Jake Remaly

A large-scale screen of urine proteins has identified molecules that may help to determine whether a patient has active lupus nephritis, according to a cross-sectional study published in Nature Communications. The proteins that best differentiate active lupus nephritis from inactive systemic lupus erythematosus (SLE) vary across ethnicities, the researchers wrote.

“A longitudinal study is warranted to investigate how these molecules relate to disease pathology and progression over time,” said senior study author Chandra Mohan, MD, PhD, of the department of biomedical engineering at the University of Houston, and colleagues. In addition, researchers should investigate the roles of protein biomarkers ALCAM, PF-4, properdin, VCAM-1, and sE-selectin in mediating lupus nephritis.
 

Limitations of renal biopsy

About 60% of patients with SLE will develop lupus nephritis, and 10%-15% of patients who develop lupus nephritis progress to end-stage renal disease. Although renal biopsy is the gold standard for the diagnosis of renal involvement in SLE, biopsies are invasive, not serially repeatable, and may not represent the entire kidney, Dr. Mohan and colleagues wrote.

To identify potential urinary biomarkers of lupus nephritis using an unbiased, proteomic approach, the investigators screened urine samples from 23 participants – 7 with active lupus nephritis, 8 with inactive SLE, and 8 healthy controls. They used an aptamer-based screen to investigate more than 1,100 proteins. The researchers then validated biomarker candidates using enzyme-linked immunosorbent assays. Independent cross-sectional cohorts included 127 patients with inactive SLE, 107 patients with active lupus nephritis, 67 patients with active nonrenal lupus, and 74 healthy controls. The cohorts included patients who were African American, Caucasian, and Asian. The researchers excluded patients with renal failure and pediatric patients.

Of the 12 urine proteins studied, 10 outperformed traditional laboratory measures, such as C3/C4 and anti–double stranded DNA, in discriminating active lupus nephritis from inactive SLE, wrote Dr. Mohan and colleagues. A Lasso regression analysis found that the best predictive model included 8 of the 12 urine proteins as well as race. The model discriminated active lupus nephritis from inactive SLE with an area under the receiver operating characteristic curve (AUC) of 0.98.

Among African Americans, urine proteins that best distinguished active lupus nephritis from inactive disease included PF-4 (AUC, 0.88), VCAM-1 (AUC, 0.87), properdin (AUC, 0.85), and ALCAM (AUC, 0.84). Among Caucasians, they included sE-selectin (AUC, 0.87), VCAM-1 (AUC, 0.84), BFL-1 (AUC, 0.81), and hemopexin (AUC, 0.80). Among Asians, they included ALCAM (AUC, 0.93), VCAM-1 (AUC, 0.92), TFPI (AUC, 0.88), and PF-4 (AUC, 0.83).

The study is “unique in highlighting the importance of tailoring the biomarkers to patient ethnicity,” the researchers wrote.

Basing subgroups on race rather than phenotypic profiles

“This is an important study because it confirms the ability to predict active lupus nephritis from urine samples and utilized advanced technologies to find key markers for that,” said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City. “It is unfortunate that investigators with access to such advanced technology are still using an outdated and extremely questionable method for distinguishing subgroups of patients, that of race.”

Grouping patients by phenotypic profiles that reflect current disease states “would be a more accurate method for finding optimal urinary markers for active nephritis,” and is “likely to prove more accurate for individuals in all races,” Dr. Merrill said. Certain racial subgroups may be more likely to have particular disease phenotypes, “which are usually identified based on gene pathway coexpression patterns.” Still, “people who self-identify as a given race are not genetically identical,” Dr. Merrill added. “In fact, this is a very blunt instrument, compared to phenotypic profiling now available for lupus patients.”

SLE and lupus nephritis are “heavily influenced by genetics,” and African Americans are three times more likely than Caucasians to develop SLE and are more like to develop end-stage renal disease, Dr. Mohan and colleagues wrote. Nevertheless, “influence from environmental triggers or socioeconomic factors cannot be ruled out,” they added. “Although patient demographics are widely known to affect SLE disease manifestations and outcomes, there are virtually no studies investigating this phenomenon in the context of disease biomarkers; most SLE biomarkers studies focus on one demographic group or all ethnic groups combined, which yield results that may not be equally predictive in all demographic groups of SLE patients.”

Dr. Mohan is collaborating with a biotechnology company to study drugs that may block ALCAM, according to a University of Houston news release. ALCAM is involved in immune and inflammatory responses, the researchers noted. “When all SLE patients were combined, urine ALCAM levels had the strongest bearing on disease activity status, in an unsupervised Bayesian network analysis,” they wrote. “Urine ALCAM also emerged as one of the few proteins that distinguished active [lupus nephritis] from active nonrenal lupus.”

National Institutes of Health grants supported the research. The investigators had no competing interests.
 

[email protected]

SOURCE: Stanley S et al. Nat Commun. 2020 May 4. doi: 10.1038/s41467-020-15986-3.

A large-scale screen of urine proteins has identified molecules that may help to determine whether a patient has active lupus nephritis, according to a cross-sectional study published in Nature Communications. The proteins that best differentiate active lupus nephritis from inactive systemic lupus erythematosus (SLE) vary across ethnicities, the researchers wrote.

“A longitudinal study is warranted to investigate how these molecules relate to disease pathology and progression over time,” said senior study author Chandra Mohan, MD, PhD, of the department of biomedical engineering at the University of Houston, and colleagues. In addition, researchers should investigate the roles of protein biomarkers ALCAM, PF-4, properdin, VCAM-1, and sE-selectin in mediating lupus nephritis.
 

Limitations of renal biopsy

About 60% of patients with SLE will develop lupus nephritis, and 10%-15% of patients who develop lupus nephritis progress to end-stage renal disease. Although renal biopsy is the gold standard for the diagnosis of renal involvement in SLE, biopsies are invasive, not serially repeatable, and may not represent the entire kidney, Dr. Mohan and colleagues wrote.

To identify potential urinary biomarkers of lupus nephritis using an unbiased, proteomic approach, the investigators screened urine samples from 23 participants – 7 with active lupus nephritis, 8 with inactive SLE, and 8 healthy controls. They used an aptamer-based screen to investigate more than 1,100 proteins. The researchers then validated biomarker candidates using enzyme-linked immunosorbent assays. Independent cross-sectional cohorts included 127 patients with inactive SLE, 107 patients with active lupus nephritis, 67 patients with active nonrenal lupus, and 74 healthy controls. The cohorts included patients who were African American, Caucasian, and Asian. The researchers excluded patients with renal failure and pediatric patients.

Of the 12 urine proteins studied, 10 outperformed traditional laboratory measures, such as C3/C4 and anti–double stranded DNA, in discriminating active lupus nephritis from inactive SLE, wrote Dr. Mohan and colleagues. A Lasso regression analysis found that the best predictive model included 8 of the 12 urine proteins as well as race. The model discriminated active lupus nephritis from inactive SLE with an area under the receiver operating characteristic curve (AUC) of 0.98.

Among African Americans, urine proteins that best distinguished active lupus nephritis from inactive disease included PF-4 (AUC, 0.88), VCAM-1 (AUC, 0.87), properdin (AUC, 0.85), and ALCAM (AUC, 0.84). Among Caucasians, they included sE-selectin (AUC, 0.87), VCAM-1 (AUC, 0.84), BFL-1 (AUC, 0.81), and hemopexin (AUC, 0.80). Among Asians, they included ALCAM (AUC, 0.93), VCAM-1 (AUC, 0.92), TFPI (AUC, 0.88), and PF-4 (AUC, 0.83).

The study is “unique in highlighting the importance of tailoring the biomarkers to patient ethnicity,” the researchers wrote.

Basing subgroups on race rather than phenotypic profiles

“This is an important study because it confirms the ability to predict active lupus nephritis from urine samples and utilized advanced technologies to find key markers for that,” said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City. “It is unfortunate that investigators with access to such advanced technology are still using an outdated and extremely questionable method for distinguishing subgroups of patients, that of race.”

Grouping patients by phenotypic profiles that reflect current disease states “would be a more accurate method for finding optimal urinary markers for active nephritis,” and is “likely to prove more accurate for individuals in all races,” Dr. Merrill said. Certain racial subgroups may be more likely to have particular disease phenotypes, “which are usually identified based on gene pathway coexpression patterns.” Still, “people who self-identify as a given race are not genetically identical,” Dr. Merrill added. “In fact, this is a very blunt instrument, compared to phenotypic profiling now available for lupus patients.”

SLE and lupus nephritis are “heavily influenced by genetics,” and African Americans are three times more likely than Caucasians to develop SLE and are more like to develop end-stage renal disease, Dr. Mohan and colleagues wrote. Nevertheless, “influence from environmental triggers or socioeconomic factors cannot be ruled out,” they added. “Although patient demographics are widely known to affect SLE disease manifestations and outcomes, there are virtually no studies investigating this phenomenon in the context of disease biomarkers; most SLE biomarkers studies focus on one demographic group or all ethnic groups combined, which yield results that may not be equally predictive in all demographic groups of SLE patients.”

Dr. Mohan is collaborating with a biotechnology company to study drugs that may block ALCAM, according to a University of Houston news release. ALCAM is involved in immune and inflammatory responses, the researchers noted. “When all SLE patients were combined, urine ALCAM levels had the strongest bearing on disease activity status, in an unsupervised Bayesian network analysis,” they wrote. “Urine ALCAM also emerged as one of the few proteins that distinguished active [lupus nephritis] from active nonrenal lupus.”

National Institutes of Health grants supported the research. The investigators had no competing interests.
 

[email protected]

SOURCE: Stanley S et al. Nat Commun. 2020 May 4. doi: 10.1038/s41467-020-15986-3.

A large-scale screen of urine proteins has identified molecules that may help to determine whether a patient has active lupus nephritis, according to a cross-sectional study published in Nature Communications. The proteins that best differentiate active lupus nephritis from inactive systemic lupus erythematosus (SLE) vary across ethnicities, the researchers wrote.

“A longitudinal study is warranted to investigate how these molecules relate to disease pathology and progression over time,” said senior study author Chandra Mohan, MD, PhD, of the department of biomedical engineering at the University of Houston, and colleagues. In addition, researchers should investigate the roles of protein biomarkers ALCAM, PF-4, properdin, VCAM-1, and sE-selectin in mediating lupus nephritis.
 

Limitations of renal biopsy

About 60% of patients with SLE will develop lupus nephritis, and 10%-15% of patients who develop lupus nephritis progress to end-stage renal disease. Although renal biopsy is the gold standard for the diagnosis of renal involvement in SLE, biopsies are invasive, not serially repeatable, and may not represent the entire kidney, Dr. Mohan and colleagues wrote.

To identify potential urinary biomarkers of lupus nephritis using an unbiased, proteomic approach, the investigators screened urine samples from 23 participants – 7 with active lupus nephritis, 8 with inactive SLE, and 8 healthy controls. They used an aptamer-based screen to investigate more than 1,100 proteins. The researchers then validated biomarker candidates using enzyme-linked immunosorbent assays. Independent cross-sectional cohorts included 127 patients with inactive SLE, 107 patients with active lupus nephritis, 67 patients with active nonrenal lupus, and 74 healthy controls. The cohorts included patients who were African American, Caucasian, and Asian. The researchers excluded patients with renal failure and pediatric patients.

Of the 12 urine proteins studied, 10 outperformed traditional laboratory measures, such as C3/C4 and anti–double stranded DNA, in discriminating active lupus nephritis from inactive SLE, wrote Dr. Mohan and colleagues. A Lasso regression analysis found that the best predictive model included 8 of the 12 urine proteins as well as race. The model discriminated active lupus nephritis from inactive SLE with an area under the receiver operating characteristic curve (AUC) of 0.98.

Among African Americans, urine proteins that best distinguished active lupus nephritis from inactive disease included PF-4 (AUC, 0.88), VCAM-1 (AUC, 0.87), properdin (AUC, 0.85), and ALCAM (AUC, 0.84). Among Caucasians, they included sE-selectin (AUC, 0.87), VCAM-1 (AUC, 0.84), BFL-1 (AUC, 0.81), and hemopexin (AUC, 0.80). Among Asians, they included ALCAM (AUC, 0.93), VCAM-1 (AUC, 0.92), TFPI (AUC, 0.88), and PF-4 (AUC, 0.83).

The study is “unique in highlighting the importance of tailoring the biomarkers to patient ethnicity,” the researchers wrote.

Basing subgroups on race rather than phenotypic profiles

“This is an important study because it confirms the ability to predict active lupus nephritis from urine samples and utilized advanced technologies to find key markers for that,” said Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City. “It is unfortunate that investigators with access to such advanced technology are still using an outdated and extremely questionable method for distinguishing subgroups of patients, that of race.”

Grouping patients by phenotypic profiles that reflect current disease states “would be a more accurate method for finding optimal urinary markers for active nephritis,” and is “likely to prove more accurate for individuals in all races,” Dr. Merrill said. Certain racial subgroups may be more likely to have particular disease phenotypes, “which are usually identified based on gene pathway coexpression patterns.” Still, “people who self-identify as a given race are not genetically identical,” Dr. Merrill added. “In fact, this is a very blunt instrument, compared to phenotypic profiling now available for lupus patients.”

SLE and lupus nephritis are “heavily influenced by genetics,” and African Americans are three times more likely than Caucasians to develop SLE and are more like to develop end-stage renal disease, Dr. Mohan and colleagues wrote. Nevertheless, “influence from environmental triggers or socioeconomic factors cannot be ruled out,” they added. “Although patient demographics are widely known to affect SLE disease manifestations and outcomes, there are virtually no studies investigating this phenomenon in the context of disease biomarkers; most SLE biomarkers studies focus on one demographic group or all ethnic groups combined, which yield results that may not be equally predictive in all demographic groups of SLE patients.”

Dr. Mohan is collaborating with a biotechnology company to study drugs that may block ALCAM, according to a University of Houston news release. ALCAM is involved in immune and inflammatory responses, the researchers noted. “When all SLE patients were combined, urine ALCAM levels had the strongest bearing on disease activity status, in an unsupervised Bayesian network analysis,” they wrote. “Urine ALCAM also emerged as one of the few proteins that distinguished active [lupus nephritis] from active nonrenal lupus.”

National Institutes of Health grants supported the research. The investigators had no competing interests.
 

[email protected]

SOURCE: Stanley S et al. Nat Commun. 2020 May 4. doi: 10.1038/s41467-020-15986-3.

Satralizumab monotherapy reduces the rate of neuromyelitis optica spectrum disorder (NMOSD) relapse, compared with placebo, according to trial results published in the Lancet Neurology.

The findings help confirm the role of interleukin-6 in the pathobiology of aquaporin-4 autoantibody (AQP4-IgG)–seropositive disease. For patients who are AQP4-IgG seronegative, however, “there is insufficient evidence to indicate a risk reduction” with this drug, the investigators wrote. In addition, satralizumab did not significantly affect pain or fatigue.

“The limitations of the study include the relatively small group sizes and low number of relapses. Despite these limitations, a significant treatment benefit was observed with satralizumab, compared with placebo in the study population, with efficacy and safety comparable to satralizumab used in combination with immunosuppressants,” reported lead author Anthony Traboulsee, MD, professor of neurology at the University of British Columbia, Vancouver, and colleagues.

Satralizumab is a humanized monoclonal antibody targeting the IL-6 receptor. A prior phase 3 study, SakuraSky, found that the drug reduces the risk of NMOSD relapse when added to immunosuppressant therapy. To assess the safety and efficacy of satralizumab monotherapy, Dr. Traboulsee and colleagues conducted SakuraStar, a randomized, double-blind, placebo-controlled trial.
 

Evaluating drug as monotherapy

The phase 3 trial enrolled 95 patients aged 18-74 years at 44 sites in 13 countries. The investigators included patients with AQP4-IgG–seropositive or –seronegative neuromyelitis optica using the 2006 Wingerchuk criteria or with AQP4-IgG–seropositive NMOSD with at least one event of longitudinally extensive myelitis or optic neuritis. The researchers limited the number of AQP4-IgG–seronegative patients to about 30% of the study population. Eligible participants had at least one NMOSD attack or relapse in the past 12 months and a score of 6.5 or less on the Expanded Disability Status Scale (EDSS). The investigators excluded patients with a clinical relapse in the 30 days before study baseline. Participants were randomly assigned 2:1 to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Concomitant immunosuppressant use was prohibited, although corticosteroids and intravenous immunoglobulin were permitted as rescue therapy for the treatment of relapse.

The primary endpoint was time to first relapse, and the trial was designed to continue until 44 relapses occurred or for 1.5 years after the last patient entered the trial, whichever occurred first.

“Because even one NMOSD attack can have serious neurological consequences, this design allowed patients who had an attack on placebo to enter the open-label phase and receive the active drug,” the researchers wrote. “The trial design used unequal randomization to minimize exposure to placebo; because patients were not permitted to receive concomitant immunosuppressant treatment in this trial, the design limited the number of patients not receiving any treatment for the disorder. Placebo was selected with the consideration that no drugs were approved for the treatment of NMOSD when the trial was designed.” Recent trials of eculizumab, inebilizumab, and satralizumab have found that the agents are effective treatments for NMOSD. In 2019, the Food and Drug Administration approved eculizumab, a complement inhibitor, for the treatment of AQP4-IgG–seropositive NMOSD.

For the primary endpoint of SakuraStar, the researchers defined relapses as new or worsening objective neurologic symptoms with at least one of the following:

• Increase of 1 or more EDSS points from a baseline EDSS score of more than 0, or increase of 2 or more EDSS points from a baseline EDSS score of 0
• Increase of 2 or more points on at least one appropriate symptom-specific functional system score for pyramidal, cerebellar, brain stem, sensory, bowel or bladder, or a single eye
• Increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1
• Increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1

In addition, symptoms had to be attributable to NMOSD; persist for more than 24 hours; and not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. Researchers assessed EDSS and functional system scores within 7 days of a patient reporting symptoms.

The double-blind treatment period ended 1.5 years after the last enrolled patient was assigned to satralizumab or placebo. More than 80% of the participants were women, including 73% of the satralizumab group and 97% of the placebo group. In all, 95 participants were assigned to a treatment between 2014 and 2017 – 63 to satralizumab and 32 to placebo. Relapses occurred in 19 patients receiving satralizumab (30%) and 16 receiving placebo (50%). The hazard ratio was 0.45.

“Patients treated with placebo showed a shorter time to relapse and a higher withdrawal rate than did patients treated with satralizumab,” wrote Dr. Traboulsee and colleagues. The Kaplan-Meier method suggested that 76% of patients on satralizumab had not relapsed at 48 weeks, compared with 62% of patients on placebo. And at 96 weeks, 72% of patients on satralizumab had not relapsed, compared with 51% of patients on placebo.

Among patients who were AQP4-IgG seropositive, the proportion with protocol-defined relapse was 22% in the satralizumab group versus 57% in the placebo group. Among patients who were AQP4-IgG seronegative, the proportion with a protocol-defined relapse was 46% in the satralizumab group versus 33% in the placebo group.

The most common adverse events were urinary tract infection and upper respiratory tract infection, and most adverse events were mild to moderate. A higher rate of severe adverse events was reported in the satralizumab group than in the placebo group (32.1 vs. 9.9 events per 100 patient-years). The investigators considered most of the severe adverse events unrelated to the study treatment. “None of the severe adverse events led to discontinuation of the study drug except one severe event of pneumonia in the satralizumab group,” the researchers wrote.
 

Data confirm efficacy of IL-6 blockade

“Satralizumab was well tolerated and no meaningful adverse effects from the drug were reported and no deaths occurred,” said Michael Levy, MD, PhD, director of the NMO clinic and research laboratory at Massachusetts General Hospital, Boston, in an accompanying editorial. “This trial of satralizumab was done shortly after the completion of a parallel trial of satralizumab in patients with NMOSD in which the same dose of satralizumab reduced the risk of relapse by 62%, compared with placebo. The main difference between these two trials is that, in the first published study, participants were permitted to use background immunotherapy; otherwise, the trial designs were nearly identical, and the enrolled participants are comparable. Together, the findings from these studies suggest that background therapy seems to provide only a small additional benefit to satralizumab alone.”

Dr. Levy also discussed findings from a phase 2 study of tocilizumab for the prevention of relapse in patients with NMOSD published in the same issue of the Lancet Neurology. The satralizumab and tocilizumab data have “confirmed that IL-6 blockade reduces the risk of relapse in patients with NMOSD,” Dr. Levy said. “IL-6 is a crucial component of the immune system, but when IL-6 production is altered during autoimmune attacks and sepsis, there can be severe consequences.”

The phase 2 trial of tocilizumab, which was described at the 2019 annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, included 118 patients, 87% of whom were AQP4-IgG seropositive. Patients received intravenous tocilizumab or oral azathioprine for up to 60 weeks. Overall, 14% of patients in the tocilizumab group relapsed, compared with 47% of patients in the azathioprine group.

“The main differences between this trial of tocilizumab and the two satralizumab trials are that the tocilizumab was administered intravenously, rather than subcutaneously, the study duration was approximately 1 year, and the investigators were not masked to the treatment allocation,” Dr. Levy said. “Similar to satralizumab, adverse effects with tocilizumab were mild, including asymptomatic elevations in liver enzymes and an increased incidence of respiratory and urinary infections, with no significant differences identified between the tocilizumab and azathioprine groups.”

Various immunopathologic mechanisms may influence outcomes in NMOSD. While satralizumab and tocilizumab target IL-6, eculizumab is a C5 complement inhibitor and inebilizumab is a CD19 B-cell depleting monoclonal antibody, Dr. Levy said. “The safety concerns regarding these approaches are all substantially outweighed by the benefit of preventing NMOSD relapses.”
 

A need to understand AQP4-IgG–seronegative disease

SakuraStar “provides convincing data for the efficacy of satralizumab monotherapy in NMOSD with subgroup analysis showing that the benefit was seen in AQP4-IgG seropositive patients,” commented Dean M. Wingerchuk, MD, director of the division of multiple sclerosis and autoimmune neurology at the Mayo Clinic in Phoenix. “The results help confirm the key role of IL-6 in the pathobiology of AQP4-IgG–seropositive disease.”

Questions about AQP4-IgG seronegative disease remain. “The results are quite similar to the SakuraSky trial, in which satralizumab was used in conjunction with other background immunosuppressive therapies, suggesting that the primary benefit may be derived primarily from satralizumab. Both trials also showed that satralizumab did not benefit the NMOSD without AQP4-IgG subgroup though the subject numbers are rather small. We need to know more about the clinical and laboratory characteristics of the seronegative patients as they likely comprise a heterogeneous group. For example, did any of them have other autoantibodies such as MOG-IgG? Depending on the results, those details may help us understand the relative role of IL-6 in AQP4-IgG–seronegative subgroups, an important area of further study.”

SakuraStar was funded by Chugai Pharmaceutical, a member of the Roche group. Dr. Traboulsee reported grants, personal fees, and nonfinancial support from Chugai Pharmaceutical during the study, and several coauthors were employees of Chugai Pharmaceutical. Additional coauthors reported personal fees from Chugai, Roche, and other companies. Dr. Levy has received consulting fees from Alexion, Viela Bio, Chugai Pharmaceutical, Quest Diagnostics, and UCB Pharmaceuticals.

[email protected]

SOURCE: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-12.

Satralizumab monotherapy reduces the rate of neuromyelitis optica spectrum disorder (NMOSD) relapse, compared with placebo, according to trial results published in the Lancet Neurology.

The findings help confirm the role of interleukin-6 in the pathobiology of aquaporin-4 autoantibody (AQP4-IgG)–seropositive disease. For patients who are AQP4-IgG seronegative, however, “there is insufficient evidence to indicate a risk reduction” with this drug, the investigators wrote. In addition, satralizumab did not significantly affect pain or fatigue.

“The limitations of the study include the relatively small group sizes and low number of relapses. Despite these limitations, a significant treatment benefit was observed with satralizumab, compared with placebo in the study population, with efficacy and safety comparable to satralizumab used in combination with immunosuppressants,” reported lead author Anthony Traboulsee, MD, professor of neurology at the University of British Columbia, Vancouver, and colleagues.

Satralizumab is a humanized monoclonal antibody targeting the IL-6 receptor. A prior phase 3 study, SakuraSky, found that the drug reduces the risk of NMOSD relapse when added to immunosuppressant therapy. To assess the safety and efficacy of satralizumab monotherapy, Dr. Traboulsee and colleagues conducted SakuraStar, a randomized, double-blind, placebo-controlled trial.
 

Evaluating drug as monotherapy

The phase 3 trial enrolled 95 patients aged 18-74 years at 44 sites in 13 countries. The investigators included patients with AQP4-IgG–seropositive or –seronegative neuromyelitis optica using the 2006 Wingerchuk criteria or with AQP4-IgG–seropositive NMOSD with at least one event of longitudinally extensive myelitis or optic neuritis. The researchers limited the number of AQP4-IgG–seronegative patients to about 30% of the study population. Eligible participants had at least one NMOSD attack or relapse in the past 12 months and a score of 6.5 or less on the Expanded Disability Status Scale (EDSS). The investigators excluded patients with a clinical relapse in the 30 days before study baseline. Participants were randomly assigned 2:1 to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Concomitant immunosuppressant use was prohibited, although corticosteroids and intravenous immunoglobulin were permitted as rescue therapy for the treatment of relapse.

The primary endpoint was time to first relapse, and the trial was designed to continue until 44 relapses occurred or for 1.5 years after the last patient entered the trial, whichever occurred first.

“Because even one NMOSD attack can have serious neurological consequences, this design allowed patients who had an attack on placebo to enter the open-label phase and receive the active drug,” the researchers wrote. “The trial design used unequal randomization to minimize exposure to placebo; because patients were not permitted to receive concomitant immunosuppressant treatment in this trial, the design limited the number of patients not receiving any treatment for the disorder. Placebo was selected with the consideration that no drugs were approved for the treatment of NMOSD when the trial was designed.” Recent trials of eculizumab, inebilizumab, and satralizumab have found that the agents are effective treatments for NMOSD. In 2019, the Food and Drug Administration approved eculizumab, a complement inhibitor, for the treatment of AQP4-IgG–seropositive NMOSD.

For the primary endpoint of SakuraStar, the researchers defined relapses as new or worsening objective neurologic symptoms with at least one of the following:

• Increase of 1 or more EDSS points from a baseline EDSS score of more than 0, or increase of 2 or more EDSS points from a baseline EDSS score of 0
• Increase of 2 or more points on at least one appropriate symptom-specific functional system score for pyramidal, cerebellar, brain stem, sensory, bowel or bladder, or a single eye
• Increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1
• Increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1

In addition, symptoms had to be attributable to NMOSD; persist for more than 24 hours; and not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. Researchers assessed EDSS and functional system scores within 7 days of a patient reporting symptoms.

The double-blind treatment period ended 1.5 years after the last enrolled patient was assigned to satralizumab or placebo. More than 80% of the participants were women, including 73% of the satralizumab group and 97% of the placebo group. In all, 95 participants were assigned to a treatment between 2014 and 2017 – 63 to satralizumab and 32 to placebo. Relapses occurred in 19 patients receiving satralizumab (30%) and 16 receiving placebo (50%). The hazard ratio was 0.45.

“Patients treated with placebo showed a shorter time to relapse and a higher withdrawal rate than did patients treated with satralizumab,” wrote Dr. Traboulsee and colleagues. The Kaplan-Meier method suggested that 76% of patients on satralizumab had not relapsed at 48 weeks, compared with 62% of patients on placebo. And at 96 weeks, 72% of patients on satralizumab had not relapsed, compared with 51% of patients on placebo.

Among patients who were AQP4-IgG seropositive, the proportion with protocol-defined relapse was 22% in the satralizumab group versus 57% in the placebo group. Among patients who were AQP4-IgG seronegative, the proportion with a protocol-defined relapse was 46% in the satralizumab group versus 33% in the placebo group.

The most common adverse events were urinary tract infection and upper respiratory tract infection, and most adverse events were mild to moderate. A higher rate of severe adverse events was reported in the satralizumab group than in the placebo group (32.1 vs. 9.9 events per 100 patient-years). The investigators considered most of the severe adverse events unrelated to the study treatment. “None of the severe adverse events led to discontinuation of the study drug except one severe event of pneumonia in the satralizumab group,” the researchers wrote.
 

Data confirm efficacy of IL-6 blockade

“Satralizumab was well tolerated and no meaningful adverse effects from the drug were reported and no deaths occurred,” said Michael Levy, MD, PhD, director of the NMO clinic and research laboratory at Massachusetts General Hospital, Boston, in an accompanying editorial. “This trial of satralizumab was done shortly after the completion of a parallel trial of satralizumab in patients with NMOSD in which the same dose of satralizumab reduced the risk of relapse by 62%, compared with placebo. The main difference between these two trials is that, in the first published study, participants were permitted to use background immunotherapy; otherwise, the trial designs were nearly identical, and the enrolled participants are comparable. Together, the findings from these studies suggest that background therapy seems to provide only a small additional benefit to satralizumab alone.”

Dr. Levy also discussed findings from a phase 2 study of tocilizumab for the prevention of relapse in patients with NMOSD published in the same issue of the Lancet Neurology. The satralizumab and tocilizumab data have “confirmed that IL-6 blockade reduces the risk of relapse in patients with NMOSD,” Dr. Levy said. “IL-6 is a crucial component of the immune system, but when IL-6 production is altered during autoimmune attacks and sepsis, there can be severe consequences.”

The phase 2 trial of tocilizumab, which was described at the 2019 annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, included 118 patients, 87% of whom were AQP4-IgG seropositive. Patients received intravenous tocilizumab or oral azathioprine for up to 60 weeks. Overall, 14% of patients in the tocilizumab group relapsed, compared with 47% of patients in the azathioprine group.

“The main differences between this trial of tocilizumab and the two satralizumab trials are that the tocilizumab was administered intravenously, rather than subcutaneously, the study duration was approximately 1 year, and the investigators were not masked to the treatment allocation,” Dr. Levy said. “Similar to satralizumab, adverse effects with tocilizumab were mild, including asymptomatic elevations in liver enzymes and an increased incidence of respiratory and urinary infections, with no significant differences identified between the tocilizumab and azathioprine groups.”

Various immunopathologic mechanisms may influence outcomes in NMOSD. While satralizumab and tocilizumab target IL-6, eculizumab is a C5 complement inhibitor and inebilizumab is a CD19 B-cell depleting monoclonal antibody, Dr. Levy said. “The safety concerns regarding these approaches are all substantially outweighed by the benefit of preventing NMOSD relapses.”
 

A need to understand AQP4-IgG–seronegative disease

SakuraStar “provides convincing data for the efficacy of satralizumab monotherapy in NMOSD with subgroup analysis showing that the benefit was seen in AQP4-IgG seropositive patients,” commented Dean M. Wingerchuk, MD, director of the division of multiple sclerosis and autoimmune neurology at the Mayo Clinic in Phoenix. “The results help confirm the key role of IL-6 in the pathobiology of AQP4-IgG–seropositive disease.”

Questions about AQP4-IgG seronegative disease remain. “The results are quite similar to the SakuraSky trial, in which satralizumab was used in conjunction with other background immunosuppressive therapies, suggesting that the primary benefit may be derived primarily from satralizumab. Both trials also showed that satralizumab did not benefit the NMOSD without AQP4-IgG subgroup though the subject numbers are rather small. We need to know more about the clinical and laboratory characteristics of the seronegative patients as they likely comprise a heterogeneous group. For example, did any of them have other autoantibodies such as MOG-IgG? Depending on the results, those details may help us understand the relative role of IL-6 in AQP4-IgG–seronegative subgroups, an important area of further study.”

SakuraStar was funded by Chugai Pharmaceutical, a member of the Roche group. Dr. Traboulsee reported grants, personal fees, and nonfinancial support from Chugai Pharmaceutical during the study, and several coauthors were employees of Chugai Pharmaceutical. Additional coauthors reported personal fees from Chugai, Roche, and other companies. Dr. Levy has received consulting fees from Alexion, Viela Bio, Chugai Pharmaceutical, Quest Diagnostics, and UCB Pharmaceuticals.

[email protected]

SOURCE: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-12.

Satralizumab monotherapy reduces the rate of neuromyelitis optica spectrum disorder (NMOSD) relapse, compared with placebo, according to trial results published in the Lancet Neurology.

The findings help confirm the role of interleukin-6 in the pathobiology of aquaporin-4 autoantibody (AQP4-IgG)–seropositive disease. For patients who are AQP4-IgG seronegative, however, “there is insufficient evidence to indicate a risk reduction” with this drug, the investigators wrote. In addition, satralizumab did not significantly affect pain or fatigue.

“The limitations of the study include the relatively small group sizes and low number of relapses. Despite these limitations, a significant treatment benefit was observed with satralizumab, compared with placebo in the study population, with efficacy and safety comparable to satralizumab used in combination with immunosuppressants,” reported lead author Anthony Traboulsee, MD, professor of neurology at the University of British Columbia, Vancouver, and colleagues.

Satralizumab is a humanized monoclonal antibody targeting the IL-6 receptor. A prior phase 3 study, SakuraSky, found that the drug reduces the risk of NMOSD relapse when added to immunosuppressant therapy. To assess the safety and efficacy of satralizumab monotherapy, Dr. Traboulsee and colleagues conducted SakuraStar, a randomized, double-blind, placebo-controlled trial.
 

Evaluating drug as monotherapy

The phase 3 trial enrolled 95 patients aged 18-74 years at 44 sites in 13 countries. The investigators included patients with AQP4-IgG–seropositive or –seronegative neuromyelitis optica using the 2006 Wingerchuk criteria or with AQP4-IgG–seropositive NMOSD with at least one event of longitudinally extensive myelitis or optic neuritis. The researchers limited the number of AQP4-IgG–seronegative patients to about 30% of the study population. Eligible participants had at least one NMOSD attack or relapse in the past 12 months and a score of 6.5 or less on the Expanded Disability Status Scale (EDSS). The investigators excluded patients with a clinical relapse in the 30 days before study baseline. Participants were randomly assigned 2:1 to receive satralizumab 120 mg or placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Concomitant immunosuppressant use was prohibited, although corticosteroids and intravenous immunoglobulin were permitted as rescue therapy for the treatment of relapse.

The primary endpoint was time to first relapse, and the trial was designed to continue until 44 relapses occurred or for 1.5 years after the last patient entered the trial, whichever occurred first.

“Because even one NMOSD attack can have serious neurological consequences, this design allowed patients who had an attack on placebo to enter the open-label phase and receive the active drug,” the researchers wrote. “The trial design used unequal randomization to minimize exposure to placebo; because patients were not permitted to receive concomitant immunosuppressant treatment in this trial, the design limited the number of patients not receiving any treatment for the disorder. Placebo was selected with the consideration that no drugs were approved for the treatment of NMOSD when the trial was designed.” Recent trials of eculizumab, inebilizumab, and satralizumab have found that the agents are effective treatments for NMOSD. In 2019, the Food and Drug Administration approved eculizumab, a complement inhibitor, for the treatment of AQP4-IgG–seropositive NMOSD.

For the primary endpoint of SakuraStar, the researchers defined relapses as new or worsening objective neurologic symptoms with at least one of the following:

• Increase of 1 or more EDSS points from a baseline EDSS score of more than 0, or increase of 2 or more EDSS points from a baseline EDSS score of 0
• Increase of 2 or more points on at least one appropriate symptom-specific functional system score for pyramidal, cerebellar, brain stem, sensory, bowel or bladder, or a single eye
• Increase of 1 or more points on more than one symptom-specific functional system score with a baseline of at least 1
• Increase of 1 or more points on a single-eye symptom-specific functional system score with a baseline score of at least 1

In addition, symptoms had to be attributable to NMOSD; persist for more than 24 hours; and not be attributable to confounding clinical factors such as fever, infection, injury, change in mood, or adverse reactions to medications. Researchers assessed EDSS and functional system scores within 7 days of a patient reporting symptoms.

The double-blind treatment period ended 1.5 years after the last enrolled patient was assigned to satralizumab or placebo. More than 80% of the participants were women, including 73% of the satralizumab group and 97% of the placebo group. In all, 95 participants were assigned to a treatment between 2014 and 2017 – 63 to satralizumab and 32 to placebo. Relapses occurred in 19 patients receiving satralizumab (30%) and 16 receiving placebo (50%). The hazard ratio was 0.45.

“Patients treated with placebo showed a shorter time to relapse and a higher withdrawal rate than did patients treated with satralizumab,” wrote Dr. Traboulsee and colleagues. The Kaplan-Meier method suggested that 76% of patients on satralizumab had not relapsed at 48 weeks, compared with 62% of patients on placebo. And at 96 weeks, 72% of patients on satralizumab had not relapsed, compared with 51% of patients on placebo.

Among patients who were AQP4-IgG seropositive, the proportion with protocol-defined relapse was 22% in the satralizumab group versus 57% in the placebo group. Among patients who were AQP4-IgG seronegative, the proportion with a protocol-defined relapse was 46% in the satralizumab group versus 33% in the placebo group.

The most common adverse events were urinary tract infection and upper respiratory tract infection, and most adverse events were mild to moderate. A higher rate of severe adverse events was reported in the satralizumab group than in the placebo group (32.1 vs. 9.9 events per 100 patient-years). The investigators considered most of the severe adverse events unrelated to the study treatment. “None of the severe adverse events led to discontinuation of the study drug except one severe event of pneumonia in the satralizumab group,” the researchers wrote.
 

Data confirm efficacy of IL-6 blockade

“Satralizumab was well tolerated and no meaningful adverse effects from the drug were reported and no deaths occurred,” said Michael Levy, MD, PhD, director of the NMO clinic and research laboratory at Massachusetts General Hospital, Boston, in an accompanying editorial. “This trial of satralizumab was done shortly after the completion of a parallel trial of satralizumab in patients with NMOSD in which the same dose of satralizumab reduced the risk of relapse by 62%, compared with placebo. The main difference between these two trials is that, in the first published study, participants were permitted to use background immunotherapy; otherwise, the trial designs were nearly identical, and the enrolled participants are comparable. Together, the findings from these studies suggest that background therapy seems to provide only a small additional benefit to satralizumab alone.”

Dr. Levy also discussed findings from a phase 2 study of tocilizumab for the prevention of relapse in patients with NMOSD published in the same issue of the Lancet Neurology. The satralizumab and tocilizumab data have “confirmed that IL-6 blockade reduces the risk of relapse in patients with NMOSD,” Dr. Levy said. “IL-6 is a crucial component of the immune system, but when IL-6 production is altered during autoimmune attacks and sepsis, there can be severe consequences.”

The phase 2 trial of tocilizumab, which was described at the 2019 annual congress of the European Committee for Treatment and Research in Multiple Sclerosis, included 118 patients, 87% of whom were AQP4-IgG seropositive. Patients received intravenous tocilizumab or oral azathioprine for up to 60 weeks. Overall, 14% of patients in the tocilizumab group relapsed, compared with 47% of patients in the azathioprine group.

“The main differences between this trial of tocilizumab and the two satralizumab trials are that the tocilizumab was administered intravenously, rather than subcutaneously, the study duration was approximately 1 year, and the investigators were not masked to the treatment allocation,” Dr. Levy said. “Similar to satralizumab, adverse effects with tocilizumab were mild, including asymptomatic elevations in liver enzymes and an increased incidence of respiratory and urinary infections, with no significant differences identified between the tocilizumab and azathioprine groups.”

Various immunopathologic mechanisms may influence outcomes in NMOSD. While satralizumab and tocilizumab target IL-6, eculizumab is a C5 complement inhibitor and inebilizumab is a CD19 B-cell depleting monoclonal antibody, Dr. Levy said. “The safety concerns regarding these approaches are all substantially outweighed by the benefit of preventing NMOSD relapses.”
 

A need to understand AQP4-IgG–seronegative disease

SakuraStar “provides convincing data for the efficacy of satralizumab monotherapy in NMOSD with subgroup analysis showing that the benefit was seen in AQP4-IgG seropositive patients,” commented Dean M. Wingerchuk, MD, director of the division of multiple sclerosis and autoimmune neurology at the Mayo Clinic in Phoenix. “The results help confirm the key role of IL-6 in the pathobiology of AQP4-IgG–seropositive disease.”

Questions about AQP4-IgG seronegative disease remain. “The results are quite similar to the SakuraSky trial, in which satralizumab was used in conjunction with other background immunosuppressive therapies, suggesting that the primary benefit may be derived primarily from satralizumab. Both trials also showed that satralizumab did not benefit the NMOSD without AQP4-IgG subgroup though the subject numbers are rather small. We need to know more about the clinical and laboratory characteristics of the seronegative patients as they likely comprise a heterogeneous group. For example, did any of them have other autoantibodies such as MOG-IgG? Depending on the results, those details may help us understand the relative role of IL-6 in AQP4-IgG–seronegative subgroups, an important area of further study.”

SakuraStar was funded by Chugai Pharmaceutical, a member of the Roche group. Dr. Traboulsee reported grants, personal fees, and nonfinancial support from Chugai Pharmaceutical during the study, and several coauthors were employees of Chugai Pharmaceutical. Additional coauthors reported personal fees from Chugai, Roche, and other companies. Dr. Levy has received consulting fees from Alexion, Viela Bio, Chugai Pharmaceutical, Quest Diagnostics, and UCB Pharmaceuticals.

[email protected]

SOURCE: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-12.

A practice advisory from the American Academy of Neurology provides guidance about when doctors may recommend closure of a patent foramen ovale (PFO) to reduce the risk of recurrent stroke. Patients with an embolic-appearing infarct who are younger than 60 years, have undergone a thorough evaluation to rule out other stroke mechanisms, and have discussed with doctors the potential risks and benefits may be candidates for the procedure.

“For patients with cryptogenic stroke and PFO, percutaneous PFO closure probably reduces the risk of stroke recurrence with [a hazard ratio] of 0.41 and an absolute risk reduction of 3.4% at 5 years; probably is associated with a periprocedural complication rate of 3.9%; and probably is associated with the development of serious nonperiprocedural atrial fibrillation, with a relative risk of 2.72,” according to the advisory authors’ meta-analysis.

Most procedural complications and instances of atrial fibrillation were “self-limited and are of uncertain long-term clinical consequence, given the lower rate of stroke in patients whose PFOs were closed,” the authors said. “Subgroup analysis suggests that the overall benefit seen across trials may not extend to those patients with small shunts and small, deep infarcts.” The authors estimated that the number of patients who need to be treated to prevent one stroke at 5 years is 29.

The advisory updates 2016 guidance that said clinicians should not routinely offer PFO closure outside of a research setting. Since then, three trials published in 2017 the New England Journal of Medicine (RESPECT, CLOSE, and REDUCE) and one trial published in 2018 in the Journal of the American College of Cardiology (DEFENSE-PFO) found that PFO closure reduces the risk of recurrent stroke in patients with a PFO who have had a cryptogenic stroke, compared with medical therapy alone. In addition, the Food and Drug Administration approved the Amplatzer PFO Occluder and Gore Cardioform Septal Occluder. These developments necessitated the practice advisory, the authors said. The advisory was published online April 29 in Neurology. It is endorsed by the American Heart Association/American Stroke Association, the Society for Cardiovascular Angiography and Interventions, and the European Academy of Neurology.
 

Systematic review

For the update, Steven R. Messé, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and a panel of neurologists, internists, and cardiologists with expertise in stroke and PFO systematically reviewed relevant randomized studies published through August 2019 and conducted meta-analyses to make their recommendations. The literature search identified eight articles that met inclusion criteria, including one article that provided follow-up from a trial that had been included in the previous practice advisory.

“The risk of a second stroke in people with PFO and no other possible causes of stroke is very low, approximately 1% per year while being treated with just medication alone,” Dr. Messé said in a news release. “Also, it is difficult to determine with absolute certainty that the PFO is the cause of a person’s stroke. So it is important that people with PFO are educated about the benefits and risks of PFO closure.” For patients who opt to take medication only, doctors may consider prescribing antiplatelet or anticoagulant drugs, according to the advisory. “All patients with previous stroke should be treated with an antithrombotic medication indefinitely if there is no bleeding contraindication, regardless of whether a PFO is present or if it is closed,” Dr. Messé and colleagues wrote. “However, specific antithrombotic management for patients with stroke thought to be caused by PFO remains uncertain.”
 

Calls for thorough work-up

“If an alternative plausible higher-risk mechanism of stroke is identified, it is likely that the PFO was an innocent bystander,” the authors said. “Secondary stroke prevention is optimized by targeting the most likely etiology of the preceding event. ... The randomized PFO closure trials all mandated thorough evaluations for participants before enrollment ... to rule out other stroke mechanisms; moreover, all studies required TEE [transesophageal echocardiography] to characterize the PFO and ensure that it was the most likely etiology for the initial event.”

In patients being considered for PFO closure, clinicians should obtain brain imaging to confirm stroke size and distribution (level B); obtain vascular imaging of the cervical and intracranial vessels to look for dissection, vasculopathy, and atherosclerosis (level B); and perform hypercoagulable studies (level B), according to the advisory. Clinicians must perform a baseline ECG to look for atrial fibrillation (level A), and patients thought to be at risk of atrial fibrillation should receive prolonged cardiac monitoring for at least 28 days (level B).

Before PFO closure, a clinician with expertise in stroke should assess the patient to ensure that the PFO is the most plausible mechanism of stroke (level B). “If a higher-risk alternative mechanism of stroke is identified, clinicians should not routinely recommend PFO closure (level B),” the authors said. Patients also should be assessed by a clinician with expertise in assessing the anatomic features of a PFO and performing PFO closure (level B).

The randomized trials focused on patients whose PFOs were closed within 6 months of a stroke, and registry studies are needed to assess long-term outcomes, noted Dr. Messé and colleagues. “It remains unclear whether closure provides a similar benefit in these patients who otherwise still fit the studies’ inclusion criteria,” the authors said. “Long-term and large-scale safety registries for patients who have received PFO closure are needed to assess the risk of device erosion, fracture, embolization, and thrombotic and endocarditis risks, and the effect of residual shunts and incidence of atrial fibrillation.”

About 25% of the general adult population has a PFO. “It’s important to note that having a PFO is common, and that most people with PFO will never know they have it because it usually does not cause any problems,” Dr. Messé said. “However, while there is generally a very low risk of stroke in patients with PFO, in younger people who have had a stroke without any other possible causes identified, closing the PFO may reduce the risk of having another stroke better than medication alone.”

The practice advisory was developed with financial support from the AAN. Dr. Messé and most of the authors had no relevant conflicts of interest. Several authors disclosed ties to medical device and pharmaceutical companies.

[email protected]

SOURCE: Messé SR et al. Neurology. 2020 Apr 29. doi: 10.1212/WNL.0000000000009443.

A practice advisory from the American Academy of Neurology provides guidance about when doctors may recommend closure of a patent foramen ovale (PFO) to reduce the risk of recurrent stroke. Patients with an embolic-appearing infarct who are younger than 60 years, have undergone a thorough evaluation to rule out other stroke mechanisms, and have discussed with doctors the potential risks and benefits may be candidates for the procedure.

“For patients with cryptogenic stroke and PFO, percutaneous PFO closure probably reduces the risk of stroke recurrence with [a hazard ratio] of 0.41 and an absolute risk reduction of 3.4% at 5 years; probably is associated with a periprocedural complication rate of 3.9%; and probably is associated with the development of serious nonperiprocedural atrial fibrillation, with a relative risk of 2.72,” according to the advisory authors’ meta-analysis.

Most procedural complications and instances of atrial fibrillation were “self-limited and are of uncertain long-term clinical consequence, given the lower rate of stroke in patients whose PFOs were closed,” the authors said. “Subgroup analysis suggests that the overall benefit seen across trials may not extend to those patients with small shunts and small, deep infarcts.” The authors estimated that the number of patients who need to be treated to prevent one stroke at 5 years is 29.

The advisory updates 2016 guidance that said clinicians should not routinely offer PFO closure outside of a research setting. Since then, three trials published in 2017 the New England Journal of Medicine (RESPECT, CLOSE, and REDUCE) and one trial published in 2018 in the Journal of the American College of Cardiology (DEFENSE-PFO) found that PFO closure reduces the risk of recurrent stroke in patients with a PFO who have had a cryptogenic stroke, compared with medical therapy alone. In addition, the Food and Drug Administration approved the Amplatzer PFO Occluder and Gore Cardioform Septal Occluder. These developments necessitated the practice advisory, the authors said. The advisory was published online April 29 in Neurology. It is endorsed by the American Heart Association/American Stroke Association, the Society for Cardiovascular Angiography and Interventions, and the European Academy of Neurology.
 

Systematic review

For the update, Steven R. Messé, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and a panel of neurologists, internists, and cardiologists with expertise in stroke and PFO systematically reviewed relevant randomized studies published through August 2019 and conducted meta-analyses to make their recommendations. The literature search identified eight articles that met inclusion criteria, including one article that provided follow-up from a trial that had been included in the previous practice advisory.

“The risk of a second stroke in people with PFO and no other possible causes of stroke is very low, approximately 1% per year while being treated with just medication alone,” Dr. Messé said in a news release. “Also, it is difficult to determine with absolute certainty that the PFO is the cause of a person’s stroke. So it is important that people with PFO are educated about the benefits and risks of PFO closure.” For patients who opt to take medication only, doctors may consider prescribing antiplatelet or anticoagulant drugs, according to the advisory. “All patients with previous stroke should be treated with an antithrombotic medication indefinitely if there is no bleeding contraindication, regardless of whether a PFO is present or if it is closed,” Dr. Messé and colleagues wrote. “However, specific antithrombotic management for patients with stroke thought to be caused by PFO remains uncertain.”
 

Calls for thorough work-up

“If an alternative plausible higher-risk mechanism of stroke is identified, it is likely that the PFO was an innocent bystander,” the authors said. “Secondary stroke prevention is optimized by targeting the most likely etiology of the preceding event. ... The randomized PFO closure trials all mandated thorough evaluations for participants before enrollment ... to rule out other stroke mechanisms; moreover, all studies required TEE [transesophageal echocardiography] to characterize the PFO and ensure that it was the most likely etiology for the initial event.”

In patients being considered for PFO closure, clinicians should obtain brain imaging to confirm stroke size and distribution (level B); obtain vascular imaging of the cervical and intracranial vessels to look for dissection, vasculopathy, and atherosclerosis (level B); and perform hypercoagulable studies (level B), according to the advisory. Clinicians must perform a baseline ECG to look for atrial fibrillation (level A), and patients thought to be at risk of atrial fibrillation should receive prolonged cardiac monitoring for at least 28 days (level B).

Before PFO closure, a clinician with expertise in stroke should assess the patient to ensure that the PFO is the most plausible mechanism of stroke (level B). “If a higher-risk alternative mechanism of stroke is identified, clinicians should not routinely recommend PFO closure (level B),” the authors said. Patients also should be assessed by a clinician with expertise in assessing the anatomic features of a PFO and performing PFO closure (level B).

The randomized trials focused on patients whose PFOs were closed within 6 months of a stroke, and registry studies are needed to assess long-term outcomes, noted Dr. Messé and colleagues. “It remains unclear whether closure provides a similar benefit in these patients who otherwise still fit the studies’ inclusion criteria,” the authors said. “Long-term and large-scale safety registries for patients who have received PFO closure are needed to assess the risk of device erosion, fracture, embolization, and thrombotic and endocarditis risks, and the effect of residual shunts and incidence of atrial fibrillation.”

About 25% of the general adult population has a PFO. “It’s important to note that having a PFO is common, and that most people with PFO will never know they have it because it usually does not cause any problems,” Dr. Messé said. “However, while there is generally a very low risk of stroke in patients with PFO, in younger people who have had a stroke without any other possible causes identified, closing the PFO may reduce the risk of having another stroke better than medication alone.”

The practice advisory was developed with financial support from the AAN. Dr. Messé and most of the authors had no relevant conflicts of interest. Several authors disclosed ties to medical device and pharmaceutical companies.

[email protected]

SOURCE: Messé SR et al. Neurology. 2020 Apr 29. doi: 10.1212/WNL.0000000000009443.

A practice advisory from the American Academy of Neurology provides guidance about when doctors may recommend closure of a patent foramen ovale (PFO) to reduce the risk of recurrent stroke. Patients with an embolic-appearing infarct who are younger than 60 years, have undergone a thorough evaluation to rule out other stroke mechanisms, and have discussed with doctors the potential risks and benefits may be candidates for the procedure.

“For patients with cryptogenic stroke and PFO, percutaneous PFO closure probably reduces the risk of stroke recurrence with [a hazard ratio] of 0.41 and an absolute risk reduction of 3.4% at 5 years; probably is associated with a periprocedural complication rate of 3.9%; and probably is associated with the development of serious nonperiprocedural atrial fibrillation, with a relative risk of 2.72,” according to the advisory authors’ meta-analysis.

Most procedural complications and instances of atrial fibrillation were “self-limited and are of uncertain long-term clinical consequence, given the lower rate of stroke in patients whose PFOs were closed,” the authors said. “Subgroup analysis suggests that the overall benefit seen across trials may not extend to those patients with small shunts and small, deep infarcts.” The authors estimated that the number of patients who need to be treated to prevent one stroke at 5 years is 29.

The advisory updates 2016 guidance that said clinicians should not routinely offer PFO closure outside of a research setting. Since then, three trials published in 2017 the New England Journal of Medicine (RESPECT, CLOSE, and REDUCE) and one trial published in 2018 in the Journal of the American College of Cardiology (DEFENSE-PFO) found that PFO closure reduces the risk of recurrent stroke in patients with a PFO who have had a cryptogenic stroke, compared with medical therapy alone. In addition, the Food and Drug Administration approved the Amplatzer PFO Occluder and Gore Cardioform Septal Occluder. These developments necessitated the practice advisory, the authors said. The advisory was published online April 29 in Neurology. It is endorsed by the American Heart Association/American Stroke Association, the Society for Cardiovascular Angiography and Interventions, and the European Academy of Neurology.
 

Systematic review

For the update, Steven R. Messé, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and a panel of neurologists, internists, and cardiologists with expertise in stroke and PFO systematically reviewed relevant randomized studies published through August 2019 and conducted meta-analyses to make their recommendations. The literature search identified eight articles that met inclusion criteria, including one article that provided follow-up from a trial that had been included in the previous practice advisory.

“The risk of a second stroke in people with PFO and no other possible causes of stroke is very low, approximately 1% per year while being treated with just medication alone,” Dr. Messé said in a news release. “Also, it is difficult to determine with absolute certainty that the PFO is the cause of a person’s stroke. So it is important that people with PFO are educated about the benefits and risks of PFO closure.” For patients who opt to take medication only, doctors may consider prescribing antiplatelet or anticoagulant drugs, according to the advisory. “All patients with previous stroke should be treated with an antithrombotic medication indefinitely if there is no bleeding contraindication, regardless of whether a PFO is present or if it is closed,” Dr. Messé and colleagues wrote. “However, specific antithrombotic management for patients with stroke thought to be caused by PFO remains uncertain.”
 

Calls for thorough work-up

“If an alternative plausible higher-risk mechanism of stroke is identified, it is likely that the PFO was an innocent bystander,” the authors said. “Secondary stroke prevention is optimized by targeting the most likely etiology of the preceding event. ... The randomized PFO closure trials all mandated thorough evaluations for participants before enrollment ... to rule out other stroke mechanisms; moreover, all studies required TEE [transesophageal echocardiography] to characterize the PFO and ensure that it was the most likely etiology for the initial event.”

In patients being considered for PFO closure, clinicians should obtain brain imaging to confirm stroke size and distribution (level B); obtain vascular imaging of the cervical and intracranial vessels to look for dissection, vasculopathy, and atherosclerosis (level B); and perform hypercoagulable studies (level B), according to the advisory. Clinicians must perform a baseline ECG to look for atrial fibrillation (level A), and patients thought to be at risk of atrial fibrillation should receive prolonged cardiac monitoring for at least 28 days (level B).

Before PFO closure, a clinician with expertise in stroke should assess the patient to ensure that the PFO is the most plausible mechanism of stroke (level B). “If a higher-risk alternative mechanism of stroke is identified, clinicians should not routinely recommend PFO closure (level B),” the authors said. Patients also should be assessed by a clinician with expertise in assessing the anatomic features of a PFO and performing PFO closure (level B).

The randomized trials focused on patients whose PFOs were closed within 6 months of a stroke, and registry studies are needed to assess long-term outcomes, noted Dr. Messé and colleagues. “It remains unclear whether closure provides a similar benefit in these patients who otherwise still fit the studies’ inclusion criteria,” the authors said. “Long-term and large-scale safety registries for patients who have received PFO closure are needed to assess the risk of device erosion, fracture, embolization, and thrombotic and endocarditis risks, and the effect of residual shunts and incidence of atrial fibrillation.”

About 25% of the general adult population has a PFO. “It’s important to note that having a PFO is common, and that most people with PFO will never know they have it because it usually does not cause any problems,” Dr. Messé said. “However, while there is generally a very low risk of stroke in patients with PFO, in younger people who have had a stroke without any other possible causes identified, closing the PFO may reduce the risk of having another stroke better than medication alone.”

The practice advisory was developed with financial support from the AAN. Dr. Messé and most of the authors had no relevant conflicts of interest. Several authors disclosed ties to medical device and pharmaceutical companies.

[email protected]

SOURCE: Messé SR et al. Neurology. 2020 Apr 29. doi: 10.1212/WNL.0000000000009443.

Patients with epilepsy may report less than half of their seizures to clinicians, according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.

Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.

[email protected]

SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.

Patients with epilepsy may report less than half of their seizures to clinicians, according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.

Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.

[email protected]

SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.

Patients with epilepsy may report less than half of their seizures to clinicians, according to survey results presented online as part of the 2020 American Academy of Neurology Science Highlights.

Clinicians, for their part, may underestimate the number of seizures that go unreported. This disconnect may contribute to complacency about epilepsy treatment regimens among patients, caregivers, and health care professionals (HCPs), despite continuations in seizures. “Improved reporting of all seizure occurrences and more frequent discussion of potential treatment changes, initiated by all groups, may be needed to optimize treatment outcomes,” said Patricia E. Penovich, MD, a neurologist at Minnesota Epilepsy Group in St. Paul, and colleagues.

[email protected]

SOURCE: Penovich PE et al. AAN 2020, Abstract S59.007.

Gastrointestinal symptoms are more common and severe in patients with Parkinson’s disease than in controls and may relate to an altered microbiome composition and reduced microbial diversity, according to research presented online as part of the 2020 American Academy of Neurology Science Highlights.

Jade E. Kenna, a PhD candidate and research assistant at the Perron Institute of Neurological and Translational Science in Perth, Australia, described findings from a multicenter assessment of 167 patients with Parkinson’s disease and 100 controls from movement disorders clinics in Australia. Participants completed the self-report Gastrointestinal Symptom Rating Scale (GSRS), which rates the frequency and severity of 15 GI symptoms. In addition, stool samples were analyzed using targeted sequencing to characterize gut microbiome composition.

Although Parkinson’s disease is recognized primarily as a motor disorder, GI dysfunction may be one of the first symptoms. “This is hypothesized to result from a change in microbiota towards an inflammatory, dysbiotic composition,” Ms. Kenna said. A limited number of studies have reported an association between altered microbiota composition, GI symptoms, and Parkinson’s disease, but not in Australian cohorts.

Total GSRS score was significantly higher in patients with Parkinson’s disease, compared with controls. Eight of the symptoms – heartburn, acid reflux, nausea or vomiting, borborygmus, increased flatus, decreased passage of stools, feeling of incomplete evacuation, and passing hard stools – were significantly increased in patients with Parkinson’s disease. GSRS symptoms can be categorized as upper, lower, general, hypoactive, or hyperactive, and patients with Parkinson’s disease had significantly increased ratings in the upper, lower, and hypoactive GI symptom domains.

“This is quite a novel finding as not only has this not been assessed in an Australian cohort of individuals before, but the majority of existing literature focuses on the presence of constipation only,” Ms. Kenna said. “The treatment and understanding of nonmotor symptoms of Parkinson’s disease, in particular GI symptoms, remain as one of the top unmet needs reported by patients with Parkinson’s disease themselves. Therefore, a better, more thorough understanding of these symptoms is clearly needed, and research into this area has such value in terms of improving current therapeutic approaches, management strategies, and patient education.”

Microbial analyses found that Firmicutes and Proteobacteria were significantly increased and Verrucomicrobia trended toward an increase in patients with Parkinson’s disease. Fusobacteria was increased in controls. “Proteobacteria and Verrucomicrobia are known to promote inflammation, which can lead to GI symptoms. Furthermore, Faecalibacterium and Ruminococcus, which are reduced in [Parkinson’s disease], can metabolize various substrates to produce [short-chain fatty acids] like butyrate, which are known to aid against intestinal barrier dysfunction and inflammation,” she said.

Individuals with Parkinson’s disease had significantly less microbial diversity. As Parkinson’s disease severity and GI symptom severity increased, microbiome diversity decreased, Ms. Kenna said. “As reduced diversity is associated with increased intestinal inflammation, this indicates that the altered microbiome we saw in [individuals with Parkinson’s disease] may be instigating the increase in incidence and severity of GI symptoms.”

Ms. Kenna reported that she had no disclosures.

[email protected]

SOURCE: Kenna JE. AAN 2020, Abstract S17.006.

Gastrointestinal symptoms are more common and severe in patients with Parkinson’s disease than in controls and may relate to an altered microbiome composition and reduced microbial diversity, according to research presented online as part of the 2020 American Academy of Neurology Science Highlights.

Jade E. Kenna, a PhD candidate and research assistant at the Perron Institute of Neurological and Translational Science in Perth, Australia, described findings from a multicenter assessment of 167 patients with Parkinson’s disease and 100 controls from movement disorders clinics in Australia. Participants completed the self-report Gastrointestinal Symptom Rating Scale (GSRS), which rates the frequency and severity of 15 GI symptoms. In addition, stool samples were analyzed using targeted sequencing to characterize gut microbiome composition.

Although Parkinson’s disease is recognized primarily as a motor disorder, GI dysfunction may be one of the first symptoms. “This is hypothesized to result from a change in microbiota towards an inflammatory, dysbiotic composition,” Ms. Kenna said. A limited number of studies have reported an association between altered microbiota composition, GI symptoms, and Parkinson’s disease, but not in Australian cohorts.

Total GSRS score was significantly higher in patients with Parkinson’s disease, compared with controls. Eight of the symptoms – heartburn, acid reflux, nausea or vomiting, borborygmus, increased flatus, decreased passage of stools, feeling of incomplete evacuation, and passing hard stools – were significantly increased in patients with Parkinson’s disease. GSRS symptoms can be categorized as upper, lower, general, hypoactive, or hyperactive, and patients with Parkinson’s disease had significantly increased ratings in the upper, lower, and hypoactive GI symptom domains.

“This is quite a novel finding as not only has this not been assessed in an Australian cohort of individuals before, but the majority of existing literature focuses on the presence of constipation only,” Ms. Kenna said. “The treatment and understanding of nonmotor symptoms of Parkinson’s disease, in particular GI symptoms, remain as one of the top unmet needs reported by patients with Parkinson’s disease themselves. Therefore, a better, more thorough understanding of these symptoms is clearly needed, and research into this area has such value in terms of improving current therapeutic approaches, management strategies, and patient education.”

Microbial analyses found that Firmicutes and Proteobacteria were significantly increased and Verrucomicrobia trended toward an increase in patients with Parkinson’s disease. Fusobacteria was increased in controls. “Proteobacteria and Verrucomicrobia are known to promote inflammation, which can lead to GI symptoms. Furthermore, Faecalibacterium and Ruminococcus, which are reduced in [Parkinson’s disease], can metabolize various substrates to produce [short-chain fatty acids] like butyrate, which are known to aid against intestinal barrier dysfunction and inflammation,” she said.

Individuals with Parkinson’s disease had significantly less microbial diversity. As Parkinson’s disease severity and GI symptom severity increased, microbiome diversity decreased, Ms. Kenna said. “As reduced diversity is associated with increased intestinal inflammation, this indicates that the altered microbiome we saw in [individuals with Parkinson’s disease] may be instigating the increase in incidence and severity of GI symptoms.”

Ms. Kenna reported that she had no disclosures.

[email protected]

SOURCE: Kenna JE. AAN 2020, Abstract S17.006.

Gastrointestinal symptoms are more common and severe in patients with Parkinson’s disease than in controls and may relate to an altered microbiome composition and reduced microbial diversity, according to research presented online as part of the 2020 American Academy of Neurology Science Highlights.

Jade E. Kenna, a PhD candidate and research assistant at the Perron Institute of Neurological and Translational Science in Perth, Australia, described findings from a multicenter assessment of 167 patients with Parkinson’s disease and 100 controls from movement disorders clinics in Australia. Participants completed the self-report Gastrointestinal Symptom Rating Scale (GSRS), which rates the frequency and severity of 15 GI symptoms. In addition, stool samples were analyzed using targeted sequencing to characterize gut microbiome composition.

Although Parkinson’s disease is recognized primarily as a motor disorder, GI dysfunction may be one of the first symptoms. “This is hypothesized to result from a change in microbiota towards an inflammatory, dysbiotic composition,” Ms. Kenna said. A limited number of studies have reported an association between altered microbiota composition, GI symptoms, and Parkinson’s disease, but not in Australian cohorts.

Total GSRS score was significantly higher in patients with Parkinson’s disease, compared with controls. Eight of the symptoms – heartburn, acid reflux, nausea or vomiting, borborygmus, increased flatus, decreased passage of stools, feeling of incomplete evacuation, and passing hard stools – were significantly increased in patients with Parkinson’s disease. GSRS symptoms can be categorized as upper, lower, general, hypoactive, or hyperactive, and patients with Parkinson’s disease had significantly increased ratings in the upper, lower, and hypoactive GI symptom domains.

“This is quite a novel finding as not only has this not been assessed in an Australian cohort of individuals before, but the majority of existing literature focuses on the presence of constipation only,” Ms. Kenna said. “The treatment and understanding of nonmotor symptoms of Parkinson’s disease, in particular GI symptoms, remain as one of the top unmet needs reported by patients with Parkinson’s disease themselves. Therefore, a better, more thorough understanding of these symptoms is clearly needed, and research into this area has such value in terms of improving current therapeutic approaches, management strategies, and patient education.”

Microbial analyses found that Firmicutes and Proteobacteria were significantly increased and Verrucomicrobia trended toward an increase in patients with Parkinson’s disease. Fusobacteria was increased in controls. “Proteobacteria and Verrucomicrobia are known to promote inflammation, which can lead to GI symptoms. Furthermore, Faecalibacterium and Ruminococcus, which are reduced in [Parkinson’s disease], can metabolize various substrates to produce [short-chain fatty acids] like butyrate, which are known to aid against intestinal barrier dysfunction and inflammation,” she said.

Individuals with Parkinson’s disease had significantly less microbial diversity. As Parkinson’s disease severity and GI symptom severity increased, microbiome diversity decreased, Ms. Kenna said. “As reduced diversity is associated with increased intestinal inflammation, this indicates that the altered microbiome we saw in [individuals with Parkinson’s disease] may be instigating the increase in incidence and severity of GI symptoms.”

Ms. Kenna reported that she had no disclosures.

[email protected]

SOURCE: Kenna JE. AAN 2020, Abstract S17.006.

Among patients with secondary progressive multiple sclerosis (MS) who received siponimod or placebo during a double-blind trial and entered an open-label extension, those who received siponimod throughout the study were less likely to experience disability progression and had a lower annualized relapse rate up to 5 years later, compared with patients who initially received placebo and switched to siponimod. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.

Benefits of siponimod gained during the controlled period were “sustained for up to 5 years, suggesting a continuous effect of siponimod and underlining the advantages of early treatment initiation with siponimod,” the researchers said. Incidence rates of adverse events during the extension study were consistent with those during the controlled treatment period.

The results “highlight the critical importance of early treatment intervention ... to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” study investigator Bruce Cree, MD, PhD, said in a news release.

“It’s never too early to stay ahead of progression in MS, since the early identification of physical and cognitive changes – even subtle ones – can indicate MS disease progression and therefore allow for timely intervention.” said Dr. Cree, who is clinical research director and George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco.

Siponimod, marketed as Mayzent, is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors. The oral drug was approved by the Food and Drug Administration in 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease in adults.

To assess the long-term efficacy and safety of siponimod in patients with secondary progressive MS, Dr. Cree and colleagues analyzed data from patients in the controlled and extension parts of the EXPAND trial. Patients could have had been in the study for as long as 5 years at the data cutoff in April 2019. Efficacy analyses included time to 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), time to 6-month confirmed disability progression, time to 6-month confirmed worsening of 4 or more points on the Symbol Digit Modalities Test (SDMT), and annualized relapse rate. In EXPAND, the researchers defined confirmed disability progression as a 1-point increase in EDSS if the baseline score was 3.0-5.0, or a 0.5-point increase if the baseline score was 5.5-6.5.

“Of the 1,224 (74% of 1,651 randomized) patients entering the extension, 878 (72%) were ongoing,” the researchers reported. Patients who received siponimod continuously were less likely to experience 3-month confirmed disability progression and 6-month confirmed disability progression, relative to patients who switched from placebo. In addition, patients who received continuous siponimod treatment had a prolonged time to 6-month confirmed disability progression, compared with patients who switched from placebo. For the 25th percentile of patients, continuous siponimod treatment corresponded to a delay of 54% (21 months vs. 13.6 months). Risk of worsening on the SDMT was reduced by 23% in the continuous siponimod–treatment group. For the 25th percentile of patients, this reduced risk corresponded to a delay of 62% (29.6 months vs. 18.3 months). ARR was 0.054 in the continuous-siponimod group, compared with 0.097 in the group that switched to siponimod from placebo, a reduction of 52%.

Dr. Cree has received personal compensation from Novartis, which markets siponimod, as well as Akili, Alexion, Atara, Biogen, EMD Serono, and TG Therapeutics. His coauthors reported receiving research support and personal compensation from Novartis and other pharmaceutical companies. Several coauthors were Novartis employees.

[email protected]

SOURCE: Kappos L et al. AAN 2020, Abstract S40.003.

Among patients with secondary progressive multiple sclerosis (MS) who received siponimod or placebo during a double-blind trial and entered an open-label extension, those who received siponimod throughout the study were less likely to experience disability progression and had a lower annualized relapse rate up to 5 years later, compared with patients who initially received placebo and switched to siponimod. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.

Benefits of siponimod gained during the controlled period were “sustained for up to 5 years, suggesting a continuous effect of siponimod and underlining the advantages of early treatment initiation with siponimod,” the researchers said. Incidence rates of adverse events during the extension study were consistent with those during the controlled treatment period.

The results “highlight the critical importance of early treatment intervention ... to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” study investigator Bruce Cree, MD, PhD, said in a news release.

“It’s never too early to stay ahead of progression in MS, since the early identification of physical and cognitive changes – even subtle ones – can indicate MS disease progression and therefore allow for timely intervention.” said Dr. Cree, who is clinical research director and George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco.

Siponimod, marketed as Mayzent, is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors. The oral drug was approved by the Food and Drug Administration in 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease in adults.

To assess the long-term efficacy and safety of siponimod in patients with secondary progressive MS, Dr. Cree and colleagues analyzed data from patients in the controlled and extension parts of the EXPAND trial. Patients could have had been in the study for as long as 5 years at the data cutoff in April 2019. Efficacy analyses included time to 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), time to 6-month confirmed disability progression, time to 6-month confirmed worsening of 4 or more points on the Symbol Digit Modalities Test (SDMT), and annualized relapse rate. In EXPAND, the researchers defined confirmed disability progression as a 1-point increase in EDSS if the baseline score was 3.0-5.0, or a 0.5-point increase if the baseline score was 5.5-6.5.

“Of the 1,224 (74% of 1,651 randomized) patients entering the extension, 878 (72%) were ongoing,” the researchers reported. Patients who received siponimod continuously were less likely to experience 3-month confirmed disability progression and 6-month confirmed disability progression, relative to patients who switched from placebo. In addition, patients who received continuous siponimod treatment had a prolonged time to 6-month confirmed disability progression, compared with patients who switched from placebo. For the 25th percentile of patients, continuous siponimod treatment corresponded to a delay of 54% (21 months vs. 13.6 months). Risk of worsening on the SDMT was reduced by 23% in the continuous siponimod–treatment group. For the 25th percentile of patients, this reduced risk corresponded to a delay of 62% (29.6 months vs. 18.3 months). ARR was 0.054 in the continuous-siponimod group, compared with 0.097 in the group that switched to siponimod from placebo, a reduction of 52%.

Dr. Cree has received personal compensation from Novartis, which markets siponimod, as well as Akili, Alexion, Atara, Biogen, EMD Serono, and TG Therapeutics. His coauthors reported receiving research support and personal compensation from Novartis and other pharmaceutical companies. Several coauthors were Novartis employees.

[email protected]

SOURCE: Kappos L et al. AAN 2020, Abstract S40.003.

Among patients with secondary progressive multiple sclerosis (MS) who received siponimod or placebo during a double-blind trial and entered an open-label extension, those who received siponimod throughout the study were less likely to experience disability progression and had a lower annualized relapse rate up to 5 years later, compared with patients who initially received placebo and switched to siponimod. This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.

Benefits of siponimod gained during the controlled period were “sustained for up to 5 years, suggesting a continuous effect of siponimod and underlining the advantages of early treatment initiation with siponimod,” the researchers said. Incidence rates of adverse events during the extension study were consistent with those during the controlled treatment period.

The results “highlight the critical importance of early treatment intervention ... to ensure the best possible long-term outcomes for patients with MS who are experiencing progression,” study investigator Bruce Cree, MD, PhD, said in a news release.

“It’s never too early to stay ahead of progression in MS, since the early identification of physical and cognitive changes – even subtle ones – can indicate MS disease progression and therefore allow for timely intervention.” said Dr. Cree, who is clinical research director and George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco.

Siponimod, marketed as Mayzent, is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors. The oral drug was approved by the Food and Drug Administration in 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease in adults.

To assess the long-term efficacy and safety of siponimod in patients with secondary progressive MS, Dr. Cree and colleagues analyzed data from patients in the controlled and extension parts of the EXPAND trial. Patients could have had been in the study for as long as 5 years at the data cutoff in April 2019. Efficacy analyses included time to 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), time to 6-month confirmed disability progression, time to 6-month confirmed worsening of 4 or more points on the Symbol Digit Modalities Test (SDMT), and annualized relapse rate. In EXPAND, the researchers defined confirmed disability progression as a 1-point increase in EDSS if the baseline score was 3.0-5.0, or a 0.5-point increase if the baseline score was 5.5-6.5.

“Of the 1,224 (74% of 1,651 randomized) patients entering the extension, 878 (72%) were ongoing,” the researchers reported. Patients who received siponimod continuously were less likely to experience 3-month confirmed disability progression and 6-month confirmed disability progression, relative to patients who switched from placebo. In addition, patients who received continuous siponimod treatment had a prolonged time to 6-month confirmed disability progression, compared with patients who switched from placebo. For the 25th percentile of patients, continuous siponimod treatment corresponded to a delay of 54% (21 months vs. 13.6 months). Risk of worsening on the SDMT was reduced by 23% in the continuous siponimod–treatment group. For the 25th percentile of patients, this reduced risk corresponded to a delay of 62% (29.6 months vs. 18.3 months). ARR was 0.054 in the continuous-siponimod group, compared with 0.097 in the group that switched to siponimod from placebo, a reduction of 52%.

Dr. Cree has received personal compensation from Novartis, which markets siponimod, as well as Akili, Alexion, Atara, Biogen, EMD Serono, and TG Therapeutics. His coauthors reported receiving research support and personal compensation from Novartis and other pharmaceutical companies. Several coauthors were Novartis employees.

[email protected]

SOURCE: Kappos L et al. AAN 2020, Abstract S40.003.

The first case of progressive multifocal leukoencephalopathy (PML) directly associated with ocrelizumab occurred in a patient with primary progressive multiple sclerosis (MS) who received 2 years of ocrelizumab monotherapy and had not received prior immunomodulatory medication. The case report was presented online as part of the 2020 American Academy of Neurology Science Highlights.

PML, an opportunistic infection of the brain caused by reactivation of the John Cunningham (JC) virus, has occurred with rituximab, another anti-CD20 therapy, in rare cases. Eight other cases of PML diagnosed after ocrelizumab initiation are considered carry-over cases related to prior treatment with natalizumab or fingolimod, according to Genentech, the manufacturer of ocrelizumab. No other PML cases have been associated with ocrelizumab alone.

The case without prior MS treatment was in a 78-year-old man. He presented with 2 weeks of progressive visual disturbance and confusion, said Marc L. Gordon, MD, chief of neurology at the Zucker Hillside Hospital in Glen Oaks, N.Y., and professor of neurology and psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y.

The patient had a right homonymous hemianopia. “MRI revealed an enlarging non-enhancing left parietal lesion without mass effect,” reported Dr. Gordon and colleagues. “CSF PCR revealed 1,000 copies/mL of JCV, confirming the diagnosis of PML. Blood work upon diagnosis revealed grade-2 lymphopenia ... and negative HIV serology.”

“The patient’s symptoms progressed over weeks to involve bilateral visual loss, right facial droop, and dysphasia,” they said. “Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated.” The patient did not respond to therapy and became bedbound, Dr. Gordon said in an interview. The patient received palliative care and died. An autopsy is pending.

“PML occurrence may have been multifactorial, due to a combination of the immunomodulatory function of ocrelizumab, possible immune senescence, and preceding mild lymphopenia,” Dr. Gordon and coauthors said. “This case emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections, such as the elderly.”

The patient, who was Dr. Gordon’s patient for 20 years, had monitored updates in drug development and had looked forward to starting ocrelizumab, the first therapy approved for primary progressive MS, when it became available after its approval in 2017. The patient was concerned about progressively worsening gait impairment and related falls caused by MS.

Antibodies indicated that the patient had prior exposure to JCV, but Dr. Gordon considered the risk of PML to be relatively small. Prior to treatment, the patient’s absolute lymphocyte count was normal or indicated mild lymphocytopenia, which Dr. Gordon did not consider clinically significant. The patient received ocrelizumab for 2 years without incident.

In an information sheet for health care professionals about ocrelizumab and PML prepared in February 2020, Genentech says the patient’s age and low absolute lymphocyte count are confounding factors, which distort “the assessment of association between exposure to a drug and an adverse event.

“As of January 31, 2020, no unconfounded PML cases associated with ocrelizumab therapy have been reported,” according to the document. “Out of more than 150,000 patients treated globally (clinical trials and post-marketing experience), there have been nine confirmed, confounded cases of PML in patients treated with ocrelizumab, of which eight were carry-over cases from a prior DMT.”

The prescribing information for the drug notes that no cases of PML were identified in ocrelizumab clinical trials, but that PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. In addition, PML “has been associated with some risk factors (eg, immunocompromised patients, polytherapy with immunosuppressants).

“At the first sign or symptom suggestive of PML, withhold ocrelizumab and perform an appropriate diagnostic evaluation,” the prescribing information says. “MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.”

“It is important for people to recognize that this is at least a possibility,” Dr. Gordon said. Any change in clinical symptomatology may warrant imaging, and CSF testing may be warranted if an MRI raises concerns about PML, he said.

Dr. Gordon has received research support from MSD (Merck), Eisai, AbbVie, and Janssen.

[email protected]

SOURCE: Sul J et al. AAN 2020. Abstract S29.001.

The first case of progressive multifocal leukoencephalopathy (PML) directly associated with ocrelizumab occurred in a patient with primary progressive multiple sclerosis (MS) who received 2 years of ocrelizumab monotherapy and had not received prior immunomodulatory medication. The case report was presented online as part of the 2020 American Academy of Neurology Science Highlights.

PML, an opportunistic infection of the brain caused by reactivation of the John Cunningham (JC) virus, has occurred with rituximab, another anti-CD20 therapy, in rare cases. Eight other cases of PML diagnosed after ocrelizumab initiation are considered carry-over cases related to prior treatment with natalizumab or fingolimod, according to Genentech, the manufacturer of ocrelizumab. No other PML cases have been associated with ocrelizumab alone.

The case without prior MS treatment was in a 78-year-old man. He presented with 2 weeks of progressive visual disturbance and confusion, said Marc L. Gordon, MD, chief of neurology at the Zucker Hillside Hospital in Glen Oaks, N.Y., and professor of neurology and psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y.

The patient had a right homonymous hemianopia. “MRI revealed an enlarging non-enhancing left parietal lesion without mass effect,” reported Dr. Gordon and colleagues. “CSF PCR revealed 1,000 copies/mL of JCV, confirming the diagnosis of PML. Blood work upon diagnosis revealed grade-2 lymphopenia ... and negative HIV serology.”

“The patient’s symptoms progressed over weeks to involve bilateral visual loss, right facial droop, and dysphasia,” they said. “Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated.” The patient did not respond to therapy and became bedbound, Dr. Gordon said in an interview. The patient received palliative care and died. An autopsy is pending.

“PML occurrence may have been multifactorial, due to a combination of the immunomodulatory function of ocrelizumab, possible immune senescence, and preceding mild lymphopenia,” Dr. Gordon and coauthors said. “This case emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections, such as the elderly.”

The patient, who was Dr. Gordon’s patient for 20 years, had monitored updates in drug development and had looked forward to starting ocrelizumab, the first therapy approved for primary progressive MS, when it became available after its approval in 2017. The patient was concerned about progressively worsening gait impairment and related falls caused by MS.

Antibodies indicated that the patient had prior exposure to JCV, but Dr. Gordon considered the risk of PML to be relatively small. Prior to treatment, the patient’s absolute lymphocyte count was normal or indicated mild lymphocytopenia, which Dr. Gordon did not consider clinically significant. The patient received ocrelizumab for 2 years without incident.

In an information sheet for health care professionals about ocrelizumab and PML prepared in February 2020, Genentech says the patient’s age and low absolute lymphocyte count are confounding factors, which distort “the assessment of association between exposure to a drug and an adverse event.

“As of January 31, 2020, no unconfounded PML cases associated with ocrelizumab therapy have been reported,” according to the document. “Out of more than 150,000 patients treated globally (clinical trials and post-marketing experience), there have been nine confirmed, confounded cases of PML in patients treated with ocrelizumab, of which eight were carry-over cases from a prior DMT.”

The prescribing information for the drug notes that no cases of PML were identified in ocrelizumab clinical trials, but that PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. In addition, PML “has been associated with some risk factors (eg, immunocompromised patients, polytherapy with immunosuppressants).

“At the first sign or symptom suggestive of PML, withhold ocrelizumab and perform an appropriate diagnostic evaluation,” the prescribing information says. “MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.”

“It is important for people to recognize that this is at least a possibility,” Dr. Gordon said. Any change in clinical symptomatology may warrant imaging, and CSF testing may be warranted if an MRI raises concerns about PML, he said.

Dr. Gordon has received research support from MSD (Merck), Eisai, AbbVie, and Janssen.

[email protected]

SOURCE: Sul J et al. AAN 2020. Abstract S29.001.

The first case of progressive multifocal leukoencephalopathy (PML) directly associated with ocrelizumab occurred in a patient with primary progressive multiple sclerosis (MS) who received 2 years of ocrelizumab monotherapy and had not received prior immunomodulatory medication. The case report was presented online as part of the 2020 American Academy of Neurology Science Highlights.

PML, an opportunistic infection of the brain caused by reactivation of the John Cunningham (JC) virus, has occurred with rituximab, another anti-CD20 therapy, in rare cases. Eight other cases of PML diagnosed after ocrelizumab initiation are considered carry-over cases related to prior treatment with natalizumab or fingolimod, according to Genentech, the manufacturer of ocrelizumab. No other PML cases have been associated with ocrelizumab alone.

The case without prior MS treatment was in a 78-year-old man. He presented with 2 weeks of progressive visual disturbance and confusion, said Marc L. Gordon, MD, chief of neurology at the Zucker Hillside Hospital in Glen Oaks, N.Y., and professor of neurology and psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y.

The patient had a right homonymous hemianopia. “MRI revealed an enlarging non-enhancing left parietal lesion without mass effect,” reported Dr. Gordon and colleagues. “CSF PCR revealed 1,000 copies/mL of JCV, confirming the diagnosis of PML. Blood work upon diagnosis revealed grade-2 lymphopenia ... and negative HIV serology.”

“The patient’s symptoms progressed over weeks to involve bilateral visual loss, right facial droop, and dysphasia,” they said. “Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated.” The patient did not respond to therapy and became bedbound, Dr. Gordon said in an interview. The patient received palliative care and died. An autopsy is pending.

“PML occurrence may have been multifactorial, due to a combination of the immunomodulatory function of ocrelizumab, possible immune senescence, and preceding mild lymphopenia,” Dr. Gordon and coauthors said. “This case emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections, such as the elderly.”

The patient, who was Dr. Gordon’s patient for 20 years, had monitored updates in drug development and had looked forward to starting ocrelizumab, the first therapy approved for primary progressive MS, when it became available after its approval in 2017. The patient was concerned about progressively worsening gait impairment and related falls caused by MS.

Antibodies indicated that the patient had prior exposure to JCV, but Dr. Gordon considered the risk of PML to be relatively small. Prior to treatment, the patient’s absolute lymphocyte count was normal or indicated mild lymphocytopenia, which Dr. Gordon did not consider clinically significant. The patient received ocrelizumab for 2 years without incident.

In an information sheet for health care professionals about ocrelizumab and PML prepared in February 2020, Genentech says the patient’s age and low absolute lymphocyte count are confounding factors, which distort “the assessment of association between exposure to a drug and an adverse event.

“As of January 31, 2020, no unconfounded PML cases associated with ocrelizumab therapy have been reported,” according to the document. “Out of more than 150,000 patients treated globally (clinical trials and post-marketing experience), there have been nine confirmed, confounded cases of PML in patients treated with ocrelizumab, of which eight were carry-over cases from a prior DMT.”

The prescribing information for the drug notes that no cases of PML were identified in ocrelizumab clinical trials, but that PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. In addition, PML “has been associated with some risk factors (eg, immunocompromised patients, polytherapy with immunosuppressants).

“At the first sign or symptom suggestive of PML, withhold ocrelizumab and perform an appropriate diagnostic evaluation,” the prescribing information says. “MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.”

“It is important for people to recognize that this is at least a possibility,” Dr. Gordon said. Any change in clinical symptomatology may warrant imaging, and CSF testing may be warranted if an MRI raises concerns about PML, he said.

Dr. Gordon has received research support from MSD (Merck), Eisai, AbbVie, and Janssen.

[email protected]

SOURCE: Sul J et al. AAN 2020. Abstract S29.001.

The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.

Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.

Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
 

Association with anti-NXP-2 autoantibodies

Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.

During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.

Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”

Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
 

Effects on organ systems vary

The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.

On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.

At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”

Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.

The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.

The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.

The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.

[email protected]

SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.

The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.

Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.

Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
 

Association with anti-NXP-2 autoantibodies

Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.

During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.

Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”

Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
 

Effects on organ systems vary

The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.

On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.

At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”

Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.

The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.

The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.

The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.

[email protected]

SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.

The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.

Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.

Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
 

Association with anti-NXP-2 autoantibodies

Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.

During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.

Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”

Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
 

Effects on organ systems vary

The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.

On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.

At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”

Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.

The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.

The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.

The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.

[email protected]

SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.

A “strikingly high number” of women have bone marrow edema on MRI of the sacroiliac joints postpartum, according to a prospective study of 35 patients published in Annals of the Rheumatic Diseases. Postpartum sacroiliac bone marrow edema decreases over time. Its occurrence may be associated with a shorter duration of labor and a lack of epidural anesthesia, the researchers wrote.

Sacroiliac bone marrow edema in postpartum women “persists mainly in subjects older than 30 years,” noted Thomas Renson, MD, of Ghent (Belgium) University Hospital and colleagues. “When suspecting AxSpA [axial spondyloarthritis], our data indicate the need to wait at least 6 months to perform an MRI [of the sacroiliac joints] in postpartum women and, if positive, repeat the MRI after 12 months.”

Sacroiliac bone marrow edema is a hallmark of axSpA. However, recent studies of young, active people without the disease have found a high prevalence of bone marrow edema meeting the Assessment of SpondyloArthritis International Society (ASAS) definition of a positive MRI for sacroiliitis. Researchers have reported sacroiliac bone marrow edema in women during pregnancy and after childbirth, but prior studies have not assessed the trajectory of sacroiliac bone marrow edema after delivery, Dr. Renson and his colleagues said.

To study this question, the researchers recruited 35 subjects from the department of obstetrics at Ghent University Hospital. All participants were aged 18-45 years and had an uncomplicated, vaginal childbirth. The investigators excluded patients with a diagnosis of spondyloarthritis, inflammatory bowel disease, severe scoliosis, treatment with anti–tumor necrosis factor-alpha agents, any contraindication for MRI, childbirth through cesarean section, or pregnancy with more than one fetus.

Researchers performed a baseline MRI within 10 days of when patients gave birth and another MRI after 6 months. If the second MRI fulfilled the ASAS definition of a positive MRI for sacroiliitis, another MRI was performed at 12 months. Bone marrow edema was scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) method.

In all, 77% of the patients had sacroiliac bone marrow edema on MRI an average of 5 days postpartum, and 60% fulfilled the ASAS definition of a positive MRI. After 6 months, 46% had bone marrow edema on MRI, and 15% had a positive MRI according to the ASAS definition. After 12 months, MRI was positive in 12% of the subjects. There was a high prevalence of bone marrow edema “even in subjects without back pain,” the researchers said.

“Four subjects would have fulfilled the ASAS classification criteria if there was a suspicion of axSpA: Three fulfilled the ASAS definition of a positive MRI for sacroiliitis and had inflammatory back pain, [and] one had chronic back pain, a positive MRI, and skin psoriasis,” the researchers wrote.

Misdiagnosis of axSpA based on MRI findings entails risks, the authors noted. NSAIDs may be less effective in patients who do not have axSpA, and patients may be “subsequently more likely to receive ineffective biological therapy, which has significant potential side effects and encompasses high socioeconomic costs,” the investigators said.

The study was supported by an ASAS research grant. The authors declared having no competing interests.

[email protected]

SOURCE: Renson T et al. Ann Rheum Dis. 2020 Apr 16. doi: 10.1136/annrheumdis-2020-217095.

A “strikingly high number” of women have bone marrow edema on MRI of the sacroiliac joints postpartum, according to a prospective study of 35 patients published in Annals of the Rheumatic Diseases. Postpartum sacroiliac bone marrow edema decreases over time. Its occurrence may be associated with a shorter duration of labor and a lack of epidural anesthesia, the researchers wrote.

Sacroiliac bone marrow edema in postpartum women “persists mainly in subjects older than 30 years,” noted Thomas Renson, MD, of Ghent (Belgium) University Hospital and colleagues. “When suspecting AxSpA [axial spondyloarthritis], our data indicate the need to wait at least 6 months to perform an MRI [of the sacroiliac joints] in postpartum women and, if positive, repeat the MRI after 12 months.”

Sacroiliac bone marrow edema is a hallmark of axSpA. However, recent studies of young, active people without the disease have found a high prevalence of bone marrow edema meeting the Assessment of SpondyloArthritis International Society (ASAS) definition of a positive MRI for sacroiliitis. Researchers have reported sacroiliac bone marrow edema in women during pregnancy and after childbirth, but prior studies have not assessed the trajectory of sacroiliac bone marrow edema after delivery, Dr. Renson and his colleagues said.

To study this question, the researchers recruited 35 subjects from the department of obstetrics at Ghent University Hospital. All participants were aged 18-45 years and had an uncomplicated, vaginal childbirth. The investigators excluded patients with a diagnosis of spondyloarthritis, inflammatory bowel disease, severe scoliosis, treatment with anti–tumor necrosis factor-alpha agents, any contraindication for MRI, childbirth through cesarean section, or pregnancy with more than one fetus.

Researchers performed a baseline MRI within 10 days of when patients gave birth and another MRI after 6 months. If the second MRI fulfilled the ASAS definition of a positive MRI for sacroiliitis, another MRI was performed at 12 months. Bone marrow edema was scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) method.

In all, 77% of the patients had sacroiliac bone marrow edema on MRI an average of 5 days postpartum, and 60% fulfilled the ASAS definition of a positive MRI. After 6 months, 46% had bone marrow edema on MRI, and 15% had a positive MRI according to the ASAS definition. After 12 months, MRI was positive in 12% of the subjects. There was a high prevalence of bone marrow edema “even in subjects without back pain,” the researchers said.

“Four subjects would have fulfilled the ASAS classification criteria if there was a suspicion of axSpA: Three fulfilled the ASAS definition of a positive MRI for sacroiliitis and had inflammatory back pain, [and] one had chronic back pain, a positive MRI, and skin psoriasis,” the researchers wrote.

Misdiagnosis of axSpA based on MRI findings entails risks, the authors noted. NSAIDs may be less effective in patients who do not have axSpA, and patients may be “subsequently more likely to receive ineffective biological therapy, which has significant potential side effects and encompasses high socioeconomic costs,” the investigators said.

The study was supported by an ASAS research grant. The authors declared having no competing interests.

[email protected]

SOURCE: Renson T et al. Ann Rheum Dis. 2020 Apr 16. doi: 10.1136/annrheumdis-2020-217095.

A “strikingly high number” of women have bone marrow edema on MRI of the sacroiliac joints postpartum, according to a prospective study of 35 patients published in Annals of the Rheumatic Diseases. Postpartum sacroiliac bone marrow edema decreases over time. Its occurrence may be associated with a shorter duration of labor and a lack of epidural anesthesia, the researchers wrote.

Sacroiliac bone marrow edema in postpartum women “persists mainly in subjects older than 30 years,” noted Thomas Renson, MD, of Ghent (Belgium) University Hospital and colleagues. “When suspecting AxSpA [axial spondyloarthritis], our data indicate the need to wait at least 6 months to perform an MRI [of the sacroiliac joints] in postpartum women and, if positive, repeat the MRI after 12 months.”

Sacroiliac bone marrow edema is a hallmark of axSpA. However, recent studies of young, active people without the disease have found a high prevalence of bone marrow edema meeting the Assessment of SpondyloArthritis International Society (ASAS) definition of a positive MRI for sacroiliitis. Researchers have reported sacroiliac bone marrow edema in women during pregnancy and after childbirth, but prior studies have not assessed the trajectory of sacroiliac bone marrow edema after delivery, Dr. Renson and his colleagues said.

To study this question, the researchers recruited 35 subjects from the department of obstetrics at Ghent University Hospital. All participants were aged 18-45 years and had an uncomplicated, vaginal childbirth. The investigators excluded patients with a diagnosis of spondyloarthritis, inflammatory bowel disease, severe scoliosis, treatment with anti–tumor necrosis factor-alpha agents, any contraindication for MRI, childbirth through cesarean section, or pregnancy with more than one fetus.

Researchers performed a baseline MRI within 10 days of when patients gave birth and another MRI after 6 months. If the second MRI fulfilled the ASAS definition of a positive MRI for sacroiliitis, another MRI was performed at 12 months. Bone marrow edema was scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) method.

In all, 77% of the patients had sacroiliac bone marrow edema on MRI an average of 5 days postpartum, and 60% fulfilled the ASAS definition of a positive MRI. After 6 months, 46% had bone marrow edema on MRI, and 15% had a positive MRI according to the ASAS definition. After 12 months, MRI was positive in 12% of the subjects. There was a high prevalence of bone marrow edema “even in subjects without back pain,” the researchers said.

“Four subjects would have fulfilled the ASAS classification criteria if there was a suspicion of axSpA: Three fulfilled the ASAS definition of a positive MRI for sacroiliitis and had inflammatory back pain, [and] one had chronic back pain, a positive MRI, and skin psoriasis,” the researchers wrote.

Misdiagnosis of axSpA based on MRI findings entails risks, the authors noted. NSAIDs may be less effective in patients who do not have axSpA, and patients may be “subsequently more likely to receive ineffective biological therapy, which has significant potential side effects and encompasses high socioeconomic costs,” the investigators said.

The study was supported by an ASAS research grant. The authors declared having no competing interests.

[email protected]

SOURCE: Renson T et al. Ann Rheum Dis. 2020 Apr 16. doi: 10.1136/annrheumdis-2020-217095.

Among patients admitted to a hospital with chronic obstructive pulmonary disease (COPD) exacerbation, obstructive sleep apnea (OSA) is prevalent and increases the likelihood of hospital readmission more than threefold, according to results from a single-center study published in CHEST.

Mario Naranjo, MD, and colleagues retrospectively examined data from Albert Einstein Medical Center in Philadelphia to assess the impact of OSA on hospital readmission within 30 days of discharge after treatment for a COPD exacerbation. Dr. Naranjo is affiliated with Johns Hopkins Medicine, Baltimore.

The researchers analyzed data from 238 patients admitted for COPD exacerbation between May 2017 and July 2018 who were screened for previously unrecognized and untreated OSA and underwent a high-resolution pulse-oximetry or portable sleep monitoring study. In all, 111 (46.6%) had OSA; 28.6% had mild OSA, 9.7% had moderate OSA, and 8.4% had severe OSA.

Most baseline characteristics were similar among patients with and without OSA, but patients with OSA had a greater mean body mass index (33.9 vs. 30.3 kg/m²) and were more likely to have comorbid heart failure (19.8% vs. 7.1%), compared with patients without OSA. In addition, the proportion of male patients was greater in the cohort with OSA (60.4% vs. 49.6%).

For patients with mild OSA (oxygen desaturation index [ODI] ≥ 5 and < 15/hour), the odds of 30-day readmission were 2.05 times higher, compared with patients without OSA (32.4% vs. 18.9%). With moderate OSA (ODI ≥ 15 and < 30/hour), the odds of 30-day readmission were 6.68 times higher (60.9% vs. 18.9%). For severe OSA (ODI ≥ 30/hour), the odds were 10.01 times higher (70.0% vs. 18.9%). “For combined OSA severity categories, the odds of 30-day readmission were 3.5 times higher,” said Dr. Naranjo and colleagues. In addition, 90- and 180-day readmission rates and 6-month mortality rates were higher among patients with OSA.

“These findings have important implications for the evaluation and care of patients admitted to the hospital for COPD exacerbations,” Dr. Naranjo and colleagues said. “Although the combination of COPD and OSA (also known as the “overlap syndrome”) in ambulatory settings has been shown to have worse outcomes in terms of COPD exacerbations and mortality, these findings have not been reported previously for hospitalized COPD patients.”

Greater degrees of nocturnal hypoxemia and hypercapnia, worse functional status, and daytime sleepiness and fatigue may contribute to the relationship between OSA and the likelihood of hospital readmission, according to the authors. A multicenter study is warranted to confirm the results, they said.

Dr. Naranjo had no conflicts of interest. Coauthors have received grants from ResMed, Dayzz, and the National Institutes of Health and consulted for Jazz Pharmaceuticals, Best Doctors, and ResMed. One author is a committee chair for the American Academy of Sleep Medicine.

[email protected]

SOURCE: Naranjo M et al. Chest. 2020 Apr 2. doi: 10.1016/j.chest.2020.03.036.

Among patients admitted to a hospital with chronic obstructive pulmonary disease (COPD) exacerbation, obstructive sleep apnea (OSA) is prevalent and increases the likelihood of hospital readmission more than threefold, according to results from a single-center study published in CHEST.

Mario Naranjo, MD, and colleagues retrospectively examined data from Albert Einstein Medical Center in Philadelphia to assess the impact of OSA on hospital readmission within 30 days of discharge after treatment for a COPD exacerbation. Dr. Naranjo is affiliated with Johns Hopkins Medicine, Baltimore.

The researchers analyzed data from 238 patients admitted for COPD exacerbation between May 2017 and July 2018 who were screened for previously unrecognized and untreated OSA and underwent a high-resolution pulse-oximetry or portable sleep monitoring study. In all, 111 (46.6%) had OSA; 28.6% had mild OSA, 9.7% had moderate OSA, and 8.4% had severe OSA.

Most baseline characteristics were similar among patients with and without OSA, but patients with OSA had a greater mean body mass index (33.9 vs. 30.3 kg/m²) and were more likely to have comorbid heart failure (19.8% vs. 7.1%), compared with patients without OSA. In addition, the proportion of male patients was greater in the cohort with OSA (60.4% vs. 49.6%).

For patients with mild OSA (oxygen desaturation index [ODI] ≥ 5 and < 15/hour), the odds of 30-day readmission were 2.05 times higher, compared with patients without OSA (32.4% vs. 18.9%). With moderate OSA (ODI ≥ 15 and < 30/hour), the odds of 30-day readmission were 6.68 times higher (60.9% vs. 18.9%). For severe OSA (ODI ≥ 30/hour), the odds were 10.01 times higher (70.0% vs. 18.9%). “For combined OSA severity categories, the odds of 30-day readmission were 3.5 times higher,” said Dr. Naranjo and colleagues. In addition, 90- and 180-day readmission rates and 6-month mortality rates were higher among patients with OSA.

“These findings have important implications for the evaluation and care of patients admitted to the hospital for COPD exacerbations,” Dr. Naranjo and colleagues said. “Although the combination of COPD and OSA (also known as the “overlap syndrome”) in ambulatory settings has been shown to have worse outcomes in terms of COPD exacerbations and mortality, these findings have not been reported previously for hospitalized COPD patients.”

Greater degrees of nocturnal hypoxemia and hypercapnia, worse functional status, and daytime sleepiness and fatigue may contribute to the relationship between OSA and the likelihood of hospital readmission, according to the authors. A multicenter study is warranted to confirm the results, they said.

Dr. Naranjo had no conflicts of interest. Coauthors have received grants from ResMed, Dayzz, and the National Institutes of Health and consulted for Jazz Pharmaceuticals, Best Doctors, and ResMed. One author is a committee chair for the American Academy of Sleep Medicine.

[email protected]

SOURCE: Naranjo M et al. Chest. 2020 Apr 2. doi: 10.1016/j.chest.2020.03.036.

Among patients admitted to a hospital with chronic obstructive pulmonary disease (COPD) exacerbation, obstructive sleep apnea (OSA) is prevalent and increases the likelihood of hospital readmission more than threefold, according to results from a single-center study published in CHEST.

Mario Naranjo, MD, and colleagues retrospectively examined data from Albert Einstein Medical Center in Philadelphia to assess the impact of OSA on hospital readmission within 30 days of discharge after treatment for a COPD exacerbation. Dr. Naranjo is affiliated with Johns Hopkins Medicine, Baltimore.

The researchers analyzed data from 238 patients admitted for COPD exacerbation between May 2017 and July 2018 who were screened for previously unrecognized and untreated OSA and underwent a high-resolution pulse-oximetry or portable sleep monitoring study. In all, 111 (46.6%) had OSA; 28.6% had mild OSA, 9.7% had moderate OSA, and 8.4% had severe OSA.

Most baseline characteristics were similar among patients with and without OSA, but patients with OSA had a greater mean body mass index (33.9 vs. 30.3 kg/m²) and were more likely to have comorbid heart failure (19.8% vs. 7.1%), compared with patients without OSA. In addition, the proportion of male patients was greater in the cohort with OSA (60.4% vs. 49.6%).

For patients with mild OSA (oxygen desaturation index [ODI] ≥ 5 and < 15/hour), the odds of 30-day readmission were 2.05 times higher, compared with patients without OSA (32.4% vs. 18.9%). With moderate OSA (ODI ≥ 15 and < 30/hour), the odds of 30-day readmission were 6.68 times higher (60.9% vs. 18.9%). For severe OSA (ODI ≥ 30/hour), the odds were 10.01 times higher (70.0% vs. 18.9%). “For combined OSA severity categories, the odds of 30-day readmission were 3.5 times higher,” said Dr. Naranjo and colleagues. In addition, 90- and 180-day readmission rates and 6-month mortality rates were higher among patients with OSA.

“These findings have important implications for the evaluation and care of patients admitted to the hospital for COPD exacerbations,” Dr. Naranjo and colleagues said. “Although the combination of COPD and OSA (also known as the “overlap syndrome”) in ambulatory settings has been shown to have worse outcomes in terms of COPD exacerbations and mortality, these findings have not been reported previously for hospitalized COPD patients.”

Greater degrees of nocturnal hypoxemia and hypercapnia, worse functional status, and daytime sleepiness and fatigue may contribute to the relationship between OSA and the likelihood of hospital readmission, according to the authors. A multicenter study is warranted to confirm the results, they said.

Dr. Naranjo had no conflicts of interest. Coauthors have received grants from ResMed, Dayzz, and the National Institutes of Health and consulted for Jazz Pharmaceuticals, Best Doctors, and ResMed. One author is a committee chair for the American Academy of Sleep Medicine.

[email protected]

SOURCE: Naranjo M et al. Chest. 2020 Apr 2. doi: 10.1016/j.chest.2020.03.036.