Jeff Evans

Amgen, maker of the adalimumab biosimilar Amjevita (adalimumab-atto) has reached an agreement with AbbVie, manufacturer of the originator adalimumab Humira, that halts marketing of Amjevita in the United States until 2023 and in Europe until 2018, according to a company statement.

The deal between the two manufacturers settles a patent infringement lawsuit that AbbVie brought against Amgen after it received Food and Drug Administration approval in September 2016 for seven of Humira’s nine indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis. Amjevita is not approved for two of Humira’s indications, hidradenitis suppurativa and uveitis.

Amgen said in its statement that AbbVie will grant patent licenses for the use and sale of Amjevita worldwide, on a country-by-country basis, with current expectations that marketing will begin in Europe on Oct. 16, 2018, and in the United States on Jan. 31, 2023. Amjevita is named Amgevita in Europe.

[email protected]

Amgen, maker of the adalimumab biosimilar Amjevita (adalimumab-atto) has reached an agreement with AbbVie, manufacturer of the originator adalimumab Humira, that halts marketing of Amjevita in the United States until 2023 and in Europe until 2018, according to a company statement.

The deal between the two manufacturers settles a patent infringement lawsuit that AbbVie brought against Amgen after it received Food and Drug Administration approval in September 2016 for seven of Humira’s nine indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis. Amjevita is not approved for two of Humira’s indications, hidradenitis suppurativa and uveitis.

Amgen said in its statement that AbbVie will grant patent licenses for the use and sale of Amjevita worldwide, on a country-by-country basis, with current expectations that marketing will begin in Europe on Oct. 16, 2018, and in the United States on Jan. 31, 2023. Amjevita is named Amgevita in Europe.

[email protected]

Amgen, maker of the adalimumab biosimilar Amjevita (adalimumab-atto) has reached an agreement with AbbVie, manufacturer of the originator adalimumab Humira, that halts marketing of Amjevita in the United States until 2023 and in Europe until 2018, according to a company statement.

The deal between the two manufacturers settles a patent infringement lawsuit that AbbVie brought against Amgen after it received Food and Drug Administration approval in September 2016 for seven of Humira’s nine indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis. Amjevita is not approved for two of Humira’s indications, hidradenitis suppurativa and uveitis.

Amgen said in its statement that AbbVie will grant patent licenses for the use and sale of Amjevita worldwide, on a country-by-country basis, with current expectations that marketing will begin in Europe on Oct. 16, 2018, and in the United States on Jan. 31, 2023. Amjevita is named Amgevita in Europe.

[email protected]

Ultrasound evaluations to look for subclinical inflammation in joints of patients with arthralgia appear best at ruling out inflammatory arthritis (IA) 1 year in the future rather than ruling it in, according to findings from a multicenter cohort study published online in Arthritis Research and Therapy.

The imaging modality’s ability to identify those who will not go on to develop IA complemented the serologic and clinical factors that help to discriminate the individuals with arthralgia who are most at risk of the condition.

Remains/Thinkstock

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Ultrasound evaluations to look for subclinical inflammation in joints of patients with arthralgia appear best at ruling out inflammatory arthritis (IA) 1 year in the future rather than ruling it in, according to findings from a multicenter cohort study published online in Arthritis Research and Therapy.

The imaging modality’s ability to identify those who will not go on to develop IA complemented the serologic and clinical factors that help to discriminate the individuals with arthralgia who are most at risk of the condition.

Remains/Thinkstock

[email protected]

Ultrasound evaluations to look for subclinical inflammation in joints of patients with arthralgia appear best at ruling out inflammatory arthritis (IA) 1 year in the future rather than ruling it in, according to findings from a multicenter cohort study published online in Arthritis Research and Therapy.

The imaging modality’s ability to identify those who will not go on to develop IA complemented the serologic and clinical factors that help to discriminate the individuals with arthralgia who are most at risk of the condition.

Remains/Thinkstock

[email protected]

The presence of specific autoantibodies may help to identify the small percentage of patients with systemic lupus erythematosus (SLE) who are at higher risk of developing pulmonary arterial hypertension after SLE diagnosis and may also detect those at lower risk of death, according to findings from a retrospective study of French patients.

Eric Hachulla, MD, of the University of Lille (France) and his coinvestigators reported that 51 SLE patients in the French Pulmonary Hypertension Registry who had a diagnosis of pulmonary arterial hypertension (PAH) confirmed by right heart catheterization were more likely to have the condition if they had anti-SSA and anti-SSB antibodies, compared with a control group of 101 SLE patients without known PAH who were selected from SLE expert centers participating in the registry. Overall, anti-SSA antibodies were present in 62% of PAH patients vs. 40% of non-PAH patients, and anti-SSB antibodies were detected in 27% with PAH, compared with 8% of those without.

Following SLE diagnosis, the 51 SLE patients had a median delay in diagnosis of PAH by about 5 years. Their survival was 89% at 3 years and 84% at 5 years. “Survival appeared to be substantially better than that still observed today in [PAH associated with systemic sclerosis], where estimated 3-year survival is about 50%. Our survival rates are comparable to those reported by Sobanski et al. in the recently published study for the U.K. SLE-PAH cohort (85% at 5 years),” the authors wrote.

In the current study, mortality during 10 years of follow-up was significantly lower among patients who had anti–U1-RNP antibodies than among those who did not (0% vs. 25%; P = .04). This finding of improved survival in patients with anti–U1-RNP antibodies mirrored the results reported in the British SLE-PAH cohort study and a 2016 Chinese study, indicating that “the presence of anti–U1-RNP antibodies appears to be a protective factor in terms of survival.”

Treatment with hydroxychloroquine followed a trend toward increased survival, but was not statistically significant (hazard ratio, 0.31; 95% confidence interval, 0.09-1.11; P = .07).

“These findings must be interpreted with caution due to the small number of untreated patients and require further investigations in other cohorts,” the investigators wrote. But “based on our results on the potential effect of hydroxychloroquine, this treatment might be used in association with the immunosuppressive strategy for SLE-PAH patients.”

Read more of the findings in CHEST (2017 Aug 26. doi: 10.1016/j.chest.2017.08.014).
 

[email protected]

The presence of specific autoantibodies may help to identify the small percentage of patients with systemic lupus erythematosus (SLE) who are at higher risk of developing pulmonary arterial hypertension after SLE diagnosis and may also detect those at lower risk of death, according to findings from a retrospective study of French patients.

Eric Hachulla, MD, of the University of Lille (France) and his coinvestigators reported that 51 SLE patients in the French Pulmonary Hypertension Registry who had a diagnosis of pulmonary arterial hypertension (PAH) confirmed by right heart catheterization were more likely to have the condition if they had anti-SSA and anti-SSB antibodies, compared with a control group of 101 SLE patients without known PAH who were selected from SLE expert centers participating in the registry. Overall, anti-SSA antibodies were present in 62% of PAH patients vs. 40% of non-PAH patients, and anti-SSB antibodies were detected in 27% with PAH, compared with 8% of those without.

Following SLE diagnosis, the 51 SLE patients had a median delay in diagnosis of PAH by about 5 years. Their survival was 89% at 3 years and 84% at 5 years. “Survival appeared to be substantially better than that still observed today in [PAH associated with systemic sclerosis], where estimated 3-year survival is about 50%. Our survival rates are comparable to those reported by Sobanski et al. in the recently published study for the U.K. SLE-PAH cohort (85% at 5 years),” the authors wrote.

In the current study, mortality during 10 years of follow-up was significantly lower among patients who had anti–U1-RNP antibodies than among those who did not (0% vs. 25%; P = .04). This finding of improved survival in patients with anti–U1-RNP antibodies mirrored the results reported in the British SLE-PAH cohort study and a 2016 Chinese study, indicating that “the presence of anti–U1-RNP antibodies appears to be a protective factor in terms of survival.”

Treatment with hydroxychloroquine followed a trend toward increased survival, but was not statistically significant (hazard ratio, 0.31; 95% confidence interval, 0.09-1.11; P = .07).

“These findings must be interpreted with caution due to the small number of untreated patients and require further investigations in other cohorts,” the investigators wrote. But “based on our results on the potential effect of hydroxychloroquine, this treatment might be used in association with the immunosuppressive strategy for SLE-PAH patients.”

Read more of the findings in CHEST (2017 Aug 26. doi: 10.1016/j.chest.2017.08.014).
 

[email protected]

The presence of specific autoantibodies may help to identify the small percentage of patients with systemic lupus erythematosus (SLE) who are at higher risk of developing pulmonary arterial hypertension after SLE diagnosis and may also detect those at lower risk of death, according to findings from a retrospective study of French patients.

Eric Hachulla, MD, of the University of Lille (France) and his coinvestigators reported that 51 SLE patients in the French Pulmonary Hypertension Registry who had a diagnosis of pulmonary arterial hypertension (PAH) confirmed by right heart catheterization were more likely to have the condition if they had anti-SSA and anti-SSB antibodies, compared with a control group of 101 SLE patients without known PAH who were selected from SLE expert centers participating in the registry. Overall, anti-SSA antibodies were present in 62% of PAH patients vs. 40% of non-PAH patients, and anti-SSB antibodies were detected in 27% with PAH, compared with 8% of those without.

Following SLE diagnosis, the 51 SLE patients had a median delay in diagnosis of PAH by about 5 years. Their survival was 89% at 3 years and 84% at 5 years. “Survival appeared to be substantially better than that still observed today in [PAH associated with systemic sclerosis], where estimated 3-year survival is about 50%. Our survival rates are comparable to those reported by Sobanski et al. in the recently published study for the U.K. SLE-PAH cohort (85% at 5 years),” the authors wrote.

In the current study, mortality during 10 years of follow-up was significantly lower among patients who had anti–U1-RNP antibodies than among those who did not (0% vs. 25%; P = .04). This finding of improved survival in patients with anti–U1-RNP antibodies mirrored the results reported in the British SLE-PAH cohort study and a 2016 Chinese study, indicating that “the presence of anti–U1-RNP antibodies appears to be a protective factor in terms of survival.”

Treatment with hydroxychloroquine followed a trend toward increased survival, but was not statistically significant (hazard ratio, 0.31; 95% confidence interval, 0.09-1.11; P = .07).

“These findings must be interpreted with caution due to the small number of untreated patients and require further investigations in other cohorts,” the investigators wrote. But “based on our results on the potential effect of hydroxychloroquine, this treatment might be used in association with the immunosuppressive strategy for SLE-PAH patients.”

Read more of the findings in CHEST (2017 Aug 26. doi: 10.1016/j.chest.2017.08.014).
 

[email protected]

Sacroiliac joint radiographic progression during the first 5 years of the onset of axial spondyloarthritis occurs to an extent related to the degree of inflammation seen on MRI at baseline, according to new findings from 416 French patients in the DESIR cohort.

Maxime Dougados, MD, of Paris Descartes University, and his colleagues found that 15% of patients at baseline met modified New York (mNY) criteria – and therefore had radiographic axial spondyloarthritis (r-axSpA) – and this increased to 20% at 5 years. During the 5-year follow-up, the net percentage of patients who progressed was 5% (those who went from nonradiographic axial spondyloarthritis [nr-axSpA] to r-axSpA minus those who regressed from r-axSpA to nr-axSpA). Overall, 13% changed at least one grade on mNY criteria, and if an mNY criteria grade change from zero to one was not considered, only 10% experienced a change in at least one grade. These patients overall had a mean age of 34 years and had inflammatory back pain that had lasted at least 3 months but less than 3 years.

[email protected]

Sacroiliac joint radiographic progression during the first 5 years of the onset of axial spondyloarthritis occurs to an extent related to the degree of inflammation seen on MRI at baseline, according to new findings from 416 French patients in the DESIR cohort.

Maxime Dougados, MD, of Paris Descartes University, and his colleagues found that 15% of patients at baseline met modified New York (mNY) criteria – and therefore had radiographic axial spondyloarthritis (r-axSpA) – and this increased to 20% at 5 years. During the 5-year follow-up, the net percentage of patients who progressed was 5% (those who went from nonradiographic axial spondyloarthritis [nr-axSpA] to r-axSpA minus those who regressed from r-axSpA to nr-axSpA). Overall, 13% changed at least one grade on mNY criteria, and if an mNY criteria grade change from zero to one was not considered, only 10% experienced a change in at least one grade. These patients overall had a mean age of 34 years and had inflammatory back pain that had lasted at least 3 months but less than 3 years.

[email protected]

Sacroiliac joint radiographic progression during the first 5 years of the onset of axial spondyloarthritis occurs to an extent related to the degree of inflammation seen on MRI at baseline, according to new findings from 416 French patients in the DESIR cohort.

Maxime Dougados, MD, of Paris Descartes University, and his colleagues found that 15% of patients at baseline met modified New York (mNY) criteria – and therefore had radiographic axial spondyloarthritis (r-axSpA) – and this increased to 20% at 5 years. During the 5-year follow-up, the net percentage of patients who progressed was 5% (those who went from nonradiographic axial spondyloarthritis [nr-axSpA] to r-axSpA minus those who regressed from r-axSpA to nr-axSpA). Overall, 13% changed at least one grade on mNY criteria, and if an mNY criteria grade change from zero to one was not considered, only 10% experienced a change in at least one grade. These patients overall had a mean age of 34 years and had inflammatory back pain that had lasted at least 3 months but less than 3 years.

[email protected]

MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.

Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).

CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.

At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.

CAPS Registry study

The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.

Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.

The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.

“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.

The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.

Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.

“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.

While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.

All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).

“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.

“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”

Guidelines

A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.

Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.

The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.

All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:

• Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
• Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
• Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
• Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
• Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
• Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
• Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.

The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.

None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.

[email protected]

MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.

Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).

CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.

At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.

CAPS Registry study

The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.

Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.

The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.

“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.

The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.

Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.

“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.

While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.

All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).

“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.

“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”

Guidelines

A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.

Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.

The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.

All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:

• Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
• Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
• Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
• Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
• Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
• Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
• Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.

The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.

None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.

[email protected]

MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.

Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).

CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.

At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.

CAPS Registry study

The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.

Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.

The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.

“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.

The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.

Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.

“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.

While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.

All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).

“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.

“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”

Guidelines

A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.

Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.

The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.

All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:

• Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
• Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
• Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
• Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
• Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
• Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
• Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.

The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.

None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.

[email protected]

Structural lesions of the sacroiliac joints (SIJ) may be present on MRI in patients with nonradiographic axial spondyloarthritis (nr-axSpA), even when radiographs are normal or inconclusive for such lesions and there is no evidence of inflammation on MRI, according to findings from a cohort of patients in a randomized trial.

In the study, the patients who exhibited such lesions, especially erosions, were more likely to have more severe disease and greater spinal inflammation than were patients who did not have the structural lesions on MRI.

Mitchel L. Zoler/Frontline Medical News

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Structural lesions of the sacroiliac joints (SIJ) may be present on MRI in patients with nonradiographic axial spondyloarthritis (nr-axSpA), even when radiographs are normal or inconclusive for such lesions and there is no evidence of inflammation on MRI, according to findings from a cohort of patients in a randomized trial.

In the study, the patients who exhibited such lesions, especially erosions, were more likely to have more severe disease and greater spinal inflammation than were patients who did not have the structural lesions on MRI.

Mitchel L. Zoler/Frontline Medical News

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Structural lesions of the sacroiliac joints (SIJ) may be present on MRI in patients with nonradiographic axial spondyloarthritis (nr-axSpA), even when radiographs are normal or inconclusive for such lesions and there is no evidence of inflammation on MRI, according to findings from a cohort of patients in a randomized trial.

In the study, the patients who exhibited such lesions, especially erosions, were more likely to have more severe disease and greater spinal inflammation than were patients who did not have the structural lesions on MRI.

Mitchel L. Zoler/Frontline Medical News

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The Food and Drug Administration approved the antioxidant drug edaravone on May 5 for the treatment of amyotrophic lateral sclerosis, making it only the second drug ever to be approved by the agency for the motor neuron disease.

The FDA granted approval for edaravone, to be marketed by Mitsubishi Tanabe Pharma America under the brand name Radicava, through its orphan drug pathway, which is meant for drugs used to treat rare diseases or conditions. The Centers for Disease Control and Prevention estimates that amyotrophic lateral sclerosis (ALS) affects 12,000-15,000 Americans.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

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The Food and Drug Administration approved the antioxidant drug edaravone on May 5 for the treatment of amyotrophic lateral sclerosis, making it only the second drug ever to be approved by the agency for the motor neuron disease.

The FDA granted approval for edaravone, to be marketed by Mitsubishi Tanabe Pharma America under the brand name Radicava, through its orphan drug pathway, which is meant for drugs used to treat rare diseases or conditions. The Centers for Disease Control and Prevention estimates that amyotrophic lateral sclerosis (ALS) affects 12,000-15,000 Americans.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

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The Food and Drug Administration approved the antioxidant drug edaravone on May 5 for the treatment of amyotrophic lateral sclerosis, making it only the second drug ever to be approved by the agency for the motor neuron disease.

The FDA granted approval for edaravone, to be marketed by Mitsubishi Tanabe Pharma America under the brand name Radicava, through its orphan drug pathway, which is meant for drugs used to treat rare diseases or conditions. The Centers for Disease Control and Prevention estimates that amyotrophic lateral sclerosis (ALS) affects 12,000-15,000 Americans.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

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BOSTON – Some of the most influential clinical research reports coming out of the annual meeting of the American Academy of Neurology raise questions on how neurologists will strike a balance between the improved efficacy and safety of drugs in new therapeutic classes and their affordability for patients.

Natalia Rost, MD, vice chair of the AAN Science Committee, discussed phase III clinical trials (ARISE and STRIVE) in episodic migraine with erenumab, an investigational humanized monoclonal antibody against calcitonin gene-related peptide receptor; phase III clinical trials (ENDEAR and CHERISH) of the antisense oligonucleotide drug nusinersen (Spinraza) that was approved by the Food and Drug Administration for spinal muscular atrophy in late 2016; as well as phase III trials of a pharmaceutical-grade extract of the cannabis-derived compound cannabidiol in patients with Dravet syndrome and Lennox-Gastaut syndrome.

Erenumab and nusinersen are “disease-specific targeted biologics” that have been developed over decades to target a specific disease pathway, and hence translate into high prices, Dr. Rost said in a video interview at the meeting.

“How you value the cost of a drug against improvement in a physiological outcome is very difficult to measure,” she noted, for relatively small gains in reducing migraine days per month and improvements in functional outcome and disability against placebo.

But this calculation is different with the potentially lifesaving effects of nusinersen for spinal muscular atrophy patients, in which “we’re not talking about days of improvement, we’re talking about days of life,” said Dr. Rost, director of acute stroke services at Massachusetts General Hospital, Boston. “And so that becomes an ethical dilemma in terms of the cost of administration, who is paying for the drug, and how this is covered. Whom do you offer treatment to?”

The development of cannabidiol as a potential adjunctive treatment for Dravet and Lennox-Gastaut syndromes is a welcome addition to the armamentarium against these conditions, Dr. Rost added, because it offers an alternative to the unregulated use of herbal medications and supplements – particularly cannabis in its various forms – that patients ask about but are difficult to dose consistently and to ensure a pharmaceutical-grade level of purity.

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BOSTON – Some of the most influential clinical research reports coming out of the annual meeting of the American Academy of Neurology raise questions on how neurologists will strike a balance between the improved efficacy and safety of drugs in new therapeutic classes and their affordability for patients.

Natalia Rost, MD, vice chair of the AAN Science Committee, discussed phase III clinical trials (ARISE and STRIVE) in episodic migraine with erenumab, an investigational humanized monoclonal antibody against calcitonin gene-related peptide receptor; phase III clinical trials (ENDEAR and CHERISH) of the antisense oligonucleotide drug nusinersen (Spinraza) that was approved by the Food and Drug Administration for spinal muscular atrophy in late 2016; as well as phase III trials of a pharmaceutical-grade extract of the cannabis-derived compound cannabidiol in patients with Dravet syndrome and Lennox-Gastaut syndrome.

Erenumab and nusinersen are “disease-specific targeted biologics” that have been developed over decades to target a specific disease pathway, and hence translate into high prices, Dr. Rost said in a video interview at the meeting.

“How you value the cost of a drug against improvement in a physiological outcome is very difficult to measure,” she noted, for relatively small gains in reducing migraine days per month and improvements in functional outcome and disability against placebo.

But this calculation is different with the potentially lifesaving effects of nusinersen for spinal muscular atrophy patients, in which “we’re not talking about days of improvement, we’re talking about days of life,” said Dr. Rost, director of acute stroke services at Massachusetts General Hospital, Boston. “And so that becomes an ethical dilemma in terms of the cost of administration, who is paying for the drug, and how this is covered. Whom do you offer treatment to?”

The development of cannabidiol as a potential adjunctive treatment for Dravet and Lennox-Gastaut syndromes is a welcome addition to the armamentarium against these conditions, Dr. Rost added, because it offers an alternative to the unregulated use of herbal medications and supplements – particularly cannabis in its various forms – that patients ask about but are difficult to dose consistently and to ensure a pharmaceutical-grade level of purity.

[email protected]

BOSTON – Some of the most influential clinical research reports coming out of the annual meeting of the American Academy of Neurology raise questions on how neurologists will strike a balance between the improved efficacy and safety of drugs in new therapeutic classes and their affordability for patients.

Natalia Rost, MD, vice chair of the AAN Science Committee, discussed phase III clinical trials (ARISE and STRIVE) in episodic migraine with erenumab, an investigational humanized monoclonal antibody against calcitonin gene-related peptide receptor; phase III clinical trials (ENDEAR and CHERISH) of the antisense oligonucleotide drug nusinersen (Spinraza) that was approved by the Food and Drug Administration for spinal muscular atrophy in late 2016; as well as phase III trials of a pharmaceutical-grade extract of the cannabis-derived compound cannabidiol in patients with Dravet syndrome and Lennox-Gastaut syndrome.

Erenumab and nusinersen are “disease-specific targeted biologics” that have been developed over decades to target a specific disease pathway, and hence translate into high prices, Dr. Rost said in a video interview at the meeting.

“How you value the cost of a drug against improvement in a physiological outcome is very difficult to measure,” she noted, for relatively small gains in reducing migraine days per month and improvements in functional outcome and disability against placebo.

But this calculation is different with the potentially lifesaving effects of nusinersen for spinal muscular atrophy patients, in which “we’re not talking about days of improvement, we’re talking about days of life,” said Dr. Rost, director of acute stroke services at Massachusetts General Hospital, Boston. “And so that becomes an ethical dilemma in terms of the cost of administration, who is paying for the drug, and how this is covered. Whom do you offer treatment to?”

The development of cannabidiol as a potential adjunctive treatment for Dravet and Lennox-Gastaut syndromes is a welcome addition to the armamentarium against these conditions, Dr. Rost added, because it offers an alternative to the unregulated use of herbal medications and supplements – particularly cannabis in its various forms – that patients ask about but are difficult to dose consistently and to ensure a pharmaceutical-grade level of purity.

[email protected]

BOSTON – Intrathecal, autologous mesenchymal stem cell (MSC) treatment provided encouraging results for modifying the disease course of multiple system atrophy with relative safety and tolerability in a phase I/II trial.

The efficacy of MSCs on slowing multiple system atrophy (MSA) progression in a small trial of 24 patients appeared to be dependent on the dose, and, in the highest dose individuals, had a painful implantation response, trial investigator Wolfgang Singer, MD, reported at the annual meeting of the American Academy of Neurology.

Dr. Singer and his colleagues at the Mayo Clinic in Rochester, Minn., chose to investigate MSCs as a treatment because they are multipotent and capable of differentiating into different cell types, including glial cells, and they secrete neurotrophic factors, such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, which are thought to occur at pathologically low levels in individuals with MSA. The intrinsic immunomodulatory action of MSCs may also contribute to a potential benefit on neuroinflammatory aspects of MSA pathology.

MSCs have previously shown promising results on slowing disease progression in an open-label study of Korean patients with MSA, who received an intra-arterial infusion of MSCs into the internal carotids and dominant vertebral artery, followed by intravenous infusions (Clin Pharmacol Ther. 2008 May;83[5]:723-30). Those results were confirmed in a double-blind, placebo-controlled study (Ann Neurol. 2012 Jul;72[1]:32-40), but evidence of microemboli raised concerns with the Mayo Clinic team about stroke risk with the intra-arterial approach, Dr. Singer said.

The intrathecal route of administration also may be advantageous over an intra-arterial approach by reaching the targets of MSCs in the brain “in a more widespread fashion,” Dr. Singer said.

The relative safety and hint of efficacy with the different route of MSC administration in the Mayo Clinic study make it “a really groundbreaking direction to take,” session comoderator Christopher H. Gibbons, MD, said in an interview. “I think this a very good, small, but critical, step in demonstrating that ... you can do this, and maybe there’s a signal that it is, in fact, working at slowing down disease progression, which I think is incredibly important in this disease.”

In the current study, Dr. Singer and his associates intrathecally administered between 10 and 200 million autologous, fat-derived MSCs via lumbar puncture in predefined dose tiers and then followed patients over 1 year. Overall, 8 patients received a single dose of 10 million cells, 12 received a dose of 50 million cells followed by a second 50-million cell dose 4 weeks later, and 4 received a dose of 100 million cells followed by a second 100-million cell dose 4 weeks later.

The 24 patients in the study all met consensus criteria for probable MSA, had at least moderate laboratory evidence of autonomic failure, and were at an early stage of disease with a Unified MSA Rating Scale part 1 score of 18 or less.

In the primary outcome of safety, the investigators reported no treatment–attributable serious adverse events and said that the treatment was generally well-tolerated. All 16 patients who took either the high or medium doses had MRI abnormalities that showed thickening/enhancement of cauda equina nerve roots at the level of the puncture that were asymptomatic and did not lead to neurologic deficits.

The 12 medium-dose patients had variable elevation of cerebrospinal fluid protein and cell counts, and 5 had mild and transient low back pain. In the highest-dose tier, three of four patients developed low back pain, some of which was severe, and the same MRI findings, which signaled to the investigators that a dose-limiting toxicity had been reached.

Some patients also reported headaches after lumbar punctures, which were expected. Two patients also developed mild febrile reactions after administrations that were self-limited.

Treatment with MSCs led to a significantly lower rate of disease progression as measured by total score on the Unified MSA Rating Scale (0.43 vs. 1.22 points/month; P = .009), and this difference was even greater for the medium-dose tier than for the low-dose tier. The investigators used the placebo group from their recently completed rifampicin treatment trial in MSA to make the efficacy assessment.

There was no change between the treatment groups and the historical control group on the Composite Autonomic Symptom Scale or the Composite Autonomic Severity Score from baseline to 1 year.

Based on the promising findings, the Food and Drug Administration granted permission for a compassionate extension study for apparent responders to receive additional injections every 6 months, and, so far, 16 patients have been reinjected, according to Dr. Singer.

Dr. Singer and his associates have used these results as the basis for a multicenter, double-blind, placebo-controlled phase II/III study that is in the late planning stages. This kind of trial will be important for determining whether it’s possible to hold the quality of the MSC treatment steady and get the same sort of response across many centers, said Dr. Gibbons, a clinical neurophysiologist at Beth Israel Deaconess Medical Center, Boston, and past-president of the American Autonomic Society.

The trial was supported by grants from the National Institutes of Health, the Cure MSA Foundation, the Food and Drug Administration, the Autonomic Rare Disease Consortium, and Mayo Clinic funds. Dr. Singer and Dr. Gibbons reported having no relevant financial disclosures.

You can watch a video interview with Dr. Singer here.

Vidyard Video

 

 

[email protected]

BOSTON – Intrathecal, autologous mesenchymal stem cell (MSC) treatment provided encouraging results for modifying the disease course of multiple system atrophy with relative safety and tolerability in a phase I/II trial.

The efficacy of MSCs on slowing multiple system atrophy (MSA) progression in a small trial of 24 patients appeared to be dependent on the dose, and, in the highest dose individuals, had a painful implantation response, trial investigator Wolfgang Singer, MD, reported at the annual meeting of the American Academy of Neurology.

Dr. Singer and his colleagues at the Mayo Clinic in Rochester, Minn., chose to investigate MSCs as a treatment because they are multipotent and capable of differentiating into different cell types, including glial cells, and they secrete neurotrophic factors, such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, which are thought to occur at pathologically low levels in individuals with MSA. The intrinsic immunomodulatory action of MSCs may also contribute to a potential benefit on neuroinflammatory aspects of MSA pathology.

MSCs have previously shown promising results on slowing disease progression in an open-label study of Korean patients with MSA, who received an intra-arterial infusion of MSCs into the internal carotids and dominant vertebral artery, followed by intravenous infusions (Clin Pharmacol Ther. 2008 May;83[5]:723-30). Those results were confirmed in a double-blind, placebo-controlled study (Ann Neurol. 2012 Jul;72[1]:32-40), but evidence of microemboli raised concerns with the Mayo Clinic team about stroke risk with the intra-arterial approach, Dr. Singer said.

The intrathecal route of administration also may be advantageous over an intra-arterial approach by reaching the targets of MSCs in the brain “in a more widespread fashion,” Dr. Singer said.

The relative safety and hint of efficacy with the different route of MSC administration in the Mayo Clinic study make it “a really groundbreaking direction to take,” session comoderator Christopher H. Gibbons, MD, said in an interview. “I think this a very good, small, but critical, step in demonstrating that ... you can do this, and maybe there’s a signal that it is, in fact, working at slowing down disease progression, which I think is incredibly important in this disease.”

In the current study, Dr. Singer and his associates intrathecally administered between 10 and 200 million autologous, fat-derived MSCs via lumbar puncture in predefined dose tiers and then followed patients over 1 year. Overall, 8 patients received a single dose of 10 million cells, 12 received a dose of 50 million cells followed by a second 50-million cell dose 4 weeks later, and 4 received a dose of 100 million cells followed by a second 100-million cell dose 4 weeks later.

The 24 patients in the study all met consensus criteria for probable MSA, had at least moderate laboratory evidence of autonomic failure, and were at an early stage of disease with a Unified MSA Rating Scale part 1 score of 18 or less.

In the primary outcome of safety, the investigators reported no treatment–attributable serious adverse events and said that the treatment was generally well-tolerated. All 16 patients who took either the high or medium doses had MRI abnormalities that showed thickening/enhancement of cauda equina nerve roots at the level of the puncture that were asymptomatic and did not lead to neurologic deficits.

The 12 medium-dose patients had variable elevation of cerebrospinal fluid protein and cell counts, and 5 had mild and transient low back pain. In the highest-dose tier, three of four patients developed low back pain, some of which was severe, and the same MRI findings, which signaled to the investigators that a dose-limiting toxicity had been reached.

Some patients also reported headaches after lumbar punctures, which were expected. Two patients also developed mild febrile reactions after administrations that were self-limited.

Treatment with MSCs led to a significantly lower rate of disease progression as measured by total score on the Unified MSA Rating Scale (0.43 vs. 1.22 points/month; P = .009), and this difference was even greater for the medium-dose tier than for the low-dose tier. The investigators used the placebo group from their recently completed rifampicin treatment trial in MSA to make the efficacy assessment.

There was no change between the treatment groups and the historical control group on the Composite Autonomic Symptom Scale or the Composite Autonomic Severity Score from baseline to 1 year.

Based on the promising findings, the Food and Drug Administration granted permission for a compassionate extension study for apparent responders to receive additional injections every 6 months, and, so far, 16 patients have been reinjected, according to Dr. Singer.

Dr. Singer and his associates have used these results as the basis for a multicenter, double-blind, placebo-controlled phase II/III study that is in the late planning stages. This kind of trial will be important for determining whether it’s possible to hold the quality of the MSC treatment steady and get the same sort of response across many centers, said Dr. Gibbons, a clinical neurophysiologist at Beth Israel Deaconess Medical Center, Boston, and past-president of the American Autonomic Society.

The trial was supported by grants from the National Institutes of Health, the Cure MSA Foundation, the Food and Drug Administration, the Autonomic Rare Disease Consortium, and Mayo Clinic funds. Dr. Singer and Dr. Gibbons reported having no relevant financial disclosures.

You can watch a video interview with Dr. Singer here.

Vidyard Video

 

 

[email protected]

BOSTON – Intrathecal, autologous mesenchymal stem cell (MSC) treatment provided encouraging results for modifying the disease course of multiple system atrophy with relative safety and tolerability in a phase I/II trial.

The efficacy of MSCs on slowing multiple system atrophy (MSA) progression in a small trial of 24 patients appeared to be dependent on the dose, and, in the highest dose individuals, had a painful implantation response, trial investigator Wolfgang Singer, MD, reported at the annual meeting of the American Academy of Neurology.

Dr. Singer and his colleagues at the Mayo Clinic in Rochester, Minn., chose to investigate MSCs as a treatment because they are multipotent and capable of differentiating into different cell types, including glial cells, and they secrete neurotrophic factors, such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, which are thought to occur at pathologically low levels in individuals with MSA. The intrinsic immunomodulatory action of MSCs may also contribute to a potential benefit on neuroinflammatory aspects of MSA pathology.

MSCs have previously shown promising results on slowing disease progression in an open-label study of Korean patients with MSA, who received an intra-arterial infusion of MSCs into the internal carotids and dominant vertebral artery, followed by intravenous infusions (Clin Pharmacol Ther. 2008 May;83[5]:723-30). Those results were confirmed in a double-blind, placebo-controlled study (Ann Neurol. 2012 Jul;72[1]:32-40), but evidence of microemboli raised concerns with the Mayo Clinic team about stroke risk with the intra-arterial approach, Dr. Singer said.

The intrathecal route of administration also may be advantageous over an intra-arterial approach by reaching the targets of MSCs in the brain “in a more widespread fashion,” Dr. Singer said.

The relative safety and hint of efficacy with the different route of MSC administration in the Mayo Clinic study make it “a really groundbreaking direction to take,” session comoderator Christopher H. Gibbons, MD, said in an interview. “I think this a very good, small, but critical, step in demonstrating that ... you can do this, and maybe there’s a signal that it is, in fact, working at slowing down disease progression, which I think is incredibly important in this disease.”

In the current study, Dr. Singer and his associates intrathecally administered between 10 and 200 million autologous, fat-derived MSCs via lumbar puncture in predefined dose tiers and then followed patients over 1 year. Overall, 8 patients received a single dose of 10 million cells, 12 received a dose of 50 million cells followed by a second 50-million cell dose 4 weeks later, and 4 received a dose of 100 million cells followed by a second 100-million cell dose 4 weeks later.

The 24 patients in the study all met consensus criteria for probable MSA, had at least moderate laboratory evidence of autonomic failure, and were at an early stage of disease with a Unified MSA Rating Scale part 1 score of 18 or less.

In the primary outcome of safety, the investigators reported no treatment–attributable serious adverse events and said that the treatment was generally well-tolerated. All 16 patients who took either the high or medium doses had MRI abnormalities that showed thickening/enhancement of cauda equina nerve roots at the level of the puncture that were asymptomatic and did not lead to neurologic deficits.

The 12 medium-dose patients had variable elevation of cerebrospinal fluid protein and cell counts, and 5 had mild and transient low back pain. In the highest-dose tier, three of four patients developed low back pain, some of which was severe, and the same MRI findings, which signaled to the investigators that a dose-limiting toxicity had been reached.

Some patients also reported headaches after lumbar punctures, which were expected. Two patients also developed mild febrile reactions after administrations that were self-limited.

Treatment with MSCs led to a significantly lower rate of disease progression as measured by total score on the Unified MSA Rating Scale (0.43 vs. 1.22 points/month; P = .009), and this difference was even greater for the medium-dose tier than for the low-dose tier. The investigators used the placebo group from their recently completed rifampicin treatment trial in MSA to make the efficacy assessment.

There was no change between the treatment groups and the historical control group on the Composite Autonomic Symptom Scale or the Composite Autonomic Severity Score from baseline to 1 year.

Based on the promising findings, the Food and Drug Administration granted permission for a compassionate extension study for apparent responders to receive additional injections every 6 months, and, so far, 16 patients have been reinjected, according to Dr. Singer.

Dr. Singer and his associates have used these results as the basis for a multicenter, double-blind, placebo-controlled phase II/III study that is in the late planning stages. This kind of trial will be important for determining whether it’s possible to hold the quality of the MSC treatment steady and get the same sort of response across many centers, said Dr. Gibbons, a clinical neurophysiologist at Beth Israel Deaconess Medical Center, Boston, and past-president of the American Autonomic Society.

The trial was supported by grants from the National Institutes of Health, the Cure MSA Foundation, the Food and Drug Administration, the Autonomic Rare Disease Consortium, and Mayo Clinic funds. Dr. Singer and Dr. Gibbons reported having no relevant financial disclosures.

You can watch a video interview with Dr. Singer here.

Vidyard Video

 

 

[email protected]

BOSTON – Survivors of sepsis face a significantly increased risk of seizures following an index hospitalization, regardless of any previous history of seizures or seizures occurring during hospitalization, according to findings from a retrospective, population-based cohort study.

The risk for having subsequent seizures was highest for patients younger than 65 years but was still elevated above the general population for those aged 65 years or older, Michael Reznik, MD, reported at the annual meeting of the American Academy of Neurology.

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BOSTON – Survivors of sepsis face a significantly increased risk of seizures following an index hospitalization, regardless of any previous history of seizures or seizures occurring during hospitalization, according to findings from a retrospective, population-based cohort study.

The risk for having subsequent seizures was highest for patients younger than 65 years but was still elevated above the general population for those aged 65 years or older, Michael Reznik, MD, reported at the annual meeting of the American Academy of Neurology.

[email protected]

BOSTON – Survivors of sepsis face a significantly increased risk of seizures following an index hospitalization, regardless of any previous history of seizures or seizures occurring during hospitalization, according to findings from a retrospective, population-based cohort study.

The risk for having subsequent seizures was highest for patients younger than 65 years but was still elevated above the general population for those aged 65 years or older, Michael Reznik, MD, reported at the annual meeting of the American Academy of Neurology.

[email protected]