ENGLAND – Hydroxychloroquine was not associated with any adverse long-term complications in the children of women with systemic lupus erythematosus who used the drug during pregnancy or while breastfeeding in a multicenter, cross-sectional survey.

In fact the research, recently reported at the British Society for Rheumatology annual conference, showed that the disease-modifying antirheumatic drug (DMARD) reduced exposed children’s risk of admission to hospital for infection (14% vs. 24.8% for nonexposed children; P = .03) and the need for outpatient visits (12.6% vs. 23.1%; P = .0.03).

There was no significant increased risk for congenital anomalies (2.1% vs. 2.2%), including congenital heart block (2.0% vs. 2.9%), or developmental problems such as attention-deficit hyperactivity disorder (0% vs. 2.9% for ADHD). Mothers who used the DMARD were also no more at risk of developing eclampsia during their pregnancy than those who did not (11% vs. 9%; P = .75).

©Jupiterimages/thinkstockphotos.com

"Hydroxychloroquine should be continued during pregnancy and breastfeeding," advised study investigator Dr. Mary Gayed of the department of rheumatology at the University of Birmingham (England).

Dr. Gayed, who presented the study findings on behalf of the British Isles Lupus Assessment Group (BILAG), said that these were hopefully reassuring findings. "We know that immunosuppressive agents, including hydroxychloroquine, are used in SLE [systemic lupus erythematosus] during pregnancy to prevent disease flare and to ensure optimum outcomes for both mother and child," she said, explaining the rationale behind the research, "but there are few published data regarding the long-term outcome of these children."

Randomized, controlled study data have shown that women who continue treatment with hydroxychloroquine during their pregnancy exhibit no disease activity and require only low doses of steroids by the end of their pregnancy, Dr. Gayed observed. This has been corroborated by other studies that have shown that discontinuing the DMARD leads to higher disease activity and the need for higher steroid doses.

Lack of good disease control during pregnancy is linked to maternal complications such as high blood pressure, proteinuria, thrombocytopenia, and secondary antiphospholipid syndrome. "We also know that women who have active lupus during pregnancy have a reduced rate of live births, earlier deliveries, increased pregnancy losses, and increased small-for-gestational-age babies, which makes it key to control disease activity throughout pregnancy," said Dr. Gayed.

Dr. Gayed and associates have previously reported their findings on the long-term out comes of all DMARDs used to treat SLE in pregnancy and will release further data from their survey on the safety of azathioprine at the upcoming European League Against Rheumatism Congress next month in Paris. The current research question was to look at their data specifically with regard to hydroxychloroquine and how this affected maternal, neonatal, and childhood outcomes.

Their retrospective survey involved 200 women with SLE, defined using American College of Rheumatology criteria, who gave birth to a total of 287 children. Of these, 118 women used the DMARD during their pregnancy or while breastfeeding, with 149 children exposed to hydroxychloroquine during the neonatal or postnatal periods. The majority of women (n = 76) used the drug during pregnancy and breastfeeding, 42 during pregnancy only, and 4 only while they were breastfeeding. There were 102 women who did not use the drug during pregnancy or breastfeeding and who gave birth to 138 nonexposed children.

At the birth of their children, the mean age of mothers was 32 years, and they had a mean disease duration of 7.5 years overall, with a mean maternal disease duration of 6.5 years versus 8.6 years comparing the hydroxychloroquine-exposed with the nonexposed children. The majority (66%) of the women were white, 15% were South Asian, 10% Afro-Caribbean, 1% Chinese, 1% Hispanic, and the remainder of other or unstated ethnicity. There was no significant difference in the use of azathioprine, aspirin, or heparin, but mothers who used hydroxychloroquine were significantly more likely to use steroids than women who did not use the DMARD (66% vs. 51%; P = .02).

The median gestational age at delivery was 38 weeks in both hydroxychloroquine-exposed and nonexposed children. There was no statistical difference in birth weight between the groups, which was a mean of 2.8 kg in both exposed and nonexposed children. The median age of children exposed to hydroxychloroquine at enrollment was 2.1 years versus 4.6 years for nonexposed children.

The findings are limited by the fact that these are self-reported data, and it was not always possible to check medical records, Dr. Gayed said. Data on disease activity and prednisolone dose were also not available. That said, "this U.K. cross-sectional survey highlights that hydroxychloroquine is compatible with pregnancy," Dr. Gayed concluded.

Dr. Gayed and coauthors reported no conflicts of interest.

LIVERPOOL, ENGLAND – Further evidence that apremilast has multiple and sustained effects in psoriatic arthritis for at least 1 year were reported at the British Society for Rheumatology annual conference.

Data from two of the phase III studies that make up the PALACE (Psoriatic Arthritis Long-term Assessment of Clinical Efficacy) clinical trials program showed that the oral phosphodiesterase 4 inhibitor continued to suppress disease activity and improved pain and physical functioning associated with the skin and joint condition.

In the PALACE 1 (Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1) trial, 75 of 119 (63%) patients treated with apremilast 20 mg twice daily and 71 of 130 (55%) patients treated with apremilast 30 mg twice daily still had an American College of Rheumatology 20% (ACR20) response at 52 weeks.

Corresponding 52-week data from the PALACE 3 trial showed ACR20 responses in 56% of 116 patients and 62% of 127 patients for the two doses of apremilast, respectively. ACR50 and ACR70 were achieved by 25%-30% of patients, and 9%-10% achieved an ACR70.

Apremilast is marketed by Celgene as Otezla and gained approval from the Food and Drug Administration for the treatment of adults with active psoriatic arthritis in March. The FDA approval came with a caution that patients’ weight should be monitored regularly and that there had been increased reports of depression.

The long-term safety data from these two PALACE trials, however, showed no new safety concerns, according to the studies’ authors. The most common side effects seen were as reported previously and included diarrhea, nausea, and headache.

PALACE 1 and PALACE 3 were designed to assess the efficacy and safety of apremilast versus placebo in patients who had active psoriatic arthritis despite treatment with conventional nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) with or without additional biologic treatment.

For inclusion in the trials, patients had to have disease duration of at least 6 months, meet Classification of Psoriatic Arthritis (CASPAR) criteria, and have three or more tender or swollen joints involved. Patients enrolled in PALACE 3 also had to have skin involvement, with at least plaque psoriasis of 2 cm in size or larger.

A total of 504 patients were enrolled into PALACE 1 (Ann. Rheum. Dis. 2013;72[Suppl. 3]:163) and 505 into PALACE 3 and initially randomized to twice-daily treatment with placebo or one of two doses of apremilast for 24 weeks. At this point, all patients in the placebo arm who had not already been rerandomized to active treatment were randomized to apremilast 20 mg or 30 mg. Patients originally randomized to active therapy continued with their treatment if they continued to respond.

"I think what comes out of these [data], and looking over time, is that the effect is sustained with all the caveats that go with that because, of course, people only stay on [the drug] if they are doing well," PALACE 3 investigator Dr. Christopher Edwards observed in an interview.

Dr. Edwards, who is a clinical rheumatologist at University Hospital Southampton, England, noted that the statistical power of long-term extension studies is perhaps a little less robust than the initial study phases, but that these long-term data from the PALACE trials do seem to show that the effects of treatment with apremilast are sustained and maybe even that the effect size improves slightly over time.

Physical function, assessed via the Health Assessment Questionnaire–Disability Index (HAQ-DI), was improved with apremilast treatment in both the PALACE 1 and PALACE 3 trials. In the latter trial, mean change in HAQ-DI scores at 16 weeks declined by 0.13 and 0.19, compared with baseline values in the apremilast 20-mg and 30-mg groups. In contrast, scores increased by 0.07 in the placebo group. Over the following year, HAQ-DI scores continued to improve, with the mean change in scores from baseline crossing the threshold of –0.30, which many think signifies a clinically meaningful change, Dr. Edwards explained.

HAQ-DI scores in PALACE 1 at 52 weeks were a respective –0.369 and –0.318 in the 20-mg and 30-mg groups, and at the 16-week assessment point, they had been –0.20 and –0.24, respectively, and –0.09 for placebo.

Furthermore, in the PALACE 3 trial, 29%-39% of patients treated with apremilast achieved a 75% improvement in skin involvement, assessed via the Psoriasis Area and Severity Index (PASI) at 1 year. PASI50 was achieved in 49%-54%.

Dr. Edwards observed that some of the additional data now available from PALACE 3 showed that there was a beneficial effect of apremilast on enthesitis and dactylitis – two unique features of psoriatic arthritis that are often not treated by the use of the nbDMARDS, such as methotrexate and sulfasalazine.

At 24 weeks, he noted that in other comparisons of patients treated with apremilast or placebo, active therapy yielded significant improvements in pain (assessed using a visual analog scale), improved Functional Assessment of Chronic Illness Therapy-Fatigue scores, a higher rate of achieving ‘good’ or ‘moderate’ European League Against Rheumatism responses, and greater modified Psoriatic Arthritis Response Criteria results.

Dr. Edwards has acted as a consultant to Celgene, the company that sponsored the studies. He has also received research support from Pfizer and honoraria from Roche, Abbott, and GlaxoSmithKline.

LIVERPOOL, ENGLAND – Further evidence that apremilast has multiple and sustained effects in psoriatic arthritis for at least 1 year were reported at the British Society for Rheumatology annual conference.

Data from two of the phase III studies that make up the PALACE (Psoriatic Arthritis Long-term Assessment of Clinical Efficacy) clinical trials program showed that the oral phosphodiesterase 4 inhibitor continued to suppress disease activity and improved pain and physical functioning associated with the skin and joint condition.

In the PALACE 1 (Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1) trial, 75 of 119 (63%) patients treated with apremilast 20 mg twice daily and 71 of 130 (55%) patients treated with apremilast 30 mg twice daily still had an American College of Rheumatology 20% (ACR20) response at 52 weeks.

Corresponding 52-week data from the PALACE 3 trial showed ACR20 responses in 56% of 116 patients and 62% of 127 patients for the two doses of apremilast, respectively. ACR50 and ACR70 were achieved by 25%-30% of patients, and 9%-10% achieved an ACR70.

Apremilast is marketed by Celgene as Otezla and gained approval from the Food and Drug Administration for the treatment of adults with active psoriatic arthritis in March. The FDA approval came with a caution that patients’ weight should be monitored regularly and that there had been increased reports of depression.

The long-term safety data from these two PALACE trials, however, showed no new safety concerns, according to the studies’ authors. The most common side effects seen were as reported previously and included diarrhea, nausea, and headache.

PALACE 1 and PALACE 3 were designed to assess the efficacy and safety of apremilast versus placebo in patients who had active psoriatic arthritis despite treatment with conventional nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) with or without additional biologic treatment.

For inclusion in the trials, patients had to have disease duration of at least 6 months, meet Classification of Psoriatic Arthritis (CASPAR) criteria, and have three or more tender or swollen joints involved. Patients enrolled in PALACE 3 also had to have skin involvement, with at least plaque psoriasis of 2 cm in size or larger.

A total of 504 patients were enrolled into PALACE 1 (Ann. Rheum. Dis. 2013;72[Suppl. 3]:163) and 505 into PALACE 3 and initially randomized to twice-daily treatment with placebo or one of two doses of apremilast for 24 weeks. At this point, all patients in the placebo arm who had not already been rerandomized to active treatment were randomized to apremilast 20 mg or 30 mg. Patients originally randomized to active therapy continued with their treatment if they continued to respond.

"I think what comes out of these [data], and looking over time, is that the effect is sustained with all the caveats that go with that because, of course, people only stay on [the drug] if they are doing well," PALACE 3 investigator Dr. Christopher Edwards observed in an interview.

Dr. Edwards, who is a clinical rheumatologist at University Hospital Southampton, England, noted that the statistical power of long-term extension studies is perhaps a little less robust than the initial study phases, but that these long-term data from the PALACE trials do seem to show that the effects of treatment with apremilast are sustained and maybe even that the effect size improves slightly over time.

Physical function, assessed via the Health Assessment Questionnaire–Disability Index (HAQ-DI), was improved with apremilast treatment in both the PALACE 1 and PALACE 3 trials. In the latter trial, mean change in HAQ-DI scores at 16 weeks declined by 0.13 and 0.19, compared with baseline values in the apremilast 20-mg and 30-mg groups. In contrast, scores increased by 0.07 in the placebo group. Over the following year, HAQ-DI scores continued to improve, with the mean change in scores from baseline crossing the threshold of –0.30, which many think signifies a clinically meaningful change, Dr. Edwards explained.

HAQ-DI scores in PALACE 1 at 52 weeks were a respective –0.369 and –0.318 in the 20-mg and 30-mg groups, and at the 16-week assessment point, they had been –0.20 and –0.24, respectively, and –0.09 for placebo.

Furthermore, in the PALACE 3 trial, 29%-39% of patients treated with apremilast achieved a 75% improvement in skin involvement, assessed via the Psoriasis Area and Severity Index (PASI) at 1 year. PASI50 was achieved in 49%-54%.

Dr. Edwards observed that some of the additional data now available from PALACE 3 showed that there was a beneficial effect of apremilast on enthesitis and dactylitis – two unique features of psoriatic arthritis that are often not treated by the use of the nbDMARDS, such as methotrexate and sulfasalazine.

At 24 weeks, he noted that in other comparisons of patients treated with apremilast or placebo, active therapy yielded significant improvements in pain (assessed using a visual analog scale), improved Functional Assessment of Chronic Illness Therapy-Fatigue scores, a higher rate of achieving ‘good’ or ‘moderate’ European League Against Rheumatism responses, and greater modified Psoriatic Arthritis Response Criteria results.

Dr. Edwards has acted as a consultant to Celgene, the company that sponsored the studies. He has also received research support from Pfizer and honoraria from Roche, Abbott, and GlaxoSmithKline.

LIVERPOOL, ENGLAND – Further evidence that apremilast has multiple and sustained effects in psoriatic arthritis for at least 1 year were reported at the British Society for Rheumatology annual conference.

Data from two of the phase III studies that make up the PALACE (Psoriatic Arthritis Long-term Assessment of Clinical Efficacy) clinical trials program showed that the oral phosphodiesterase 4 inhibitor continued to suppress disease activity and improved pain and physical functioning associated with the skin and joint condition.

In the PALACE 1 (Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1) trial, 75 of 119 (63%) patients treated with apremilast 20 mg twice daily and 71 of 130 (55%) patients treated with apremilast 30 mg twice daily still had an American College of Rheumatology 20% (ACR20) response at 52 weeks.

Corresponding 52-week data from the PALACE 3 trial showed ACR20 responses in 56% of 116 patients and 62% of 127 patients for the two doses of apremilast, respectively. ACR50 and ACR70 were achieved by 25%-30% of patients, and 9%-10% achieved an ACR70.

Apremilast is marketed by Celgene as Otezla and gained approval from the Food and Drug Administration for the treatment of adults with active psoriatic arthritis in March. The FDA approval came with a caution that patients’ weight should be monitored regularly and that there had been increased reports of depression.

The long-term safety data from these two PALACE trials, however, showed no new safety concerns, according to the studies’ authors. The most common side effects seen were as reported previously and included diarrhea, nausea, and headache.

PALACE 1 and PALACE 3 were designed to assess the efficacy and safety of apremilast versus placebo in patients who had active psoriatic arthritis despite treatment with conventional nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) with or without additional biologic treatment.

For inclusion in the trials, patients had to have disease duration of at least 6 months, meet Classification of Psoriatic Arthritis (CASPAR) criteria, and have three or more tender or swollen joints involved. Patients enrolled in PALACE 3 also had to have skin involvement, with at least plaque psoriasis of 2 cm in size or larger.

A total of 504 patients were enrolled into PALACE 1 (Ann. Rheum. Dis. 2013;72[Suppl. 3]:163) and 505 into PALACE 3 and initially randomized to twice-daily treatment with placebo or one of two doses of apremilast for 24 weeks. At this point, all patients in the placebo arm who had not already been rerandomized to active treatment were randomized to apremilast 20 mg or 30 mg. Patients originally randomized to active therapy continued with their treatment if they continued to respond.

"I think what comes out of these [data], and looking over time, is that the effect is sustained with all the caveats that go with that because, of course, people only stay on [the drug] if they are doing well," PALACE 3 investigator Dr. Christopher Edwards observed in an interview.

Dr. Edwards, who is a clinical rheumatologist at University Hospital Southampton, England, noted that the statistical power of long-term extension studies is perhaps a little less robust than the initial study phases, but that these long-term data from the PALACE trials do seem to show that the effects of treatment with apremilast are sustained and maybe even that the effect size improves slightly over time.

Physical function, assessed via the Health Assessment Questionnaire–Disability Index (HAQ-DI), was improved with apremilast treatment in both the PALACE 1 and PALACE 3 trials. In the latter trial, mean change in HAQ-DI scores at 16 weeks declined by 0.13 and 0.19, compared with baseline values in the apremilast 20-mg and 30-mg groups. In contrast, scores increased by 0.07 in the placebo group. Over the following year, HAQ-DI scores continued to improve, with the mean change in scores from baseline crossing the threshold of –0.30, which many think signifies a clinically meaningful change, Dr. Edwards explained.

HAQ-DI scores in PALACE 1 at 52 weeks were a respective –0.369 and –0.318 in the 20-mg and 30-mg groups, and at the 16-week assessment point, they had been –0.20 and –0.24, respectively, and –0.09 for placebo.

Furthermore, in the PALACE 3 trial, 29%-39% of patients treated with apremilast achieved a 75% improvement in skin involvement, assessed via the Psoriasis Area and Severity Index (PASI) at 1 year. PASI50 was achieved in 49%-54%.

Dr. Edwards observed that some of the additional data now available from PALACE 3 showed that there was a beneficial effect of apremilast on enthesitis and dactylitis – two unique features of psoriatic arthritis that are often not treated by the use of the nbDMARDS, such as methotrexate and sulfasalazine.

At 24 weeks, he noted that in other comparisons of patients treated with apremilast or placebo, active therapy yielded significant improvements in pain (assessed using a visual analog scale), improved Functional Assessment of Chronic Illness Therapy-Fatigue scores, a higher rate of achieving ‘good’ or ‘moderate’ European League Against Rheumatism responses, and greater modified Psoriatic Arthritis Response Criteria results.

Dr. Edwards has acted as a consultant to Celgene, the company that sponsored the studies. He has also received research support from Pfizer and honoraria from Roche, Abbott, and GlaxoSmithKline.

LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.

The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.

How common are atypical femoral fractures?

"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.

"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."

"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.

However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.

Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).

There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.

Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.

What are atypical hip fractures?

Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.

"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.

There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.

The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).

The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."

Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.

What should clinicians do if AFF is suspected?

"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.

In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.

In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.

Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.

In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."

Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."

Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.

Atypical femoral fracture register planned

"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.

"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.

Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.

LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.

The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.

How common are atypical femoral fractures?

"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.

"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."

"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.

However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.

Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).

There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.

Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.

What are atypical hip fractures?

Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.

"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.

There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.

The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).

The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."

Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.

What should clinicians do if AFF is suspected?

"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.

In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.

In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.

Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.

In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."

Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."

Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.

Atypical femoral fracture register planned

"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.

"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.

Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.

LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.

The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.

How common are atypical femoral fractures?

"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.

"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."

"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.

However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.

Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).

There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.

Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.

What are atypical hip fractures?

Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.

"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.

There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.

The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).

The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."

Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.

What should clinicians do if AFF is suspected?

"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.

In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.

In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.

Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.

In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."

Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."

Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.

Atypical femoral fracture register planned

"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.

"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.

Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.

LIVERPOOL, ENGLAND – Rituximab and mycophenolate mofetil could offer patients with rheumatoid arthritis and concomitant interstitial lung disease a survival advantage over other therapies, according to findings from a large, retrospective, multicenter study.

Data collated by the British Rheumatoid Interstitial Lung (BRILL) network found all-cause mortality in patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD) treated with rituximab was 8% versus 31% for those treated with anti-tumor necrosis factor (TNF) alpha therapies (P = .03). Death from respiratory causes was also significantly lower in the rituximab-treated patients (4% vs. 15%, P = .04).

All-cause mortality was also significantly lower in patients with RA and ILD treated with mycophenolate mofetil (relative risk, 0.65) when compared with azathioprine (RR, 1.42) or other immunosuppressants, which included cyclophosphamide (RR, 1.65) and tacrolimus (RR, 1.74).

However, these data were retrospective, so prospective therapeutic trials are now needed, said Dr. Clive Kelly of Queen Elizabeth Hospital, Gateshead, England. Dr. Kelly, who was the driving force behind the set up of the BRILL network 2 years ago, stated that plans were already afoot to set up these trials with the intention of recruiting 200 patients with RA and ILD across the United Kingdom.

The aim of future studies would be to compare the use of rituximab versus anti-TNF therapies, with or without methotrexate, and mycophenolate mofetil versus azathioprine, with or without oral steroids, to see if the anticipated survival benefit associated with the newer agents is confirmed. Funding for the trials is yet to be secured, but it is hoped that recruitment can begin next year.

When people think of comorbidity in RA, they tend to think about cardiovascular disease first, Dr. Kelly noted at the British Society for Rheumatology annual conference. He observed that ILD has been associated with RA for well over 50 years and that respiratory disease, largely due to ILD and chronic lung damage, is now a "close second" behind heart disease as a cause of death in patients with RA.

Up to 40% of all cases of ILD are discovered in RA patients postmortem, he said, but with the increased use of high-resolution computed tomography (HRCT) in the 1990s, around a quarter of patients with RA were found to have changes on lung scanning.

Today, the prevalence of clinically significant lung disease is estimated to be around 5% in RA, with a lifetime risk thought to be around 7.7%. Patients with RA who develop ILD are around three times more likely to die than are those who do not, with a reported mean survival around 2.6 years from the diagnosis of lung disease until the advent of these recent studies.

The BRILL network consists of 16 centers located throughout the United Kingdom and was set up to establish a national database of all cases of ILD in RA patients that had been reported by these centers over a 25-year period, beginning in 1988. Patients were included in the database if clinical symptoms, such as shortness of breath or chest crackles, or pulmonary function tests had indicated ILD, and abnormal findings had been confirmed via HRCT.

For the current study, Dr. Kelly and coinvestigators from the BRILL Network looked at a subset of 188 patients with RA and ILD who had been diagnosed between 2000 and 2012. A control group of 188 patients with RA without ILD were included for comparison, matched for age, sex, and duration of RA.

Patients with ILD were more likely than those without to use biologics or immunosuppressants. Of the 188 patients with ILD, 57 were treated with either rituximab or anti-TNF drugs and 83 were treated with immunosuppressants.

The median age at which ILD was identified was 64 years, ranging from 42 to 87 years. The median duration of RA at ILD diagnosis was 9 years and the median duration of ILD was 4 years.

Dr. Kelly reported that RA preceded lung disease in the majority (83%) of cases, while 10% of patients developed ILD before the articular features of their disease became apparent. The onset of RA and ILD was "synchronous" in the remaining 7%.

HRCT results showed that the most common subtype of lung disease was interstitial pneumonia in 65% of cases, which carries the worst overall prognosis, he said. Nonspecific interstitial pneumonia, which is more responsive to early therapy, accounted for 24% of cases. The remaining patients had cryptogenic organizing pneumonia (6%) and or mixed subtypes (5%).

Survival over the 25 years improved, with 67% of RA-ILD patients dying from ILD in 1987-1993, compared with 30% in 2006-2012 (P less than .01). Nevertheless, these data are retrospective, Dr. Kelly observed, and trials are warranted to confirm the effects of specific treatments. He encouraged delegates at the meeting to participate in forthcoming BRILL network studies.

Dr. Kelly had no disclosures.

LIVERPOOL, ENGLAND – Rituximab and mycophenolate mofetil could offer patients with rheumatoid arthritis and concomitant interstitial lung disease a survival advantage over other therapies, according to findings from a large, retrospective, multicenter study.

Data collated by the British Rheumatoid Interstitial Lung (BRILL) network found all-cause mortality in patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD) treated with rituximab was 8% versus 31% for those treated with anti-tumor necrosis factor (TNF) alpha therapies (P = .03). Death from respiratory causes was also significantly lower in the rituximab-treated patients (4% vs. 15%, P = .04).

All-cause mortality was also significantly lower in patients with RA and ILD treated with mycophenolate mofetil (relative risk, 0.65) when compared with azathioprine (RR, 1.42) or other immunosuppressants, which included cyclophosphamide (RR, 1.65) and tacrolimus (RR, 1.74).

However, these data were retrospective, so prospective therapeutic trials are now needed, said Dr. Clive Kelly of Queen Elizabeth Hospital, Gateshead, England. Dr. Kelly, who was the driving force behind the set up of the BRILL network 2 years ago, stated that plans were already afoot to set up these trials with the intention of recruiting 200 patients with RA and ILD across the United Kingdom.

The aim of future studies would be to compare the use of rituximab versus anti-TNF therapies, with or without methotrexate, and mycophenolate mofetil versus azathioprine, with or without oral steroids, to see if the anticipated survival benefit associated with the newer agents is confirmed. Funding for the trials is yet to be secured, but it is hoped that recruitment can begin next year.

When people think of comorbidity in RA, they tend to think about cardiovascular disease first, Dr. Kelly noted at the British Society for Rheumatology annual conference. He observed that ILD has been associated with RA for well over 50 years and that respiratory disease, largely due to ILD and chronic lung damage, is now a "close second" behind heart disease as a cause of death in patients with RA.

Up to 40% of all cases of ILD are discovered in RA patients postmortem, he said, but with the increased use of high-resolution computed tomography (HRCT) in the 1990s, around a quarter of patients with RA were found to have changes on lung scanning.

Today, the prevalence of clinically significant lung disease is estimated to be around 5% in RA, with a lifetime risk thought to be around 7.7%. Patients with RA who develop ILD are around three times more likely to die than are those who do not, with a reported mean survival around 2.6 years from the diagnosis of lung disease until the advent of these recent studies.

The BRILL network consists of 16 centers located throughout the United Kingdom and was set up to establish a national database of all cases of ILD in RA patients that had been reported by these centers over a 25-year period, beginning in 1988. Patients were included in the database if clinical symptoms, such as shortness of breath or chest crackles, or pulmonary function tests had indicated ILD, and abnormal findings had been confirmed via HRCT.

For the current study, Dr. Kelly and coinvestigators from the BRILL Network looked at a subset of 188 patients with RA and ILD who had been diagnosed between 2000 and 2012. A control group of 188 patients with RA without ILD were included for comparison, matched for age, sex, and duration of RA.

Patients with ILD were more likely than those without to use biologics or immunosuppressants. Of the 188 patients with ILD, 57 were treated with either rituximab or anti-TNF drugs and 83 were treated with immunosuppressants.

The median age at which ILD was identified was 64 years, ranging from 42 to 87 years. The median duration of RA at ILD diagnosis was 9 years and the median duration of ILD was 4 years.

Dr. Kelly reported that RA preceded lung disease in the majority (83%) of cases, while 10% of patients developed ILD before the articular features of their disease became apparent. The onset of RA and ILD was "synchronous" in the remaining 7%.

HRCT results showed that the most common subtype of lung disease was interstitial pneumonia in 65% of cases, which carries the worst overall prognosis, he said. Nonspecific interstitial pneumonia, which is more responsive to early therapy, accounted for 24% of cases. The remaining patients had cryptogenic organizing pneumonia (6%) and or mixed subtypes (5%).

Survival over the 25 years improved, with 67% of RA-ILD patients dying from ILD in 1987-1993, compared with 30% in 2006-2012 (P less than .01). Nevertheless, these data are retrospective, Dr. Kelly observed, and trials are warranted to confirm the effects of specific treatments. He encouraged delegates at the meeting to participate in forthcoming BRILL network studies.

Dr. Kelly had no disclosures.

LIVERPOOL, ENGLAND – Rituximab and mycophenolate mofetil could offer patients with rheumatoid arthritis and concomitant interstitial lung disease a survival advantage over other therapies, according to findings from a large, retrospective, multicenter study.

Data collated by the British Rheumatoid Interstitial Lung (BRILL) network found all-cause mortality in patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD) treated with rituximab was 8% versus 31% for those treated with anti-tumor necrosis factor (TNF) alpha therapies (P = .03). Death from respiratory causes was also significantly lower in the rituximab-treated patients (4% vs. 15%, P = .04).

All-cause mortality was also significantly lower in patients with RA and ILD treated with mycophenolate mofetil (relative risk, 0.65) when compared with azathioprine (RR, 1.42) or other immunosuppressants, which included cyclophosphamide (RR, 1.65) and tacrolimus (RR, 1.74).

However, these data were retrospective, so prospective therapeutic trials are now needed, said Dr. Clive Kelly of Queen Elizabeth Hospital, Gateshead, England. Dr. Kelly, who was the driving force behind the set up of the BRILL network 2 years ago, stated that plans were already afoot to set up these trials with the intention of recruiting 200 patients with RA and ILD across the United Kingdom.

The aim of future studies would be to compare the use of rituximab versus anti-TNF therapies, with or without methotrexate, and mycophenolate mofetil versus azathioprine, with or without oral steroids, to see if the anticipated survival benefit associated with the newer agents is confirmed. Funding for the trials is yet to be secured, but it is hoped that recruitment can begin next year.

When people think of comorbidity in RA, they tend to think about cardiovascular disease first, Dr. Kelly noted at the British Society for Rheumatology annual conference. He observed that ILD has been associated with RA for well over 50 years and that respiratory disease, largely due to ILD and chronic lung damage, is now a "close second" behind heart disease as a cause of death in patients with RA.

Up to 40% of all cases of ILD are discovered in RA patients postmortem, he said, but with the increased use of high-resolution computed tomography (HRCT) in the 1990s, around a quarter of patients with RA were found to have changes on lung scanning.

Today, the prevalence of clinically significant lung disease is estimated to be around 5% in RA, with a lifetime risk thought to be around 7.7%. Patients with RA who develop ILD are around three times more likely to die than are those who do not, with a reported mean survival around 2.6 years from the diagnosis of lung disease until the advent of these recent studies.

The BRILL network consists of 16 centers located throughout the United Kingdom and was set up to establish a national database of all cases of ILD in RA patients that had been reported by these centers over a 25-year period, beginning in 1988. Patients were included in the database if clinical symptoms, such as shortness of breath or chest crackles, or pulmonary function tests had indicated ILD, and abnormal findings had been confirmed via HRCT.

For the current study, Dr. Kelly and coinvestigators from the BRILL Network looked at a subset of 188 patients with RA and ILD who had been diagnosed between 2000 and 2012. A control group of 188 patients with RA without ILD were included for comparison, matched for age, sex, and duration of RA.

Patients with ILD were more likely than those without to use biologics or immunosuppressants. Of the 188 patients with ILD, 57 were treated with either rituximab or anti-TNF drugs and 83 were treated with immunosuppressants.

The median age at which ILD was identified was 64 years, ranging from 42 to 87 years. The median duration of RA at ILD diagnosis was 9 years and the median duration of ILD was 4 years.

Dr. Kelly reported that RA preceded lung disease in the majority (83%) of cases, while 10% of patients developed ILD before the articular features of their disease became apparent. The onset of RA and ILD was "synchronous" in the remaining 7%.

HRCT results showed that the most common subtype of lung disease was interstitial pneumonia in 65% of cases, which carries the worst overall prognosis, he said. Nonspecific interstitial pneumonia, which is more responsive to early therapy, accounted for 24% of cases. The remaining patients had cryptogenic organizing pneumonia (6%) and or mixed subtypes (5%).

Survival over the 25 years improved, with 67% of RA-ILD patients dying from ILD in 1987-1993, compared with 30% in 2006-2012 (P less than .01). Nevertheless, these data are retrospective, Dr. Kelly observed, and trials are warranted to confirm the effects of specific treatments. He encouraged delegates at the meeting to participate in forthcoming BRILL network studies.

Dr. Kelly had no disclosures.

LIVERPOOL, ENGLAND – Biologic therapy has shown sustained benefits for the signs and symptoms of juvenile idiopathic arthritis as well as improved height over the course of up to 2 years of treatment, according to data from four studies presented at the British Society for Rheumatology annual conference.

The studies provided evidence indicating that:

• Treatment with etanercept over 2 years helped children with juvenile idiopathic arthritis (JIA) to gain height, although their overall vertical growth still lagged behind children in the general reference population.

• When etanercept was not used as a first-line biologic, it was most common to use adalimumab instead, followed by tocilizumab and infliximab.

• Adalimumab reduced the signs and symptoms of enthesitis-related arthritis (ERA) in children by week 12 of treatment and the effects were sustained at 1-year of follow up.

• The benefits of tocilizumab in reducing disease activity to a minimal level were preserved from 40 weeks to 2 years in most patients.

Etanercept and growth in JIA

"Etanercept therapy was associated with improvement in height z score over the first 2 years of therapy," and the effect was most apparent in children who were not receiving concomitant steroids, said Lianne Kearsley-Fleet, who reported data from the British Society for Paediatric and Adolescent Rheumatology (BSPAR Etanercept Cohort Study). The prospective, observational study was initiated in 2004 with the aim of recruiting all children with JIA who were starting treatment with etanercept. For comparison, a cohort of children newly starting methotrexate was also included.

The current analysis focused on the growth of children taking the biologic therapy because children with JIA are known to have restricted growth, which may be linked to inflammation and the use of corticosteroids. Of 658 children registered in the study, 191 had height data available at baseline and at 1 and 2 years’ follow-up.

Mean height and changes in height during biologic therapy over time were assessed by calculating z scores, and compared with values set by the World Health Organization for girls and boys of a similar age who did not have JIA.

The mean age of children included in the current analysis was 11 years, with a mean disease duration of 3.5 years. The majority (65%) were female, with concomitant oral steroids in 38% and methotrexate in 58%.

The mean height z score of the study population was –0.67 at baseline, –0.57 after 1 year, and –0.45 after 2 years’ etanercept therapy. "While it is still negative [compared with children of a similar sex and age], there is still significant improvement," said Ms. Kearsley-Fleet, a research assistant from the Arthritis Research UK Centre for Epidemiology at the University of Manchester, England.

"There was a lack of evidence for association between disease activity and improved growth," the researcher noted, adding that "anti-TNF inhibitors alone may be insufficient to increase growth."

Use of non–etanercept biologics

In a poster presentation at the meeting, Ms. Kearsley-Fleet and her colleagues at her institution also presented the findings from the Biologics for Children with Rheumatic Diseases Study. This ongoing, prospective, observational cohort study is looking at the use of biologics other than etanercept in the treatment of JIA.

Since the study started in 2010, and up until early April 2014, a total of 280 children with JIA had been recruited into the biologic cohort. The study also includes a parallel control cohort of 295 children being treated with methotrexate. Just under half (46%) of the children recruited into the biologic cohort started a non–etanercept biologic as their first biologic treatment, of which the majority (75%) received the medications off label. The main alternatives to etanercept being used were adalimumab in 38% of cases, followed by tocilizumab in 25% of children, and infliximab in 23%. Other drugs used as the first biologic was anakinra (13%), rituximab (less than 1%), and abatacept (less than 1%).

Adalimumab was also a popular subsequent biologic choice in 30% of cases, with 20% of patients using tocilizumab, and 25% infliximab as a subsequent biologic choice.

The research team reported that patients using a biologic for the first time were significantly younger and had shorter disease durations than did subsequent biologic users. The mean ages of first-, second-, and third-line users were 9, 12, and 11 years, respectively, and the mean disease durations were 2, 6, and 4 years. Subsequent biologic users also had higher active and limited joint counts than did first-time users.

Adalimumab reduces enthesitis-related arthritis symptoms

"Enthesitis-related arthritis is a category of juvenile idiopathic arthritis that primarily affects the peripheral joints and entheses, but can also affect the sacroiliac joints and spine," said Iain Sainsbury, Ph.D., associate director for RA in global medical affairs at AbbVie, in a presentation of data on the efficacy and safety of adalimumab in children with enthesitis-related arthritis (ERA) from the M11-328 study on behalf of the study’s authors.

Since adalimumab had been previously been shown to be an effective treatment for children aged 2-17 years with polyarticular JIA, the aim of the current study was to see if it could also be of benefit in patients with ERA.

The M11-328 study was a 12-week, multicenter, double-blind trial that enrolled 46 children aged 6-18 years. They were randomized 2:1 to receive adalimumab or placebo, with continued open-label treatment for up to 3 years.

The primary endpoint, the percent change in the number of active joints with arthritis from baseline to week 12, showed a clear benefit of treatment with the biologic. Indeed, adalimumab reduced the active joint count by 62.6% vs. a reduction of 11.6% with placebo (P = .039). The treatment response was maintained with continued adalimumab treatment for 1 year. Other signs and symptoms of ERA, such as pain and enthesitis, were also reduced by the active treatment.

Dr. Sainsbury said, "The safety profile in this patient population is consistent with what we see in all other patient populations," including children aged 2 years or older with polyarticular JIA.

CHERISH 2-year data show sustained tocilizumab benefits

Dr. Eileen Baildam of Alder Hey Children’s Hospital in Liverpool, England, reported 2-year follow-up data from the CHERISH phase III trial. This trial was conducted in 58 centers in 15 countries and consisted of three phases: an open-label, lead-in phase that involved 188 children who were treated with tocilizumab for 16 weeks; a double-blind phase in which 166 children were randomized to receive tocilizumab or placebo for 24 weeks; and an open-label extension involving 60 children who were treated with tocilizumab for a further 64 weeks, bringing the total duration of therapy to 104 weeks.

Data from the second phase of the trial, at 40 weeks’ follow-up have been previously reported and "showed a very significant improvement in the flare rate in those treated vs. those on placebo," Dr. Baildam said.

A total of 82% of the 188 children enrolled in the study completed 2 years’ treatment and exhibited improvements in JIA American College of Rheumatology (ACR) 50, 70, and 90 criteria. The percentage of children who were ACR70 responders at 40 weeks and at 104 weeks were 79.3% and 86.6%, respectively, and the percentage who were ACR90 responders were a respective 50% and 70.7%.

Dr. Baildam reported a continued benefit of the anti–interleukin-6 receptor therapy, with 73.5% of children showing minimal disease activity at 40 weeks and 58.5% showing minimal disease activity at 2 years. Benefit was also seen in children who had received prior biologics.

"Overall the safety profiles remained unchanged from those at week 40, there were no deaths, and no new or unexpected safety concerns," she concluded.

The Etanercept Cohort Study is supported by Pfizer; Ms. Kearsley-Fleet had no disclosures. The CHERISH trial was supported by Pfizer; Dr. Baildam has received speaker or advisory board fees from Roche and Pfizer. The adalimumab trial was supported by AbbVie; Dr. Sainsbury is an employee of AbbVie.

LIVERPOOL, ENGLAND – Biologic therapy has shown sustained benefits for the signs and symptoms of juvenile idiopathic arthritis as well as improved height over the course of up to 2 years of treatment, according to data from four studies presented at the British Society for Rheumatology annual conference.

The studies provided evidence indicating that:

• Treatment with etanercept over 2 years helped children with juvenile idiopathic arthritis (JIA) to gain height, although their overall vertical growth still lagged behind children in the general reference population.

• When etanercept was not used as a first-line biologic, it was most common to use adalimumab instead, followed by tocilizumab and infliximab.

• Adalimumab reduced the signs and symptoms of enthesitis-related arthritis (ERA) in children by week 12 of treatment and the effects were sustained at 1-year of follow up.

• The benefits of tocilizumab in reducing disease activity to a minimal level were preserved from 40 weeks to 2 years in most patients.

Etanercept and growth in JIA

"Etanercept therapy was associated with improvement in height z score over the first 2 years of therapy," and the effect was most apparent in children who were not receiving concomitant steroids, said Lianne Kearsley-Fleet, who reported data from the British Society for Paediatric and Adolescent Rheumatology (BSPAR Etanercept Cohort Study). The prospective, observational study was initiated in 2004 with the aim of recruiting all children with JIA who were starting treatment with etanercept. For comparison, a cohort of children newly starting methotrexate was also included.

The current analysis focused on the growth of children taking the biologic therapy because children with JIA are known to have restricted growth, which may be linked to inflammation and the use of corticosteroids. Of 658 children registered in the study, 191 had height data available at baseline and at 1 and 2 years’ follow-up.

Mean height and changes in height during biologic therapy over time were assessed by calculating z scores, and compared with values set by the World Health Organization for girls and boys of a similar age who did not have JIA.

The mean age of children included in the current analysis was 11 years, with a mean disease duration of 3.5 years. The majority (65%) were female, with concomitant oral steroids in 38% and methotrexate in 58%.

The mean height z score of the study population was –0.67 at baseline, –0.57 after 1 year, and –0.45 after 2 years’ etanercept therapy. "While it is still negative [compared with children of a similar sex and age], there is still significant improvement," said Ms. Kearsley-Fleet, a research assistant from the Arthritis Research UK Centre for Epidemiology at the University of Manchester, England.

"There was a lack of evidence for association between disease activity and improved growth," the researcher noted, adding that "anti-TNF inhibitors alone may be insufficient to increase growth."

Use of non–etanercept biologics

In a poster presentation at the meeting, Ms. Kearsley-Fleet and her colleagues at her institution also presented the findings from the Biologics for Children with Rheumatic Diseases Study. This ongoing, prospective, observational cohort study is looking at the use of biologics other than etanercept in the treatment of JIA.

Since the study started in 2010, and up until early April 2014, a total of 280 children with JIA had been recruited into the biologic cohort. The study also includes a parallel control cohort of 295 children being treated with methotrexate. Just under half (46%) of the children recruited into the biologic cohort started a non–etanercept biologic as their first biologic treatment, of which the majority (75%) received the medications off label. The main alternatives to etanercept being used were adalimumab in 38% of cases, followed by tocilizumab in 25% of children, and infliximab in 23%. Other drugs used as the first biologic was anakinra (13%), rituximab (less than 1%), and abatacept (less than 1%).

Adalimumab was also a popular subsequent biologic choice in 30% of cases, with 20% of patients using tocilizumab, and 25% infliximab as a subsequent biologic choice.

The research team reported that patients using a biologic for the first time were significantly younger and had shorter disease durations than did subsequent biologic users. The mean ages of first-, second-, and third-line users were 9, 12, and 11 years, respectively, and the mean disease durations were 2, 6, and 4 years. Subsequent biologic users also had higher active and limited joint counts than did first-time users.

Adalimumab reduces enthesitis-related arthritis symptoms

"Enthesitis-related arthritis is a category of juvenile idiopathic arthritis that primarily affects the peripheral joints and entheses, but can also affect the sacroiliac joints and spine," said Iain Sainsbury, Ph.D., associate director for RA in global medical affairs at AbbVie, in a presentation of data on the efficacy and safety of adalimumab in children with enthesitis-related arthritis (ERA) from the M11-328 study on behalf of the study’s authors.

Since adalimumab had been previously been shown to be an effective treatment for children aged 2-17 years with polyarticular JIA, the aim of the current study was to see if it could also be of benefit in patients with ERA.

The M11-328 study was a 12-week, multicenter, double-blind trial that enrolled 46 children aged 6-18 years. They were randomized 2:1 to receive adalimumab or placebo, with continued open-label treatment for up to 3 years.

The primary endpoint, the percent change in the number of active joints with arthritis from baseline to week 12, showed a clear benefit of treatment with the biologic. Indeed, adalimumab reduced the active joint count by 62.6% vs. a reduction of 11.6% with placebo (P = .039). The treatment response was maintained with continued adalimumab treatment for 1 year. Other signs and symptoms of ERA, such as pain and enthesitis, were also reduced by the active treatment.

Dr. Sainsbury said, "The safety profile in this patient population is consistent with what we see in all other patient populations," including children aged 2 years or older with polyarticular JIA.

CHERISH 2-year data show sustained tocilizumab benefits

Dr. Eileen Baildam of Alder Hey Children’s Hospital in Liverpool, England, reported 2-year follow-up data from the CHERISH phase III trial. This trial was conducted in 58 centers in 15 countries and consisted of three phases: an open-label, lead-in phase that involved 188 children who were treated with tocilizumab for 16 weeks; a double-blind phase in which 166 children were randomized to receive tocilizumab or placebo for 24 weeks; and an open-label extension involving 60 children who were treated with tocilizumab for a further 64 weeks, bringing the total duration of therapy to 104 weeks.

Data from the second phase of the trial, at 40 weeks’ follow-up have been previously reported and "showed a very significant improvement in the flare rate in those treated vs. those on placebo," Dr. Baildam said.

A total of 82% of the 188 children enrolled in the study completed 2 years’ treatment and exhibited improvements in JIA American College of Rheumatology (ACR) 50, 70, and 90 criteria. The percentage of children who were ACR70 responders at 40 weeks and at 104 weeks were 79.3% and 86.6%, respectively, and the percentage who were ACR90 responders were a respective 50% and 70.7%.

Dr. Baildam reported a continued benefit of the anti–interleukin-6 receptor therapy, with 73.5% of children showing minimal disease activity at 40 weeks and 58.5% showing minimal disease activity at 2 years. Benefit was also seen in children who had received prior biologics.

"Overall the safety profiles remained unchanged from those at week 40, there were no deaths, and no new or unexpected safety concerns," she concluded.

The Etanercept Cohort Study is supported by Pfizer; Ms. Kearsley-Fleet had no disclosures. The CHERISH trial was supported by Pfizer; Dr. Baildam has received speaker or advisory board fees from Roche and Pfizer. The adalimumab trial was supported by AbbVie; Dr. Sainsbury is an employee of AbbVie.

LIVERPOOL, ENGLAND – Biologic therapy has shown sustained benefits for the signs and symptoms of juvenile idiopathic arthritis as well as improved height over the course of up to 2 years of treatment, according to data from four studies presented at the British Society for Rheumatology annual conference.

The studies provided evidence indicating that:

• Treatment with etanercept over 2 years helped children with juvenile idiopathic arthritis (JIA) to gain height, although their overall vertical growth still lagged behind children in the general reference population.

• When etanercept was not used as a first-line biologic, it was most common to use adalimumab instead, followed by tocilizumab and infliximab.

• Adalimumab reduced the signs and symptoms of enthesitis-related arthritis (ERA) in children by week 12 of treatment and the effects were sustained at 1-year of follow up.

• The benefits of tocilizumab in reducing disease activity to a minimal level were preserved from 40 weeks to 2 years in most patients.

Etanercept and growth in JIA

"Etanercept therapy was associated with improvement in height z score over the first 2 years of therapy," and the effect was most apparent in children who were not receiving concomitant steroids, said Lianne Kearsley-Fleet, who reported data from the British Society for Paediatric and Adolescent Rheumatology (BSPAR Etanercept Cohort Study). The prospective, observational study was initiated in 2004 with the aim of recruiting all children with JIA who were starting treatment with etanercept. For comparison, a cohort of children newly starting methotrexate was also included.

The current analysis focused on the growth of children taking the biologic therapy because children with JIA are known to have restricted growth, which may be linked to inflammation and the use of corticosteroids. Of 658 children registered in the study, 191 had height data available at baseline and at 1 and 2 years’ follow-up.

Mean height and changes in height during biologic therapy over time were assessed by calculating z scores, and compared with values set by the World Health Organization for girls and boys of a similar age who did not have JIA.

The mean age of children included in the current analysis was 11 years, with a mean disease duration of 3.5 years. The majority (65%) were female, with concomitant oral steroids in 38% and methotrexate in 58%.

The mean height z score of the study population was –0.67 at baseline, –0.57 after 1 year, and –0.45 after 2 years’ etanercept therapy. "While it is still negative [compared with children of a similar sex and age], there is still significant improvement," said Ms. Kearsley-Fleet, a research assistant from the Arthritis Research UK Centre for Epidemiology at the University of Manchester, England.

"There was a lack of evidence for association between disease activity and improved growth," the researcher noted, adding that "anti-TNF inhibitors alone may be insufficient to increase growth."

Use of non–etanercept biologics

In a poster presentation at the meeting, Ms. Kearsley-Fleet and her colleagues at her institution also presented the findings from the Biologics for Children with Rheumatic Diseases Study. This ongoing, prospective, observational cohort study is looking at the use of biologics other than etanercept in the treatment of JIA.

Since the study started in 2010, and up until early April 2014, a total of 280 children with JIA had been recruited into the biologic cohort. The study also includes a parallel control cohort of 295 children being treated with methotrexate. Just under half (46%) of the children recruited into the biologic cohort started a non–etanercept biologic as their first biologic treatment, of which the majority (75%) received the medications off label. The main alternatives to etanercept being used were adalimumab in 38% of cases, followed by tocilizumab in 25% of children, and infliximab in 23%. Other drugs used as the first biologic was anakinra (13%), rituximab (less than 1%), and abatacept (less than 1%).

Adalimumab was also a popular subsequent biologic choice in 30% of cases, with 20% of patients using tocilizumab, and 25% infliximab as a subsequent biologic choice.

The research team reported that patients using a biologic for the first time were significantly younger and had shorter disease durations than did subsequent biologic users. The mean ages of first-, second-, and third-line users were 9, 12, and 11 years, respectively, and the mean disease durations were 2, 6, and 4 years. Subsequent biologic users also had higher active and limited joint counts than did first-time users.

Adalimumab reduces enthesitis-related arthritis symptoms

"Enthesitis-related arthritis is a category of juvenile idiopathic arthritis that primarily affects the peripheral joints and entheses, but can also affect the sacroiliac joints and spine," said Iain Sainsbury, Ph.D., associate director for RA in global medical affairs at AbbVie, in a presentation of data on the efficacy and safety of adalimumab in children with enthesitis-related arthritis (ERA) from the M11-328 study on behalf of the study’s authors.

Since adalimumab had been previously been shown to be an effective treatment for children aged 2-17 years with polyarticular JIA, the aim of the current study was to see if it could also be of benefit in patients with ERA.

The M11-328 study was a 12-week, multicenter, double-blind trial that enrolled 46 children aged 6-18 years. They were randomized 2:1 to receive adalimumab or placebo, with continued open-label treatment for up to 3 years.

The primary endpoint, the percent change in the number of active joints with arthritis from baseline to week 12, showed a clear benefit of treatment with the biologic. Indeed, adalimumab reduced the active joint count by 62.6% vs. a reduction of 11.6% with placebo (P = .039). The treatment response was maintained with continued adalimumab treatment for 1 year. Other signs and symptoms of ERA, such as pain and enthesitis, were also reduced by the active treatment.

Dr. Sainsbury said, "The safety profile in this patient population is consistent with what we see in all other patient populations," including children aged 2 years or older with polyarticular JIA.

CHERISH 2-year data show sustained tocilizumab benefits

Dr. Eileen Baildam of Alder Hey Children’s Hospital in Liverpool, England, reported 2-year follow-up data from the CHERISH phase III trial. This trial was conducted in 58 centers in 15 countries and consisted of three phases: an open-label, lead-in phase that involved 188 children who were treated with tocilizumab for 16 weeks; a double-blind phase in which 166 children were randomized to receive tocilizumab or placebo for 24 weeks; and an open-label extension involving 60 children who were treated with tocilizumab for a further 64 weeks, bringing the total duration of therapy to 104 weeks.

Data from the second phase of the trial, at 40 weeks’ follow-up have been previously reported and "showed a very significant improvement in the flare rate in those treated vs. those on placebo," Dr. Baildam said.

A total of 82% of the 188 children enrolled in the study completed 2 years’ treatment and exhibited improvements in JIA American College of Rheumatology (ACR) 50, 70, and 90 criteria. The percentage of children who were ACR70 responders at 40 weeks and at 104 weeks were 79.3% and 86.6%, respectively, and the percentage who were ACR90 responders were a respective 50% and 70.7%.

Dr. Baildam reported a continued benefit of the anti–interleukin-6 receptor therapy, with 73.5% of children showing minimal disease activity at 40 weeks and 58.5% showing minimal disease activity at 2 years. Benefit was also seen in children who had received prior biologics.

"Overall the safety profiles remained unchanged from those at week 40, there were no deaths, and no new or unexpected safety concerns," she concluded.

The Etanercept Cohort Study is supported by Pfizer; Ms. Kearsley-Fleet had no disclosures. The CHERISH trial was supported by Pfizer; Dr. Baildam has received speaker or advisory board fees from Roche and Pfizer. The adalimumab trial was supported by AbbVie; Dr. Sainsbury is an employee of AbbVie.