Nancy Walsh

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — Repeated treatment with a new type of B-cell-depleting agent was well tolerated and reduced signs and symptoms of rheumatoid arthritis, according to an interim analysis of an ongoing open-label study.

Analysis of pooled clinical responses from two dosage groups found that approximately 50% of patients achieved a 20% improvement in American College of Rheumatology parameters (ACR20); 25% had ACR50 responses, and 10%–15% had ACR70 responses, Dr. Richard W. Martin said at the annual European Congress of Rheumatology.

TRU-015 is a small modular immunopharmaceutical (SMIP), a single-chain protein that is approximately one-half to one-third the size of a monoclonal antibody. It is directed against CD20 markers on the surfaces of B cells, Dr. Martin said.

TRU-015 differs from rituximab in that it is human rather than chimeric, and was designed using a custom drug assembly technology that reduces complement activation, which is thought to contribute to some rituximab-associated adverse events, such as infusion reactions, and may play a role in disease activity in RA.

In all, 36 patients have now had at least one retreatment (that is, a second infusion), and 29 have had more than one retreatment (at least three infusions).

At this point, more than 100 courses of the experimental agent have been administered, with some patients receiving up to six courses over 3 years, Dr. Martin said. Patients who had previously received an infusion of at least 5 mg/kg and who completed 24 weeks of follow-up with at least 70% of B-cell recovery were eligible for retreatment with either 5 mg/kg or 15 mg/kg of TRU-015.

The infusions have generally been well tolerated, and there have been no grade 3 or 4 adverse events. Four patients had grade 2 adverse events, including facial flushing, erythema, and pruritus, as well as worsening insomnia.

Whether these events were caused by the study agent or by pretreatment with corticosteroids is not known, said Dr. Martin, professor of medicine and rheumatology at Michigan State University, Grand Rapids.

Six patients withdrew from the study, primarily for administrative reasons. There were no withdrawals because of adverse events, and there have been no opportunistic infections or deaths.

Headache was reported by 28% of patients after their first infusion; this fell to 8% and 7% after the second and third infusions. Other adverse events, such as fatigue and edema, also decreased with repeated treatments.

Nine serious adverse events were seen in seven patients. One patient had two hospitalizations for exacerbations of chronic obstructive pulmonary disease, another patient experienced an episode of cholecystitis, and one reported shortness of breath of unknown cause.

The retreatment pharmacokinetics of TRU-015 following repeated infusions are indistinguishable from those seen with the initial treatment, suggesting that there is no significant early development of neutralizing antibodies. There also was no attenuation in B-cell depletion following retreatment.

Clinical responses have been maintained from the first treatment to the second and beyond, he added.

Dr. Martin did not say when the trial was expected to be complete.

The manufacturer of TRU-015, Trubion Pharmaceuticals Inc., is creating a pipeline of customized therapeutic products, including SMIPs, for the treatment of autoimmune and inflammatory diseases and cancer.

Additionally, Wyeth Pharmaceuticals and Trubion have a worldwide licensing and commercialization agreement for the development of TRU-015 and other CD20-targeted therapies.

Dr. Martin disclosed that he has had contracts for clinical trials with Trubion, but owns no stock in the company and is not a paid consultant.

PARIS — Repeated treatment with a new type of B-cell-depleting agent was well tolerated and reduced signs and symptoms of rheumatoid arthritis, according to an interim analysis of an ongoing open-label study.

Analysis of pooled clinical responses from two dosage groups found that approximately 50% of patients achieved a 20% improvement in American College of Rheumatology parameters (ACR20); 25% had ACR50 responses, and 10%–15% had ACR70 responses, Dr. Richard W. Martin said at the annual European Congress of Rheumatology.

TRU-015 is a small modular immunopharmaceutical (SMIP), a single-chain protein that is approximately one-half to one-third the size of a monoclonal antibody. It is directed against CD20 markers on the surfaces of B cells, Dr. Martin said.

TRU-015 differs from rituximab in that it is human rather than chimeric, and was designed using a custom drug assembly technology that reduces complement activation, which is thought to contribute to some rituximab-associated adverse events, such as infusion reactions, and may play a role in disease activity in RA.

In all, 36 patients have now had at least one retreatment (that is, a second infusion), and 29 have had more than one retreatment (at least three infusions).

At this point, more than 100 courses of the experimental agent have been administered, with some patients receiving up to six courses over 3 years, Dr. Martin said. Patients who had previously received an infusion of at least 5 mg/kg and who completed 24 weeks of follow-up with at least 70% of B-cell recovery were eligible for retreatment with either 5 mg/kg or 15 mg/kg of TRU-015.

The infusions have generally been well tolerated, and there have been no grade 3 or 4 adverse events. Four patients had grade 2 adverse events, including facial flushing, erythema, and pruritus, as well as worsening insomnia.

Whether these events were caused by the study agent or by pretreatment with corticosteroids is not known, said Dr. Martin, professor of medicine and rheumatology at Michigan State University, Grand Rapids.

Six patients withdrew from the study, primarily for administrative reasons. There were no withdrawals because of adverse events, and there have been no opportunistic infections or deaths.

Headache was reported by 28% of patients after their first infusion; this fell to 8% and 7% after the second and third infusions. Other adverse events, such as fatigue and edema, also decreased with repeated treatments.

Nine serious adverse events were seen in seven patients. One patient had two hospitalizations for exacerbations of chronic obstructive pulmonary disease, another patient experienced an episode of cholecystitis, and one reported shortness of breath of unknown cause.

The retreatment pharmacokinetics of TRU-015 following repeated infusions are indistinguishable from those seen with the initial treatment, suggesting that there is no significant early development of neutralizing antibodies. There also was no attenuation in B-cell depletion following retreatment.

Clinical responses have been maintained from the first treatment to the second and beyond, he added.

Dr. Martin did not say when the trial was expected to be complete.

The manufacturer of TRU-015, Trubion Pharmaceuticals Inc., is creating a pipeline of customized therapeutic products, including SMIPs, for the treatment of autoimmune and inflammatory diseases and cancer.

Additionally, Wyeth Pharmaceuticals and Trubion have a worldwide licensing and commercialization agreement for the development of TRU-015 and other CD20-targeted therapies.

Dr. Martin disclosed that he has had contracts for clinical trials with Trubion, but owns no stock in the company and is not a paid consultant.

PARIS — Repeated treatment with a new type of B-cell-depleting agent was well tolerated and reduced signs and symptoms of rheumatoid arthritis, according to an interim analysis of an ongoing open-label study.

Analysis of pooled clinical responses from two dosage groups found that approximately 50% of patients achieved a 20% improvement in American College of Rheumatology parameters (ACR20); 25% had ACR50 responses, and 10%–15% had ACR70 responses, Dr. Richard W. Martin said at the annual European Congress of Rheumatology.

TRU-015 is a small modular immunopharmaceutical (SMIP), a single-chain protein that is approximately one-half to one-third the size of a monoclonal antibody. It is directed against CD20 markers on the surfaces of B cells, Dr. Martin said.

TRU-015 differs from rituximab in that it is human rather than chimeric, and was designed using a custom drug assembly technology that reduces complement activation, which is thought to contribute to some rituximab-associated adverse events, such as infusion reactions, and may play a role in disease activity in RA.

In all, 36 patients have now had at least one retreatment (that is, a second infusion), and 29 have had more than one retreatment (at least three infusions).

At this point, more than 100 courses of the experimental agent have been administered, with some patients receiving up to six courses over 3 years, Dr. Martin said. Patients who had previously received an infusion of at least 5 mg/kg and who completed 24 weeks of follow-up with at least 70% of B-cell recovery were eligible for retreatment with either 5 mg/kg or 15 mg/kg of TRU-015.

The infusions have generally been well tolerated, and there have been no grade 3 or 4 adverse events. Four patients had grade 2 adverse events, including facial flushing, erythema, and pruritus, as well as worsening insomnia.

Whether these events were caused by the study agent or by pretreatment with corticosteroids is not known, said Dr. Martin, professor of medicine and rheumatology at Michigan State University, Grand Rapids.

Six patients withdrew from the study, primarily for administrative reasons. There were no withdrawals because of adverse events, and there have been no opportunistic infections or deaths.

Headache was reported by 28% of patients after their first infusion; this fell to 8% and 7% after the second and third infusions. Other adverse events, such as fatigue and edema, also decreased with repeated treatments.

Nine serious adverse events were seen in seven patients. One patient had two hospitalizations for exacerbations of chronic obstructive pulmonary disease, another patient experienced an episode of cholecystitis, and one reported shortness of breath of unknown cause.

The retreatment pharmacokinetics of TRU-015 following repeated infusions are indistinguishable from those seen with the initial treatment, suggesting that there is no significant early development of neutralizing antibodies. There also was no attenuation in B-cell depletion following retreatment.

Clinical responses have been maintained from the first treatment to the second and beyond, he added.

Dr. Martin did not say when the trial was expected to be complete.

The manufacturer of TRU-015, Trubion Pharmaceuticals Inc., is creating a pipeline of customized therapeutic products, including SMIPs, for the treatment of autoimmune and inflammatory diseases and cancer.

Additionally, Wyeth Pharmaceuticals and Trubion have a worldwide licensing and commercialization agreement for the development of TRU-015 and other CD20-targeted therapies.

Dr. Martin disclosed that he has had contracts for clinical trials with Trubion, but owns no stock in the company and is not a paid consultant.

The first comprehensive guidelines for the diagnosis and management of stroke in children are intended to provide a wide range of clinicians responsible for treating cerebrovascular disease in infants and children with evidence- and consensus-based recommendations, according to the American Heart Association.

“Management of Stroke in Infants and Children,” written by a group of experts from the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, was recently released online.

“Only a few centers in the country have a high level of expertise in dealing with stroke in children, and these guidelines share this concentrated knowledge with physicians who don't have access to that expertise,” committee chair E. Steve Roach said in an interview.

One important message of the statement is that stroke in children is much more common than is generally realized. Data from the National Hospital Discharge Survey from 1980 to 1998 suggested that the overall risk of stroke from birth through 18 years is 13.5/100,000 and that the rate of hemorrhagic stroke for term infants is 6.7/100,000 per year. Other recent investigations found that neonatal stroke occurs in about 1 in 4,000 live births, with about 80% being ischemic.

Strokes in children differ from those in adults, in that few are associated with atherosclerosis. One similarity, however, is that in both adults and children once the stroke has occurred, no medicine can reverse it, said Dr. Roach, chief of neurology at Nationwide Children's Hospital and professor of pediatric neurology, Ohio State University, both in Columbus.

“However, an aggressive approach to finding out the cause of the stroke is your best chance for preventing stroke No. 2 or 3 and preventing the cumulative pileup of brain damage that will determine whether that child grows into a normally functioning adult,” he said.

Among the causes and risk factors for stroke in infants and children discussed in the statement are sickle cell disease, congenital heart disease, and cervicocephalic arterial dissection (Circulation 2008 [doi:10.1161/strokeaha.108.189696]). For sickle cell disease, detailed recommendations are included on primary and secondary stroke prevention.

Management of acute ischemic stroke should include optimal hydration and correction of hypoxemia and hypotension. Periodic transfusions are recommended for children aged 2–16 years with abnormal transcranial Doppler findings, and those with a confirmed cerebral infarction should be on a program of red cell transfusion with measures to prevent iron overload.

For hemorrhagic stroke, recommendations include noninvasive testing and standard cerebral angiography if needed, along with stabilizing measures such as controlling hypertension and seizures and managing increased intracranial pressure. Surgical evacuation of a supratentorial intracerebral hematoma is not recommended in most circumstances, although in certain selected patients with developing brain herniation or very high intracranial pressure, surgery may be helpful.

With cerebral venous sinus thrombosis (CVST) in children, anticoagulation is reasonable, with the exception of neonates. “Until there is more evidence of safety and effectiveness, anticoagulation is not appropriate for most neonates with CVST,” the authors wrote.

Some recommendations are likely to cause controversy, according to Dr. Heather J. Fullerton, who directs the pediatric stroke and cerebrovascular disease center at the University of California, San Francisco. “For example, the guidelines recommend anticoagulation only for neonates who have some evidence of progression of venous sinus thrombosis, either radiographically or clinically, whereas in many institutions neonates with venous sinus thrombosis are routinely anticoagulated,” she said in an interview.

Nonetheless, “these are landmark comprehensive guidelines,” said Dr. Fullerton, who was not a member of the writing group.

“These guidelines will be helpful in that they express the consensus opinion of a group of experts based on the existing literature and will be extremely useful for clinicians who have struggled with how to manage these patients in the absence of more evidence,” she said.

The first comprehensive guidelines for the diagnosis and management of stroke in children are intended to provide a wide range of clinicians responsible for treating cerebrovascular disease in infants and children with evidence- and consensus-based recommendations, according to the American Heart Association.

“Management of Stroke in Infants and Children,” written by a group of experts from the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, was recently released online.

“Only a few centers in the country have a high level of expertise in dealing with stroke in children, and these guidelines share this concentrated knowledge with physicians who don't have access to that expertise,” committee chair E. Steve Roach said in an interview.

One important message of the statement is that stroke in children is much more common than is generally realized. Data from the National Hospital Discharge Survey from 1980 to 1998 suggested that the overall risk of stroke from birth through 18 years is 13.5/100,000 and that the rate of hemorrhagic stroke for term infants is 6.7/100,000 per year. Other recent investigations found that neonatal stroke occurs in about 1 in 4,000 live births, with about 80% being ischemic.

Strokes in children differ from those in adults, in that few are associated with atherosclerosis. One similarity, however, is that in both adults and children once the stroke has occurred, no medicine can reverse it, said Dr. Roach, chief of neurology at Nationwide Children's Hospital and professor of pediatric neurology, Ohio State University, both in Columbus.

“However, an aggressive approach to finding out the cause of the stroke is your best chance for preventing stroke No. 2 or 3 and preventing the cumulative pileup of brain damage that will determine whether that child grows into a normally functioning adult,” he said.

Among the causes and risk factors for stroke in infants and children discussed in the statement are sickle cell disease, congenital heart disease, and cervicocephalic arterial dissection (Circulation 2008 [doi:10.1161/strokeaha.108.189696]). For sickle cell disease, detailed recommendations are included on primary and secondary stroke prevention.

Management of acute ischemic stroke should include optimal hydration and correction of hypoxemia and hypotension. Periodic transfusions are recommended for children aged 2–16 years with abnormal transcranial Doppler findings, and those with a confirmed cerebral infarction should be on a program of red cell transfusion with measures to prevent iron overload.

For hemorrhagic stroke, recommendations include noninvasive testing and standard cerebral angiography if needed, along with stabilizing measures such as controlling hypertension and seizures and managing increased intracranial pressure. Surgical evacuation of a supratentorial intracerebral hematoma is not recommended in most circumstances, although in certain selected patients with developing brain herniation or very high intracranial pressure, surgery may be helpful.

With cerebral venous sinus thrombosis (CVST) in children, anticoagulation is reasonable, with the exception of neonates. “Until there is more evidence of safety and effectiveness, anticoagulation is not appropriate for most neonates with CVST,” the authors wrote.

Some recommendations are likely to cause controversy, according to Dr. Heather J. Fullerton, who directs the pediatric stroke and cerebrovascular disease center at the University of California, San Francisco. “For example, the guidelines recommend anticoagulation only for neonates who have some evidence of progression of venous sinus thrombosis, either radiographically or clinically, whereas in many institutions neonates with venous sinus thrombosis are routinely anticoagulated,” she said in an interview.

Nonetheless, “these are landmark comprehensive guidelines,” said Dr. Fullerton, who was not a member of the writing group.

“These guidelines will be helpful in that they express the consensus opinion of a group of experts based on the existing literature and will be extremely useful for clinicians who have struggled with how to manage these patients in the absence of more evidence,” she said.

The first comprehensive guidelines for the diagnosis and management of stroke in children are intended to provide a wide range of clinicians responsible for treating cerebrovascular disease in infants and children with evidence- and consensus-based recommendations, according to the American Heart Association.

“Management of Stroke in Infants and Children,” written by a group of experts from the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, was recently released online.

“Only a few centers in the country have a high level of expertise in dealing with stroke in children, and these guidelines share this concentrated knowledge with physicians who don't have access to that expertise,” committee chair E. Steve Roach said in an interview.

One important message of the statement is that stroke in children is much more common than is generally realized. Data from the National Hospital Discharge Survey from 1980 to 1998 suggested that the overall risk of stroke from birth through 18 years is 13.5/100,000 and that the rate of hemorrhagic stroke for term infants is 6.7/100,000 per year. Other recent investigations found that neonatal stroke occurs in about 1 in 4,000 live births, with about 80% being ischemic.

Strokes in children differ from those in adults, in that few are associated with atherosclerosis. One similarity, however, is that in both adults and children once the stroke has occurred, no medicine can reverse it, said Dr. Roach, chief of neurology at Nationwide Children's Hospital and professor of pediatric neurology, Ohio State University, both in Columbus.

“However, an aggressive approach to finding out the cause of the stroke is your best chance for preventing stroke No. 2 or 3 and preventing the cumulative pileup of brain damage that will determine whether that child grows into a normally functioning adult,” he said.

Among the causes and risk factors for stroke in infants and children discussed in the statement are sickle cell disease, congenital heart disease, and cervicocephalic arterial dissection (Circulation 2008 [doi:10.1161/strokeaha.108.189696]). For sickle cell disease, detailed recommendations are included on primary and secondary stroke prevention.

Management of acute ischemic stroke should include optimal hydration and correction of hypoxemia and hypotension. Periodic transfusions are recommended for children aged 2–16 years with abnormal transcranial Doppler findings, and those with a confirmed cerebral infarction should be on a program of red cell transfusion with measures to prevent iron overload.

For hemorrhagic stroke, recommendations include noninvasive testing and standard cerebral angiography if needed, along with stabilizing measures such as controlling hypertension and seizures and managing increased intracranial pressure. Surgical evacuation of a supratentorial intracerebral hematoma is not recommended in most circumstances, although in certain selected patients with developing brain herniation or very high intracranial pressure, surgery may be helpful.

With cerebral venous sinus thrombosis (CVST) in children, anticoagulation is reasonable, with the exception of neonates. “Until there is more evidence of safety and effectiveness, anticoagulation is not appropriate for most neonates with CVST,” the authors wrote.

Some recommendations are likely to cause controversy, according to Dr. Heather J. Fullerton, who directs the pediatric stroke and cerebrovascular disease center at the University of California, San Francisco. “For example, the guidelines recommend anticoagulation only for neonates who have some evidence of progression of venous sinus thrombosis, either radiographically or clinically, whereas in many institutions neonates with venous sinus thrombosis are routinely anticoagulated,” she said in an interview.

Nonetheless, “these are landmark comprehensive guidelines,” said Dr. Fullerton, who was not a member of the writing group.

“These guidelines will be helpful in that they express the consensus opinion of a group of experts based on the existing literature and will be extremely useful for clinicians who have struggled with how to manage these patients in the absence of more evidence,” she said.

Early childhood colonization with the major human commensal microbe Helicobacter pylori may be protective against asthma, study findings show.

According to the “hygiene hypothesis,” the rise in asthma and allergic disorders that occurred during the 20th century relates to a reduction in exposure to environmental antigens and alterations in gut microbiota during development of the immune system.

Changes in human colonization with H. pylori represent a “biologically plausible” candidate in the hygiene hypothesis, asserted Dr. Yu Chen of New York University and Dr. Martin J. Blaser of New York University and the Veterans Affairs Medical Center, New York..

The investigators explained that there has been a near universal association of this organism and humans for at least 58,000 years, since the time of the initial human migration out of Africa. Seropositivity is generally acquired during the first few years of life and remains lifelong unless eradicated by antibiotics.

The prevalence of seropositivity began to decline early in the last century, a trend that was paralleled by an increase in asthma. Today the seroprevalence in native-born children younger than 10 years in the United States stands at less than 10%, wrote the researchers (J. Infect. Dis. 2008;198: 553-60).

To investigate whether this decline in H. pylori colonization could be linked to the increase in asthma in children, the investigators analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999–2000, which is a representative sample of the U.S. population.

They estimated odds ratios for asthma, wheezing, and other allergic conditions such as allergic rhinitis and eczema, with adjustment for age, body mass index, smoking, education level, race, country of origin, and also for antibiotic and corticosteroid use in the previous month, medical insurance status, and household income.

The sample included 7,412 participants, 3,327 of whom were younger than 20 years. Overall seroprevalence for H. pylori was 26%, but prevalence was lower in younger groups, with only 5% of children younger than 10 years being seropositive.

For the entire cohort there was a trend toward an inverse association between seropositivity for H. pylori and ever having had asthma and for having had one or more asthma attacks during the past year. There was a significant inverse association between H. pylori seropositivity and having had eczema or dermatitis in the past year, with an odds ratio of 0.73.

Among the 3,327 subjects who were age 19 years or younger at the time of data collection, there was a strong inverse association between H. pylori positivity and onset of asthma before 5 years of age, with an odds ratio of 0.58.

Furthermore, among those aged 3–13 years, strong inverse associations were seen for seropositivity and current asthma, ever having had asthma, and having had allergic rhinitis during the previous year.

A possible explanation for the recent decline in H. pylori colonization is the widespread use of antibiotics in children for conditions such as otitis media, according to Dr. Chen and Dr. Blaser. In fact, they noted, their study population was “strongly impacted” by antibiotics, with 11% of those younger than 10 years having had an antibiotic during the month before data collection. Eradication rates of H. pylori with antibiotic monotherapy range from 10% to 50%.

“Our findings suggest H. pylori status is one of the measurable risk factors for asthma and atopic conditions in children,” they wrote. Among the characteristics favoring H. pylori as protective is its dominance in the gastric microbiota and its “intimate relationship with the gastric mucosa, where it injects bacterial constituents into epithelial cells.”

In seropositive subjects, lymphoid cells such as helper and regulatory T cells are found in the gastric lamina propria. These lymphoid cell populations are absent in seronegative persons.

Dr. Chen and Dr. Blaser commented that the loss of the lymphoid compartment in the stomach, with its activator and regulatory T cells, could potentially lower an age-dependent threshold for allergic sensitization.

Early childhood colonization with the major human commensal microbe Helicobacter pylori may be protective against asthma, study findings show.

According to the “hygiene hypothesis,” the rise in asthma and allergic disorders that occurred during the 20th century relates to a reduction in exposure to environmental antigens and alterations in gut microbiota during development of the immune system.

Changes in human colonization with H. pylori represent a “biologically plausible” candidate in the hygiene hypothesis, asserted Dr. Yu Chen of New York University and Dr. Martin J. Blaser of New York University and the Veterans Affairs Medical Center, New York..

The investigators explained that there has been a near universal association of this organism and humans for at least 58,000 years, since the time of the initial human migration out of Africa. Seropositivity is generally acquired during the first few years of life and remains lifelong unless eradicated by antibiotics.

The prevalence of seropositivity began to decline early in the last century, a trend that was paralleled by an increase in asthma. Today the seroprevalence in native-born children younger than 10 years in the United States stands at less than 10%, wrote the researchers (J. Infect. Dis. 2008;198: 553-60).

To investigate whether this decline in H. pylori colonization could be linked to the increase in asthma in children, the investigators analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999–2000, which is a representative sample of the U.S. population.

They estimated odds ratios for asthma, wheezing, and other allergic conditions such as allergic rhinitis and eczema, with adjustment for age, body mass index, smoking, education level, race, country of origin, and also for antibiotic and corticosteroid use in the previous month, medical insurance status, and household income.

The sample included 7,412 participants, 3,327 of whom were younger than 20 years. Overall seroprevalence for H. pylori was 26%, but prevalence was lower in younger groups, with only 5% of children younger than 10 years being seropositive.

For the entire cohort there was a trend toward an inverse association between seropositivity for H. pylori and ever having had asthma and for having had one or more asthma attacks during the past year. There was a significant inverse association between H. pylori seropositivity and having had eczema or dermatitis in the past year, with an odds ratio of 0.73.

Among the 3,327 subjects who were age 19 years or younger at the time of data collection, there was a strong inverse association between H. pylori positivity and onset of asthma before 5 years of age, with an odds ratio of 0.58.

Furthermore, among those aged 3–13 years, strong inverse associations were seen for seropositivity and current asthma, ever having had asthma, and having had allergic rhinitis during the previous year.

A possible explanation for the recent decline in H. pylori colonization is the widespread use of antibiotics in children for conditions such as otitis media, according to Dr. Chen and Dr. Blaser. In fact, they noted, their study population was “strongly impacted” by antibiotics, with 11% of those younger than 10 years having had an antibiotic during the month before data collection. Eradication rates of H. pylori with antibiotic monotherapy range from 10% to 50%.

“Our findings suggest H. pylori status is one of the measurable risk factors for asthma and atopic conditions in children,” they wrote. Among the characteristics favoring H. pylori as protective is its dominance in the gastric microbiota and its “intimate relationship with the gastric mucosa, where it injects bacterial constituents into epithelial cells.”

In seropositive subjects, lymphoid cells such as helper and regulatory T cells are found in the gastric lamina propria. These lymphoid cell populations are absent in seronegative persons.

Dr. Chen and Dr. Blaser commented that the loss of the lymphoid compartment in the stomach, with its activator and regulatory T cells, could potentially lower an age-dependent threshold for allergic sensitization.

Early childhood colonization with the major human commensal microbe Helicobacter pylori may be protective against asthma, study findings show.

According to the “hygiene hypothesis,” the rise in asthma and allergic disorders that occurred during the 20th century relates to a reduction in exposure to environmental antigens and alterations in gut microbiota during development of the immune system.

Changes in human colonization with H. pylori represent a “biologically plausible” candidate in the hygiene hypothesis, asserted Dr. Yu Chen of New York University and Dr. Martin J. Blaser of New York University and the Veterans Affairs Medical Center, New York..

The investigators explained that there has been a near universal association of this organism and humans for at least 58,000 years, since the time of the initial human migration out of Africa. Seropositivity is generally acquired during the first few years of life and remains lifelong unless eradicated by antibiotics.

The prevalence of seropositivity began to decline early in the last century, a trend that was paralleled by an increase in asthma. Today the seroprevalence in native-born children younger than 10 years in the United States stands at less than 10%, wrote the researchers (J. Infect. Dis. 2008;198: 553-60).

To investigate whether this decline in H. pylori colonization could be linked to the increase in asthma in children, the investigators analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999–2000, which is a representative sample of the U.S. population.

They estimated odds ratios for asthma, wheezing, and other allergic conditions such as allergic rhinitis and eczema, with adjustment for age, body mass index, smoking, education level, race, country of origin, and also for antibiotic and corticosteroid use in the previous month, medical insurance status, and household income.

The sample included 7,412 participants, 3,327 of whom were younger than 20 years. Overall seroprevalence for H. pylori was 26%, but prevalence was lower in younger groups, with only 5% of children younger than 10 years being seropositive.

For the entire cohort there was a trend toward an inverse association between seropositivity for H. pylori and ever having had asthma and for having had one or more asthma attacks during the past year. There was a significant inverse association between H. pylori seropositivity and having had eczema or dermatitis in the past year, with an odds ratio of 0.73.

Among the 3,327 subjects who were age 19 years or younger at the time of data collection, there was a strong inverse association between H. pylori positivity and onset of asthma before 5 years of age, with an odds ratio of 0.58.

Furthermore, among those aged 3–13 years, strong inverse associations were seen for seropositivity and current asthma, ever having had asthma, and having had allergic rhinitis during the previous year.

A possible explanation for the recent decline in H. pylori colonization is the widespread use of antibiotics in children for conditions such as otitis media, according to Dr. Chen and Dr. Blaser. In fact, they noted, their study population was “strongly impacted” by antibiotics, with 11% of those younger than 10 years having had an antibiotic during the month before data collection. Eradication rates of H. pylori with antibiotic monotherapy range from 10% to 50%.

“Our findings suggest H. pylori status is one of the measurable risk factors for asthma and atopic conditions in children,” they wrote. Among the characteristics favoring H. pylori as protective is its dominance in the gastric microbiota and its “intimate relationship with the gastric mucosa, where it injects bacterial constituents into epithelial cells.”

In seropositive subjects, lymphoid cells such as helper and regulatory T cells are found in the gastric lamina propria. These lymphoid cell populations are absent in seronegative persons.

Dr. Chen and Dr. Blaser commented that the loss of the lymphoid compartment in the stomach, with its activator and regulatory T cells, could potentially lower an age-dependent threshold for allergic sensitization.

TORONTO — Treatment of patients with idiopathic pulmonary fibrosis with pirfenidone was “encouraging” in a phase III study conducted in Japan.

Few treatment options are available for patients with idiopathic pulmonary fibrosis (IPF), Dr. Takashi Ogura said at an international conference of the American Thoracic Society.

A previous phase II study suggested the agent, which has antifibrotic, anti-inflammatory, and antioxidant effects, could be beneficial.

In that study, 107 patients aged 20–75 years were randomized to receive pirfenidone in dosages up to 1,800 mg/day or placebo, and were followed for 9 months, during which time improvements were seen on vital capacity (VC), although not on a 6-minute walk test (Am. J. Respir. Crit. Care Med. 2005;171:1040-7).

The current study included 267 patients from 73 centers. Two radiologists verified the diagnosis in each patient after reviewing chest x-rays and high-resolution CT scans.

Patients were then randomized to receive pirfenidone 1,800 mg/day or 1,200 mg/day, or placebo. Vital capacity was measured every 4 weeks, and lowest oxygen saturation by pulse oximetry (SpO₂) on exertion was measured every 12 weeks.

Statistically significant improvements were seen in both pirfenidone groups on the primary end point, which was change in VC, as well as in an overall slowing of deterioration from the progressive, fatal disease, Dr. Ogura said.

“At week 52, the difference between the pirfenidone high-dose group and placebo was 70 mL, and the difference between the lower-dose group and placebo was 80 mL,” said Dr. Ogura of Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

Statistically significant changes also were seen in progression-free survival, although not in the lowest SpO₂ on exertion or the incidence of acute exacerbations.

The most common adverse events associated with the treatment were photosensitivity, dizziness, anorexia, and elevated γ-glutamyl transpeptidase. The drug was generally well tolerated, with no significant differences being seen among the three groups for serious adverse events.

A total of 32% of patients dropped out during the course of the study, including 37% of the patients taking 1,800 mg of pirfenidone, 28% of those taking 1,200 mg, and 27% of patients in the placebo group.

The researchers will continue to follow the patients to see if pirfenidone can improve survival, and to see if the drug also may prove useful in other fibrotic lung diseases.

Dr. Ogura noted that he had no relevant financial disclosures.

TORONTO — Treatment of patients with idiopathic pulmonary fibrosis with pirfenidone was “encouraging” in a phase III study conducted in Japan.

Few treatment options are available for patients with idiopathic pulmonary fibrosis (IPF), Dr. Takashi Ogura said at an international conference of the American Thoracic Society.

A previous phase II study suggested the agent, which has antifibrotic, anti-inflammatory, and antioxidant effects, could be beneficial.

In that study, 107 patients aged 20–75 years were randomized to receive pirfenidone in dosages up to 1,800 mg/day or placebo, and were followed for 9 months, during which time improvements were seen on vital capacity (VC), although not on a 6-minute walk test (Am. J. Respir. Crit. Care Med. 2005;171:1040-7).

The current study included 267 patients from 73 centers. Two radiologists verified the diagnosis in each patient after reviewing chest x-rays and high-resolution CT scans.

Patients were then randomized to receive pirfenidone 1,800 mg/day or 1,200 mg/day, or placebo. Vital capacity was measured every 4 weeks, and lowest oxygen saturation by pulse oximetry (SpO₂) on exertion was measured every 12 weeks.

Statistically significant improvements were seen in both pirfenidone groups on the primary end point, which was change in VC, as well as in an overall slowing of deterioration from the progressive, fatal disease, Dr. Ogura said.

“At week 52, the difference between the pirfenidone high-dose group and placebo was 70 mL, and the difference between the lower-dose group and placebo was 80 mL,” said Dr. Ogura of Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

Statistically significant changes also were seen in progression-free survival, although not in the lowest SpO₂ on exertion or the incidence of acute exacerbations.

The most common adverse events associated with the treatment were photosensitivity, dizziness, anorexia, and elevated γ-glutamyl transpeptidase. The drug was generally well tolerated, with no significant differences being seen among the three groups for serious adverse events.

A total of 32% of patients dropped out during the course of the study, including 37% of the patients taking 1,800 mg of pirfenidone, 28% of those taking 1,200 mg, and 27% of patients in the placebo group.

The researchers will continue to follow the patients to see if pirfenidone can improve survival, and to see if the drug also may prove useful in other fibrotic lung diseases.

Dr. Ogura noted that he had no relevant financial disclosures.

TORONTO — Treatment of patients with idiopathic pulmonary fibrosis with pirfenidone was “encouraging” in a phase III study conducted in Japan.

Few treatment options are available for patients with idiopathic pulmonary fibrosis (IPF), Dr. Takashi Ogura said at an international conference of the American Thoracic Society.

A previous phase II study suggested the agent, which has antifibrotic, anti-inflammatory, and antioxidant effects, could be beneficial.

In that study, 107 patients aged 20–75 years were randomized to receive pirfenidone in dosages up to 1,800 mg/day or placebo, and were followed for 9 months, during which time improvements were seen on vital capacity (VC), although not on a 6-minute walk test (Am. J. Respir. Crit. Care Med. 2005;171:1040-7).

The current study included 267 patients from 73 centers. Two radiologists verified the diagnosis in each patient after reviewing chest x-rays and high-resolution CT scans.

Patients were then randomized to receive pirfenidone 1,800 mg/day or 1,200 mg/day, or placebo. Vital capacity was measured every 4 weeks, and lowest oxygen saturation by pulse oximetry (SpO₂) on exertion was measured every 12 weeks.

Statistically significant improvements were seen in both pirfenidone groups on the primary end point, which was change in VC, as well as in an overall slowing of deterioration from the progressive, fatal disease, Dr. Ogura said.

“At week 52, the difference between the pirfenidone high-dose group and placebo was 70 mL, and the difference between the lower-dose group and placebo was 80 mL,” said Dr. Ogura of Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

Statistically significant changes also were seen in progression-free survival, although not in the lowest SpO₂ on exertion or the incidence of acute exacerbations.

The most common adverse events associated with the treatment were photosensitivity, dizziness, anorexia, and elevated γ-glutamyl transpeptidase. The drug was generally well tolerated, with no significant differences being seen among the three groups for serious adverse events.

A total of 32% of patients dropped out during the course of the study, including 37% of the patients taking 1,800 mg of pirfenidone, 28% of those taking 1,200 mg, and 27% of patients in the placebo group.

The researchers will continue to follow the patients to see if pirfenidone can improve survival, and to see if the drug also may prove useful in other fibrotic lung diseases.

Dr. Ogura noted that he had no relevant financial disclosures.

PARIS — Treatment of patients with systemic lupus erythematosus with the monoclonal antibody belimumab permitted reductions in corticosteroids through 3 years of observation, according to a post hoc analysis of a large phase II study.

Treatment options for systemic lupus erythematosus (SLE) are limited, and most of the available options are associated with significant and even debilitating adverse effects. Cortico-steroids, for example, are associated with weight gain, risk of infection, psychosis, and hypertension and so generally are reserved for use during times of disease activity. An agent that could be steroid sparing remains a critical unmet need in the SLE treatment regimen, according to Dr. Daniel J. Wallace of Cedars-Sinai Medical Center, University of California, Los Angeles.

Belimumab targets and inhibits soluble B-lymphocyte stimulator (BLyS), a protein that is overexpressed in SLE.

Following the completion of a double-blind trial, patients were allowed to enroll in an open-label extension trial in which they received 10 mg/kg of belimumab monthly. A total of 296 participants chose to continue in the study and 233 remained enrolled at the time of Dr. Wallace's EULAR presentation.

At baseline, the majority of patients were women whose mean age was 42 years. Mean disease duration was 8.8 years, and most patients had a reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA).

A total of 69% were on daily prednisone, with a mean dose of 11 mg/day, and 36% were on doses higher than 7.5 mg/day.

At the end of the randomized phase, reductions in average prednisone dose to 7.5 mg/day or lower were seen in 34%, 28%, 31%, and 44% of patients in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, while increases from low-dose prednisone to doses of 7.5 mg/day or higher were needed in 17%, 11%, 10%, and 4%, respectively.

At the end of year 3, when patients from all groups were on the highest dose of active treatment, prednisone reductions were seen in 56%, 45%, 61%, and 62% of patients originally in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, and increases were seen in 8%, 5%, 12%, and 7%, respectively.

Dr. Wallace has declared no conflicts of interest.

Treatment options for lupus are limited, and most are associated with significant adverse effects. DR. WALLACE

PARIS — Treatment of patients with systemic lupus erythematosus with the monoclonal antibody belimumab permitted reductions in corticosteroids through 3 years of observation, according to a post hoc analysis of a large phase II study.

Treatment options for systemic lupus erythematosus (SLE) are limited, and most of the available options are associated with significant and even debilitating adverse effects. Cortico-steroids, for example, are associated with weight gain, risk of infection, psychosis, and hypertension and so generally are reserved for use during times of disease activity. An agent that could be steroid sparing remains a critical unmet need in the SLE treatment regimen, according to Dr. Daniel J. Wallace of Cedars-Sinai Medical Center, University of California, Los Angeles.

Belimumab targets and inhibits soluble B-lymphocyte stimulator (BLyS), a protein that is overexpressed in SLE.

Following the completion of a double-blind trial, patients were allowed to enroll in an open-label extension trial in which they received 10 mg/kg of belimumab monthly. A total of 296 participants chose to continue in the study and 233 remained enrolled at the time of Dr. Wallace's EULAR presentation.

At baseline, the majority of patients were women whose mean age was 42 years. Mean disease duration was 8.8 years, and most patients had a reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA).

A total of 69% were on daily prednisone, with a mean dose of 11 mg/day, and 36% were on doses higher than 7.5 mg/day.

At the end of the randomized phase, reductions in average prednisone dose to 7.5 mg/day or lower were seen in 34%, 28%, 31%, and 44% of patients in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, while increases from low-dose prednisone to doses of 7.5 mg/day or higher were needed in 17%, 11%, 10%, and 4%, respectively.

At the end of year 3, when patients from all groups were on the highest dose of active treatment, prednisone reductions were seen in 56%, 45%, 61%, and 62% of patients originally in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, and increases were seen in 8%, 5%, 12%, and 7%, respectively.

Dr. Wallace has declared no conflicts of interest.

Treatment options for lupus are limited, and most are associated with significant adverse effects. DR. WALLACE

PARIS — Treatment of patients with systemic lupus erythematosus with the monoclonal antibody belimumab permitted reductions in corticosteroids through 3 years of observation, according to a post hoc analysis of a large phase II study.

Treatment options for systemic lupus erythematosus (SLE) are limited, and most of the available options are associated with significant and even debilitating adverse effects. Cortico-steroids, for example, are associated with weight gain, risk of infection, psychosis, and hypertension and so generally are reserved for use during times of disease activity. An agent that could be steroid sparing remains a critical unmet need in the SLE treatment regimen, according to Dr. Daniel J. Wallace of Cedars-Sinai Medical Center, University of California, Los Angeles.

Belimumab targets and inhibits soluble B-lymphocyte stimulator (BLyS), a protein that is overexpressed in SLE.

Following the completion of a double-blind trial, patients were allowed to enroll in an open-label extension trial in which they received 10 mg/kg of belimumab monthly. A total of 296 participants chose to continue in the study and 233 remained enrolled at the time of Dr. Wallace's EULAR presentation.

At baseline, the majority of patients were women whose mean age was 42 years. Mean disease duration was 8.8 years, and most patients had a reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA).

A total of 69% were on daily prednisone, with a mean dose of 11 mg/day, and 36% were on doses higher than 7.5 mg/day.

At the end of the randomized phase, reductions in average prednisone dose to 7.5 mg/day or lower were seen in 34%, 28%, 31%, and 44% of patients in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, while increases from low-dose prednisone to doses of 7.5 mg/day or higher were needed in 17%, 11%, 10%, and 4%, respectively.

At the end of year 3, when patients from all groups were on the highest dose of active treatment, prednisone reductions were seen in 56%, 45%, 61%, and 62% of patients originally in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, and increases were seen in 8%, 5%, 12%, and 7%, respectively.

Dr. Wallace has declared no conflicts of interest.

Treatment options for lupus are limited, and most are associated with significant adverse effects. DR. WALLACE

PARIS — Patients with early rheumatoid arthritis had greater improvements with abatacept treatment than did those with longstanding disease, according to a new post hoc analysis of two clinical trials.

In the first report of the efficacy of this selective T-cell costimulation modulator in patients whose disease duration is 2 years or less and who have an inadequate response to methotrexate but are biologically naive, almost half were in disease remission at year 3, according to Dr. Yusuf Yazici.

This study included 462 patients from both a phase II trial and a double-blind placebo controlled trial who had been randomized to receive abatacept 10 mg/kg once monthly and who had entered a long-term extension phase, with assessments at years 1 and 3.

Patients' mean age was 55 years, 76% were female, and 82% were rheumatoid factor positive. Mean baseline disease activity score 28 (DAS28) was 6.4, health assessment questionnaire (HAQ) was 1.5, and C-reactive protein (CRP) was 3.2 mg/dL.

Among the entire cohort, 25% of the patients were in DAS28 remission at year 1, as were 36% at year 3, said Dr. Yazici of New York University, and director of the Seligman Center for Advanced Therapeutics, NYU Hospital for Joint Diseases, New York.

A total of 108 patients had early disease, while 159 had longstanding disease. A comparison of these groups showed that 46% of those with early disease were in remission at year 3, compared with 31% of those with longstanding disease, Dr. Yusuf Yazici said at the annual European Congress of Rheumatology.

Remission rates were also significantly better for the early disease group at year 1 and year 3, as were ACR 70 rates. Moreover, among the early disease group, significantly more patients had clinically meaningful improvements in their HAQ scores. (See box.)

“These data support the use of abatacept in biologic-naive patients who have early disease and who have had an inadequate response to methotrexate,” Dr. Yazici concluded.

Dr. Yazici disclosed that he is a consultant for BMS, Roche, Celgene, UCB, Pfizer, and Centocor.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — Patients with early rheumatoid arthritis had greater improvements with abatacept treatment than did those with longstanding disease, according to a new post hoc analysis of two clinical trials.

In the first report of the efficacy of this selective T-cell costimulation modulator in patients whose disease duration is 2 years or less and who have an inadequate response to methotrexate but are biologically naive, almost half were in disease remission at year 3, according to Dr. Yusuf Yazici.

This study included 462 patients from both a phase II trial and a double-blind placebo controlled trial who had been randomized to receive abatacept 10 mg/kg once monthly and who had entered a long-term extension phase, with assessments at years 1 and 3.

Patients' mean age was 55 years, 76% were female, and 82% were rheumatoid factor positive. Mean baseline disease activity score 28 (DAS28) was 6.4, health assessment questionnaire (HAQ) was 1.5, and C-reactive protein (CRP) was 3.2 mg/dL.

Among the entire cohort, 25% of the patients were in DAS28 remission at year 1, as were 36% at year 3, said Dr. Yazici of New York University, and director of the Seligman Center for Advanced Therapeutics, NYU Hospital for Joint Diseases, New York.

A total of 108 patients had early disease, while 159 had longstanding disease. A comparison of these groups showed that 46% of those with early disease were in remission at year 3, compared with 31% of those with longstanding disease, Dr. Yusuf Yazici said at the annual European Congress of Rheumatology.

Remission rates were also significantly better for the early disease group at year 1 and year 3, as were ACR 70 rates. Moreover, among the early disease group, significantly more patients had clinically meaningful improvements in their HAQ scores. (See box.)

“These data support the use of abatacept in biologic-naive patients who have early disease and who have had an inadequate response to methotrexate,” Dr. Yazici concluded.

Dr. Yazici disclosed that he is a consultant for BMS, Roche, Celgene, UCB, Pfizer, and Centocor.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — Patients with early rheumatoid arthritis had greater improvements with abatacept treatment than did those with longstanding disease, according to a new post hoc analysis of two clinical trials.

In the first report of the efficacy of this selective T-cell costimulation modulator in patients whose disease duration is 2 years or less and who have an inadequate response to methotrexate but are biologically naive, almost half were in disease remission at year 3, according to Dr. Yusuf Yazici.

This study included 462 patients from both a phase II trial and a double-blind placebo controlled trial who had been randomized to receive abatacept 10 mg/kg once monthly and who had entered a long-term extension phase, with assessments at years 1 and 3.

Patients' mean age was 55 years, 76% were female, and 82% were rheumatoid factor positive. Mean baseline disease activity score 28 (DAS28) was 6.4, health assessment questionnaire (HAQ) was 1.5, and C-reactive protein (CRP) was 3.2 mg/dL.

Among the entire cohort, 25% of the patients were in DAS28 remission at year 1, as were 36% at year 3, said Dr. Yazici of New York University, and director of the Seligman Center for Advanced Therapeutics, NYU Hospital for Joint Diseases, New York.

A total of 108 patients had early disease, while 159 had longstanding disease. A comparison of these groups showed that 46% of those with early disease were in remission at year 3, compared with 31% of those with longstanding disease, Dr. Yusuf Yazici said at the annual European Congress of Rheumatology.

Remission rates were also significantly better for the early disease group at year 1 and year 3, as were ACR 70 rates. Moreover, among the early disease group, significantly more patients had clinically meaningful improvements in their HAQ scores. (See box.)

“These data support the use of abatacept in biologic-naive patients who have early disease and who have had an inadequate response to methotrexate,” Dr. Yazici concluded.

Dr. Yazici disclosed that he is a consultant for BMS, Roche, Celgene, UCB, Pfizer, and Centocor.

ELSEVIER GLOBAL MEDICAL NEWS

The first comprehensive guidelines for the diagnosis and management of stroke in children are intended to provide a wide range of clinicians responsible for treating cerebrovascular disease in infants and children with evidence- and consensus-based recommendations, according to the American Heart Association.

The recommendations, written by a group of experts from the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, have been released online.

“Only a few centers in the country have a high level of expertise in dealing with stroke in children, and these guidelines share this concentrated knowledge with physicians who don't have access to that expertise,” committee chair Dr. E. Steve Roach said in an interview.

One important message in the statement is that stroke in children is far more common than is generally realized. Data from the National Hospital Discharge Survey from 1980 to 1998 suggested that the overall risk of stroke from birth through 18 years is 13.5/100,000, and the rate of hemorrhagic stroke for term infants is 6.7/100,000 per year. Other recent investigations found that neonatal stroke occurs in about 1 in 4,000 live births, with about of those 80% being ischemic.

“Strokes actually are twice as common as brain tumors in children,” said Dr. Roach, chief of neurology at Nationwide Children's Hospital and professor of pediatric neurology, Ohio State University, both in Columbus.

Strokes in children differ from those in adults in that few are associated with atherosclerosis, but they are similar in that once the stroke has occurred, no medicine can reverse it, Dr. Roach said. “However, an aggressive approach to finding out the cause of the stroke is your best chance for preventing [subsequent] strokes and the cumulative pileup of brain damage that will determine whether that child grows into a normally functioning adult.”

Among the causes and risk factors for stroke cited in the statement are sickle cell disease and cervicocephalic arterial dissection (Circulation 2008 [doi:10.1161/strokeaha.108.189696

The guidelines offer detailed recommendations on primary and secondary stroke prevention in sickle cell disease. Management of acute ischemic stroke should include optimal hydration and correction of hypoxemia and hypotension. Periodic transfusions are recommended for children aged 2-16 years with abnormal transcranial Doppler findings, and those with a confirmed cerebral infarction should be on a program of red cell transfusion with measures to prevent iron overload.

In sickle cell disease with acute cerebral infarction, exchange transfusion with the goal of reducing sickle hemoglobin to less than 30% of total hemoglobin is “reasonable,” and hydroxyurea may be considered for children who are unable to continue on long-term transfusion.

Cervicocephalic arterial dissection is described as an important but underrecognized cause of stroke in children. For extracranial cervicocephalic arterial dissection, it is reasonable to institute unfractionated heparin or low-molecular-weight heparin as a bridge to oral anticoagulation. Anticoagulant therapy can continue for 3-6 months or longer for patients with recurrent symptoms, according to the guidelines.

For hemorrhagic stroke, recommendations include noninvasive testing and standard cerebral angiography if needed, along with stabilizing measures such as controlling hypertension and seizures and managing increased intracranial pressure. Surgical evacuation of a supratentorial intracerebral hematoma is not usually recommended, although in certain selected patients with developing brain herniation or very high intracranial pressure, surgery may be helpful.

With cerebral venous sinus thrombosis (CVST) in children, anticoagulation is reasonable, with the exception of neonates. “Until there is more evidence of safety and effectiveness, anticoagulation is not appropriate for most neonates with CVST,” the authors wrote, adding that it may be considered in the context of severe prothrombotic disorders, multiple emboli, or radiologic evidence of propagating CVST despite supportive care.

Some recommendations, such as those that suggest using anticoagulation only for neonates with some evidence of progression of venous sinus thrombosis, are likely to cause controversy, said Dr. Heather J. Fullerton, who directs the pediatric stroke and cerebrovascular disease center at the University of California, San Francisco.

Nonetheless, “these are landmark comprehensive guidelines” for clinicians who have “struggled with how to manage these patients in the absence of more evidence,” said Dr. Fullerton, who was not a member of the writing group. The guidelines are at www.americanheart.org/presenter.jhtml?identifier=3003999

The first comprehensive guidelines for the diagnosis and management of stroke in children are intended to provide a wide range of clinicians responsible for treating cerebrovascular disease in infants and children with evidence- and consensus-based recommendations, according to the American Heart Association.

The recommendations, written by a group of experts from the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, have been released online.

“Only a few centers in the country have a high level of expertise in dealing with stroke in children, and these guidelines share this concentrated knowledge with physicians who don't have access to that expertise,” committee chair Dr. E. Steve Roach said in an interview.

One important message in the statement is that stroke in children is far more common than is generally realized. Data from the National Hospital Discharge Survey from 1980 to 1998 suggested that the overall risk of stroke from birth through 18 years is 13.5/100,000, and the rate of hemorrhagic stroke for term infants is 6.7/100,000 per year. Other recent investigations found that neonatal stroke occurs in about 1 in 4,000 live births, with about of those 80% being ischemic.

“Strokes actually are twice as common as brain tumors in children,” said Dr. Roach, chief of neurology at Nationwide Children's Hospital and professor of pediatric neurology, Ohio State University, both in Columbus.

Strokes in children differ from those in adults in that few are associated with atherosclerosis, but they are similar in that once the stroke has occurred, no medicine can reverse it, Dr. Roach said. “However, an aggressive approach to finding out the cause of the stroke is your best chance for preventing [subsequent] strokes and the cumulative pileup of brain damage that will determine whether that child grows into a normally functioning adult.”

Among the causes and risk factors for stroke cited in the statement are sickle cell disease and cervicocephalic arterial dissection (Circulation 2008 [doi:10.1161/strokeaha.108.189696

The guidelines offer detailed recommendations on primary and secondary stroke prevention in sickle cell disease. Management of acute ischemic stroke should include optimal hydration and correction of hypoxemia and hypotension. Periodic transfusions are recommended for children aged 2-16 years with abnormal transcranial Doppler findings, and those with a confirmed cerebral infarction should be on a program of red cell transfusion with measures to prevent iron overload.

In sickle cell disease with acute cerebral infarction, exchange transfusion with the goal of reducing sickle hemoglobin to less than 30% of total hemoglobin is “reasonable,” and hydroxyurea may be considered for children who are unable to continue on long-term transfusion.

Cervicocephalic arterial dissection is described as an important but underrecognized cause of stroke in children. For extracranial cervicocephalic arterial dissection, it is reasonable to institute unfractionated heparin or low-molecular-weight heparin as a bridge to oral anticoagulation. Anticoagulant therapy can continue for 3-6 months or longer for patients with recurrent symptoms, according to the guidelines.

For hemorrhagic stroke, recommendations include noninvasive testing and standard cerebral angiography if needed, along with stabilizing measures such as controlling hypertension and seizures and managing increased intracranial pressure. Surgical evacuation of a supratentorial intracerebral hematoma is not usually recommended, although in certain selected patients with developing brain herniation or very high intracranial pressure, surgery may be helpful.

With cerebral venous sinus thrombosis (CVST) in children, anticoagulation is reasonable, with the exception of neonates. “Until there is more evidence of safety and effectiveness, anticoagulation is not appropriate for most neonates with CVST,” the authors wrote, adding that it may be considered in the context of severe prothrombotic disorders, multiple emboli, or radiologic evidence of propagating CVST despite supportive care.

Some recommendations, such as those that suggest using anticoagulation only for neonates with some evidence of progression of venous sinus thrombosis, are likely to cause controversy, said Dr. Heather J. Fullerton, who directs the pediatric stroke and cerebrovascular disease center at the University of California, San Francisco.

Nonetheless, “these are landmark comprehensive guidelines” for clinicians who have “struggled with how to manage these patients in the absence of more evidence,” said Dr. Fullerton, who was not a member of the writing group. The guidelines are at www.americanheart.org/presenter.jhtml?identifier=3003999

The first comprehensive guidelines for the diagnosis and management of stroke in children are intended to provide a wide range of clinicians responsible for treating cerebrovascular disease in infants and children with evidence- and consensus-based recommendations, according to the American Heart Association.

The recommendations, written by a group of experts from the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young, have been released online.

“Only a few centers in the country have a high level of expertise in dealing with stroke in children, and these guidelines share this concentrated knowledge with physicians who don't have access to that expertise,” committee chair Dr. E. Steve Roach said in an interview.

One important message in the statement is that stroke in children is far more common than is generally realized. Data from the National Hospital Discharge Survey from 1980 to 1998 suggested that the overall risk of stroke from birth through 18 years is 13.5/100,000, and the rate of hemorrhagic stroke for term infants is 6.7/100,000 per year. Other recent investigations found that neonatal stroke occurs in about 1 in 4,000 live births, with about of those 80% being ischemic.

“Strokes actually are twice as common as brain tumors in children,” said Dr. Roach, chief of neurology at Nationwide Children's Hospital and professor of pediatric neurology, Ohio State University, both in Columbus.

Strokes in children differ from those in adults in that few are associated with atherosclerosis, but they are similar in that once the stroke has occurred, no medicine can reverse it, Dr. Roach said. “However, an aggressive approach to finding out the cause of the stroke is your best chance for preventing [subsequent] strokes and the cumulative pileup of brain damage that will determine whether that child grows into a normally functioning adult.”

Among the causes and risk factors for stroke cited in the statement are sickle cell disease and cervicocephalic arterial dissection (Circulation 2008 [doi:10.1161/strokeaha.108.189696

The guidelines offer detailed recommendations on primary and secondary stroke prevention in sickle cell disease. Management of acute ischemic stroke should include optimal hydration and correction of hypoxemia and hypotension. Periodic transfusions are recommended for children aged 2-16 years with abnormal transcranial Doppler findings, and those with a confirmed cerebral infarction should be on a program of red cell transfusion with measures to prevent iron overload.

In sickle cell disease with acute cerebral infarction, exchange transfusion with the goal of reducing sickle hemoglobin to less than 30% of total hemoglobin is “reasonable,” and hydroxyurea may be considered for children who are unable to continue on long-term transfusion.

Cervicocephalic arterial dissection is described as an important but underrecognized cause of stroke in children. For extracranial cervicocephalic arterial dissection, it is reasonable to institute unfractionated heparin or low-molecular-weight heparin as a bridge to oral anticoagulation. Anticoagulant therapy can continue for 3-6 months or longer for patients with recurrent symptoms, according to the guidelines.

For hemorrhagic stroke, recommendations include noninvasive testing and standard cerebral angiography if needed, along with stabilizing measures such as controlling hypertension and seizures and managing increased intracranial pressure. Surgical evacuation of a supratentorial intracerebral hematoma is not usually recommended, although in certain selected patients with developing brain herniation or very high intracranial pressure, surgery may be helpful.

With cerebral venous sinus thrombosis (CVST) in children, anticoagulation is reasonable, with the exception of neonates. “Until there is more evidence of safety and effectiveness, anticoagulation is not appropriate for most neonates with CVST,” the authors wrote, adding that it may be considered in the context of severe prothrombotic disorders, multiple emboli, or radiologic evidence of propagating CVST despite supportive care.

Some recommendations, such as those that suggest using anticoagulation only for neonates with some evidence of progression of venous sinus thrombosis, are likely to cause controversy, said Dr. Heather J. Fullerton, who directs the pediatric stroke and cerebrovascular disease center at the University of California, San Francisco.

Nonetheless, “these are landmark comprehensive guidelines” for clinicians who have “struggled with how to manage these patients in the absence of more evidence,” said Dr. Fullerton, who was not a member of the writing group. The guidelines are at www.americanheart.org/presenter.jhtml?identifier=3003999

PARIS — A severe headache with near-instantaneous onset—a “thunderclap” headache—is likely to represent a reversible cerebral vasoconstrictive process rather than central nervous system vasculitis, Dr. Leonard H. Calabrese said at the annual European Congress of Rheumatology.

The reversible cerebral vasoconstriction syndrome (RCVS) has been associated with a variety of conditions, including pregnancy, head trauma, and exposure to drugs such as nasal decongestants, selective serotonin reuptake inhibitors, and cannabis.

“RCVS can be readily diagnosed if you understand the clinical picture, but despite remarkable progress in understanding this condition in the past 5 years, it is still misdiagnosed and mismanaged as CNS vasculitis,” said Dr. Calabrese, who holds the R.J. Fasenmeyer Chair of Clinical Immunology at the Cleveland Clinic.

CNS vasculitis requires a brain biopsy for diagnosis, and treatment involves extended immunosuppression. Neither is typically necessary in RCVS.

The rapid-onset headache of RCVS, developing over 1-2 minutes, is the hallmark of the condition and can occur with or without other neurologic signs and symptoms. It is more common in women and often develops in the wake of sexual activity, exercise, coughing, or the Valsalva maneuver and is “the worst headache of the patient's life,” he said.

Headache associated with CNS vasculitis, in contrast, is indolent and progressive and typically is associated with episodes of neurologic dysfunction.

Angiographic findings in the two conditions can be indistinguishable, with multiple areas of stenosis and beading, but the abnormalities are reversible, usually within 3 months, in RCVS.

In contrast, although few follow-up angiographic studies have been done in patients with CNS vasculitis, the data that exist suggest that resolution does not occur.

Analysis of spinal fluid is essential for the patient with thunderclap headache to rule out not only CNS vasculitis but also subarachnoid hemorrhage. The fluid should be within normal limits, with only a few cells and a little protein, Dr. Calabrese said.

“However, we do not advocate biopsy with the classic presentation of RCVS—female patients, pristine spinal fluid, and thunderclap headache,” he said.

But if the pretest probability for RCVS is low and vasculitis seems more likely, with a more insidious onset of headache, abnormal spinal fluid, or other abnormalities such as elevated acute phase reactants, biopsy may be warranted.

The headache associated with RCVS can abate but may recur within a week or two, and unfortunately may be accompanied by stroke, seizures, or other sequelae, he said.

In one recent prospective series of 67 patients, complications included cortical subarachnoid hemorrhage in 22%, intracerebral hemorrhage in 6%, and reversible posterior leukoencephalopathy in 9% (Brain 2007;130:3091-4101). Treatment thus far has been guided by observational data and experience, because no trials of any therapy have been conducted. “Some patients have recovered with no treatment whatsoever, but we often use calcium channel blockers, in conjunction with glucocorticoids if stroke is present,” he said.

The reason for using glucocorticoids in RCVS—which is not an inflammatory condition, but rather is thought to be an endothelial disease with increased expression of adhesion molecules—is that in experimental models of induced vasoconstriction, their use represents the most potent pharmacologic intervention, he explained.

PARIS — A severe headache with near-instantaneous onset—a “thunderclap” headache—is likely to represent a reversible cerebral vasoconstrictive process rather than central nervous system vasculitis, Dr. Leonard H. Calabrese said at the annual European Congress of Rheumatology.

The reversible cerebral vasoconstriction syndrome (RCVS) has been associated with a variety of conditions, including pregnancy, head trauma, and exposure to drugs such as nasal decongestants, selective serotonin reuptake inhibitors, and cannabis.

“RCVS can be readily diagnosed if you understand the clinical picture, but despite remarkable progress in understanding this condition in the past 5 years, it is still misdiagnosed and mismanaged as CNS vasculitis,” said Dr. Calabrese, who holds the R.J. Fasenmeyer Chair of Clinical Immunology at the Cleveland Clinic.

CNS vasculitis requires a brain biopsy for diagnosis, and treatment involves extended immunosuppression. Neither is typically necessary in RCVS.

The rapid-onset headache of RCVS, developing over 1-2 minutes, is the hallmark of the condition and can occur with or without other neurologic signs and symptoms. It is more common in women and often develops in the wake of sexual activity, exercise, coughing, or the Valsalva maneuver and is “the worst headache of the patient's life,” he said.

Headache associated with CNS vasculitis, in contrast, is indolent and progressive and typically is associated with episodes of neurologic dysfunction.

Angiographic findings in the two conditions can be indistinguishable, with multiple areas of stenosis and beading, but the abnormalities are reversible, usually within 3 months, in RCVS.

In contrast, although few follow-up angiographic studies have been done in patients with CNS vasculitis, the data that exist suggest that resolution does not occur.

Analysis of spinal fluid is essential for the patient with thunderclap headache to rule out not only CNS vasculitis but also subarachnoid hemorrhage. The fluid should be within normal limits, with only a few cells and a little protein, Dr. Calabrese said.

“However, we do not advocate biopsy with the classic presentation of RCVS—female patients, pristine spinal fluid, and thunderclap headache,” he said.

But if the pretest probability for RCVS is low and vasculitis seems more likely, with a more insidious onset of headache, abnormal spinal fluid, or other abnormalities such as elevated acute phase reactants, biopsy may be warranted.

The headache associated with RCVS can abate but may recur within a week or two, and unfortunately may be accompanied by stroke, seizures, or other sequelae, he said.

In one recent prospective series of 67 patients, complications included cortical subarachnoid hemorrhage in 22%, intracerebral hemorrhage in 6%, and reversible posterior leukoencephalopathy in 9% (Brain 2007;130:3091-4101). Treatment thus far has been guided by observational data and experience, because no trials of any therapy have been conducted. “Some patients have recovered with no treatment whatsoever, but we often use calcium channel blockers, in conjunction with glucocorticoids if stroke is present,” he said.

The reason for using glucocorticoids in RCVS—which is not an inflammatory condition, but rather is thought to be an endothelial disease with increased expression of adhesion molecules—is that in experimental models of induced vasoconstriction, their use represents the most potent pharmacologic intervention, he explained.

PARIS — A severe headache with near-instantaneous onset—a “thunderclap” headache—is likely to represent a reversible cerebral vasoconstrictive process rather than central nervous system vasculitis, Dr. Leonard H. Calabrese said at the annual European Congress of Rheumatology.

The reversible cerebral vasoconstriction syndrome (RCVS) has been associated with a variety of conditions, including pregnancy, head trauma, and exposure to drugs such as nasal decongestants, selective serotonin reuptake inhibitors, and cannabis.

“RCVS can be readily diagnosed if you understand the clinical picture, but despite remarkable progress in understanding this condition in the past 5 years, it is still misdiagnosed and mismanaged as CNS vasculitis,” said Dr. Calabrese, who holds the R.J. Fasenmeyer Chair of Clinical Immunology at the Cleveland Clinic.

CNS vasculitis requires a brain biopsy for diagnosis, and treatment involves extended immunosuppression. Neither is typically necessary in RCVS.

The rapid-onset headache of RCVS, developing over 1-2 minutes, is the hallmark of the condition and can occur with or without other neurologic signs and symptoms. It is more common in women and often develops in the wake of sexual activity, exercise, coughing, or the Valsalva maneuver and is “the worst headache of the patient's life,” he said.

Headache associated with CNS vasculitis, in contrast, is indolent and progressive and typically is associated with episodes of neurologic dysfunction.

Angiographic findings in the two conditions can be indistinguishable, with multiple areas of stenosis and beading, but the abnormalities are reversible, usually within 3 months, in RCVS.

In contrast, although few follow-up angiographic studies have been done in patients with CNS vasculitis, the data that exist suggest that resolution does not occur.

Analysis of spinal fluid is essential for the patient with thunderclap headache to rule out not only CNS vasculitis but also subarachnoid hemorrhage. The fluid should be within normal limits, with only a few cells and a little protein, Dr. Calabrese said.

“However, we do not advocate biopsy with the classic presentation of RCVS—female patients, pristine spinal fluid, and thunderclap headache,” he said.

But if the pretest probability for RCVS is low and vasculitis seems more likely, with a more insidious onset of headache, abnormal spinal fluid, or other abnormalities such as elevated acute phase reactants, biopsy may be warranted.

The headache associated with RCVS can abate but may recur within a week or two, and unfortunately may be accompanied by stroke, seizures, or other sequelae, he said.

In one recent prospective series of 67 patients, complications included cortical subarachnoid hemorrhage in 22%, intracerebral hemorrhage in 6%, and reversible posterior leukoencephalopathy in 9% (Brain 2007;130:3091-4101). Treatment thus far has been guided by observational data and experience, because no trials of any therapy have been conducted. “Some patients have recovered with no treatment whatsoever, but we often use calcium channel blockers, in conjunction with glucocorticoids if stroke is present,” he said.

The reason for using glucocorticoids in RCVS—which is not an inflammatory condition, but rather is thought to be an endothelial disease with increased expression of adhesion molecules—is that in experimental models of induced vasoconstriction, their use represents the most potent pharmacologic intervention, he explained.

PARIS — Treatment of patients with systemic lupus erythematosus with the monoclonal antibody belimumab permitted reductions in corticosteroids through 3 years of observation, according to a post hoc analysis of a large phase II study.

Treatment options for systemic lupus erythematosus (SLE) are limited, and most of the available options are associated with significant and even debilitating adverse effects.

Corticosteroids, for example, are associated with weight gain, risk of infection, psychosis, and hypertension and so generally are reserved for use during times of disease activity. An agent that could be steroid sparing remains a critical unmet need in the SLE treatment regimen, according to Dr. Daniel J. Wallace of Cedars-Sinai Medical Center, University of California, Los Angeles.

Belimumab targets and inhibits soluble B-lymphocyte stimulator (BLyS), a protein that is overexpressed in SLE. In the original trial, patients were randomized to receive belimumab in doses of 1 mg/kg, 4 mg/kg, or 10 mg/kg monthly or placebo plus standard-of-care background therapy for 52 weeks.

The use of steroids and tapering of steroids were standardized in the trial according to clinical need, Dr. Wallace explained at the annual European Congress of Rheumatology.

The primary end point was a reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks.

Although the primary end point of the double-blind trial was not met, subsequent analyses of seropositive patients (72% of the original cohort) found that the drug reduced SLE activity and flare rate in patients with antinuclear antibody titers of 1:80 or higher and/or anti-double stranded DNA antibody levels of 30 IU/mL or greater.

Following the completion of the double-blind trial, patients were allowed to enroll in an open-label extension trial in which they received 10 mg/kg of belimumab monthly. A total of 296 participants chose to continue in the study and 233 remained enrolled at the time of Dr. Wallace's EULAR presentation.

At baseline, the majority of patients were women whose mean age was 42 years. Mean disease duration was 8.8 years, and most patients had a SELENA-SLEDAI score of 8 or higher, indicating moderate disease. A total of 69% were on daily prednisone, with a mean dose of 11 mg/day, and 36% were on doses higher than 7.5 mg/day. At the end of the randomized phase, reductions in average prednisone dose to 7.5 mg/day or lower were seen in 34%, 28%, 31%, and 44% of patients in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, while increases from low-dose prednisone to doses of 7.5 mg/day or higher were needed in 17%, 11%, 10%, and 4%, respectively.

At the end of year 3, when patients from all groups were on the highest dose of active treatment, prednisone dose reductions were seen in 56%, 45%, 61%, and 62% of patients originally in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, and predisone dose increases were seen in 8%, 5%, 12%, and 7%, respectively.

Among patients taking 7.5 mg prednisone per day plus immunosuppressants at baseline, more than 30% of belimumab treated patients were able to decrease the prednisone dose and stop the concomitant immunosuppressants by the end of year 3.

“Based on these initial analyses, belimumab has shown potential steroid-sparing activity in the treatment of SLE and may have an additional role as an immunosuppressant-reducing agent,” Dr. Wallace wrote.

Dr. Wallace has declared no conflicts of interest.

Perhaps belimumab use will let patients lower their doses of immuno-suppressants. DR. WALLACE

PARIS — Treatment of patients with systemic lupus erythematosus with the monoclonal antibody belimumab permitted reductions in corticosteroids through 3 years of observation, according to a post hoc analysis of a large phase II study.

Treatment options for systemic lupus erythematosus (SLE) are limited, and most of the available options are associated with significant and even debilitating adverse effects.

Corticosteroids, for example, are associated with weight gain, risk of infection, psychosis, and hypertension and so generally are reserved for use during times of disease activity. An agent that could be steroid sparing remains a critical unmet need in the SLE treatment regimen, according to Dr. Daniel J. Wallace of Cedars-Sinai Medical Center, University of California, Los Angeles.

Belimumab targets and inhibits soluble B-lymphocyte stimulator (BLyS), a protein that is overexpressed in SLE. In the original trial, patients were randomized to receive belimumab in doses of 1 mg/kg, 4 mg/kg, or 10 mg/kg monthly or placebo plus standard-of-care background therapy for 52 weeks.

The use of steroids and tapering of steroids were standardized in the trial according to clinical need, Dr. Wallace explained at the annual European Congress of Rheumatology.

The primary end point was a reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks.

Although the primary end point of the double-blind trial was not met, subsequent analyses of seropositive patients (72% of the original cohort) found that the drug reduced SLE activity and flare rate in patients with antinuclear antibody titers of 1:80 or higher and/or anti-double stranded DNA antibody levels of 30 IU/mL or greater.

Following the completion of the double-blind trial, patients were allowed to enroll in an open-label extension trial in which they received 10 mg/kg of belimumab monthly. A total of 296 participants chose to continue in the study and 233 remained enrolled at the time of Dr. Wallace's EULAR presentation.

At baseline, the majority of patients were women whose mean age was 42 years. Mean disease duration was 8.8 years, and most patients had a SELENA-SLEDAI score of 8 or higher, indicating moderate disease. A total of 69% were on daily prednisone, with a mean dose of 11 mg/day, and 36% were on doses higher than 7.5 mg/day. At the end of the randomized phase, reductions in average prednisone dose to 7.5 mg/day or lower were seen in 34%, 28%, 31%, and 44% of patients in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, while increases from low-dose prednisone to doses of 7.5 mg/day or higher were needed in 17%, 11%, 10%, and 4%, respectively.

At the end of year 3, when patients from all groups were on the highest dose of active treatment, prednisone dose reductions were seen in 56%, 45%, 61%, and 62% of patients originally in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, and predisone dose increases were seen in 8%, 5%, 12%, and 7%, respectively.

Among patients taking 7.5 mg prednisone per day plus immunosuppressants at baseline, more than 30% of belimumab treated patients were able to decrease the prednisone dose and stop the concomitant immunosuppressants by the end of year 3.

“Based on these initial analyses, belimumab has shown potential steroid-sparing activity in the treatment of SLE and may have an additional role as an immunosuppressant-reducing agent,” Dr. Wallace wrote.

Dr. Wallace has declared no conflicts of interest.

Perhaps belimumab use will let patients lower their doses of immuno-suppressants. DR. WALLACE

PARIS — Treatment of patients with systemic lupus erythematosus with the monoclonal antibody belimumab permitted reductions in corticosteroids through 3 years of observation, according to a post hoc analysis of a large phase II study.

Treatment options for systemic lupus erythematosus (SLE) are limited, and most of the available options are associated with significant and even debilitating adverse effects.

Corticosteroids, for example, are associated with weight gain, risk of infection, psychosis, and hypertension and so generally are reserved for use during times of disease activity. An agent that could be steroid sparing remains a critical unmet need in the SLE treatment regimen, according to Dr. Daniel J. Wallace of Cedars-Sinai Medical Center, University of California, Los Angeles.

Belimumab targets and inhibits soluble B-lymphocyte stimulator (BLyS), a protein that is overexpressed in SLE. In the original trial, patients were randomized to receive belimumab in doses of 1 mg/kg, 4 mg/kg, or 10 mg/kg monthly or placebo plus standard-of-care background therapy for 52 weeks.

The use of steroids and tapering of steroids were standardized in the trial according to clinical need, Dr. Wallace explained at the annual European Congress of Rheumatology.

The primary end point was a reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks.

Although the primary end point of the double-blind trial was not met, subsequent analyses of seropositive patients (72% of the original cohort) found that the drug reduced SLE activity and flare rate in patients with antinuclear antibody titers of 1:80 or higher and/or anti-double stranded DNA antibody levels of 30 IU/mL or greater.

Following the completion of the double-blind trial, patients were allowed to enroll in an open-label extension trial in which they received 10 mg/kg of belimumab monthly. A total of 296 participants chose to continue in the study and 233 remained enrolled at the time of Dr. Wallace's EULAR presentation.

At baseline, the majority of patients were women whose mean age was 42 years. Mean disease duration was 8.8 years, and most patients had a SELENA-SLEDAI score of 8 or higher, indicating moderate disease. A total of 69% were on daily prednisone, with a mean dose of 11 mg/day, and 36% were on doses higher than 7.5 mg/day. At the end of the randomized phase, reductions in average prednisone dose to 7.5 mg/day or lower were seen in 34%, 28%, 31%, and 44% of patients in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, while increases from low-dose prednisone to doses of 7.5 mg/day or higher were needed in 17%, 11%, 10%, and 4%, respectively.

At the end of year 3, when patients from all groups were on the highest dose of active treatment, prednisone dose reductions were seen in 56%, 45%, 61%, and 62% of patients originally in the placebo, 1-mg/kg, 4-mg/kg, and 10-mg/kg groups, and predisone dose increases were seen in 8%, 5%, 12%, and 7%, respectively.

Among patients taking 7.5 mg prednisone per day plus immunosuppressants at baseline, more than 30% of belimumab treated patients were able to decrease the prednisone dose and stop the concomitant immunosuppressants by the end of year 3.

“Based on these initial analyses, belimumab has shown potential steroid-sparing activity in the treatment of SLE and may have an additional role as an immunosuppressant-reducing agent,” Dr. Wallace wrote.

Dr. Wallace has declared no conflicts of interest.

Perhaps belimumab use will let patients lower their doses of immuno-suppressants. DR. WALLACE