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Stem Cell Extension Study Reinforces Signal of Benefit for Progressive MS
WEST PALM BEACH, FLORIDA — , according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
No Disease Activity Seen in 60% at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.
Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.
The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.
Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
Mechanism of MSC Benefit Incompletely Documented
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.
Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.
While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.
“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.
Dr. Karussis reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
No Disease Activity Seen in 60% at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.
Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.
The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.
Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
Mechanism of MSC Benefit Incompletely Documented
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.
Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.
While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.
“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.
Dr. Karussis reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to data presented as a late-breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
After at least 1 year of follow-up in 23 patients participating in the extension analysis, “there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration,” reported Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomized to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an IV injection of MSCs harvested from their bone marrow.
No Disease Activity Seen in 60% at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group. The intrathecal injection of MSCs, which was well tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
Forty of the patients in the initial study were enrolled in the extension. In the late-breaker presentation, Dr. Karussis provided interim results on 23, of which all had been followed for at least another additional year. These patients had been treated with one to three intrathecal injects of MSCs at intervals of 3 to 6 months.
Of further gains during the extension, Dr. Karussis described gains in cognitive function, represented by a 3-degree improvement in the Symbol Digit Modalities Test (SDMT), a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Dr. Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Dr. Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments.
The safety and tolerability remained encouraging with longer follow-up. As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time-limited.
Although Dr. Karussis emphasized that these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides “an additional hint of possible neuroprotective and neurotrophic effects.”
Mechanism of MSC Benefit Incompletely Documented
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far is unresolved.
Others evaluating MSCs in the experimental setting have shown that these “produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties,” said Jeffrey A. Cohen, MD, who was asked to comment on the findings. Dr. Cohen is director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis, Cleveland Clinic. He said that previous experimental work has encouraged clinical studies, including the work presented by Dr. Karussis.
While the late-breaker presentation provided data suggesting “persistent potent efficacy with good safety and tolerability,” Dr. Cohen pointed out that “the results from this group are substantially better than those reported by several other groups.” He called the difference in results “uncertain,” suggesting that more work is needed to prove that clinical benefit is reliably achieved.
“I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing,” Dr. Cohen said.
Dr. Karussis reports no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
Studies Reinforce JAK Inhibitor Efficacy for Most Challenging Alopecia Types
FROM AAD 2024
SAN DIEGO — , according to late-breaking data presented at the annual meeting of the American Academy of Dermatology.
In one study of brepocitinib, the target was cicatricial alopecia (CA), a form of hair loss for which there are no approved therapies. In the other, a subanalysis from phase 3 trials of ritlecitinib for alopecia areata (AA), hair regrowth was shown in the subset of patients who entered the study with alopecia totalis or alopecia universalis (AT/AU).
Reflecting comments from several experts, including one of the late-breaking session moderators, April W. Armstrong, MD, MPH, professor and chief of dermatology, University of California, Los Angeles, said that the CA study, which matched clinical response to changes in CA biomarkers, suggested that the results are a potential breakthrough.
“This is the first placebo-controlled study with an oral JAK inhibitor that not only shows that scarring alopecia can be reversible but also gives insights to the mechanism of action and which patients might respond best,” Emma Guttman-Yassky, MD, PhD, said in an interview. Dr. Guttman-Yassky, professor of Dermatology and Immunology, and director of the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York City, was the study’s senior investigator.
Scarring Alopecia and Brepocitinib
For the study of scarring alopecia, 49 patients with CA were randomized in a 3:1 ratio to brepocitinib, a first-in-class inhibitor that targets both JAK1 and TYK2, or placebo. Because of the small size of the study, the primary endpoint was the change in CA biomarkers. The secondary outcome was clinical response, but because of a correlation between the two, these were mutually reinforcing.
Of the subtypes, nine patients enrolled in the study had frontal fibrosing alopecia (FFA), 16 had lichen planopilaris (LPP) alopecia, and 24 had central centrifugal cicatricial alopecia (CCCA). All of the forms of CA are more common in women overall and women of color specifically, particularly CCCA. For this analysis, the FFA and LPP subtypes were considered similar for assessing response and were combined.
The data included a comparison of response and safety during the 24-week randomization phase, as well as an additional follow-up conducted after another 24 weeks of open-label treatment. During the second phase, all patients on placebo were switched to active treatment.
Overall, there was a reduction in all four of the key scalp inflammatory biomarkers measured among those in the combined FFA/LLP group. In the placebo group, each of these markers — interferon gamma (IFN-gamma), CCLS, CXCL10, and STAT1 — increased over the same time period. In almost all cases, the differences were statistically significant.
In the CCCA subgroup, the same pattern (an increase among those on placebo but a decrease among those on brepocitinib) was observed for CCLS and CXCL10. For IFN-gamma and STAT1, a rise was observed among those on placebo and those on active treatment, although the rise was greater for placebo.
For clinical response, improvement on brepocitinib was observed on disease activity indexes, particularly among those in the FFA/LLP group, according to Marguerite Meariman, MD, a dermatology resident at Mount Sinai, who presented the results. She called the improvement in clinical activity scores at 48 weeks “dramatic.” Moreover, improvement was apparent within 4 weeks of starting therapy.
For CCCA, a more challenging condition to treat, Dr. Meariman said that no further progression might represent an acceptable response for many patients, but there were also cases of hair regrowth in this subset. Although improvement was not generally on the order seen among those with FFA/LLP, she suggested that there is promise even in these more difficult patients.
Further studies are planned, but Dr. Meariman said that it might be important to focus on early treatment regardless of CA subtype. She noted that patients with less than 5 years disease duration typically did better than those with longer durations.
Ritlecitinib for AT/AU
The analysis of patients with AT/AU was based on a subset analysis from the ALLEGRO phase 2b/3 study of ritlecitinib, which targets JAK3 and TEC kinases. The full results of the ALLEGRO trial were published last year in The Lancet. In the new late-breaker analysis, Severity of Alopecia Tool (SALT) scores were evaluated on an observed or last-observation-carried-forward basis. Generally, responses in the subgroup of patients with AT/AU, who had a median SALT score of 80.3 (signifying 80.3% hair loss) at baseline, were only modestly lower than those in the overall trial.
At 24 months, about 50% of patients achieved a SALT score of 20, according to Melissa Piliang, MD, chair of Dermatology at the Cleveland Clinic, Cleveland, Ohio, who presented the data. In this group, as in the non-AT/AU population, responses climbed over time, and these responses have been maintained for as long as patients have remained on therapy.
At the more rigorous threshold of SALT < 10, the proportion of responders was only slightly lower, meaning a substantial proportion of patients with AT/AU “are achieving 90% or more of hair regrowth, so really an excellent response,” Dr. Piliang said.
For the subgroup with AU, specifically, regrowth of eyebrows and eyelashes was also observed in a substantial proportion, according to Dr. Piliang. Attributed to the often-devastating psychological burden of hair loss, patient-reported assessments of these responses global were generally “even better” than those reported by the investigators.
However, Dr. Piliang advised clinicians to treat AA as early as possible. Despite the benefits seen in the AT/AU subgroup, she pointed out that starting treatment before total hair loss is associated with a higher likelihood of complete or nearly complete hair regrowth.
There are no data from the ALLEGRO trial to determine how long hair regrowth persists after discontinuation of ritlecitinib, which has been approved for the treatment of AA, but Dr. Piliang said that patients should be told that lifelong therapy should be expected in the vast majority of individuals, whether or not AA has advanced to AT/AU.
“In my experience with JAK inhibitors, you lose response when you come off these drugs,” she said.
Dr. Meariman reported a financial relationship with AbbVie. Dr. Piliang reported financial relationships with Eli Lilly, Pfizer, and Proctor & Gamble. Dr. Armstrong reported financial relationships with more than 30 pharmaceutical companies, including those that manufacture JAK inhibitors. Dr. Guttman-Yassky reported financial relationships with more than 30 companies, including those that manufacture JAK inhibitors.
A version of this article appeared on Medscape.com.
FROM AAD 2024
SAN DIEGO — , according to late-breaking data presented at the annual meeting of the American Academy of Dermatology.
In one study of brepocitinib, the target was cicatricial alopecia (CA), a form of hair loss for which there are no approved therapies. In the other, a subanalysis from phase 3 trials of ritlecitinib for alopecia areata (AA), hair regrowth was shown in the subset of patients who entered the study with alopecia totalis or alopecia universalis (AT/AU).
Reflecting comments from several experts, including one of the late-breaking session moderators, April W. Armstrong, MD, MPH, professor and chief of dermatology, University of California, Los Angeles, said that the CA study, which matched clinical response to changes in CA biomarkers, suggested that the results are a potential breakthrough.
“This is the first placebo-controlled study with an oral JAK inhibitor that not only shows that scarring alopecia can be reversible but also gives insights to the mechanism of action and which patients might respond best,” Emma Guttman-Yassky, MD, PhD, said in an interview. Dr. Guttman-Yassky, professor of Dermatology and Immunology, and director of the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York City, was the study’s senior investigator.
Scarring Alopecia and Brepocitinib
For the study of scarring alopecia, 49 patients with CA were randomized in a 3:1 ratio to brepocitinib, a first-in-class inhibitor that targets both JAK1 and TYK2, or placebo. Because of the small size of the study, the primary endpoint was the change in CA biomarkers. The secondary outcome was clinical response, but because of a correlation between the two, these were mutually reinforcing.
Of the subtypes, nine patients enrolled in the study had frontal fibrosing alopecia (FFA), 16 had lichen planopilaris (LPP) alopecia, and 24 had central centrifugal cicatricial alopecia (CCCA). All of the forms of CA are more common in women overall and women of color specifically, particularly CCCA. For this analysis, the FFA and LPP subtypes were considered similar for assessing response and were combined.
The data included a comparison of response and safety during the 24-week randomization phase, as well as an additional follow-up conducted after another 24 weeks of open-label treatment. During the second phase, all patients on placebo were switched to active treatment.
Overall, there was a reduction in all four of the key scalp inflammatory biomarkers measured among those in the combined FFA/LLP group. In the placebo group, each of these markers — interferon gamma (IFN-gamma), CCLS, CXCL10, and STAT1 — increased over the same time period. In almost all cases, the differences were statistically significant.
In the CCCA subgroup, the same pattern (an increase among those on placebo but a decrease among those on brepocitinib) was observed for CCLS and CXCL10. For IFN-gamma and STAT1, a rise was observed among those on placebo and those on active treatment, although the rise was greater for placebo.
For clinical response, improvement on brepocitinib was observed on disease activity indexes, particularly among those in the FFA/LLP group, according to Marguerite Meariman, MD, a dermatology resident at Mount Sinai, who presented the results. She called the improvement in clinical activity scores at 48 weeks “dramatic.” Moreover, improvement was apparent within 4 weeks of starting therapy.
For CCCA, a more challenging condition to treat, Dr. Meariman said that no further progression might represent an acceptable response for many patients, but there were also cases of hair regrowth in this subset. Although improvement was not generally on the order seen among those with FFA/LLP, she suggested that there is promise even in these more difficult patients.
Further studies are planned, but Dr. Meariman said that it might be important to focus on early treatment regardless of CA subtype. She noted that patients with less than 5 years disease duration typically did better than those with longer durations.
Ritlecitinib for AT/AU
The analysis of patients with AT/AU was based on a subset analysis from the ALLEGRO phase 2b/3 study of ritlecitinib, which targets JAK3 and TEC kinases. The full results of the ALLEGRO trial were published last year in The Lancet. In the new late-breaker analysis, Severity of Alopecia Tool (SALT) scores were evaluated on an observed or last-observation-carried-forward basis. Generally, responses in the subgroup of patients with AT/AU, who had a median SALT score of 80.3 (signifying 80.3% hair loss) at baseline, were only modestly lower than those in the overall trial.
At 24 months, about 50% of patients achieved a SALT score of 20, according to Melissa Piliang, MD, chair of Dermatology at the Cleveland Clinic, Cleveland, Ohio, who presented the data. In this group, as in the non-AT/AU population, responses climbed over time, and these responses have been maintained for as long as patients have remained on therapy.
At the more rigorous threshold of SALT < 10, the proportion of responders was only slightly lower, meaning a substantial proportion of patients with AT/AU “are achieving 90% or more of hair regrowth, so really an excellent response,” Dr. Piliang said.
For the subgroup with AU, specifically, regrowth of eyebrows and eyelashes was also observed in a substantial proportion, according to Dr. Piliang. Attributed to the often-devastating psychological burden of hair loss, patient-reported assessments of these responses global were generally “even better” than those reported by the investigators.
However, Dr. Piliang advised clinicians to treat AA as early as possible. Despite the benefits seen in the AT/AU subgroup, she pointed out that starting treatment before total hair loss is associated with a higher likelihood of complete or nearly complete hair regrowth.
There are no data from the ALLEGRO trial to determine how long hair regrowth persists after discontinuation of ritlecitinib, which has been approved for the treatment of AA, but Dr. Piliang said that patients should be told that lifelong therapy should be expected in the vast majority of individuals, whether or not AA has advanced to AT/AU.
“In my experience with JAK inhibitors, you lose response when you come off these drugs,” she said.
Dr. Meariman reported a financial relationship with AbbVie. Dr. Piliang reported financial relationships with Eli Lilly, Pfizer, and Proctor & Gamble. Dr. Armstrong reported financial relationships with more than 30 pharmaceutical companies, including those that manufacture JAK inhibitors. Dr. Guttman-Yassky reported financial relationships with more than 30 companies, including those that manufacture JAK inhibitors.
A version of this article appeared on Medscape.com.
FROM AAD 2024
SAN DIEGO — , according to late-breaking data presented at the annual meeting of the American Academy of Dermatology.
In one study of brepocitinib, the target was cicatricial alopecia (CA), a form of hair loss for which there are no approved therapies. In the other, a subanalysis from phase 3 trials of ritlecitinib for alopecia areata (AA), hair regrowth was shown in the subset of patients who entered the study with alopecia totalis or alopecia universalis (AT/AU).
Reflecting comments from several experts, including one of the late-breaking session moderators, April W. Armstrong, MD, MPH, professor and chief of dermatology, University of California, Los Angeles, said that the CA study, which matched clinical response to changes in CA biomarkers, suggested that the results are a potential breakthrough.
“This is the first placebo-controlled study with an oral JAK inhibitor that not only shows that scarring alopecia can be reversible but also gives insights to the mechanism of action and which patients might respond best,” Emma Guttman-Yassky, MD, PhD, said in an interview. Dr. Guttman-Yassky, professor of Dermatology and Immunology, and director of the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York City, was the study’s senior investigator.
Scarring Alopecia and Brepocitinib
For the study of scarring alopecia, 49 patients with CA were randomized in a 3:1 ratio to brepocitinib, a first-in-class inhibitor that targets both JAK1 and TYK2, or placebo. Because of the small size of the study, the primary endpoint was the change in CA biomarkers. The secondary outcome was clinical response, but because of a correlation between the two, these were mutually reinforcing.
Of the subtypes, nine patients enrolled in the study had frontal fibrosing alopecia (FFA), 16 had lichen planopilaris (LPP) alopecia, and 24 had central centrifugal cicatricial alopecia (CCCA). All of the forms of CA are more common in women overall and women of color specifically, particularly CCCA. For this analysis, the FFA and LPP subtypes were considered similar for assessing response and were combined.
The data included a comparison of response and safety during the 24-week randomization phase, as well as an additional follow-up conducted after another 24 weeks of open-label treatment. During the second phase, all patients on placebo were switched to active treatment.
Overall, there was a reduction in all four of the key scalp inflammatory biomarkers measured among those in the combined FFA/LLP group. In the placebo group, each of these markers — interferon gamma (IFN-gamma), CCLS, CXCL10, and STAT1 — increased over the same time period. In almost all cases, the differences were statistically significant.
In the CCCA subgroup, the same pattern (an increase among those on placebo but a decrease among those on brepocitinib) was observed for CCLS and CXCL10. For IFN-gamma and STAT1, a rise was observed among those on placebo and those on active treatment, although the rise was greater for placebo.
For clinical response, improvement on brepocitinib was observed on disease activity indexes, particularly among those in the FFA/LLP group, according to Marguerite Meariman, MD, a dermatology resident at Mount Sinai, who presented the results. She called the improvement in clinical activity scores at 48 weeks “dramatic.” Moreover, improvement was apparent within 4 weeks of starting therapy.
For CCCA, a more challenging condition to treat, Dr. Meariman said that no further progression might represent an acceptable response for many patients, but there were also cases of hair regrowth in this subset. Although improvement was not generally on the order seen among those with FFA/LLP, she suggested that there is promise even in these more difficult patients.
Further studies are planned, but Dr. Meariman said that it might be important to focus on early treatment regardless of CA subtype. She noted that patients with less than 5 years disease duration typically did better than those with longer durations.
Ritlecitinib for AT/AU
The analysis of patients with AT/AU was based on a subset analysis from the ALLEGRO phase 2b/3 study of ritlecitinib, which targets JAK3 and TEC kinases. The full results of the ALLEGRO trial were published last year in The Lancet. In the new late-breaker analysis, Severity of Alopecia Tool (SALT) scores were evaluated on an observed or last-observation-carried-forward basis. Generally, responses in the subgroup of patients with AT/AU, who had a median SALT score of 80.3 (signifying 80.3% hair loss) at baseline, were only modestly lower than those in the overall trial.
At 24 months, about 50% of patients achieved a SALT score of 20, according to Melissa Piliang, MD, chair of Dermatology at the Cleveland Clinic, Cleveland, Ohio, who presented the data. In this group, as in the non-AT/AU population, responses climbed over time, and these responses have been maintained for as long as patients have remained on therapy.
At the more rigorous threshold of SALT < 10, the proportion of responders was only slightly lower, meaning a substantial proportion of patients with AT/AU “are achieving 90% or more of hair regrowth, so really an excellent response,” Dr. Piliang said.
For the subgroup with AU, specifically, regrowth of eyebrows and eyelashes was also observed in a substantial proportion, according to Dr. Piliang. Attributed to the often-devastating psychological burden of hair loss, patient-reported assessments of these responses global were generally “even better” than those reported by the investigators.
However, Dr. Piliang advised clinicians to treat AA as early as possible. Despite the benefits seen in the AT/AU subgroup, she pointed out that starting treatment before total hair loss is associated with a higher likelihood of complete or nearly complete hair regrowth.
There are no data from the ALLEGRO trial to determine how long hair regrowth persists after discontinuation of ritlecitinib, which has been approved for the treatment of AA, but Dr. Piliang said that patients should be told that lifelong therapy should be expected in the vast majority of individuals, whether or not AA has advanced to AT/AU.
“In my experience with JAK inhibitors, you lose response when you come off these drugs,” she said.
Dr. Meariman reported a financial relationship with AbbVie. Dr. Piliang reported financial relationships with Eli Lilly, Pfizer, and Proctor & Gamble. Dr. Armstrong reported financial relationships with more than 30 pharmaceutical companies, including those that manufacture JAK inhibitors. Dr. Guttman-Yassky reported financial relationships with more than 30 companies, including those that manufacture JAK inhibitors.
A version of this article appeared on Medscape.com.
The Power of Patient-Reported Outcomes Is Inhibited by Multiple Barriers
WEST PALM BEACH, FLORIDA — , according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
Potentially Useful Clinical Information
PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.
A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.
Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.
The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.
More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.
Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.
By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
A Path Forward
In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.
But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.
“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.
The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.
“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.
PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.
Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.
WEST PALM BEACH, FLORIDA — , according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
Potentially Useful Clinical Information
PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.
A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.
Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.
The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.
More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.
Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.
By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
A Path Forward
In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.
But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.
“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.
The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.
“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.
PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.
Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.
WEST PALM BEACH, FLORIDA — , according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
Potentially Useful Clinical Information
PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.
A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.
Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.
The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.
More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.
Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.
By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
A Path Forward
In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.
But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.
“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.
The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.
“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.
PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.
Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.
FROM ACTRIMS FORUM 2024
Randomized Trial Confirms Prognostic Value of Neurofilament Light Chains in MS
WEST PALM BEACH, FLORIDA — regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.
When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).
These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.
The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
Is sNfL Relevant Independent of Treatment?
In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).
Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.
While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
Optimal sNfL Threshold May Not Be Defined
Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.
Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.
However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.
Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.
When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).
These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.
The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
Is sNfL Relevant Independent of Treatment?
In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).
Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.
While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
Optimal sNfL Threshold May Not Be Defined
Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.
Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.
However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.
Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.
These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.
When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).
These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.
The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
Is sNfL Relevant Independent of Treatment?
In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).
Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.
While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
Optimal sNfL Threshold May Not Be Defined
Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.
Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.
However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.
Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
Barriers to Remyelinating Drugs in MS Are Falling as Science Advances
WEST PALM BEACH, FLORIDA — , according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.
“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.
“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”
The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
Remyelinating Effect Documented at Multiple Sites
The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.
The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.
Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.
Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.
“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.
One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.
“We might need to provide drugs with a remyelinating effect very early in the process,” he said.
The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
Late-breaker: Two Remyelinating Drugs with Promise
Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).
Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.
The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.
“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.
He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.
Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.
“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.
“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”
The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
Remyelinating Effect Documented at Multiple Sites
The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.
The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.
Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.
Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.
“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.
One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.
“We might need to provide drugs with a remyelinating effect very early in the process,” he said.
The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
Late-breaker: Two Remyelinating Drugs with Promise
Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).
Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.
The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.
“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.
He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.
Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.
“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.
“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”
The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
Remyelinating Effect Documented at Multiple Sites
The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.
The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.
Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.
Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.
“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.
One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.
“We might need to provide drugs with a remyelinating effect very early in the process,” he said.
The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
Late-breaker: Two Remyelinating Drugs with Promise
Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).
Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.
The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.
“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.
He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.
Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.
FROM ACTRIMS FORUM 2024
Latest NCCN Melanoma Guidelines Capture Dynamic of Constantly Evolving Best Practice
SAN DIEGO — that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.
Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.
Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time.
Next AAD Guidelines More Than 1 Year Away
The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago.
Many of the changes in the 2024 NCCN guidelines capture incremental advances rather than a radical departure from previous practice. One example involves shave biopsies. According to a new recommendation, residual pigment or tumor found at the base of a shave procedure, whether for tumor removal or biopsy, should prompt a deeper punch or elliptical biopsy.
The additional biopsy “should be performed immediately and submitted in a separate container to the pathologist,” Dr. Swetter said.
Further, the biopsy should be accompanied with a note to the pathologist that the shave specimen was transected. She added that the Breslow thickness (the measurement of the depth of the melanoma from the top of the granular layer down to the deepest point of the tumor) can accompany each of the two tissue specimens submitted to the pathologist.
This update — like most of the NCCN guidelines — is a category 2A recommendation. Category 1 recommendations signal a high level of evidence, such as a multicenter randomized trial. A 2A recommendation is based on nondefinitive evidence, but it does represent near uniform (≥ 85% agreement) expert consensus.
More Than 50% Consensus Generally Required
The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.
Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website.
Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.
Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.
There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
Best Margins for MIS Undefined
So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.
The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.
Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.
Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.
“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.
This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.
Dr. Swetter and Dr. Kim report no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO — that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.
Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.
Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time.
Next AAD Guidelines More Than 1 Year Away
The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago.
Many of the changes in the 2024 NCCN guidelines capture incremental advances rather than a radical departure from previous practice. One example involves shave biopsies. According to a new recommendation, residual pigment or tumor found at the base of a shave procedure, whether for tumor removal or biopsy, should prompt a deeper punch or elliptical biopsy.
The additional biopsy “should be performed immediately and submitted in a separate container to the pathologist,” Dr. Swetter said.
Further, the biopsy should be accompanied with a note to the pathologist that the shave specimen was transected. She added that the Breslow thickness (the measurement of the depth of the melanoma from the top of the granular layer down to the deepest point of the tumor) can accompany each of the two tissue specimens submitted to the pathologist.
This update — like most of the NCCN guidelines — is a category 2A recommendation. Category 1 recommendations signal a high level of evidence, such as a multicenter randomized trial. A 2A recommendation is based on nondefinitive evidence, but it does represent near uniform (≥ 85% agreement) expert consensus.
More Than 50% Consensus Generally Required
The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.
Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website.
Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.
Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.
There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
Best Margins for MIS Undefined
So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.
The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.
Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.
Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.
“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.
This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.
Dr. Swetter and Dr. Kim report no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO — that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.
Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.
Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time.
Next AAD Guidelines More Than 1 Year Away
The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago.
Many of the changes in the 2024 NCCN guidelines capture incremental advances rather than a radical departure from previous practice. One example involves shave biopsies. According to a new recommendation, residual pigment or tumor found at the base of a shave procedure, whether for tumor removal or biopsy, should prompt a deeper punch or elliptical biopsy.
The additional biopsy “should be performed immediately and submitted in a separate container to the pathologist,” Dr. Swetter said.
Further, the biopsy should be accompanied with a note to the pathologist that the shave specimen was transected. She added that the Breslow thickness (the measurement of the depth of the melanoma from the top of the granular layer down to the deepest point of the tumor) can accompany each of the two tissue specimens submitted to the pathologist.
This update — like most of the NCCN guidelines — is a category 2A recommendation. Category 1 recommendations signal a high level of evidence, such as a multicenter randomized trial. A 2A recommendation is based on nondefinitive evidence, but it does represent near uniform (≥ 85% agreement) expert consensus.
More Than 50% Consensus Generally Required
The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.
Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website.
Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.
Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.
There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
Best Margins for MIS Undefined
So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.
The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.
Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.
Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.
“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.
This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.
Dr. Swetter and Dr. Kim report no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM AAD 2024
Paramagnetic Rim Lesions Gain Traction as Prognostic Biomarker in MS
WEST PALM BEACH, FLORIDA — , according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.
In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.
Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.
Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).
Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
Cognitive Function Changes at 4 Years
Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.
The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.
Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
Routine Measurement of PRLs Is Feasible
One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.
Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.
The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.
In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.
One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.
Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
Can PRLs Be Prevented or Reversed?
The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.
In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.
In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.
When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.
While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.
Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”
PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.
Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.
In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.
Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.
Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).
Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
Cognitive Function Changes at 4 Years
Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.
The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.
Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
Routine Measurement of PRLs Is Feasible
One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.
Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.
The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.
In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.
One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.
Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
Can PRLs Be Prevented or Reversed?
The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.
In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.
In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.
When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.
While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.
Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”
PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.
Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.
WEST PALM BEACH, FLORIDA — , according to one of numerous PRL studies at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“We think this supports other evidence that PRLs are going to be a useful biomarker for MS,” reported Susan Gauthier, DO, an associate professor of neurology and radiology at Weill Cornell University in New York City.
In a simple study, patients with PRLs at baseline were compared with patients without PRLs over a 4-year period, showing that baseline PRLs correlated with worse cognitive function over time.
Of the study cohort, with a median age of 42 years, 5 patients had clinically isolated syndrome (CIS), 81 had relapsing-remitting MS, and 5 had secondary progressive MS. On baseline MRI, 41% of patients had PRLs.
Cognitive function was tracked over time with the Brief International Cognitive Assessment for MS (BICAMS). The components include the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test (BVMT).
Univariate linear model relationships were used to look for a relationship between baseline PRLs and cognitive function. Multiple linear models were performed “with all possible iterations” to further explore the most significant variables. At baseline, no differences were seen in any cognitive test between those with or without PRLs.
Cognitive Function Changes at 4 Years
Those with at least one PRL had significantly lower SDMT (P = 0.046) and BVLT (P = 0.0292) at 4 years. There was no significant difference for CVLT scores.
The findings are consistent with the potential for PRLs to serve “as an imaging marker to identify MS patients at risk for cognitive decline,” said Hannah Schwartz, BA, a mentee of Dr. Gauthier and senior clinical research coordinator in the Department of Neurology at Weill Cornell. Ms. Schwartz presented the data at ACTRIMS Forum Cutting Edge symposium.
Over the past 10 years, there has been a growing body of evidence that the presence of PRLs, which are generally described as a spot of demyelination in the central nervous system surrounded by a rim of iron-laden immune cells such as microglia and macrophages, are prognostically important. The sizable number of studies at the ACTRIMS meeting on PRLs, which so far appear to be unique to MS, suggests the field is maturing.
Routine Measurement of PRLs Is Feasible
One set of data from the CAVS-MS study suggest that routine measurement of this biomarker can be integrated into routine imaging. CAVS-MS is a 2-year international multicenter evaluation of MS biomarkers with 11 participating sites that has collected PRL data on 420 patients.
Overall, PRLs were identified in 39% of these patients. However, patients were divided by typical versus atypical presentation, defined by such factors as an uncharacteristic pattern of attacks, accelerated progression, or radiologically isolated lesions. Among the 201 patients with a typical presentation, at least 1 PRL was found in 53%. Among the 219 with atypical presentations, PRLs were seen in only 26%.
The greater rate of PRLs and the greater number of PRLs per positive patient in the typical presentation group (median 3 vs 2) were highly significant (both P < .0001), reported Brian Renner, MD, a research associate in the neuroimaging program, Department of Neurology, Cedars-Sinai Hospital, Los Angeles.
In this analysis, the PRLs were identified by a single experienced rater with T2- and T1-weighted imaging using 2024 North American Imaging in Multiple Sclerosis (NAIMS) criteria for PRL. These criteria were published earlier this year in Brain.
One message from this study is that “PRL measurement in a large multicenter cohort is feasible,” according to Dr. Renner. This is not only important based on the potential role of PRLs as a prognostic biomarker but also for diagnosis, given the fact that PRLs when present appear to confirm a diagnosis of MS.
Misdiagnosis of MS continues to be a problem, and Dr. Renner said that these appear “to be capable of differentiating MS lesions from non-MS disease mimics.” However, he stated that further validation studies are needed.
Can PRLs Be Prevented or Reversed?
The data on PRLs have generated interest in whether they can be prevented or reversed once they appear. This might be dependent on first determining who is at risk. Another study presented at ACTRIMS suggested that it might not be complex. Lesion size might be critical.
In this study, 233 images were evaluated in 64 patients participating in an observational study at the UMass Memorial Medical Center, Worcester, Massachusetts.
In a univariable analysis, a long list of patient factors, disease characteristics, and imaging characteristics correlated with an increased risk of develop PRLs. These included patient age, disease duration, lesion volume, enhancement pattern (ring vs nodular), and use of disease modifying therapies.
When a regression analysis of these factors was performed, “none of the predictive factors on the univariable analyses were significant after including lesion size in the model,” reported Mustafa Al Gburi, MD, a fellow in neuroimaging at UMass.
While his data did show that exposure to steroids did not appear to reduce risk of developing PRLs, he is now running follow-up to see if specific disease-modifying therapies are more or less preventive for the development of PRL. Because of the limited number of patients and follow-up, it is now too early to tell.
Overall, the risk of PRLs appears to grow substantially at a lesion size of greater than 11 mm, Dr. Al Gburi reported. He believes that this might be “a simple bedside marker to determine patients at future risk of chronic active lesions.”
PRLs might not just be a diagnostic and prognostic tool. Dr. Gauthier said that PRLs are at least a theoretical treatment target. While their immediate promise is in monitoring disease, she thinks the evidence would predict a benefit if PRLs could be prevented or reversed.
Dr. Gauthier reports financial relationships with Genentech, Sanofi-Genzyme, and Mallinckrodt. Dr. Renner and Dr. Al Gburi report no potential conflicts of interest.
FROM ACRIMS FORUM 2024
PFO closure may reduce migraine days and prevent stroke
, according to a discussion at the 2023 Scottsdale Headache Symposium.
In two clinical trials evaluating whether PFO closure reduces migraine risk, the primary endpoints were not met, but a signal of benefit on secondary endpoints and the association between PFO, migraine, and stroke are among the reasons that PFO closure should be reevaluated, according to Andrew Charles MD, Director of the Goldberg Migraine Program, University of California, Los Angeles.
Other right-to-left shunt defects have also been associated with both migraine and stroke, leading Dr. Charles to suggest these defects are more a common denominator.
“Stroke during a migraine is, in fact, very uncommon,” Dr. Charles said. “This raises the possibility that it is not the migraine causing the stroke but rather there is a shared risk factor for stroke and migraine,” said Dr. Charles, referring to PFO as well as other right-to-left shunt defects, such as hereditary hemorrhaging telangiectasia in the lungs.
One Intervention, Two Potential Benefits
Fixing these defects is therefore at least theoretically attractive for preventing both migraine and stroke, but Dr. Charles said the opportunity for preventing both migraine and stroke is most attractive in migraine patients who have additional stroke risk factors.
Use of oral contraceptives, which produce a hypercoagulable state, is an example.
“Are these the people we should really be thinking about if they have PFO and migraine, particularly migraine with aura?” Dr. Charles asked.
The association between right-to-left shunts and migraine is strong. Although PFO is common, presenting in 20%-25% of the adult population, it has been found in up to 50% of individuals who have migraine with aura. In patients with migraine but no aura, the prevalence of PFO has been estimated to be approximately 35% or still somewhat elevated relative to the general population.
Primary Endpoint Missed in Clinical Trials
The question of whether risk of migraine can be reduced with repair of PFO or other right-to-left shunts remains unresolved. In two high-quality randomized trials undertaken in PFO repair, neither met its primary endpoint. In one of these, called PRIMA, which was terminated early for slow enrollment, the reduction in mean headache attacks was not significant relative to medical therapy.
In the second, called PREMIUM, device closure of PFO also failed to significantly reduce migraine attacks over sham procedure although it was associated with complete migraine remission (10% vs 1%).
A pooled analysis of these two studies that was conducted subsequently concluded that PFO closure reduces mean monthly migraine days (-3.1 vs. -1.9 days; P = -.02) and increases the likelihood of complete migraine cessation (9% vs. 0.7%; P < .001), but Dr. Charles pointed out the primary endpoint was migraine attacks not migraine days, so other analyses can only be considered hypothesis-generating.
There are several reasons to relook at the relationship between migraine and PFO but the potential to prevent both migraine and stroke with PFO closure could be one of the most important.
Several years ago, Dr. Charles and his coinvestigators from UCLA evaluated more than 700 ischemic strokes. Of these, 127 strokes were characterized as cryptogenic because of lack of another identifiable etiology. While 59% of these patients had PFO, which is several times higher than the general population, the prevalence of PFO in patients with a cryptogenic stroke and a history of migraine was 79% in this published study.
“So, in this group of patients who did not have any other clear cause for a stroke, a diagnosis of PFO was very much overrepresented,” Dr. Charles said.
Migraine Days Might Be a Better Endpoint
For patients with migraine who have risk factors for stroke, this makes PFO closure an attractive intervention, but a positive randomized trial is needed. Several are underway. Importantly, the trials now enrolling are using migraine days, which was significantly reduced in both PREMIUM and PRIMA, rather than migraine attacks as the primary endpoint.
“Migraine days is now accepted by the Food and Drug Administration as a criterion of benefit,” reported Jonathan Tobis, MD, Research Director, Interventional Cardiology, UCLA David Geffen School of Medicine, Los Angeles.
He explained that the FDA insisted on migraine attacks as the endpoint for the PREMIUM trial, but this was a far more challenging endpoint on which to show a statistical benefit. He emphasized that a new set of trials will now test efficacy on the basis of migraine days.
One of these trials, called RELIEF, which is randomizing patients to device closure of PFO or a sham procedure. Both groups are receiving clopidogrel or prasugrel based on a previous observation that patients who respond to these drugs are also more likely to respond to PFO closure.
Another trial, called COMPETE-2, is comparing PFO closure with a device to aspirin plus a sham closure. This trial is ongoing in China.
Stroke is not being evaluated as an endpoint in either trial, but Dr. Charles suggested that this does warrant attention.
“I would also just put it out there that, apart from simply migraine, this is a therapeutic approach that we might actually think about in terms of helping to prevent stroke in our migraine patients,” he said.
Senior author of a recent meta-analysis of trials evaluating PFO closure and control of migraine, Ling Liu, MD, Department of Neurology, University of Sichuan, Chengdu, China, agreed that PFO closure for the treatment of migraine deserves “a reevaluation.”
In his meta-analysis of three randomized trials, one pooled study, and eight retrospective case series with 1,165 patients, PFO closure was associated with a nearly 75% reduction (odds ratio [OR], 0.259; P = .0048) reduction in migraine days and 50% increase in resolution of migraine in patients with a history of migraine with aura (OR, 1.586; P = .227).
The incidence of stroke was not evaluated in this meta-analysis, but Dr. Liu believes that the evidence of reducing the burden of migraine with PFO closure is compelling. Given the evidence from this meta-analysis that PFO closure is safe, Dr. Liu maintained that a definitive trial is needed “especially for migraine with frequent aura.”
As an interventional cardiologist, Dr. Tobis said that when PFO closures is performed for prevention of stroke in patients with migraine, it often leads to reduced migraine activity and, in some cases, elimination of migraine. Like others, he believes new analyses should be conducted.
“Everyone involved in this field believes there is something there,” Dr. Tobis said. The missing link is a clinical trial to confirm it.
Dr. Charles and Dr. Liu report no potential conflicts of interest. Dr. Tobis reports a financial relationship with Holistick Medical.
, according to a discussion at the 2023 Scottsdale Headache Symposium.
In two clinical trials evaluating whether PFO closure reduces migraine risk, the primary endpoints were not met, but a signal of benefit on secondary endpoints and the association between PFO, migraine, and stroke are among the reasons that PFO closure should be reevaluated, according to Andrew Charles MD, Director of the Goldberg Migraine Program, University of California, Los Angeles.
Other right-to-left shunt defects have also been associated with both migraine and stroke, leading Dr. Charles to suggest these defects are more a common denominator.
“Stroke during a migraine is, in fact, very uncommon,” Dr. Charles said. “This raises the possibility that it is not the migraine causing the stroke but rather there is a shared risk factor for stroke and migraine,” said Dr. Charles, referring to PFO as well as other right-to-left shunt defects, such as hereditary hemorrhaging telangiectasia in the lungs.
One Intervention, Two Potential Benefits
Fixing these defects is therefore at least theoretically attractive for preventing both migraine and stroke, but Dr. Charles said the opportunity for preventing both migraine and stroke is most attractive in migraine patients who have additional stroke risk factors.
Use of oral contraceptives, which produce a hypercoagulable state, is an example.
“Are these the people we should really be thinking about if they have PFO and migraine, particularly migraine with aura?” Dr. Charles asked.
The association between right-to-left shunts and migraine is strong. Although PFO is common, presenting in 20%-25% of the adult population, it has been found in up to 50% of individuals who have migraine with aura. In patients with migraine but no aura, the prevalence of PFO has been estimated to be approximately 35% or still somewhat elevated relative to the general population.
Primary Endpoint Missed in Clinical Trials
The question of whether risk of migraine can be reduced with repair of PFO or other right-to-left shunts remains unresolved. In two high-quality randomized trials undertaken in PFO repair, neither met its primary endpoint. In one of these, called PRIMA, which was terminated early for slow enrollment, the reduction in mean headache attacks was not significant relative to medical therapy.
In the second, called PREMIUM, device closure of PFO also failed to significantly reduce migraine attacks over sham procedure although it was associated with complete migraine remission (10% vs 1%).
A pooled analysis of these two studies that was conducted subsequently concluded that PFO closure reduces mean monthly migraine days (-3.1 vs. -1.9 days; P = -.02) and increases the likelihood of complete migraine cessation (9% vs. 0.7%; P < .001), but Dr. Charles pointed out the primary endpoint was migraine attacks not migraine days, so other analyses can only be considered hypothesis-generating.
There are several reasons to relook at the relationship between migraine and PFO but the potential to prevent both migraine and stroke with PFO closure could be one of the most important.
Several years ago, Dr. Charles and his coinvestigators from UCLA evaluated more than 700 ischemic strokes. Of these, 127 strokes were characterized as cryptogenic because of lack of another identifiable etiology. While 59% of these patients had PFO, which is several times higher than the general population, the prevalence of PFO in patients with a cryptogenic stroke and a history of migraine was 79% in this published study.
“So, in this group of patients who did not have any other clear cause for a stroke, a diagnosis of PFO was very much overrepresented,” Dr. Charles said.
Migraine Days Might Be a Better Endpoint
For patients with migraine who have risk factors for stroke, this makes PFO closure an attractive intervention, but a positive randomized trial is needed. Several are underway. Importantly, the trials now enrolling are using migraine days, which was significantly reduced in both PREMIUM and PRIMA, rather than migraine attacks as the primary endpoint.
“Migraine days is now accepted by the Food and Drug Administration as a criterion of benefit,” reported Jonathan Tobis, MD, Research Director, Interventional Cardiology, UCLA David Geffen School of Medicine, Los Angeles.
He explained that the FDA insisted on migraine attacks as the endpoint for the PREMIUM trial, but this was a far more challenging endpoint on which to show a statistical benefit. He emphasized that a new set of trials will now test efficacy on the basis of migraine days.
One of these trials, called RELIEF, which is randomizing patients to device closure of PFO or a sham procedure. Both groups are receiving clopidogrel or prasugrel based on a previous observation that patients who respond to these drugs are also more likely to respond to PFO closure.
Another trial, called COMPETE-2, is comparing PFO closure with a device to aspirin plus a sham closure. This trial is ongoing in China.
Stroke is not being evaluated as an endpoint in either trial, but Dr. Charles suggested that this does warrant attention.
“I would also just put it out there that, apart from simply migraine, this is a therapeutic approach that we might actually think about in terms of helping to prevent stroke in our migraine patients,” he said.
Senior author of a recent meta-analysis of trials evaluating PFO closure and control of migraine, Ling Liu, MD, Department of Neurology, University of Sichuan, Chengdu, China, agreed that PFO closure for the treatment of migraine deserves “a reevaluation.”
In his meta-analysis of three randomized trials, one pooled study, and eight retrospective case series with 1,165 patients, PFO closure was associated with a nearly 75% reduction (odds ratio [OR], 0.259; P = .0048) reduction in migraine days and 50% increase in resolution of migraine in patients with a history of migraine with aura (OR, 1.586; P = .227).
The incidence of stroke was not evaluated in this meta-analysis, but Dr. Liu believes that the evidence of reducing the burden of migraine with PFO closure is compelling. Given the evidence from this meta-analysis that PFO closure is safe, Dr. Liu maintained that a definitive trial is needed “especially for migraine with frequent aura.”
As an interventional cardiologist, Dr. Tobis said that when PFO closures is performed for prevention of stroke in patients with migraine, it often leads to reduced migraine activity and, in some cases, elimination of migraine. Like others, he believes new analyses should be conducted.
“Everyone involved in this field believes there is something there,” Dr. Tobis said. The missing link is a clinical trial to confirm it.
Dr. Charles and Dr. Liu report no potential conflicts of interest. Dr. Tobis reports a financial relationship with Holistick Medical.
, according to a discussion at the 2023 Scottsdale Headache Symposium.
In two clinical trials evaluating whether PFO closure reduces migraine risk, the primary endpoints were not met, but a signal of benefit on secondary endpoints and the association between PFO, migraine, and stroke are among the reasons that PFO closure should be reevaluated, according to Andrew Charles MD, Director of the Goldberg Migraine Program, University of California, Los Angeles.
Other right-to-left shunt defects have also been associated with both migraine and stroke, leading Dr. Charles to suggest these defects are more a common denominator.
“Stroke during a migraine is, in fact, very uncommon,” Dr. Charles said. “This raises the possibility that it is not the migraine causing the stroke but rather there is a shared risk factor for stroke and migraine,” said Dr. Charles, referring to PFO as well as other right-to-left shunt defects, such as hereditary hemorrhaging telangiectasia in the lungs.
One Intervention, Two Potential Benefits
Fixing these defects is therefore at least theoretically attractive for preventing both migraine and stroke, but Dr. Charles said the opportunity for preventing both migraine and stroke is most attractive in migraine patients who have additional stroke risk factors.
Use of oral contraceptives, which produce a hypercoagulable state, is an example.
“Are these the people we should really be thinking about if they have PFO and migraine, particularly migraine with aura?” Dr. Charles asked.
The association between right-to-left shunts and migraine is strong. Although PFO is common, presenting in 20%-25% of the adult population, it has been found in up to 50% of individuals who have migraine with aura. In patients with migraine but no aura, the prevalence of PFO has been estimated to be approximately 35% or still somewhat elevated relative to the general population.
Primary Endpoint Missed in Clinical Trials
The question of whether risk of migraine can be reduced with repair of PFO or other right-to-left shunts remains unresolved. In two high-quality randomized trials undertaken in PFO repair, neither met its primary endpoint. In one of these, called PRIMA, which was terminated early for slow enrollment, the reduction in mean headache attacks was not significant relative to medical therapy.
In the second, called PREMIUM, device closure of PFO also failed to significantly reduce migraine attacks over sham procedure although it was associated with complete migraine remission (10% vs 1%).
A pooled analysis of these two studies that was conducted subsequently concluded that PFO closure reduces mean monthly migraine days (-3.1 vs. -1.9 days; P = -.02) and increases the likelihood of complete migraine cessation (9% vs. 0.7%; P < .001), but Dr. Charles pointed out the primary endpoint was migraine attacks not migraine days, so other analyses can only be considered hypothesis-generating.
There are several reasons to relook at the relationship between migraine and PFO but the potential to prevent both migraine and stroke with PFO closure could be one of the most important.
Several years ago, Dr. Charles and his coinvestigators from UCLA evaluated more than 700 ischemic strokes. Of these, 127 strokes were characterized as cryptogenic because of lack of another identifiable etiology. While 59% of these patients had PFO, which is several times higher than the general population, the prevalence of PFO in patients with a cryptogenic stroke and a history of migraine was 79% in this published study.
“So, in this group of patients who did not have any other clear cause for a stroke, a diagnosis of PFO was very much overrepresented,” Dr. Charles said.
Migraine Days Might Be a Better Endpoint
For patients with migraine who have risk factors for stroke, this makes PFO closure an attractive intervention, but a positive randomized trial is needed. Several are underway. Importantly, the trials now enrolling are using migraine days, which was significantly reduced in both PREMIUM and PRIMA, rather than migraine attacks as the primary endpoint.
“Migraine days is now accepted by the Food and Drug Administration as a criterion of benefit,” reported Jonathan Tobis, MD, Research Director, Interventional Cardiology, UCLA David Geffen School of Medicine, Los Angeles.
He explained that the FDA insisted on migraine attacks as the endpoint for the PREMIUM trial, but this was a far more challenging endpoint on which to show a statistical benefit. He emphasized that a new set of trials will now test efficacy on the basis of migraine days.
One of these trials, called RELIEF, which is randomizing patients to device closure of PFO or a sham procedure. Both groups are receiving clopidogrel or prasugrel based on a previous observation that patients who respond to these drugs are also more likely to respond to PFO closure.
Another trial, called COMPETE-2, is comparing PFO closure with a device to aspirin plus a sham closure. This trial is ongoing in China.
Stroke is not being evaluated as an endpoint in either trial, but Dr. Charles suggested that this does warrant attention.
“I would also just put it out there that, apart from simply migraine, this is a therapeutic approach that we might actually think about in terms of helping to prevent stroke in our migraine patients,” he said.
Senior author of a recent meta-analysis of trials evaluating PFO closure and control of migraine, Ling Liu, MD, Department of Neurology, University of Sichuan, Chengdu, China, agreed that PFO closure for the treatment of migraine deserves “a reevaluation.”
In his meta-analysis of three randomized trials, one pooled study, and eight retrospective case series with 1,165 patients, PFO closure was associated with a nearly 75% reduction (odds ratio [OR], 0.259; P = .0048) reduction in migraine days and 50% increase in resolution of migraine in patients with a history of migraine with aura (OR, 1.586; P = .227).
The incidence of stroke was not evaluated in this meta-analysis, but Dr. Liu believes that the evidence of reducing the burden of migraine with PFO closure is compelling. Given the evidence from this meta-analysis that PFO closure is safe, Dr. Liu maintained that a definitive trial is needed “especially for migraine with frequent aura.”
As an interventional cardiologist, Dr. Tobis said that when PFO closures is performed for prevention of stroke in patients with migraine, it often leads to reduced migraine activity and, in some cases, elimination of migraine. Like others, he believes new analyses should be conducted.
“Everyone involved in this field believes there is something there,” Dr. Tobis said. The missing link is a clinical trial to confirm it.
Dr. Charles and Dr. Liu report no potential conflicts of interest. Dr. Tobis reports a financial relationship with Holistick Medical.
FROM THE 2023 SCOTTSDALE HEADACHE SYMPOSIUM
Drugs to prevent versus those to treat migraine might not share targets
, according to experts attempting to put these puzzle pieces together at the 2023 Scottsdale Headache Symposium.
As the details of the complex chain of molecular events become better understood, there is reason to believe that the targets for aborting events early in the process are not necessarily therapeutic at later stages or vice versa, according to Peter Goadsby, MBBS, MD, PhD, director of the National Institute for Health Research and professor of neurology, King’s College, London.
“I think this explains some of the frustration at trigger modulation. I think we are often trying to modulate a process that has already got started,” he said. The analogy might be closing the barn door after the animals have escaped.
Migraine phases might explain pathology
Given the progress in understanding each step that leads from one phase to the next in migraine onset, this premise is not surprising. Increased blood flow, trigeminal activation, and release of calcitonin gene–related peptide (CGRP) are early events in this process, according to Dr. Goadsby, but there is still uncertainty about the triggers of brainstem stimulation and cranial blood flow that precedes these events.
In his talk about the advances that led to the development of CGRP-targeted therapy, Dr. Goadsby explained how and why CGRP inhibition, along with triptans, pituitary adenylate cyclase–activating polypeptide (PACAP) inhibitors, and ditans, have been developed as treatment targets in migraine, while other once-promising targets, such as substance P inhibition and inducible nitric oxide synthase (INOS) inhibition, have not.
Much of this progress has been by trial and error through clinical studies in which efficacy has or has not been seen. Despite the progress in mapping the release of CGRP and its activity, Dr. Goadsby acknowledged that there is still much about its participation in migraine pathophysiology that remains poorly defined.
“Anyone who tells you that they know how CGRP works I think is blowing smoke, frankly,” Dr. Goadsby said. “Clearly these things are complex.”
CGRP is active in the CSF
This includes the site of action. Dr. Goadsby said that it is widely believed that CGRP inhibitors are active in the dura and not in the cerebrospinal fluid (CSF). However, Dr. Goadsby said that a study undertaken with monoclonal antibodies targeting CGRP have produced compelling evidence that CGRP is reduced in the CSF.
“They clearly get into the CSF,” said Dr. Goadsby, noting that the barrier between peripheral blood and the CSF “is different from the blood-brain barrier.”
Widely regarded as playing a pivotal role in the development of CGRP as a therapeutic target in migraine, Dr. Goadsby spent some time speculating about its potential for preventing the earliest steps in the process that leads from the premonitory state to allodynia, prodromal symptoms, migraine, and postdromal recovery.
Of triggers, “light is my favorite example,” he said. He noted that many patients are convinced that light initiates the subsequent steps that end in a migraine. This is fair assumption for those who have seen a sequence of events in which light in the absence of any other symptom always precedes prodromal symptoms and migraine.
“Why would you not think that?” he asked. “Unless you point out that the attack had already started and the reason that you are noticing the light is because of photophobia that started during the premonitory phase.”
It is increasingly clear that CGRP inhibition does have clinical benefit when started at early signs of a coming migraine, according to Dr. Goadsby. He cited a phase 3 study published just days before he spoke at the Scottsdale Headache Symposium. Called PRODROME, the study associated the CGRP receptor antagonist ubrogepant, which is already approved for treatment of migraine, with a significant reduction in the risk of moderate to severe headache relative to placebo when measured 24 hours after randomization (46% vs. 29%; P < .0001).
Brain activity monitoring supports phases
Citing imaging studies in his own laboratory, Todd J. Schwedt, MD, chair of neurology research, Mayo Clinic, Phoenix, substantiated several of the points made by Dr. Goadsby in a separate talk he made on migraine phases. By monitoring brain activity during each phase of migraine, he suggested his data support the role of CGRP in producing an inflammatory response as well as sensitizing the trigeminal cervical system in steps that appear to be important to the pain process.
Dr. Schwedt showed several pieces of evidence suggesting that CGRP is an early mediator even if it is not necessarily the first step in a process for every patient. However, like Dr. Goadsby, Dr. Schwedt also acknowledged that the interplay between events is complex and might differ between patients.
Yet, he says that brain activity on imaging is not the only evidence of the role of CGRP activation early in the process leading toward migraine.
“I am a little biased towards imaging, but it’s not just about imaging,” Dr. Schwedt said.
“If we look at preictal salivary CGRP levels and then follow them into the headache phase, we see the levels increase, but they go back to normal a couple of hours into the attack and then stay normal, presumably, until the patient gets closer to the next attack,” Dr. Schwedt said.
Despite progress there is more to be done to determine why CGRP is released and whether it can be inhibited early to abort migraine before the headache phase, but both Dr. Goadsby and Dr. Schwedt pointed to this as a very early event. This is not to say that others, such as cortical spreading depression, do not have an equally important role in the evolution of migraine, but each expert considers migraine phases to be useful divisions for tracing the sequence of pathogenic events.
The phase of a migraine attack and their corresponding symptoms “can be mapped to altered brain function and release of neuropeptides and neurotransmitters,” Dr. Schwedt said. The implication is that better targets for blocking migraine before it reaches the headache phase might be discovered in these early phases.
Dr. Goadsby and Dr. Schwedt listed more than 10 pharmaceutical companies to which they have financial relationships, but both claimed that none of these relationships posed a potential conflict of interest.
, according to experts attempting to put these puzzle pieces together at the 2023 Scottsdale Headache Symposium.
As the details of the complex chain of molecular events become better understood, there is reason to believe that the targets for aborting events early in the process are not necessarily therapeutic at later stages or vice versa, according to Peter Goadsby, MBBS, MD, PhD, director of the National Institute for Health Research and professor of neurology, King’s College, London.
“I think this explains some of the frustration at trigger modulation. I think we are often trying to modulate a process that has already got started,” he said. The analogy might be closing the barn door after the animals have escaped.
Migraine phases might explain pathology
Given the progress in understanding each step that leads from one phase to the next in migraine onset, this premise is not surprising. Increased blood flow, trigeminal activation, and release of calcitonin gene–related peptide (CGRP) are early events in this process, according to Dr. Goadsby, but there is still uncertainty about the triggers of brainstem stimulation and cranial blood flow that precedes these events.
In his talk about the advances that led to the development of CGRP-targeted therapy, Dr. Goadsby explained how and why CGRP inhibition, along with triptans, pituitary adenylate cyclase–activating polypeptide (PACAP) inhibitors, and ditans, have been developed as treatment targets in migraine, while other once-promising targets, such as substance P inhibition and inducible nitric oxide synthase (INOS) inhibition, have not.
Much of this progress has been by trial and error through clinical studies in which efficacy has or has not been seen. Despite the progress in mapping the release of CGRP and its activity, Dr. Goadsby acknowledged that there is still much about its participation in migraine pathophysiology that remains poorly defined.
“Anyone who tells you that they know how CGRP works I think is blowing smoke, frankly,” Dr. Goadsby said. “Clearly these things are complex.”
CGRP is active in the CSF
This includes the site of action. Dr. Goadsby said that it is widely believed that CGRP inhibitors are active in the dura and not in the cerebrospinal fluid (CSF). However, Dr. Goadsby said that a study undertaken with monoclonal antibodies targeting CGRP have produced compelling evidence that CGRP is reduced in the CSF.
“They clearly get into the CSF,” said Dr. Goadsby, noting that the barrier between peripheral blood and the CSF “is different from the blood-brain barrier.”
Widely regarded as playing a pivotal role in the development of CGRP as a therapeutic target in migraine, Dr. Goadsby spent some time speculating about its potential for preventing the earliest steps in the process that leads from the premonitory state to allodynia, prodromal symptoms, migraine, and postdromal recovery.
Of triggers, “light is my favorite example,” he said. He noted that many patients are convinced that light initiates the subsequent steps that end in a migraine. This is fair assumption for those who have seen a sequence of events in which light in the absence of any other symptom always precedes prodromal symptoms and migraine.
“Why would you not think that?” he asked. “Unless you point out that the attack had already started and the reason that you are noticing the light is because of photophobia that started during the premonitory phase.”
It is increasingly clear that CGRP inhibition does have clinical benefit when started at early signs of a coming migraine, according to Dr. Goadsby. He cited a phase 3 study published just days before he spoke at the Scottsdale Headache Symposium. Called PRODROME, the study associated the CGRP receptor antagonist ubrogepant, which is already approved for treatment of migraine, with a significant reduction in the risk of moderate to severe headache relative to placebo when measured 24 hours after randomization (46% vs. 29%; P < .0001).
Brain activity monitoring supports phases
Citing imaging studies in his own laboratory, Todd J. Schwedt, MD, chair of neurology research, Mayo Clinic, Phoenix, substantiated several of the points made by Dr. Goadsby in a separate talk he made on migraine phases. By monitoring brain activity during each phase of migraine, he suggested his data support the role of CGRP in producing an inflammatory response as well as sensitizing the trigeminal cervical system in steps that appear to be important to the pain process.
Dr. Schwedt showed several pieces of evidence suggesting that CGRP is an early mediator even if it is not necessarily the first step in a process for every patient. However, like Dr. Goadsby, Dr. Schwedt also acknowledged that the interplay between events is complex and might differ between patients.
Yet, he says that brain activity on imaging is not the only evidence of the role of CGRP activation early in the process leading toward migraine.
“I am a little biased towards imaging, but it’s not just about imaging,” Dr. Schwedt said.
“If we look at preictal salivary CGRP levels and then follow them into the headache phase, we see the levels increase, but they go back to normal a couple of hours into the attack and then stay normal, presumably, until the patient gets closer to the next attack,” Dr. Schwedt said.
Despite progress there is more to be done to determine why CGRP is released and whether it can be inhibited early to abort migraine before the headache phase, but both Dr. Goadsby and Dr. Schwedt pointed to this as a very early event. This is not to say that others, such as cortical spreading depression, do not have an equally important role in the evolution of migraine, but each expert considers migraine phases to be useful divisions for tracing the sequence of pathogenic events.
The phase of a migraine attack and their corresponding symptoms “can be mapped to altered brain function and release of neuropeptides and neurotransmitters,” Dr. Schwedt said. The implication is that better targets for blocking migraine before it reaches the headache phase might be discovered in these early phases.
Dr. Goadsby and Dr. Schwedt listed more than 10 pharmaceutical companies to which they have financial relationships, but both claimed that none of these relationships posed a potential conflict of interest.
, according to experts attempting to put these puzzle pieces together at the 2023 Scottsdale Headache Symposium.
As the details of the complex chain of molecular events become better understood, there is reason to believe that the targets for aborting events early in the process are not necessarily therapeutic at later stages or vice versa, according to Peter Goadsby, MBBS, MD, PhD, director of the National Institute for Health Research and professor of neurology, King’s College, London.
“I think this explains some of the frustration at trigger modulation. I think we are often trying to modulate a process that has already got started,” he said. The analogy might be closing the barn door after the animals have escaped.
Migraine phases might explain pathology
Given the progress in understanding each step that leads from one phase to the next in migraine onset, this premise is not surprising. Increased blood flow, trigeminal activation, and release of calcitonin gene–related peptide (CGRP) are early events in this process, according to Dr. Goadsby, but there is still uncertainty about the triggers of brainstem stimulation and cranial blood flow that precedes these events.
In his talk about the advances that led to the development of CGRP-targeted therapy, Dr. Goadsby explained how and why CGRP inhibition, along with triptans, pituitary adenylate cyclase–activating polypeptide (PACAP) inhibitors, and ditans, have been developed as treatment targets in migraine, while other once-promising targets, such as substance P inhibition and inducible nitric oxide synthase (INOS) inhibition, have not.
Much of this progress has been by trial and error through clinical studies in which efficacy has or has not been seen. Despite the progress in mapping the release of CGRP and its activity, Dr. Goadsby acknowledged that there is still much about its participation in migraine pathophysiology that remains poorly defined.
“Anyone who tells you that they know how CGRP works I think is blowing smoke, frankly,” Dr. Goadsby said. “Clearly these things are complex.”
CGRP is active in the CSF
This includes the site of action. Dr. Goadsby said that it is widely believed that CGRP inhibitors are active in the dura and not in the cerebrospinal fluid (CSF). However, Dr. Goadsby said that a study undertaken with monoclonal antibodies targeting CGRP have produced compelling evidence that CGRP is reduced in the CSF.
“They clearly get into the CSF,” said Dr. Goadsby, noting that the barrier between peripheral blood and the CSF “is different from the blood-brain barrier.”
Widely regarded as playing a pivotal role in the development of CGRP as a therapeutic target in migraine, Dr. Goadsby spent some time speculating about its potential for preventing the earliest steps in the process that leads from the premonitory state to allodynia, prodromal symptoms, migraine, and postdromal recovery.
Of triggers, “light is my favorite example,” he said. He noted that many patients are convinced that light initiates the subsequent steps that end in a migraine. This is fair assumption for those who have seen a sequence of events in which light in the absence of any other symptom always precedes prodromal symptoms and migraine.
“Why would you not think that?” he asked. “Unless you point out that the attack had already started and the reason that you are noticing the light is because of photophobia that started during the premonitory phase.”
It is increasingly clear that CGRP inhibition does have clinical benefit when started at early signs of a coming migraine, according to Dr. Goadsby. He cited a phase 3 study published just days before he spoke at the Scottsdale Headache Symposium. Called PRODROME, the study associated the CGRP receptor antagonist ubrogepant, which is already approved for treatment of migraine, with a significant reduction in the risk of moderate to severe headache relative to placebo when measured 24 hours after randomization (46% vs. 29%; P < .0001).
Brain activity monitoring supports phases
Citing imaging studies in his own laboratory, Todd J. Schwedt, MD, chair of neurology research, Mayo Clinic, Phoenix, substantiated several of the points made by Dr. Goadsby in a separate talk he made on migraine phases. By monitoring brain activity during each phase of migraine, he suggested his data support the role of CGRP in producing an inflammatory response as well as sensitizing the trigeminal cervical system in steps that appear to be important to the pain process.
Dr. Schwedt showed several pieces of evidence suggesting that CGRP is an early mediator even if it is not necessarily the first step in a process for every patient. However, like Dr. Goadsby, Dr. Schwedt also acknowledged that the interplay between events is complex and might differ between patients.
Yet, he says that brain activity on imaging is not the only evidence of the role of CGRP activation early in the process leading toward migraine.
“I am a little biased towards imaging, but it’s not just about imaging,” Dr. Schwedt said.
“If we look at preictal salivary CGRP levels and then follow them into the headache phase, we see the levels increase, but they go back to normal a couple of hours into the attack and then stay normal, presumably, until the patient gets closer to the next attack,” Dr. Schwedt said.
Despite progress there is more to be done to determine why CGRP is released and whether it can be inhibited early to abort migraine before the headache phase, but both Dr. Goadsby and Dr. Schwedt pointed to this as a very early event. This is not to say that others, such as cortical spreading depression, do not have an equally important role in the evolution of migraine, but each expert considers migraine phases to be useful divisions for tracing the sequence of pathogenic events.
The phase of a migraine attack and their corresponding symptoms “can be mapped to altered brain function and release of neuropeptides and neurotransmitters,” Dr. Schwedt said. The implication is that better targets for blocking migraine before it reaches the headache phase might be discovered in these early phases.
Dr. Goadsby and Dr. Schwedt listed more than 10 pharmaceutical companies to which they have financial relationships, but both claimed that none of these relationships posed a potential conflict of interest.
FROM THE 2023 SCOTTSDALE HEADACHE SYMPOSIUM
Nail psoriasis in Black patients often overlooked
NEW YORK – From clinical trials to textbooks, , even when the skin disease has already been diagnosed, according to Shari R. Lipner, MD.
In a recently published review of 45 randomized controlled trials of therapies for nail psoriasis, almost all included information about the gender of the patients enrolled, but only about 35% reported race and/or ethnicity, Dr. Lipner, associate professor of dermatology, Weill Cornell Medical College, New York, said at the Skin of Color Update 2023. The proportion climbed to 59% in trials that included at least one study site in the United States, although representation of non-White patients in studies conducted in the United States was not proportional to the population (13.4% vs. 39.9%), said Dr. Lipner, senior author of the review .
Black patients largely unrepresented in photos
When an Internet search was conducted for images of nail psoriasis, the proportion of images fell as the number of the Fitzpatrick scale increased. Fitzpatrick skin types 1 or 2 represented 70% of the images, skin types 3 to 4 represented about 27%, leaving just 3% represented by darker skin types, Dr. Lipner said.
“Unfortunately, things are not much better if you look at the dermatology and nail-specific textbooks. In fact, the percentages we see are almost identical,” said Dr. Lipner, noting that her review of images suggested that only about 3% of images in textbooks are of Fitzpatrick skin types 5 or 6, an obstacle for clinicians learning to recognize nail involvement in skin of color patients with psoriasis.
“We have written a couple of papers on this topic, including a call to action” in a letter to the editor in the Journal of the American Academy of Dermatology, Dr. Lipner noted. “To ensure access to safe and effective treatments for all patient populations,” she and her coauthor wrote, “we advocate the prioritized enrollment of racial and ethnic minority groups in psoriasis, PsA [psoriatic arthritis], and NP [nail psoriasis] clinical trials.”
Data from the 2009-2010 U.S. National Health and Nutrition Examination Survey (NHANES) confirms that psoriasis is less common in Blacks (1.9%) and Hispanics (1.6%) than Whites (3.6%). But these lower numbers still translate into substantial numbers nationally. Of those with psoriasis, the lifetime incidence of nail involvement has been variously estimated between 80% and 90%, Dr. Lipner said.
In about 10% of patients with psoriasis, nail involvement is isolated, occurring in the absence of skin lesions, a proportion that appears to be similar in Blacks and Whites according to Dr. Lipner.
Patient characteristics similar by race
In a study conducted at her own center, many of the characteristics of psoriasis were similar when those with a Fitzpatrick skin type 4 or higher were compared to those of 3 or lower. This included male-female distribution, smoking history, and presence of accompanying psoriatic arthritis. There was one discrepancy between lighter and darker skin.
“The big difference was that it took almost 3 years longer [on average] for darker skin to be diagnosed, and there was worse severity of disease,” Dr. Lipner said.
Like cutaneous manifestations of psoriasis, there are differences in appearance in the nail, many of which are simply produced by how skin color alters the appearance, such as the brownish hue of erythema in darker versus lighter skin. Dr. Lipner also noted that many of the features, such as keratosis, can be more severe in patients with darker skin types, but this is likely because of the delay in diagnosis.
The problem with overlooking nail psoriasis in patients of any skin color is the significant and independent adverse impact imposed by nail disease on quality of life, she added. She recounted the case of a 22-year-old Black patient whose nail psoriasis was overlooked even as she was being treated for her skin lesions.
“The diagnosis of nail psoriasis was missed for 3 years,” said Dr. Lipner, noting that the nail involvement was not trivial. “She had trouble doing her daily activities of life, but also, she was very embarrassed by her nails, not surprisingly.”
The problem of underrepresentation of Blacks in photos depicting nail diseases is not going unnoticed.
“Recently, there has been a concerted effort on the part of authors and editors to include more images of skin of color patients in published articles and textbooks,” said Jane S. Bellet, MD, professor of dermatology, Duke University, Durham, N.C.
An expert in nail disorders, particularly in children, Dr. Bellet said in an interview that this trend “must continue and increase in volume.” She said that the need for more images of nail disease in skin of color is not restricted to textbooks but includes “other learning materials, such as online atlases.”
Dr. Lipner and Dr. Bellet reported no potential conflicts of interest relative to this topic.
NEW YORK – From clinical trials to textbooks, , even when the skin disease has already been diagnosed, according to Shari R. Lipner, MD.
In a recently published review of 45 randomized controlled trials of therapies for nail psoriasis, almost all included information about the gender of the patients enrolled, but only about 35% reported race and/or ethnicity, Dr. Lipner, associate professor of dermatology, Weill Cornell Medical College, New York, said at the Skin of Color Update 2023. The proportion climbed to 59% in trials that included at least one study site in the United States, although representation of non-White patients in studies conducted in the United States was not proportional to the population (13.4% vs. 39.9%), said Dr. Lipner, senior author of the review .
Black patients largely unrepresented in photos
When an Internet search was conducted for images of nail psoriasis, the proportion of images fell as the number of the Fitzpatrick scale increased. Fitzpatrick skin types 1 or 2 represented 70% of the images, skin types 3 to 4 represented about 27%, leaving just 3% represented by darker skin types, Dr. Lipner said.
“Unfortunately, things are not much better if you look at the dermatology and nail-specific textbooks. In fact, the percentages we see are almost identical,” said Dr. Lipner, noting that her review of images suggested that only about 3% of images in textbooks are of Fitzpatrick skin types 5 or 6, an obstacle for clinicians learning to recognize nail involvement in skin of color patients with psoriasis.
“We have written a couple of papers on this topic, including a call to action” in a letter to the editor in the Journal of the American Academy of Dermatology, Dr. Lipner noted. “To ensure access to safe and effective treatments for all patient populations,” she and her coauthor wrote, “we advocate the prioritized enrollment of racial and ethnic minority groups in psoriasis, PsA [psoriatic arthritis], and NP [nail psoriasis] clinical trials.”
Data from the 2009-2010 U.S. National Health and Nutrition Examination Survey (NHANES) confirms that psoriasis is less common in Blacks (1.9%) and Hispanics (1.6%) than Whites (3.6%). But these lower numbers still translate into substantial numbers nationally. Of those with psoriasis, the lifetime incidence of nail involvement has been variously estimated between 80% and 90%, Dr. Lipner said.
In about 10% of patients with psoriasis, nail involvement is isolated, occurring in the absence of skin lesions, a proportion that appears to be similar in Blacks and Whites according to Dr. Lipner.
Patient characteristics similar by race
In a study conducted at her own center, many of the characteristics of psoriasis were similar when those with a Fitzpatrick skin type 4 or higher were compared to those of 3 or lower. This included male-female distribution, smoking history, and presence of accompanying psoriatic arthritis. There was one discrepancy between lighter and darker skin.
“The big difference was that it took almost 3 years longer [on average] for darker skin to be diagnosed, and there was worse severity of disease,” Dr. Lipner said.
Like cutaneous manifestations of psoriasis, there are differences in appearance in the nail, many of which are simply produced by how skin color alters the appearance, such as the brownish hue of erythema in darker versus lighter skin. Dr. Lipner also noted that many of the features, such as keratosis, can be more severe in patients with darker skin types, but this is likely because of the delay in diagnosis.
The problem with overlooking nail psoriasis in patients of any skin color is the significant and independent adverse impact imposed by nail disease on quality of life, she added. She recounted the case of a 22-year-old Black patient whose nail psoriasis was overlooked even as she was being treated for her skin lesions.
“The diagnosis of nail psoriasis was missed for 3 years,” said Dr. Lipner, noting that the nail involvement was not trivial. “She had trouble doing her daily activities of life, but also, she was very embarrassed by her nails, not surprisingly.”
The problem of underrepresentation of Blacks in photos depicting nail diseases is not going unnoticed.
“Recently, there has been a concerted effort on the part of authors and editors to include more images of skin of color patients in published articles and textbooks,” said Jane S. Bellet, MD, professor of dermatology, Duke University, Durham, N.C.
An expert in nail disorders, particularly in children, Dr. Bellet said in an interview that this trend “must continue and increase in volume.” She said that the need for more images of nail disease in skin of color is not restricted to textbooks but includes “other learning materials, such as online atlases.”
Dr. Lipner and Dr. Bellet reported no potential conflicts of interest relative to this topic.
NEW YORK – From clinical trials to textbooks, , even when the skin disease has already been diagnosed, according to Shari R. Lipner, MD.
In a recently published review of 45 randomized controlled trials of therapies for nail psoriasis, almost all included information about the gender of the patients enrolled, but only about 35% reported race and/or ethnicity, Dr. Lipner, associate professor of dermatology, Weill Cornell Medical College, New York, said at the Skin of Color Update 2023. The proportion climbed to 59% in trials that included at least one study site in the United States, although representation of non-White patients in studies conducted in the United States was not proportional to the population (13.4% vs. 39.9%), said Dr. Lipner, senior author of the review .
Black patients largely unrepresented in photos
When an Internet search was conducted for images of nail psoriasis, the proportion of images fell as the number of the Fitzpatrick scale increased. Fitzpatrick skin types 1 or 2 represented 70% of the images, skin types 3 to 4 represented about 27%, leaving just 3% represented by darker skin types, Dr. Lipner said.
“Unfortunately, things are not much better if you look at the dermatology and nail-specific textbooks. In fact, the percentages we see are almost identical,” said Dr. Lipner, noting that her review of images suggested that only about 3% of images in textbooks are of Fitzpatrick skin types 5 or 6, an obstacle for clinicians learning to recognize nail involvement in skin of color patients with psoriasis.
“We have written a couple of papers on this topic, including a call to action” in a letter to the editor in the Journal of the American Academy of Dermatology, Dr. Lipner noted. “To ensure access to safe and effective treatments for all patient populations,” she and her coauthor wrote, “we advocate the prioritized enrollment of racial and ethnic minority groups in psoriasis, PsA [psoriatic arthritis], and NP [nail psoriasis] clinical trials.”
Data from the 2009-2010 U.S. National Health and Nutrition Examination Survey (NHANES) confirms that psoriasis is less common in Blacks (1.9%) and Hispanics (1.6%) than Whites (3.6%). But these lower numbers still translate into substantial numbers nationally. Of those with psoriasis, the lifetime incidence of nail involvement has been variously estimated between 80% and 90%, Dr. Lipner said.
In about 10% of patients with psoriasis, nail involvement is isolated, occurring in the absence of skin lesions, a proportion that appears to be similar in Blacks and Whites according to Dr. Lipner.
Patient characteristics similar by race
In a study conducted at her own center, many of the characteristics of psoriasis were similar when those with a Fitzpatrick skin type 4 or higher were compared to those of 3 or lower. This included male-female distribution, smoking history, and presence of accompanying psoriatic arthritis. There was one discrepancy between lighter and darker skin.
“The big difference was that it took almost 3 years longer [on average] for darker skin to be diagnosed, and there was worse severity of disease,” Dr. Lipner said.
Like cutaneous manifestations of psoriasis, there are differences in appearance in the nail, many of which are simply produced by how skin color alters the appearance, such as the brownish hue of erythema in darker versus lighter skin. Dr. Lipner also noted that many of the features, such as keratosis, can be more severe in patients with darker skin types, but this is likely because of the delay in diagnosis.
The problem with overlooking nail psoriasis in patients of any skin color is the significant and independent adverse impact imposed by nail disease on quality of life, she added. She recounted the case of a 22-year-old Black patient whose nail psoriasis was overlooked even as she was being treated for her skin lesions.
“The diagnosis of nail psoriasis was missed for 3 years,” said Dr. Lipner, noting that the nail involvement was not trivial. “She had trouble doing her daily activities of life, but also, she was very embarrassed by her nails, not surprisingly.”
The problem of underrepresentation of Blacks in photos depicting nail diseases is not going unnoticed.
“Recently, there has been a concerted effort on the part of authors and editors to include more images of skin of color patients in published articles and textbooks,” said Jane S. Bellet, MD, professor of dermatology, Duke University, Durham, N.C.
An expert in nail disorders, particularly in children, Dr. Bellet said in an interview that this trend “must continue and increase in volume.” She said that the need for more images of nail disease in skin of color is not restricted to textbooks but includes “other learning materials, such as online atlases.”
Dr. Lipner and Dr. Bellet reported no potential conflicts of interest relative to this topic.
AT SOC 2023