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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
SPF is only the start when recommending sunscreens
CHICAGO – at the inaugural Pigmentary Disorders Exchange Symposium.
Among the first factors physicians should consider before recommending sunscreen are a patient’s Fitzpatrick skin type, risks for burning or tanning, underlying skin disorders, and medications the patient is taking, Dr. Taylor, professor of dermatology at the University of Pennsylvania, Philadelphia, said at the meeting, provided by MedscapeLIVE! If patients are on hypertensives, for example, medications can make them more photosensitive.
Consider skin type
Dr. Taylor said she was dismayed by the results of a recent study, which found that 43% of dermatologists who responded to a survey reported that they never, rarely, or only sometimes took a patient’s skin type into account when making sunscreen recommendations. The article is referenced in a 2022 expert panel consensus paper she coauthored on photoprotection “for skin of all color.” But she pointed out that considering skin type alone is inadequate.
Questions for patients in joint decision-making should include lifestyle and work choices such as whether they work inside or outside, and how much sun exposure they get in a typical day. Heat and humidity levels should also be considered as should a patient’s susceptibility to dyspigmentation. “That could be overall darkening of the skin, mottled hyperpigmentation, actinic dyspigmentation, and, of course, propensity for skin cancer,” she said.
Use differs by race
Dr. Taylor, who is also vice chair for diversity, equity and inclusion in the department of dermatology at the University of Pennsylvania, pointed out that sunscreen use differs considerably by race.
In study of 8,952 adults in the United States who reported that they were sun sensitive found that a subset of adults with skin of color were significantly less likely to use sunscreen when compared with non-Hispanic White adults: Non-Hispanic Black (adjusted odds ratio, 0.43); non-Hispanic Asian (aOR. 0.54); and Hispanic (aOR, 0.70) adults.
In the study, non-Hispanic Black and Hispanic adults were significantly less likely to use sunscreens with an SPF greater than 15. In addition, non-Hispanic Black, non-Hispanic Asian, and Hispanic adults were significantly more likely than non-Hispanic Whites to wear long sleeves when outside. Such differences are important to keep in mind when advising patients about sunscreens, she said.
Protection for lighter-colored skin
Dr. Taylor said that, for patients with lighter skin tones, “we really want to protect against ultraviolet B as well as ultraviolet A, particularly ultraviolet A2. Ultraviolet radiation is going to cause DNA damage.” Patients with Fitzpatrick skin types I, II, or III are most susceptible to the effects of UVB with sunburn inflammation, which will cause erythema and tanning, and immunosuppression.
“For those who are I, II, and III, we do want to recommend a broad-spectrum, photostable sunscreen with a critical wavelength of 370 nanometers, which is going to protect from both UVB and UVA2,” she said.
Sunscreen recommendations are meant to be paired with advice to avoid midday sun from 10 a.m. to 2 p.m., wearing protective clothing and accessories, and seeking shade, she noted.
Dr. Taylor said, for those patients with lighter skin who are more susceptible to photodamage and premature aging, physicians should recommend sunscreens that contain DNA repair enzymes such as photolyases and sunscreens that contain antioxidants that can prevent or reverse DNA damage. “The exogenous form of these lyases have been manufactured and added to sunscreens,” Dr. Taylor said. “They’re readily available in the United States. That is something to consider for patients with significant photodamage.”
Retinoids can also help alleviate or reverse photodamage, she added.
Protection for darker-colored skin
“Many people of color do not believe they need sunscreen,” Dr. Taylor said. But studies show that, although there may be more intrinsic protection, sunscreen is still needed.
Over 30 years ago, Halder and colleagues reported that melanin in skin of color can filter two to five times more UV radiation, and in a paper on the photoprotective role of melanin, Kaidbey and colleagues found that skin types V and VI had an intrinsic SPF of 13 when compared with those who have lighter complexions, which had an SPF of 3.
Sunburns seem to occur less frequently in people with skin of color, but that may be because erythema is less apparent in people with darker skin tones or because of differences in personal definitions of sunburn, Dr. Taylor said.
“Skin of color can and does sustain sunburns and sunscreen will help prevent that,” she said, adding that a recommendation of an SPF 30 is likely sufficient for these patients. Dr. Taylor noted that sunscreens for patients with darker skin often cost substantially more than those for lighter skin, and that should be considered in recommendations.
Tinted sunscreens
Dr. Taylor said that, while broad-spectrum photostable sunscreens protect against UVB and UVA 2, they don’t protect from visible light and UVA1. Two methods to add that protection are using inorganic tinted sunscreens that contain iron oxide or pigmentary titanium dioxide. Dr. Taylor was a coauthor of a practical guide to tinted sunscreens published in 2022.
“For iron oxide, we want a concentration of 3% or greater,” she said, adding that the percentage often is not known because if it is contained in a sunscreen, it is listed as an inactive ingredient.
Another method to address visible light and UVA1 is the use of antioxidant-containing sunscreens with vitamin E, vitamin C, or licochalcone A, Dr. Taylor said.
During the question-and-answer period following her presentation, Amit Pandya, MD, adjunct professor of dermatology at University of Texas Southwestern Medical Center, Dallas, asked why “every makeup, every sunscreen, just says iron oxide,” since it is known that visible light will cause pigmentation, especially in those with darker skin tones.
He urged pushing for a law that would require listing the percentage of iron oxide on products to assure it is sufficient, according to what the literature recommends.
Conference Chair Pearl Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, said that she recommends tinted sunscreens almost exclusively for her patients, but those with darker skin colors struggle to match color.
Dr. Taylor referred to an analysis published in 2022 of 58 over-the counter sunscreens, which found that only 38% of tinted sunscreens was available in more than one shade, “which is a problem for many of our patients.” She said that providing samples with different hues and tactile sensations may help patients find the right product.
Dr. Taylor disclosed being on the advisory boards for AbbVie, Avita Medical, Beiersdorf, Biorez, Eli Lily, EPI Health, Evolus, Galderma, Hugel America, Johnson and Johnson, L’Oreal USA, MedScape, Pfizer, Scientis US, UCB, Vichy Laboratories. She is a consultant for Arcutis Biothermapeutics, Beiersdorf, Bristol-Myers Squibb, Cara Therapeutics, Dior, and Sanofi. She has done contracted research for Allergan Aesthetics, Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer, and has an ownership interest in Armis Scientific, GloGetter, and Piction Health.
Medscape and this news organization are owned by the same parent company.
CHICAGO – at the inaugural Pigmentary Disorders Exchange Symposium.
Among the first factors physicians should consider before recommending sunscreen are a patient’s Fitzpatrick skin type, risks for burning or tanning, underlying skin disorders, and medications the patient is taking, Dr. Taylor, professor of dermatology at the University of Pennsylvania, Philadelphia, said at the meeting, provided by MedscapeLIVE! If patients are on hypertensives, for example, medications can make them more photosensitive.
Consider skin type
Dr. Taylor said she was dismayed by the results of a recent study, which found that 43% of dermatologists who responded to a survey reported that they never, rarely, or only sometimes took a patient’s skin type into account when making sunscreen recommendations. The article is referenced in a 2022 expert panel consensus paper she coauthored on photoprotection “for skin of all color.” But she pointed out that considering skin type alone is inadequate.
Questions for patients in joint decision-making should include lifestyle and work choices such as whether they work inside or outside, and how much sun exposure they get in a typical day. Heat and humidity levels should also be considered as should a patient’s susceptibility to dyspigmentation. “That could be overall darkening of the skin, mottled hyperpigmentation, actinic dyspigmentation, and, of course, propensity for skin cancer,” she said.
Use differs by race
Dr. Taylor, who is also vice chair for diversity, equity and inclusion in the department of dermatology at the University of Pennsylvania, pointed out that sunscreen use differs considerably by race.
In study of 8,952 adults in the United States who reported that they were sun sensitive found that a subset of adults with skin of color were significantly less likely to use sunscreen when compared with non-Hispanic White adults: Non-Hispanic Black (adjusted odds ratio, 0.43); non-Hispanic Asian (aOR. 0.54); and Hispanic (aOR, 0.70) adults.
In the study, non-Hispanic Black and Hispanic adults were significantly less likely to use sunscreens with an SPF greater than 15. In addition, non-Hispanic Black, non-Hispanic Asian, and Hispanic adults were significantly more likely than non-Hispanic Whites to wear long sleeves when outside. Such differences are important to keep in mind when advising patients about sunscreens, she said.
Protection for lighter-colored skin
Dr. Taylor said that, for patients with lighter skin tones, “we really want to protect against ultraviolet B as well as ultraviolet A, particularly ultraviolet A2. Ultraviolet radiation is going to cause DNA damage.” Patients with Fitzpatrick skin types I, II, or III are most susceptible to the effects of UVB with sunburn inflammation, which will cause erythema and tanning, and immunosuppression.
“For those who are I, II, and III, we do want to recommend a broad-spectrum, photostable sunscreen with a critical wavelength of 370 nanometers, which is going to protect from both UVB and UVA2,” she said.
Sunscreen recommendations are meant to be paired with advice to avoid midday sun from 10 a.m. to 2 p.m., wearing protective clothing and accessories, and seeking shade, she noted.
Dr. Taylor said, for those patients with lighter skin who are more susceptible to photodamage and premature aging, physicians should recommend sunscreens that contain DNA repair enzymes such as photolyases and sunscreens that contain antioxidants that can prevent or reverse DNA damage. “The exogenous form of these lyases have been manufactured and added to sunscreens,” Dr. Taylor said. “They’re readily available in the United States. That is something to consider for patients with significant photodamage.”
Retinoids can also help alleviate or reverse photodamage, she added.
Protection for darker-colored skin
“Many people of color do not believe they need sunscreen,” Dr. Taylor said. But studies show that, although there may be more intrinsic protection, sunscreen is still needed.
Over 30 years ago, Halder and colleagues reported that melanin in skin of color can filter two to five times more UV radiation, and in a paper on the photoprotective role of melanin, Kaidbey and colleagues found that skin types V and VI had an intrinsic SPF of 13 when compared with those who have lighter complexions, which had an SPF of 3.
Sunburns seem to occur less frequently in people with skin of color, but that may be because erythema is less apparent in people with darker skin tones or because of differences in personal definitions of sunburn, Dr. Taylor said.
“Skin of color can and does sustain sunburns and sunscreen will help prevent that,” she said, adding that a recommendation of an SPF 30 is likely sufficient for these patients. Dr. Taylor noted that sunscreens for patients with darker skin often cost substantially more than those for lighter skin, and that should be considered in recommendations.
Tinted sunscreens
Dr. Taylor said that, while broad-spectrum photostable sunscreens protect against UVB and UVA 2, they don’t protect from visible light and UVA1. Two methods to add that protection are using inorganic tinted sunscreens that contain iron oxide or pigmentary titanium dioxide. Dr. Taylor was a coauthor of a practical guide to tinted sunscreens published in 2022.
“For iron oxide, we want a concentration of 3% or greater,” she said, adding that the percentage often is not known because if it is contained in a sunscreen, it is listed as an inactive ingredient.
Another method to address visible light and UVA1 is the use of antioxidant-containing sunscreens with vitamin E, vitamin C, or licochalcone A, Dr. Taylor said.
During the question-and-answer period following her presentation, Amit Pandya, MD, adjunct professor of dermatology at University of Texas Southwestern Medical Center, Dallas, asked why “every makeup, every sunscreen, just says iron oxide,” since it is known that visible light will cause pigmentation, especially in those with darker skin tones.
He urged pushing for a law that would require listing the percentage of iron oxide on products to assure it is sufficient, according to what the literature recommends.
Conference Chair Pearl Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, said that she recommends tinted sunscreens almost exclusively for her patients, but those with darker skin colors struggle to match color.
Dr. Taylor referred to an analysis published in 2022 of 58 over-the counter sunscreens, which found that only 38% of tinted sunscreens was available in more than one shade, “which is a problem for many of our patients.” She said that providing samples with different hues and tactile sensations may help patients find the right product.
Dr. Taylor disclosed being on the advisory boards for AbbVie, Avita Medical, Beiersdorf, Biorez, Eli Lily, EPI Health, Evolus, Galderma, Hugel America, Johnson and Johnson, L’Oreal USA, MedScape, Pfizer, Scientis US, UCB, Vichy Laboratories. She is a consultant for Arcutis Biothermapeutics, Beiersdorf, Bristol-Myers Squibb, Cara Therapeutics, Dior, and Sanofi. She has done contracted research for Allergan Aesthetics, Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer, and has an ownership interest in Armis Scientific, GloGetter, and Piction Health.
Medscape and this news organization are owned by the same parent company.
CHICAGO – at the inaugural Pigmentary Disorders Exchange Symposium.
Among the first factors physicians should consider before recommending sunscreen are a patient’s Fitzpatrick skin type, risks for burning or tanning, underlying skin disorders, and medications the patient is taking, Dr. Taylor, professor of dermatology at the University of Pennsylvania, Philadelphia, said at the meeting, provided by MedscapeLIVE! If patients are on hypertensives, for example, medications can make them more photosensitive.
Consider skin type
Dr. Taylor said she was dismayed by the results of a recent study, which found that 43% of dermatologists who responded to a survey reported that they never, rarely, or only sometimes took a patient’s skin type into account when making sunscreen recommendations. The article is referenced in a 2022 expert panel consensus paper she coauthored on photoprotection “for skin of all color.” But she pointed out that considering skin type alone is inadequate.
Questions for patients in joint decision-making should include lifestyle and work choices such as whether they work inside or outside, and how much sun exposure they get in a typical day. Heat and humidity levels should also be considered as should a patient’s susceptibility to dyspigmentation. “That could be overall darkening of the skin, mottled hyperpigmentation, actinic dyspigmentation, and, of course, propensity for skin cancer,” she said.
Use differs by race
Dr. Taylor, who is also vice chair for diversity, equity and inclusion in the department of dermatology at the University of Pennsylvania, pointed out that sunscreen use differs considerably by race.
In study of 8,952 adults in the United States who reported that they were sun sensitive found that a subset of adults with skin of color were significantly less likely to use sunscreen when compared with non-Hispanic White adults: Non-Hispanic Black (adjusted odds ratio, 0.43); non-Hispanic Asian (aOR. 0.54); and Hispanic (aOR, 0.70) adults.
In the study, non-Hispanic Black and Hispanic adults were significantly less likely to use sunscreens with an SPF greater than 15. In addition, non-Hispanic Black, non-Hispanic Asian, and Hispanic adults were significantly more likely than non-Hispanic Whites to wear long sleeves when outside. Such differences are important to keep in mind when advising patients about sunscreens, she said.
Protection for lighter-colored skin
Dr. Taylor said that, for patients with lighter skin tones, “we really want to protect against ultraviolet B as well as ultraviolet A, particularly ultraviolet A2. Ultraviolet radiation is going to cause DNA damage.” Patients with Fitzpatrick skin types I, II, or III are most susceptible to the effects of UVB with sunburn inflammation, which will cause erythema and tanning, and immunosuppression.
“For those who are I, II, and III, we do want to recommend a broad-spectrum, photostable sunscreen with a critical wavelength of 370 nanometers, which is going to protect from both UVB and UVA2,” she said.
Sunscreen recommendations are meant to be paired with advice to avoid midday sun from 10 a.m. to 2 p.m., wearing protective clothing and accessories, and seeking shade, she noted.
Dr. Taylor said, for those patients with lighter skin who are more susceptible to photodamage and premature aging, physicians should recommend sunscreens that contain DNA repair enzymes such as photolyases and sunscreens that contain antioxidants that can prevent or reverse DNA damage. “The exogenous form of these lyases have been manufactured and added to sunscreens,” Dr. Taylor said. “They’re readily available in the United States. That is something to consider for patients with significant photodamage.”
Retinoids can also help alleviate or reverse photodamage, she added.
Protection for darker-colored skin
“Many people of color do not believe they need sunscreen,” Dr. Taylor said. But studies show that, although there may be more intrinsic protection, sunscreen is still needed.
Over 30 years ago, Halder and colleagues reported that melanin in skin of color can filter two to five times more UV radiation, and in a paper on the photoprotective role of melanin, Kaidbey and colleagues found that skin types V and VI had an intrinsic SPF of 13 when compared with those who have lighter complexions, which had an SPF of 3.
Sunburns seem to occur less frequently in people with skin of color, but that may be because erythema is less apparent in people with darker skin tones or because of differences in personal definitions of sunburn, Dr. Taylor said.
“Skin of color can and does sustain sunburns and sunscreen will help prevent that,” she said, adding that a recommendation of an SPF 30 is likely sufficient for these patients. Dr. Taylor noted that sunscreens for patients with darker skin often cost substantially more than those for lighter skin, and that should be considered in recommendations.
Tinted sunscreens
Dr. Taylor said that, while broad-spectrum photostable sunscreens protect against UVB and UVA 2, they don’t protect from visible light and UVA1. Two methods to add that protection are using inorganic tinted sunscreens that contain iron oxide or pigmentary titanium dioxide. Dr. Taylor was a coauthor of a practical guide to tinted sunscreens published in 2022.
“For iron oxide, we want a concentration of 3% or greater,” she said, adding that the percentage often is not known because if it is contained in a sunscreen, it is listed as an inactive ingredient.
Another method to address visible light and UVA1 is the use of antioxidant-containing sunscreens with vitamin E, vitamin C, or licochalcone A, Dr. Taylor said.
During the question-and-answer period following her presentation, Amit Pandya, MD, adjunct professor of dermatology at University of Texas Southwestern Medical Center, Dallas, asked why “every makeup, every sunscreen, just says iron oxide,” since it is known that visible light will cause pigmentation, especially in those with darker skin tones.
He urged pushing for a law that would require listing the percentage of iron oxide on products to assure it is sufficient, according to what the literature recommends.
Conference Chair Pearl Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, Los Angeles, said that she recommends tinted sunscreens almost exclusively for her patients, but those with darker skin colors struggle to match color.
Dr. Taylor referred to an analysis published in 2022 of 58 over-the counter sunscreens, which found that only 38% of tinted sunscreens was available in more than one shade, “which is a problem for many of our patients.” She said that providing samples with different hues and tactile sensations may help patients find the right product.
Dr. Taylor disclosed being on the advisory boards for AbbVie, Avita Medical, Beiersdorf, Biorez, Eli Lily, EPI Health, Evolus, Galderma, Hugel America, Johnson and Johnson, L’Oreal USA, MedScape, Pfizer, Scientis US, UCB, Vichy Laboratories. She is a consultant for Arcutis Biothermapeutics, Beiersdorf, Bristol-Myers Squibb, Cara Therapeutics, Dior, and Sanofi. She has done contracted research for Allergan Aesthetics, Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer, and has an ownership interest in Armis Scientific, GloGetter, and Piction Health.
Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPELIVE! PIGMENTARY DISORDERS SYMPOSIUM
Lomitapide shows promise in pediatric homozygous FH
MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early diagnosis ‘imperative’
The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.
“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”
Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.
He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.
However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”
Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”
Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
Life-limiting condition
HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.
For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.
He said that, despite these figures, the adverse events were “mostly mild or moderate.”
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”
The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
A version of this article first appeared on Medscape.com.
MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early diagnosis ‘imperative’
The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.
“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”
Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.
He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.
However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”
Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”
Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
Life-limiting condition
HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.
For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.
He said that, despite these figures, the adverse events were “mostly mild or moderate.”
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”
The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
A version of this article first appeared on Medscape.com.
MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early diagnosis ‘imperative’
The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.
“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”
Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.
He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.
However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”
Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”
Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
Life-limiting condition
HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.
For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.
He said that, despite these figures, the adverse events were “mostly mild or moderate.”
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”
The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
A version of this article first appeared on Medscape.com.
Encouraging telitacicept results reported in phase 3 for lupus, phase 2 for Sjögren’s
MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.
“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.
Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
SLE trial
The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m2, and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.
Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.
At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.
Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).
“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.
A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).
Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
Sjögren’s trial
The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.
“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”
ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.
“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
Studies yield promising but confusing results
In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.
“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.
“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”
Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.
MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.
“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.
Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
SLE trial
The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m2, and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.
Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.
At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.
Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).
“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.
A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).
Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
Sjögren’s trial
The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.
“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”
ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.
“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
Studies yield promising but confusing results
In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.
“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.
“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”
Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.
MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.
“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.
Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
SLE trial
The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m2, and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.
Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.
At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.
Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).
“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.
A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).
Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
Sjögren’s trial
The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.
“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”
ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.
“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
Studies yield promising but confusing results
In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.
“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.
“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”
Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.
AT EULAR 2023
Preventive antipyretics, antibiotics not needed in stroke
“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.
“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.
“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”
The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.
Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.
“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.
Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions.
The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.
The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.
They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.
Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.
“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.
The primary outcome was modified Rankin Scale (mRS) score at 90 days.
The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.
Results showed no effect on the primary outcome of any of the prophylactic treatments.
“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”
A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.
“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.
There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.
Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development.
He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.
He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.
A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.
Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.
She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.
Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.”
On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.”
Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”
She added that although the trial was stopped prematurely, it had produced decisive results.
“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.
A version of this article first appeared on Medscape.com.
“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.
“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.
“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”
The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.
Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.
“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.
Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions.
The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.
The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.
They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.
Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.
“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.
The primary outcome was modified Rankin Scale (mRS) score at 90 days.
The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.
Results showed no effect on the primary outcome of any of the prophylactic treatments.
“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”
A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.
“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.
There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.
Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development.
He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.
He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.
A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.
Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.
She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.
Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.”
On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.”
Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”
She added that although the trial was stopped prematurely, it had produced decisive results.
“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.
A version of this article first appeared on Medscape.com.
“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.
“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.
“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”
The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.
Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.
“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.
Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions.
The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.
The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.
They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.
Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.
“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.
The primary outcome was modified Rankin Scale (mRS) score at 90 days.
The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.
Results showed no effect on the primary outcome of any of the prophylactic treatments.
“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”
A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.
“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.
There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.
Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development.
He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.
He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.
A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.
Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.
She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.
Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.”
On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.”
Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”
She added that although the trial was stopped prematurely, it had produced decisive results.
“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.
A version of this article first appeared on Medscape.com.
FROM ESOC 2023
Intensive BP reduction after stroke recanalization harmful
MUNICH, GERMANY – suggests results from the OPTIMAL-BP trial.
The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.
For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.
Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.
The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.
Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.
Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.
He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.
“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”
On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.
Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”
Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.
He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.
“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”
He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.
Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”
Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”
Yet the management of BP after successful recanalization with IAT is “largely unknown.”
He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”
Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.
The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.
They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.
The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.
Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.
The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.
Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.
The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).
At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).
Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.
Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).
Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.
In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).
There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).
There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.
However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).
Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.
Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.
He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.
The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
MUNICH, GERMANY – suggests results from the OPTIMAL-BP trial.
The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.
For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.
Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.
The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.
Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.
Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.
He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.
“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”
On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.
Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”
Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.
He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.
“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”
He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.
Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”
Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”
Yet the management of BP after successful recanalization with IAT is “largely unknown.”
He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”
Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.
The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.
They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.
The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.
Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.
The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.
Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.
The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).
At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).
Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.
Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).
Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.
In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).
There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).
There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.
However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).
Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.
Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.
He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.
The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
MUNICH, GERMANY – suggests results from the OPTIMAL-BP trial.
The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.
For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.
Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.
The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.
Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.
Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.
He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.
“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”
On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.
Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”
Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.
He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.
“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”
He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.
Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”
Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”
Yet the management of BP after successful recanalization with IAT is “largely unknown.”
He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”
Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.
The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.
They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.
The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.
Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.
The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.
Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.
The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).
At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).
Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.
Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).
Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.
In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).
There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).
There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.
However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).
Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.
Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.
He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.
The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
AT ESOC 2023
Tenecteplase late after stroke misses endpoint: TIMELESS
However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.
The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.
“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.
“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.
“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.
The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.
Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.
He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.
The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.
The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.
The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.
The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).
The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).
Promising safety data
There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.
“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”
The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
Benefit in M1 occlusions?
Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).
The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).
But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.
“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.
“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
Timing of TNK
Dr. Albers said that there was also information from in the study on the timing of TNK administration.
In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.
“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.
“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.
He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.
“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.
Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”
Dr. Tsivgoulis concluded that these points need to be addressed in future trials.
The TIMELESS trial was funded by Genentech.
A version of this article first appeared on Medscape.com.
However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.
The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.
“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.
“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.
“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.
The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.
Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.
He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.
The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.
The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.
The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.
The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).
The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).
Promising safety data
There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.
“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”
The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
Benefit in M1 occlusions?
Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).
The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).
But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.
“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.
“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
Timing of TNK
Dr. Albers said that there was also information from in the study on the timing of TNK administration.
In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.
“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.
“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.
He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.
“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.
Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”
Dr. Tsivgoulis concluded that these points need to be addressed in future trials.
The TIMELESS trial was funded by Genentech.
A version of this article first appeared on Medscape.com.
However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.
The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.
“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.
“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.
“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.
The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.
Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.
He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.
The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.
The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.
The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.
The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).
The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).
Promising safety data
There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.
“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”
The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
Benefit in M1 occlusions?
Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).
The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).
But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.
“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.
“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
Timing of TNK
Dr. Albers said that there was also information from in the study on the timing of TNK administration.
In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.
“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.
“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.
He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.
“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.
Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”
Dr. Tsivgoulis concluded that these points need to be addressed in future trials.
The TIMELESS trial was funded by Genentech.
A version of this article first appeared on Medscape.com.
FROM ESOC 2023
Two biologics show no difference in axial spondyloarthritis radiographic progression over 2 years
MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.
The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.
Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.
The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.
Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.
Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.
No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.
“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”
When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
Not a definitive answer about structural progression
An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”
“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.
“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”
Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.
A version of this article first appeared on Medscape.com.
MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.
The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.
Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.
The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.
Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.
Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.
No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.
“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”
When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
Not a definitive answer about structural progression
An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”
“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.
“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”
Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.
A version of this article first appeared on Medscape.com.
MILAN – Secukinumab (Cosentyx) and biosimilar adalimumab-adaz (Hyrimoz) injection proved to have similar efficacy for limiting spinal radiographic progression over a 2-year period in patients with radiographic axial spondyloarthritis (r-axSpA) in the SURPASS study, a phase 3b, randomized controlled trial.
The study, presented at the annual European Congress of Rheumatology, represents the first head-to-head trial comparing the effects of two biologic disease-modifying antirheumatic drugs (bDMARDs) in axSpA. Notably, secukinumab and adalimumab-adaz target different pathways as an interleukin-17A inhibitor and a tumor necrosis factor (TNF) inhibitor, respectively.
Both TNF and IL-17A have been implicated in the pathogenesis of axSpA. Anti-TNF agents and the IL-17A inhibitor secukinumab have demonstrated effectiveness in improving symptoms, signs, and physical function in patients with axSpA and are approved therapies for the disease. However, limited data exist regarding the effect of bDMARDs in slowing radiographic progression, which is a key therapeutic goal in axSpA to prevent irreversible structural damage.
The SURPASS trial, funded by Novartis, enrolled 859 biologic-naive adult patients with moderate to severe r-axSpA. Participants were randomly assigned (1:1:1) to receive secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or adalimumab-adaz 40 mg (n = 286). The primary endpoint was the proportion of patients with no radiographic progression at the 2-year mark (week 104). Radiographic progression was defined as a change from baseline in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; range, 0-72) of 0.5 or less. The radiographic assessments were conducted by three independent evaluators who were blinded to treatment and the chronology of images.
Baseline characteristics indicated that the study population (78.5% male; mean age, 42.1 years) had a high risk of radiographic progression. The proportion of patients with no radiographic progression at week 104 was 66.1% in the secukinumab 150-mg arm, 66.9% in the secukinumab 300-mg arm, and 65.6% in the adalimumab-adaz arm. The mean change from baseline in mSASSS was 0.54, 0.55, and 0.72, respectively.
Notably, more than half of the patients (56.9%, 53.8%, and 53.3%, respectively) with at least one syndesmophyte at baseline did not develop new syndesmophytes over the 2-year period. The observed reductions in sacroiliac joint and spinal edema were comparable across all treatment groups. The safety profile of secukinumab and adalimumab-adaz was consistent with their well-established profiles.
No significant differences were observed between the treatment groups in terms of the primary and secondary endpoints. Study presenter and lead author Xenofon Baraliakos, MD, PhD, medical director of the Rheumatism Centre and professor of internal medicine and rheumatology at Ruhr University Bochum (Germany), stated: “Anti-TNF therapy has been considered the gold-standard treatment for axial spondyloarthritis in terms of slowing or halting radiographic progression. Our aim was to investigate whether other modes of action, such as IL-17 inhibition, achieve the same results. The primary hypothesis was that IL-17 inhibition could be even more effective than TNF blockade. However, our data indicate that secukinumab is at least as good as TNF blockers.
“Several risk factors, including high C-reactive protein [CRP] levels, male gender, high disease activity, and baseline radiographic damage (e.g., presence of syndesmophytes), are associated with structural progression,” Dr. Baraliakos explained. “We performed subgroup analyses and found no differences. This is a positive outcome as it suggests that there is no need to select patients based on either secukinumab or anti-TNF agents.”
When making treatment decisions, other factors must be taken into consideration. “Our study specifically examined radiographic progression. The clinical outcomes, indications, and contraindications for anti-TNF agents and secukinumab differ,” Dr. Baraliakos explained. “For instance, secukinumab may be preferred for patients with psoriasis, while adalimumab is more suitable for those with inflammatory bowel disease. Although these bDMARDs are not interchangeable, they have the same positive effect on radiographic progression.”
Not a definitive answer about structural progression
An open question remains. Alexandre Sepriano, MD, PhD, a rheumatologist at Hospital Egas Moniz and researcher at NOVA Medical School, both in Lisbon, commented: “The study was designed to maximize the chances of detecting a difference, if any, in spinal radiographic progression between secukinumab 150 mg and 300 mg and adalimumab. The included patients had a high risk of progression at baseline; in addition to back pain, they either had elevated CRP or at least one syndesmophyte on spine radiographs. Consequently, baseline structural damage was high [mean mSASSS, 17].”
“After 2 years, no difference was observed in the percentage of patients with no progression across the study arms. This finding does not definitively answer whether bDMARDs can modify structural progression or if secukinumab and adalimumab are equally effective in this regard,” explained Dr. Sepriano, who was not involved in the study. “However, there is good news for patients. Both secukinumab and adalimumab are potent anti-inflammatory drugs that effectively alleviate axial inflammation caused by the disease. This was demonstrated by the reduction in inflammatory scores on MRI in the SURPASS study. It aligns with robust evidence that both IL-17 inhibitors and TNF inhibitors are effective in improving symptoms in individuals with axSpA.
“Researchers continue to make significant efforts to understand how axial inflammation contributes to pathological new bone formation in axSpA,” Dr. Sepriano continued. “Understanding these mechanisms can guide future research aimed at interfering with disease progression. Furthermore, the use of new methods to quantify structural progression in axSpA, such as low-dose CT, which has shown greater sensitivity to change than traditional methods, can pave the way for new studies with fewer patients and shorter follow-up periods, thereby increasing the likelihood of detecting treatment effects.”
Dr. Baraliakos has received speaking and consulting fees and grant/research support from AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, and UCB. Dr. Sepriano has received speaking and/or consulting fees from AbbVie, Novartis, UCB, and Lilly. The trial was sponsored by Novartis.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
Lupus nephritis: Hopes, questions arise for baricitinib
MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.
Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.
“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”
The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m2 (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).
The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.
The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.
Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.
However, there were some concerns expressed by audience members during the presentation.
“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.
Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.
Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.
A version of this article first appeared on Medscape.com.
MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.
Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.
“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”
The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m2 (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).
The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.
The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.
Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.
However, there were some concerns expressed by audience members during the presentation.
“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.
Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.
Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.
A version of this article first appeared on Medscape.com.
MILAN – The oral Janus kinase (JAK) 1/2 inhibitor baricitinib (Olumiant) demonstrated significantly better efficacy than cyclophosphamide infusions in the treatment of lupus nephritis in a small, independently funded, phase 3, double-blind clinical trial, Manal Hassanien, MD, reported at the annual European Congress of Rheumatology.
Baricitinib, licensed by Eli Lilly, has been recognized as a potential therapeutic option in systemic lupus, and is approved in the United States to treat RA, alopecia areata, and COVID-19 in certain hospitalized adults. It is also approved to treat atopic dermatitis in Europe. However, it previously yielded disappointing results in phase 3 clinical trials SLE-BRAVE-I and SLE-BRAVE-II for systemic lupus erythematosus. The trial results presented at EULAR suggest that baricitinib could be beneficial in the treatment of lupus nephritis, further establishing the role of JAK inhibitors in autoimmune disease therapy.
“Lupus nephritis typically develops within 5 years of initial lupus symptoms,” said Dr. Hassanien, of the rheumatology research and advanced therapeutics department at Assiut (Egypt) University. “Research has shown that up to 60% of lupus patients will eventually develop lupus nephritis. The management of proliferative lupus nephritis usually involves an initial phase focused on preventing the development of irreversible damage, followed by a maintenance phase to control lupus activity. Despite significant progress, lupus nephritis still carries an increased risk of end-stage renal disease and mortality.”
The study’s primary endpoint of 24-hour proteinuria response rate (≥ 50% reduction from baseline) at week 12 was significantly greater with baricitinib 4 mg daily, compared with monthly cyclophosphamide infusions at 0.7 mg/m2 (70% vs. 43%; P < .0001). At week 24, 76.6% of the baricitinib group met the primary endpoint, compared with 50% in the cyclophosphamide group. Two multiplicity-controlled secondary endpoints, C3 serum level and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), also showed statistical significance at 12 weeks (P < .01).
The 6-month trial included 60 adult patients (age 18 years and older) with a clinical diagnosis of lupus nephritis fulfilling classification criteria for LN grade III and IV. Patients needed to demonstrate objective signs of active nephritis consistent with persistent proteinuria greater than 0.5 g/day and/or cellular casts at screening to be included. Additional inclusion criteria were SLEDAI-2K greater than 4 and assessment of anti–double-stranded DNA and C3 serum levels at study entry. The patients were randomly assigned to two equal-sized groups, with one group receiving baricitinib 4 mg daily and a monthly placebo saline infusion, and the other group receiving monthly cyclophosphamide infusions and oral placebo tablets.
The incidence of adverse events was comparable between the two treatment groups, with 48% of patients in the baricitinib group and 46% in the cyclophosphamide group experiencing adverse events. Only three serious adverse events, specifically serious infection or herpes zoster, were recorded, leading to treatment discontinuation.
Two patients (6.6%) in the baricitinib group and one patient (3.3%) in the cyclophosphamide group were affected. The researchers recorded no major adverse cardiovascular or venous thromboembolic events, which are known to occur at higher rates among some users of baricitinib and other JAK inhibitors. The safety profile of baricitinib was consistent with observations made in other inflammatory musculoskeletal diseases, and no new risks were identified.
However, there were some concerns expressed by audience members during the presentation.
“The primary endpoint is limited at proteinuria, while biopsy is considered the gold standard for measuring efficacy,” said Eric F. Morand, MD, head of the Monash Health rheumatology unit, Melbourne. This was not the only critical comment regarding the study that emerged during the discussion. The use of a 4-mg dosage regimen throughout the entire study duration (despite official recommendations suggesting a 2-mg dosage in the long run) and the positive outcomes observed in the control group treated with cyclophosphamide were also mentioned.
Dr. Hassanien acknowledged that this is a small and relatively short study and disclosed plans to extend the follow-up period to 1 year and conduct a renal biopsy.
Dr. Hassanien reported no relevant financial relationships. Assiut University funded the trial.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
Buprenorphine update: Looser rules and a helpful injectable
SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.
John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.
As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.
COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.
On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”
Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.
New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.
“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”
In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.
“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”
Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”
Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”
Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.
SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.
John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.
As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.
COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.
On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”
Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.
New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.
“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”
In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.
“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”
Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”
Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”
Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.
SAN FRANCISCO – As the opioid epidemic continues to grow and evolve, the federal government is trying to make it easier for clinicians to treat abusers with the drug buprenorphine, psychiatrists told colleagues at the annual meeting of the American Psychiatric Association. And an injectable version of the drug is making a big difference.
John A. Renner Jr., MD, of Boston University, said in a presentation at the APA meeting.
As Dr. Renner explained, the United States is now in the fourth wave of nearly a quarter-century of opioid overdose-related deaths. The outbreak began in 1999 as prescription opioids spurred deaths, and heroin overdoses began to rise in 2010. The third wave brought rises in deaths from synthetic opioids such as fentanyl in 2013. In 2015, the fourth wave – driven by deaths from combinations of synthetic opioids and psychostimulants like methamphetamines – started in 2015.
COVID-19 seems to have played a role too: In 2020, opioid overdose deaths spiked during the early months of the pandemic. In 2021, drug-related overdose deaths overall hit a high of 106,889, including 80,411 linked to opioids. In contrast, fewer than 20,000 drug-related overdose deaths were reported in 1999.
On the other hand, deaths from prescription drug overdoses are falling, Dr. Renner said, suggesting “improvement in terms of how clinicians are handling medications and our prescribing practices. But that’s being masked by what’s happened with fentanyl and methamphetamine.”
Buprenorphine (Subutex), used to treat opioid use withdrawal, is itself an opioid and can cause addiction and death in some cases. However, Dr. Renner highlighted a 2023 study that determined that efforts to increase its use from 2019 to 2021 didn’t appear to boost buprenorphine-related overdose deaths in the United States.
New federal regulations aim to make it easier to prescribe buprenorphine. Thanks to Congressional legislation, the Drug Enforcement Administration in January 2023 eliminated regulations requiring clinicians to undergo special training to get an “X-waiver” to be able to prescribe buprenorphine. But they’re not off the hook entirely: As of June 27, 2023, providers must have undergone training in order to apply for – or renew – a DEA license to prescribe certain controlled substances like buprenorphine.
“I’m afraid that people will be able to meet that requirement easily, and they’re not going to get good coordinated teaching,” Dr. Renner said. “I’m not sure that’s really going to improve the quality of care that we’re delivering.”
In regard to treatment, psychiatrist Dong Chan Park, MD, of Boston University, touted a long-acting injectable form of buprenorphine known by the brand name Sublocade. The FDA approved Sublocade in 2017 for patients who’ve been taking sublingual buprenorphine for at least 7 days, although Dr. Park said research suggests the 7-day period may not be necessary.
“We’ve utilized this about 2.5-plus years in my hospital, and it’s really been a game changer for some of our sickest, most challenging patients,” he said at the APA presentation. As he explained, one benefit is that patients can’t repeatedly avoid doses depending on how they feel, as they may do with the sublingual version. “On the first day of injection, you can actually stop the sublingual buprenorphine.”
Dr. Renner emphasized the importance of getting users on buprenorphine as fast as possible. If the treatment begins in the ED, he said, “they need to have a system that is going to be able to pick them up and continue the care.”
Otherwise, the risk is high. “We’re in a very dangerous era,” he said, “where the patient walks out the door, and then they die.”
Dr. Park had no disclosures, and Dr. Renner disclosed royalties from the APA.
AT APA 2023
ILD risk elevated in RA, PsA after starting biologic or targeted synthetic DMARDs
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
MILAN – Patients with psoriatic arthritis (PsA) who are using biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have fivefold higher risk for interstitial lung disease (ILD) than does the general population, according to the first study to explore risk of ILD in this particular patient group.
The study also found 10-fold higher risk of ILD in patients with RA who were starting a b/tsDMARD, compared with the general population, while the addition of methotrexate did not appear to be associated with increased risk for ILD in either RA nor PsA.
Sella Aarrestad Provan, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital, Oslo, presented the results at the annual European Congress of Rheumatology.
Explaining the motivation for the study, Dr. Aarrestad Provan said that, in RA, methotrexate’s role in ILD development remained unclear, while some small studies linked b/tsDMARDs with risk for ILD. “In PsA, very few studies have explored the risk of ILD, and no systematic studies have looked at ILD risk factors in this disease.”
The researchers analyzed patient data from hospital and death registries across five Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) and compared them with general population controls. They calculated risk ratios for people who developed ILD within 5 years of starting a b/tsDMARD (with or without methotrexate).
A total of 37,010 patients with RA, 12,341 with PsA, and 569,451 members of the general population were included in the analysis, with respective disease durations of 10 and 8.9 years. Methotrexate was used along with b/tsDMARDs in 49% of patients with RA and 41% with PsA, and most patients were already on methotrexate when b/tsDMARDs were started. The tumor necrosis factor inhibitor etanercept (Enbrel) was the most commonly used b/tsDMARD in both RA and PsA, followed by infliximab (Remicade and biosimilars) and adalimumab (Humira and biosimilars).
The incidence of ILD within 5 years of starting a b/tsDMARD was 0.8% in patients with RA, 0.2% with PsA, and 0.1% in the general population, and these findings generated hazard ratios of 10.1 (95% confidence interval, 8.6-11.9) for RA and 5.0 (95% CI, 3.4-7.4) for PsA, compared with the general population as reference.
When the risk for ILD was explored according to methotrexate use in RA patients, “there was no signal of increased risk across patients using methotrexate,” Dr. Aarrestad Provan reported. When risk of ILD was explored according to b/tsDMARD use in RA patients, a signal of increased risk was observed with rituximab, she noted, “but upon adjusting for age, sex, and comorbidities, this association was no longer significant, but was still numerically increased.”
Iain McInnes, MD, PhD, vice principal, professor of rheumatology, and head of the College of Medical, Veterinary and Life Sciences at the University of Glasgow, remarked that he “loves results that are unexpected” and thanked the researcher for such an “important study.”
“For years, we’ve been interested in the potential for DMARDs to impact interstitial lung disease, with potential that drugs could make it worse, or better,” he said. “This study is wonderful and novel because first of all, there hasn’t, until now, been a direct comparison between RA and PsA in quite this way, and secondly, we haven’t really assessed whether there is a drug-related risk in PsA. Note that drug related does not necessarily imply causality.”
Regarding mechanisms, Dr. McInnes added that “epidemiologic studies suggest that PsA often coexists with the presence of cardiometabolic syndrome and obesity, which has a higher prevalence in PsA than in RA. Obesity is also related to ILD. As such, it begs the question of whether cardiometabolic, diabetes, or obesity-related features may give us a clue as to what is going on in these PsA patients.”
The research was supported by NordForsk and FOREUM. Dr. Aarrestad Provan reported serving as a consultant to Boehringer Ingelheim and Novartis and receiving grant/research support from Boehringer Ingelheim. Dr. McInnes declared no disclosures relevant to this study.
AT EULAR 2023