Ask Joanna Melia, MD, what her biggest practice challenge is, and she’d say the need for more precision medicine in inflammatory bowel disease.

Gastroenterologists have more treatments at their disposal today than ever before, particularly in the last decade. “We have had tremendous advances in many areas of understanding contributors to disease,” said Dr. Melia, an assistant professor of medicine at Johns Hopkins Medicine in Baltimore who specializes in inflammatory bowel disease (IBD). But the hurdle is in translating the science to clinical care that is individualized to each patient based on condition and stage of the condition.

“That still remains a bit of a dream,” she said. Much of her career has been devoted to chasing down a particular genetic variant that contributes to IBD, with the goal of reaching more precise treatments for patients.

In an interview, she shared how she entered this line of work, and what her research has revealed about Crohn’s disease, manganese, and a common genetic variant known as ZIP8.

Q: Your expertise is in inflammatory bowel disease and manganese deficiency. Why did you choose these two areas as your focus in GI?

Dr. Melia: In talking to many patients with IBD, I was always struck by the questions around nutritional factors related to disease. As a fellow, I was embedded in a lab that focused on genetics of IBD. A micronutrient transporter, ZIP8, has a mutation in it that increases the risk of Crohn’s disease.

I’ve dedicated the last 8 years to understanding how this mutation can increase risk. It initially started out as a project focused on zinc, because that’s what the transporter was thought to regulate. However, it’s evolved as we’ve learned more about it, underscoring the importance of manganese, another micronutrient that we derive from food.

We have established that having this mutation changes how the body handles manganese and affects downstream processes that involve manganese. What I’m doing now is trying to connect those dots on why those processes are important in Crohn’s disease and whether we can target them for treatment.

Q: How does manganese deficiency lead to chronic IBD?

Dr. Melia: In individuals with this mutation, their blood manganese levels are lower than people who don’t have this mutation. When we talk about manganese deficiency or insufficiency, what we’re really talking about is lower blood levels. But it’s more complicated than that at the tissue level.

What we and other groups are working on right now is trying to understand if the manganese levels change in the gut and what happens in inflammation. The gut is a particularly interesting area for manganese, in that much of the manganese that we eat is excreted. We only absorb a small amount of it. And so, manganese levels within the gut lumen may actually be quite high – and may be even higher in inflammation. But there are things we don’t understand about that and how it relates to mucosal levels of manganese and Crohn’s disease. The ileum, the site of the Crohn’s disease that’s specifically associated with this mutation, might be particularly sensitive to changes in the manganese levels or the downstream processes that changing manganese availability affects.

One of those processes is glycosylation. Manganese is important to properly glycosylate your proteins. Many enzymes help cells put sugars on proteins, and many of those enzymes need manganese to do it. Glycosylation of proteins is important so cells know where those proteins should go, and the sugars help them stay where they need to be. When you change protein glycosylation, you can stress the cells. We know individuals who carry this mutation have changes in the glycosylation of their proteins. What we’re working on right now is understanding which key proteins might change when that happens, and why that’s a potential problem, especially in the ileum.

Q: How might your research inform clinical practice?

Dr. Melia: We’ve seen significant progress in new medications and new pathways that have emerged. We still have this fundamental problem that our immune-targeting medicines are only helping about 50% of the patients.

It’s critical that we begin to identify new pathways. And my hope is that in studying genes like the ZIP8 (SLC39A8), which is associated with the dysregulated processing of manganese, we can understand different pathways and mechanisms to target.

As an example, if we could help correct the glycosylation problem, that would help to boost the barrier function of the gut and perhaps decrease the activation of those immune cells, because you’re just reinforcing the barrier integrity of the gut.

We want to target that glycosylation problem as we would treat patients with congenital disorders of glycosylation by giving supplemental sugars. We think this problem of glycosylation extends beyond patients with the ZIP8 mutation, but it is also really important for patients with the mutation. So, the goal would be to use ZIP8 genetics to help prioritize patients for therapy targeting this problem.

Q: You’re involved in the American Gastroenterological Association Future Leaders Program. What is your role in this program? Why is it important?

Dr. Melia: I was very grateful for the opportunity to participate in the AGA’s Future Leaders Program. I think it was exceedingly valuable for two main reasons. One, it really offered an insight into the role of the AGA and the important role that the AGA plays in the careers of gastroenterologists. Two, it was such a unique opportunity to work with colleagues nationwide and to build a network of individuals who are all at a similar stage in their careers. It was a very inspiring group to meet and to have the opportunity to work with as part of that program, and I thank the AGA for supporting such an initiative.

Q: What teacher or mentor had the greatest impact on you?

Dr. Melia: I have been blessed by many clinical and research mentors through my career. I was inspired to do science at the lab of Ramnik Xavier, MD, at Massachusetts General Hospital. At Johns Hopkins, I credit Cindy Sears, MD, and Anne Marie O’Broin Lennon, MBBCh, PhD, as two physician scientists who have really shaped how I have tried to integrate my clinical and research career.

LIGHTNING ROUND

Do you prefer texting or talking?
Texting

If you weren’t a gastroenterologist, what would you be?
Teacher

What was the last movie you watched?
Great Bear Rainforest

What is your most favorite city in the U.S.?
Surry, Maine

What song do you absolutely have to sing along with when you hear it?
Any song by Whitney Houston.

Are you an introvert or extrovert?
Introvert

How many cups of coffee do you drink per day?
One

Ask Joanna Melia, MD, what her biggest practice challenge is, and she’d say the need for more precision medicine in inflammatory bowel disease.

Gastroenterologists have more treatments at their disposal today than ever before, particularly in the last decade. “We have had tremendous advances in many areas of understanding contributors to disease,” said Dr. Melia, an assistant professor of medicine at Johns Hopkins Medicine in Baltimore who specializes in inflammatory bowel disease (IBD). But the hurdle is in translating the science to clinical care that is individualized to each patient based on condition and stage of the condition.

“That still remains a bit of a dream,” she said. Much of her career has been devoted to chasing down a particular genetic variant that contributes to IBD, with the goal of reaching more precise treatments for patients.

In an interview, she shared how she entered this line of work, and what her research has revealed about Crohn’s disease, manganese, and a common genetic variant known as ZIP8.

Q: Your expertise is in inflammatory bowel disease and manganese deficiency. Why did you choose these two areas as your focus in GI?

Dr. Melia: In talking to many patients with IBD, I was always struck by the questions around nutritional factors related to disease. As a fellow, I was embedded in a lab that focused on genetics of IBD. A micronutrient transporter, ZIP8, has a mutation in it that increases the risk of Crohn’s disease.

I’ve dedicated the last 8 years to understanding how this mutation can increase risk. It initially started out as a project focused on zinc, because that’s what the transporter was thought to regulate. However, it’s evolved as we’ve learned more about it, underscoring the importance of manganese, another micronutrient that we derive from food.

We have established that having this mutation changes how the body handles manganese and affects downstream processes that involve manganese. What I’m doing now is trying to connect those dots on why those processes are important in Crohn’s disease and whether we can target them for treatment.

Q: How does manganese deficiency lead to chronic IBD?

Dr. Melia: In individuals with this mutation, their blood manganese levels are lower than people who don’t have this mutation. When we talk about manganese deficiency or insufficiency, what we’re really talking about is lower blood levels. But it’s more complicated than that at the tissue level.

What we and other groups are working on right now is trying to understand if the manganese levels change in the gut and what happens in inflammation. The gut is a particularly interesting area for manganese, in that much of the manganese that we eat is excreted. We only absorb a small amount of it. And so, manganese levels within the gut lumen may actually be quite high – and may be even higher in inflammation. But there are things we don’t understand about that and how it relates to mucosal levels of manganese and Crohn’s disease. The ileum, the site of the Crohn’s disease that’s specifically associated with this mutation, might be particularly sensitive to changes in the manganese levels or the downstream processes that changing manganese availability affects.

One of those processes is glycosylation. Manganese is important to properly glycosylate your proteins. Many enzymes help cells put sugars on proteins, and many of those enzymes need manganese to do it. Glycosylation of proteins is important so cells know where those proteins should go, and the sugars help them stay where they need to be. When you change protein glycosylation, you can stress the cells. We know individuals who carry this mutation have changes in the glycosylation of their proteins. What we’re working on right now is understanding which key proteins might change when that happens, and why that’s a potential problem, especially in the ileum.

Q: How might your research inform clinical practice?

Dr. Melia: We’ve seen significant progress in new medications and new pathways that have emerged. We still have this fundamental problem that our immune-targeting medicines are only helping about 50% of the patients.

It’s critical that we begin to identify new pathways. And my hope is that in studying genes like the ZIP8 (SLC39A8), which is associated with the dysregulated processing of manganese, we can understand different pathways and mechanisms to target.

As an example, if we could help correct the glycosylation problem, that would help to boost the barrier function of the gut and perhaps decrease the activation of those immune cells, because you’re just reinforcing the barrier integrity of the gut.

We want to target that glycosylation problem as we would treat patients with congenital disorders of glycosylation by giving supplemental sugars. We think this problem of glycosylation extends beyond patients with the ZIP8 mutation, but it is also really important for patients with the mutation. So, the goal would be to use ZIP8 genetics to help prioritize patients for therapy targeting this problem.

Q: You’re involved in the American Gastroenterological Association Future Leaders Program. What is your role in this program? Why is it important?

Dr. Melia: I was very grateful for the opportunity to participate in the AGA’s Future Leaders Program. I think it was exceedingly valuable for two main reasons. One, it really offered an insight into the role of the AGA and the important role that the AGA plays in the careers of gastroenterologists. Two, it was such a unique opportunity to work with colleagues nationwide and to build a network of individuals who are all at a similar stage in their careers. It was a very inspiring group to meet and to have the opportunity to work with as part of that program, and I thank the AGA for supporting such an initiative.

Q: What teacher or mentor had the greatest impact on you?

Dr. Melia: I have been blessed by many clinical and research mentors through my career. I was inspired to do science at the lab of Ramnik Xavier, MD, at Massachusetts General Hospital. At Johns Hopkins, I credit Cindy Sears, MD, and Anne Marie O’Broin Lennon, MBBCh, PhD, as two physician scientists who have really shaped how I have tried to integrate my clinical and research career.

LIGHTNING ROUND

Do you prefer texting or talking?
Texting

If you weren’t a gastroenterologist, what would you be?
Teacher

What was the last movie you watched?
Great Bear Rainforest

What is your most favorite city in the U.S.?
Surry, Maine

What song do you absolutely have to sing along with when you hear it?
Any song by Whitney Houston.

Are you an introvert or extrovert?
Introvert

How many cups of coffee do you drink per day?
One

Ask Joanna Melia, MD, what her biggest practice challenge is, and she’d say the need for more precision medicine in inflammatory bowel disease.

Gastroenterologists have more treatments at their disposal today than ever before, particularly in the last decade. “We have had tremendous advances in many areas of understanding contributors to disease,” said Dr. Melia, an assistant professor of medicine at Johns Hopkins Medicine in Baltimore who specializes in inflammatory bowel disease (IBD). But the hurdle is in translating the science to clinical care that is individualized to each patient based on condition and stage of the condition.

“That still remains a bit of a dream,” she said. Much of her career has been devoted to chasing down a particular genetic variant that contributes to IBD, with the goal of reaching more precise treatments for patients.

In an interview, she shared how she entered this line of work, and what her research has revealed about Crohn’s disease, manganese, and a common genetic variant known as ZIP8.

Q: Your expertise is in inflammatory bowel disease and manganese deficiency. Why did you choose these two areas as your focus in GI?

Dr. Melia: In talking to many patients with IBD, I was always struck by the questions around nutritional factors related to disease. As a fellow, I was embedded in a lab that focused on genetics of IBD. A micronutrient transporter, ZIP8, has a mutation in it that increases the risk of Crohn’s disease.

I’ve dedicated the last 8 years to understanding how this mutation can increase risk. It initially started out as a project focused on zinc, because that’s what the transporter was thought to regulate. However, it’s evolved as we’ve learned more about it, underscoring the importance of manganese, another micronutrient that we derive from food.

We have established that having this mutation changes how the body handles manganese and affects downstream processes that involve manganese. What I’m doing now is trying to connect those dots on why those processes are important in Crohn’s disease and whether we can target them for treatment.

Q: How does manganese deficiency lead to chronic IBD?

Dr. Melia: In individuals with this mutation, their blood manganese levels are lower than people who don’t have this mutation. When we talk about manganese deficiency or insufficiency, what we’re really talking about is lower blood levels. But it’s more complicated than that at the tissue level.

What we and other groups are working on right now is trying to understand if the manganese levels change in the gut and what happens in inflammation. The gut is a particularly interesting area for manganese, in that much of the manganese that we eat is excreted. We only absorb a small amount of it. And so, manganese levels within the gut lumen may actually be quite high – and may be even higher in inflammation. But there are things we don’t understand about that and how it relates to mucosal levels of manganese and Crohn’s disease. The ileum, the site of the Crohn’s disease that’s specifically associated with this mutation, might be particularly sensitive to changes in the manganese levels or the downstream processes that changing manganese availability affects.

One of those processes is glycosylation. Manganese is important to properly glycosylate your proteins. Many enzymes help cells put sugars on proteins, and many of those enzymes need manganese to do it. Glycosylation of proteins is important so cells know where those proteins should go, and the sugars help them stay where they need to be. When you change protein glycosylation, you can stress the cells. We know individuals who carry this mutation have changes in the glycosylation of their proteins. What we’re working on right now is understanding which key proteins might change when that happens, and why that’s a potential problem, especially in the ileum.

Q: How might your research inform clinical practice?

Dr. Melia: We’ve seen significant progress in new medications and new pathways that have emerged. We still have this fundamental problem that our immune-targeting medicines are only helping about 50% of the patients.

It’s critical that we begin to identify new pathways. And my hope is that in studying genes like the ZIP8 (SLC39A8), which is associated with the dysregulated processing of manganese, we can understand different pathways and mechanisms to target.

As an example, if we could help correct the glycosylation problem, that would help to boost the barrier function of the gut and perhaps decrease the activation of those immune cells, because you’re just reinforcing the barrier integrity of the gut.

We want to target that glycosylation problem as we would treat patients with congenital disorders of glycosylation by giving supplemental sugars. We think this problem of glycosylation extends beyond patients with the ZIP8 mutation, but it is also really important for patients with the mutation. So, the goal would be to use ZIP8 genetics to help prioritize patients for therapy targeting this problem.

Q: You’re involved in the American Gastroenterological Association Future Leaders Program. What is your role in this program? Why is it important?

Dr. Melia: I was very grateful for the opportunity to participate in the AGA’s Future Leaders Program. I think it was exceedingly valuable for two main reasons. One, it really offered an insight into the role of the AGA and the important role that the AGA plays in the careers of gastroenterologists. Two, it was such a unique opportunity to work with colleagues nationwide and to build a network of individuals who are all at a similar stage in their careers. It was a very inspiring group to meet and to have the opportunity to work with as part of that program, and I thank the AGA for supporting such an initiative.

Q: What teacher or mentor had the greatest impact on you?

Dr. Melia: I have been blessed by many clinical and research mentors through my career. I was inspired to do science at the lab of Ramnik Xavier, MD, at Massachusetts General Hospital. At Johns Hopkins, I credit Cindy Sears, MD, and Anne Marie O’Broin Lennon, MBBCh, PhD, as two physician scientists who have really shaped how I have tried to integrate my clinical and research career.

LIGHTNING ROUND

Do you prefer texting or talking?
Texting

If you weren’t a gastroenterologist, what would you be?
Teacher

What was the last movie you watched?
Great Bear Rainforest

What is your most favorite city in the U.S.?
Surry, Maine

What song do you absolutely have to sing along with when you hear it?
Any song by Whitney Houston.

Are you an introvert or extrovert?
Introvert

How many cups of coffee do you drink per day?
One

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic & Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic & Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic & Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

BERLIN – Based on a phase 3 trial, treatment with the topical Janus kinase (JAK) inhibitor ruxolitinib appears to be as safe and effective for the control of atopic dermatitis (AD) in children aged 2-11 years as previously shown in adolescents and adults for whom it already has an approved indication.

In this study – TRUE-AD3 – systemic exposure to ruxolitinib, which is selective for JAK1 and 2, was followed closely, and the low mean plasma concentrations “suggest systemic JAK inhibition is highly unlikely,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the annual congress of the European Academy of Dermatology and Venereology.

Ted Bosworth/MDedge News

For example, at a plasma concentration no greater than 27 nM in both younger and older patients at 4 weeks and again at 8 weeks, the systemic exposure was about a tenth of that (281 nM) previously associated with myelosuppression, he reported.

Given the boxed warning for oral JAK inhibitors, which was based largely on a 2022 study in adults with rheumatoid arthritis that associated tofacitinib, a nonspecific JAK inhibitor, with an increased risk of thrombotic events in adults already at risk for these events, safety was a focus of this phase 3 trial. The boxed warning is also in the labeling for topical ruxolitinib, 1.5% (Opzelura), approved for treating to mild to moderate atopic dermatitis in patients 12 years of age and older.

Dr. Eichenfield said there were no significant safety signals in the younger pediatric population. “There were no treatment-emergent adverse events suggestive of systemic JAK inhibition,” he said. This not only included the absence of serious infections, cardiac events, thromboses, or malignancies, but there was no signal of hematologic abnormalities, such as change in hemoglobin or neutrophil count.
 

Application site reactions

Rather, in the study of children ages 2-11, the only adverse events associated with topical ruxolitinib not observed in the control arm, which received the vehicle alone, were application site reactions, such as pain, erythema, and irritation. None of these occurred in more than 3% of those randomized to ruxolitinib regardless of dose.

Overall, in the trial, which randomized 329 patients ages from 2 to under 12 years with mild to moderate AD to ruxolitinib 1.5% cream, ruxolitinib 0.75% cream, or vehicle in a 2:2:1 fashion, there were just two (0.8%) discontinuations in the ruxolitinib groups (one in each dosing arm). There were none in the vehicle arm.

The safety supports an expansion of the AD indication for topical ruxolitinib in young children, because the rates of response were very similar to that seen in adolescents and adults in the previously published TRUE AD-1 and TRUE AD-2 trials, he said.

For the primary endpoint of Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2 grade improvement in IGA score from baseline, the response rates were 56.5%, 36.6%, and 10.8% for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively, at 8 weeks (P < .0001 for both doses relative to vehicle).

For the secondary efficacy endpoint of 75% or greater clearance on the Eczema Area and Severity Index, the rates were 67.2%, 51.5%, and 15.4%, for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively. Again, the advantage of both doses of ruxolitinib relative to vehicle was highly statistically significant (P < .0001).

Control of itch, evaluated with the Numerical Rating Scale was only evaluated in children 6-2 because of concern of the reliability of reporting in younger children. Control was defined as at least a 4-point improvement from baseline. It was achieved by 43.4%, 37.5%, and 29.7% by week 8 in the arms receiving the higher dose of ruxolitinib, the lower dose, and vehicle, respectively. The median time to achieving itch control was 11 days, 13 days, and 23 days, respectively. For all of these endpoints, the separation of the curves was readily apparent within the first 2 weeks.

The efficacy and tolerability of ruxolitinib appeared to be similar in younger children (ages 2-6) relative to older children.
 

Extension study in children near completion

Most of the patients who participated in TRUE AD-3 have been rolled over to the open-label extension trial, which is nearing completion. Those originally randomized to vehicle have been rerandomized to the lower or higher dose of ruxolitinib.

While this trial was focused on ruxolitinib as monotherapy, Thrasyvoulos Tzellos, MD, head of the department of dermatology, Nordland Hospital Trust, Bødo, Norway, questioned whether this is will be how it will be used in clinical practice. With the increasing array of therapies for AD, the “concept of combination therapy becomes more and more relevant,” he said after Dr. Eichenfield’s presentation.

Questioning whether an effective nonsteroidal anti-inflammatory agent like ruxolitinib should be considered a first-line treatment in mild disease or an adjunctive treatment for AD of any severity, he suggested that it might be best considered within a combination.

Dr. Eichenfield agreed. “Once we get the drug approved in a controlled trial, I think we then figure out how to use it in clinical practice.” Based on his own use of ruxolitinib in adults, he noted that he has not seen this drug replace other therapies so much as provide another option for control.

“We have an increasing armamentarium of drugs to use for involvement in different areas of the body in order to get more long-term control of disease,” he said. As an effective topical nonsteroidal drug, he believes its addition to clinical care in younger children, if approved, will be meaningful.

Dr. Eichenfield disclosed financial relationships with more multiple pharmaceutical companies, including Incyte, the manufacturer of ruxolitinib cream that provided funding for the True-AD trials. Dr. Tzellos reported financial relationships with AbbVie and UCB.

BERLIN – Based on a phase 3 trial, treatment with the topical Janus kinase (JAK) inhibitor ruxolitinib appears to be as safe and effective for the control of atopic dermatitis (AD) in children aged 2-11 years as previously shown in adolescents and adults for whom it already has an approved indication.

In this study – TRUE-AD3 – systemic exposure to ruxolitinib, which is selective for JAK1 and 2, was followed closely, and the low mean plasma concentrations “suggest systemic JAK inhibition is highly unlikely,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the annual congress of the European Academy of Dermatology and Venereology.

Ted Bosworth/MDedge News

For example, at a plasma concentration no greater than 27 nM in both younger and older patients at 4 weeks and again at 8 weeks, the systemic exposure was about a tenth of that (281 nM) previously associated with myelosuppression, he reported.

Given the boxed warning for oral JAK inhibitors, which was based largely on a 2022 study in adults with rheumatoid arthritis that associated tofacitinib, a nonspecific JAK inhibitor, with an increased risk of thrombotic events in adults already at risk for these events, safety was a focus of this phase 3 trial. The boxed warning is also in the labeling for topical ruxolitinib, 1.5% (Opzelura), approved for treating to mild to moderate atopic dermatitis in patients 12 years of age and older.

Dr. Eichenfield said there were no significant safety signals in the younger pediatric population. “There were no treatment-emergent adverse events suggestive of systemic JAK inhibition,” he said. This not only included the absence of serious infections, cardiac events, thromboses, or malignancies, but there was no signal of hematologic abnormalities, such as change in hemoglobin or neutrophil count.
 

Application site reactions

Rather, in the study of children ages 2-11, the only adverse events associated with topical ruxolitinib not observed in the control arm, which received the vehicle alone, were application site reactions, such as pain, erythema, and irritation. None of these occurred in more than 3% of those randomized to ruxolitinib regardless of dose.

Overall, in the trial, which randomized 329 patients ages from 2 to under 12 years with mild to moderate AD to ruxolitinib 1.5% cream, ruxolitinib 0.75% cream, or vehicle in a 2:2:1 fashion, there were just two (0.8%) discontinuations in the ruxolitinib groups (one in each dosing arm). There were none in the vehicle arm.

The safety supports an expansion of the AD indication for topical ruxolitinib in young children, because the rates of response were very similar to that seen in adolescents and adults in the previously published TRUE AD-1 and TRUE AD-2 trials, he said.

For the primary endpoint of Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2 grade improvement in IGA score from baseline, the response rates were 56.5%, 36.6%, and 10.8% for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively, at 8 weeks (P < .0001 for both doses relative to vehicle).

For the secondary efficacy endpoint of 75% or greater clearance on the Eczema Area and Severity Index, the rates were 67.2%, 51.5%, and 15.4%, for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively. Again, the advantage of both doses of ruxolitinib relative to vehicle was highly statistically significant (P < .0001).

Control of itch, evaluated with the Numerical Rating Scale was only evaluated in children 6-2 because of concern of the reliability of reporting in younger children. Control was defined as at least a 4-point improvement from baseline. It was achieved by 43.4%, 37.5%, and 29.7% by week 8 in the arms receiving the higher dose of ruxolitinib, the lower dose, and vehicle, respectively. The median time to achieving itch control was 11 days, 13 days, and 23 days, respectively. For all of these endpoints, the separation of the curves was readily apparent within the first 2 weeks.

The efficacy and tolerability of ruxolitinib appeared to be similar in younger children (ages 2-6) relative to older children.
 

Extension study in children near completion

Most of the patients who participated in TRUE AD-3 have been rolled over to the open-label extension trial, which is nearing completion. Those originally randomized to vehicle have been rerandomized to the lower or higher dose of ruxolitinib.

While this trial was focused on ruxolitinib as monotherapy, Thrasyvoulos Tzellos, MD, head of the department of dermatology, Nordland Hospital Trust, Bødo, Norway, questioned whether this is will be how it will be used in clinical practice. With the increasing array of therapies for AD, the “concept of combination therapy becomes more and more relevant,” he said after Dr. Eichenfield’s presentation.

Questioning whether an effective nonsteroidal anti-inflammatory agent like ruxolitinib should be considered a first-line treatment in mild disease or an adjunctive treatment for AD of any severity, he suggested that it might be best considered within a combination.

Dr. Eichenfield agreed. “Once we get the drug approved in a controlled trial, I think we then figure out how to use it in clinical practice.” Based on his own use of ruxolitinib in adults, he noted that he has not seen this drug replace other therapies so much as provide another option for control.

“We have an increasing armamentarium of drugs to use for involvement in different areas of the body in order to get more long-term control of disease,” he said. As an effective topical nonsteroidal drug, he believes its addition to clinical care in younger children, if approved, will be meaningful.

Dr. Eichenfield disclosed financial relationships with more multiple pharmaceutical companies, including Incyte, the manufacturer of ruxolitinib cream that provided funding for the True-AD trials. Dr. Tzellos reported financial relationships with AbbVie and UCB.

BERLIN – Based on a phase 3 trial, treatment with the topical Janus kinase (JAK) inhibitor ruxolitinib appears to be as safe and effective for the control of atopic dermatitis (AD) in children aged 2-11 years as previously shown in adolescents and adults for whom it already has an approved indication.

In this study – TRUE-AD3 – systemic exposure to ruxolitinib, which is selective for JAK1 and 2, was followed closely, and the low mean plasma concentrations “suggest systemic JAK inhibition is highly unlikely,” Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, said at the annual congress of the European Academy of Dermatology and Venereology.

Ted Bosworth/MDedge News

For example, at a plasma concentration no greater than 27 nM in both younger and older patients at 4 weeks and again at 8 weeks, the systemic exposure was about a tenth of that (281 nM) previously associated with myelosuppression, he reported.

Given the boxed warning for oral JAK inhibitors, which was based largely on a 2022 study in adults with rheumatoid arthritis that associated tofacitinib, a nonspecific JAK inhibitor, with an increased risk of thrombotic events in adults already at risk for these events, safety was a focus of this phase 3 trial. The boxed warning is also in the labeling for topical ruxolitinib, 1.5% (Opzelura), approved for treating to mild to moderate atopic dermatitis in patients 12 years of age and older.

Dr. Eichenfield said there were no significant safety signals in the younger pediatric population. “There were no treatment-emergent adverse events suggestive of systemic JAK inhibition,” he said. This not only included the absence of serious infections, cardiac events, thromboses, or malignancies, but there was no signal of hematologic abnormalities, such as change in hemoglobin or neutrophil count.
 

Application site reactions

Rather, in the study of children ages 2-11, the only adverse events associated with topical ruxolitinib not observed in the control arm, which received the vehicle alone, were application site reactions, such as pain, erythema, and irritation. None of these occurred in more than 3% of those randomized to ruxolitinib regardless of dose.

Overall, in the trial, which randomized 329 patients ages from 2 to under 12 years with mild to moderate AD to ruxolitinib 1.5% cream, ruxolitinib 0.75% cream, or vehicle in a 2:2:1 fashion, there were just two (0.8%) discontinuations in the ruxolitinib groups (one in each dosing arm). There were none in the vehicle arm.

The safety supports an expansion of the AD indication for topical ruxolitinib in young children, because the rates of response were very similar to that seen in adolescents and adults in the previously published TRUE AD-1 and TRUE AD-2 trials, he said.

For the primary endpoint of Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2 grade improvement in IGA score from baseline, the response rates were 56.5%, 36.6%, and 10.8% for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively, at 8 weeks (P < .0001 for both doses relative to vehicle).

For the secondary efficacy endpoint of 75% or greater clearance on the Eczema Area and Severity Index, the rates were 67.2%, 51.5%, and 15.4%, for ruxolitinib 1.5%, ruxolitinib 0.75%, and vehicle respectively. Again, the advantage of both doses of ruxolitinib relative to vehicle was highly statistically significant (P < .0001).

Control of itch, evaluated with the Numerical Rating Scale was only evaluated in children 6-2 because of concern of the reliability of reporting in younger children. Control was defined as at least a 4-point improvement from baseline. It was achieved by 43.4%, 37.5%, and 29.7% by week 8 in the arms receiving the higher dose of ruxolitinib, the lower dose, and vehicle, respectively. The median time to achieving itch control was 11 days, 13 days, and 23 days, respectively. For all of these endpoints, the separation of the curves was readily apparent within the first 2 weeks.

The efficacy and tolerability of ruxolitinib appeared to be similar in younger children (ages 2-6) relative to older children.
 

Extension study in children near completion

Most of the patients who participated in TRUE AD-3 have been rolled over to the open-label extension trial, which is nearing completion. Those originally randomized to vehicle have been rerandomized to the lower or higher dose of ruxolitinib.

While this trial was focused on ruxolitinib as monotherapy, Thrasyvoulos Tzellos, MD, head of the department of dermatology, Nordland Hospital Trust, Bødo, Norway, questioned whether this is will be how it will be used in clinical practice. With the increasing array of therapies for AD, the “concept of combination therapy becomes more and more relevant,” he said after Dr. Eichenfield’s presentation.

Questioning whether an effective nonsteroidal anti-inflammatory agent like ruxolitinib should be considered a first-line treatment in mild disease or an adjunctive treatment for AD of any severity, he suggested that it might be best considered within a combination.

Dr. Eichenfield agreed. “Once we get the drug approved in a controlled trial, I think we then figure out how to use it in clinical practice.” Based on his own use of ruxolitinib in adults, he noted that he has not seen this drug replace other therapies so much as provide another option for control.

“We have an increasing armamentarium of drugs to use for involvement in different areas of the body in order to get more long-term control of disease,” he said. As an effective topical nonsteroidal drug, he believes its addition to clinical care in younger children, if approved, will be meaningful.

Dr. Eichenfield disclosed financial relationships with more multiple pharmaceutical companies, including Incyte, the manufacturer of ruxolitinib cream that provided funding for the True-AD trials. Dr. Tzellos reported financial relationships with AbbVie and UCB.

The persistent scars with recurrent abscesses and sinuses are indicative of advanced hidradenitis suppurativa. This painful and debilitating disease is characterized by the recurrent formation and inflammation of papules, cysts, sinuses, and scars in the axillae, inguinal folds, gluteal cleft, and inframammary folds. Pain, social isolation, depression, increased risk of substance abuse, and increased suicidality are all associated with hidradenitis suppurativa.

The disease may be graded based on severity, which can guide medical treatment options. The earliest stage appears similar to acne without significant sinus tract or scar formation and may be treated with topical therapies—including clindamycin 1% lotion or gel. When larger cysts associated with sinus tracts occur, systemic options with oral antibiotics (including doxycycline 100 mg bid for 3 months or combination clindamycin 300 mg and rifampin 300 mg, both bid for 3 months) are reasonable options. Intralesional triamcinolone in a concentration of 10 mg/mL injected directly into an inflamed cyst can provide acute relief. Severe disease is characterized by diffuse scars and sinus tracts. The TNF-alpha inhibitors adalimumab and infliximab are excellent options for severe disease that does not respond to antibiotics.

Surgical treatment may include either “deroofing” the sinuses or performing a wide excision of the whole area of involvement. Widely excised areas may be grafted, allowed to granulate, or closed if small enough. Although these options create significant wounds, patients experience good results; there is a 27% recurrence with deroofing and a 13% recurrence with wide excision.¹

This patient underwent wide local excision of both axillae and the areas of involvement were allowed to granulate. Secondary intention healing occurred over 12 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The persistent scars with recurrent abscesses and sinuses are indicative of advanced hidradenitis suppurativa. This painful and debilitating disease is characterized by the recurrent formation and inflammation of papules, cysts, sinuses, and scars in the axillae, inguinal folds, gluteal cleft, and inframammary folds. Pain, social isolation, depression, increased risk of substance abuse, and increased suicidality are all associated with hidradenitis suppurativa.

The disease may be graded based on severity, which can guide medical treatment options. The earliest stage appears similar to acne without significant sinus tract or scar formation and may be treated with topical therapies—including clindamycin 1% lotion or gel. When larger cysts associated with sinus tracts occur, systemic options with oral antibiotics (including doxycycline 100 mg bid for 3 months or combination clindamycin 300 mg and rifampin 300 mg, both bid for 3 months) are reasonable options. Intralesional triamcinolone in a concentration of 10 mg/mL injected directly into an inflamed cyst can provide acute relief. Severe disease is characterized by diffuse scars and sinus tracts. The TNF-alpha inhibitors adalimumab and infliximab are excellent options for severe disease that does not respond to antibiotics.

Surgical treatment may include either “deroofing” the sinuses or performing a wide excision of the whole area of involvement. Widely excised areas may be grafted, allowed to granulate, or closed if small enough. Although these options create significant wounds, patients experience good results; there is a 27% recurrence with deroofing and a 13% recurrence with wide excision.¹

This patient underwent wide local excision of both axillae and the areas of involvement were allowed to granulate. Secondary intention healing occurred over 12 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

The persistent scars with recurrent abscesses and sinuses are indicative of advanced hidradenitis suppurativa. This painful and debilitating disease is characterized by the recurrent formation and inflammation of papules, cysts, sinuses, and scars in the axillae, inguinal folds, gluteal cleft, and inframammary folds. Pain, social isolation, depression, increased risk of substance abuse, and increased suicidality are all associated with hidradenitis suppurativa.

The disease may be graded based on severity, which can guide medical treatment options. The earliest stage appears similar to acne without significant sinus tract or scar formation and may be treated with topical therapies—including clindamycin 1% lotion or gel. When larger cysts associated with sinus tracts occur, systemic options with oral antibiotics (including doxycycline 100 mg bid for 3 months or combination clindamycin 300 mg and rifampin 300 mg, both bid for 3 months) are reasonable options. Intralesional triamcinolone in a concentration of 10 mg/mL injected directly into an inflamed cyst can provide acute relief. Severe disease is characterized by diffuse scars and sinus tracts. The TNF-alpha inhibitors adalimumab and infliximab are excellent options for severe disease that does not respond to antibiotics.

Surgical treatment may include either “deroofing” the sinuses or performing a wide excision of the whole area of involvement. Widely excised areas may be grafted, allowed to granulate, or closed if small enough. Although these options create significant wounds, patients experience good results; there is a 27% recurrence with deroofing and a 13% recurrence with wide excision.¹

This patient underwent wide local excision of both axillae and the areas of involvement were allowed to granulate. Secondary intention healing occurred over 12 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

TOPLINE:

Ketamine was no more effective than placebo in reducing depressive symptoms in surgical patients with major depressive disorder (MDD), results of a new study suggest, contradicting prior research. Although symptoms improved in both study groups, investigators say participants’ expectations of an improvement from ketamine may be driving that result.

METHODOLOGY:

• The randomized, placebo-controlled trial included 40 patients who had previously been diagnosed with MDD and who were scheduled for elective noncardiac, nonintracranial surgery.
• Participants completed pre- and postsurgery depression screenings with the Patient Health Questionnaire–8 (inclusion score was ≥ 12) and the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Patients received an infusion of 0.5 mg/kg of saline (placebo group; n = 20) or ketamine (n = 20) during surgery, along with general anesthesia.
• At the end of a 14-day follow-up, patients were asked to guess whether they had received ketamine or placebo.

TAKEAWAY:

• MADRS scores dropped by around half 1 day after treatment, indicating an improvement in depressive symptoms in both the group that received ketamine (mean decrease from 25 to 12.6 points) and the group that received placebo (mean decrease from 30 to 15.3 points). There was no significant difference between the two.
• Participants in the ketamine and placebo groups also reported high rates of clinical response (60% and 50%, respectively) and remission (50% and 35%, respectively), again with no significant difference based on treatment with ketamine or placebo.
• Only 36.8% of participants accurately guessed their treatment group. Those who guessed they had received ketamine had higher MADRS scores than those who guessed they had received placebo or said they didn’t know (10.1 vs. 19.2 vs. 23.0).
• The ketamine group had a significantly shorter hospital stay (1.9 days) than the placebo group (4 days) (P = .02).

IN PRACTICE:

“Our primary findings differ from those of previous antidepressant trials with ketamine conducted without adequate masking, which find robust effects of ketamine,” the authors wrote, adding that “regardless of the intervention being tested, participant expectations of a positive outcome – also known as hope – may drive large decreases in depression symptoms seen in antidepressant trials.”

SOURCE:

Boris D. Heifets, MD, PhD, led the study, which was published online in Nature Mental Health. The study was funded by the Society for Neuroscience in Anesthesiology and Critical Care, the National Institutes of Health, and the Stanford School of Medicine Research Office.

LIMITATIONS:

The investigators did not measure participants’ treatment expectations prior to randomization and could not determine what effect participant expectancy bias may have had on the results. In addition, there was no assessment of the blind for anesthesiologists who administered the ketamine or placebo to patients.

DISCLOSURES:

Dr. Heifets is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant to Clairvoyant Therapeutics and Vine Ventures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Ketamine was no more effective than placebo in reducing depressive symptoms in surgical patients with major depressive disorder (MDD), results of a new study suggest, contradicting prior research. Although symptoms improved in both study groups, investigators say participants’ expectations of an improvement from ketamine may be driving that result.

METHODOLOGY:

• The randomized, placebo-controlled trial included 40 patients who had previously been diagnosed with MDD and who were scheduled for elective noncardiac, nonintracranial surgery.
• Participants completed pre- and postsurgery depression screenings with the Patient Health Questionnaire–8 (inclusion score was ≥ 12) and the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Patients received an infusion of 0.5 mg/kg of saline (placebo group; n = 20) or ketamine (n = 20) during surgery, along with general anesthesia.
• At the end of a 14-day follow-up, patients were asked to guess whether they had received ketamine or placebo.

TAKEAWAY:

• MADRS scores dropped by around half 1 day after treatment, indicating an improvement in depressive symptoms in both the group that received ketamine (mean decrease from 25 to 12.6 points) and the group that received placebo (mean decrease from 30 to 15.3 points). There was no significant difference between the two.
• Participants in the ketamine and placebo groups also reported high rates of clinical response (60% and 50%, respectively) and remission (50% and 35%, respectively), again with no significant difference based on treatment with ketamine or placebo.
• Only 36.8% of participants accurately guessed their treatment group. Those who guessed they had received ketamine had higher MADRS scores than those who guessed they had received placebo or said they didn’t know (10.1 vs. 19.2 vs. 23.0).
• The ketamine group had a significantly shorter hospital stay (1.9 days) than the placebo group (4 days) (P = .02).

IN PRACTICE:

“Our primary findings differ from those of previous antidepressant trials with ketamine conducted without adequate masking, which find robust effects of ketamine,” the authors wrote, adding that “regardless of the intervention being tested, participant expectations of a positive outcome – also known as hope – may drive large decreases in depression symptoms seen in antidepressant trials.”

SOURCE:

Boris D. Heifets, MD, PhD, led the study, which was published online in Nature Mental Health. The study was funded by the Society for Neuroscience in Anesthesiology and Critical Care, the National Institutes of Health, and the Stanford School of Medicine Research Office.

LIMITATIONS:

The investigators did not measure participants’ treatment expectations prior to randomization and could not determine what effect participant expectancy bias may have had on the results. In addition, there was no assessment of the blind for anesthesiologists who administered the ketamine or placebo to patients.

DISCLOSURES:

Dr. Heifets is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant to Clairvoyant Therapeutics and Vine Ventures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Ketamine was no more effective than placebo in reducing depressive symptoms in surgical patients with major depressive disorder (MDD), results of a new study suggest, contradicting prior research. Although symptoms improved in both study groups, investigators say participants’ expectations of an improvement from ketamine may be driving that result.

METHODOLOGY:

• The randomized, placebo-controlled trial included 40 patients who had previously been diagnosed with MDD and who were scheduled for elective noncardiac, nonintracranial surgery.
• Participants completed pre- and postsurgery depression screenings with the Patient Health Questionnaire–8 (inclusion score was ≥ 12) and the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Patients received an infusion of 0.5 mg/kg of saline (placebo group; n = 20) or ketamine (n = 20) during surgery, along with general anesthesia.
• At the end of a 14-day follow-up, patients were asked to guess whether they had received ketamine or placebo.

TAKEAWAY:

• MADRS scores dropped by around half 1 day after treatment, indicating an improvement in depressive symptoms in both the group that received ketamine (mean decrease from 25 to 12.6 points) and the group that received placebo (mean decrease from 30 to 15.3 points). There was no significant difference between the two.
• Participants in the ketamine and placebo groups also reported high rates of clinical response (60% and 50%, respectively) and remission (50% and 35%, respectively), again with no significant difference based on treatment with ketamine or placebo.
• Only 36.8% of participants accurately guessed their treatment group. Those who guessed they had received ketamine had higher MADRS scores than those who guessed they had received placebo or said they didn’t know (10.1 vs. 19.2 vs. 23.0).
• The ketamine group had a significantly shorter hospital stay (1.9 days) than the placebo group (4 days) (P = .02).

IN PRACTICE:

“Our primary findings differ from those of previous antidepressant trials with ketamine conducted without adequate masking, which find robust effects of ketamine,” the authors wrote, adding that “regardless of the intervention being tested, participant expectations of a positive outcome – also known as hope – may drive large decreases in depression symptoms seen in antidepressant trials.”

SOURCE:

Boris D. Heifets, MD, PhD, led the study, which was published online in Nature Mental Health. The study was funded by the Society for Neuroscience in Anesthesiology and Critical Care, the National Institutes of Health, and the Stanford School of Medicine Research Office.

LIMITATIONS:

The investigators did not measure participants’ treatment expectations prior to randomization and could not determine what effect participant expectancy bias may have had on the results. In addition, there was no assessment of the blind for anesthesiologists who administered the ketamine or placebo to patients.

DISCLOSURES:

Dr. Heifets is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant to Clairvoyant Therapeutics and Vine Ventures.

A version of this article first appeared on Medscape.com.

Researchers have yet to crack how to analyze synovial tissue biopsy specimens to predict treatment responses for patients with rheumatoid arthritis.

According to new research, classifying patients by synovial fluid B-cell status was not reliable in predicting treatment response to etanercept, tocilizumab, or rituximab. More comprehensive molecular analyses may hold promise in developing models to predict treatment of a disease as heterogeneous as RA, wrote the authors, led by chief investigator Costantino Pitzalis, MD, head of the Centre for Experimental Medicine and Rheumatology at Queen Mary University of London.

The article was published in the November 2023 issue of The Lancet Rheumatology..
 

Trial-and-error treatment

Because clinicians do not have a way to reliably predict how patients may respond to certain medications, the current RA treatments involve trial and error.

Courtesy Dr. Arthur Mandelin, Northwestern University

“Both with regard to the first conventional synthetic disease-modifying antirheumatic drug (DMARD) for all patients and the first biologic DMARD for the subgroup of patients requiring these drugs, the choice of a drug is based on pragmatic arguments rather than on individual patient characteristics,” Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at the Leiden University Medical Center, the Netherlands, wrote in an accompanying editorial.

Most research on predicting treatment response has used clinical features and blood biomarkers, but neither approach is reliably predictive. “Precision medicine, therefore, remains elusive,” she said. Newer research has focused on synovial tissue biopsy to inform research decisions.
 

The STRAP studies

In this newest study, researchers combined data from two clinical studies with identical design: the Stratification of Biological Therapies by Pathobiology in Biologic-Naive Patients With Rheumatoid Arthritis (STRAP) trial, taking place in the United Kingdom, and STRAP-EU, which recruited patients from the European Union. The trials are the largest biopsy-driven trials to date, according to the researchers.

In total, researchers recruited 223 biologic-naive adult patients from 26 universities in the United Kingdom and Europe. Participants underwent ultrasound-guided synovial tissue biopsy and were then randomly assigned to receive etanercept (72 patients), tocilizumab (73 patients), or rituximab (78 patients). In a histologic analysis, 121 patients were characterized as B-cell poor (BCP), 100 patients were classified as B-cell rich (BCR), and two patients were classified as undetermined.

“We hypothesized that patients with a low synovial histological or molecular B-cell score would have a lower response to rituximab than to etanercept or tocilizumab,” the authors wrote.

However, among the BCP patients, there were no significant differences between responses to treatment at week 16 in the rituximab group compared with the etanercept and tocilizumab groups put together. In both groups, around 60% of patients achieved the primary endpoint of at least 20% improvement in American College of Rheumatology response criteria.

The results suggest that “a dichotomic classification into synovial B cell poor versus rich is unable to predict treatment response in patients treated with rituximab compared with etanercept or tocilizumab,” the authors wrote.

The findings echo work from the same group of researchers in 2021. This study – the R4RA trial – enrolled 164 patients who previously had an inadequate response to tumor necrosis factor blockers. Researchers then used a similar histologic approach to compare patients’ responses to tocilizumab or rituximab.

Among patients classified as BCP, there was not a significant difference in treatment response between the tocilizumab group and the rituximab group. However, classifying patients as BCP with RNA sequencing did make a difference. In this subgroup, patients given tocilizumab demonstrated a significantly higher response rate than those treated with rituximab.
 

Molecular-level analyses needed

This 2021 study showed – and this most recent study further confirmed – that “histology is not the way to understand what’s going on with or be predictive with tissue,” said Harris R. Perlman, PhD, chief of rheumatology at Northwestern University in Chicago. He was not involved with the research.

Dr. Perlman

“Most people now believe that you really have to understand the tissue on a single-cell basis – using the gene expression of each individual cell – to really give you an idea of what’s happening in tissue,” he noted.

“RA continues to tell us that it is more complex than just something dichotomous,” added Elena Myasoedova, MD, PhD, director of the Inflammatory Arthritis Subspecialty Group at the Mayo Clinic in Rochester, Minn. She was not involved with the work.

Dr. Myasoedova

“Understanding more about the heterogeneity using different ‘-omics’ approaches and introducing a two- or three-dimensional approach with spatial biology can be helpful,” she said.

Spatial transcriptomics, for example, allows scientists to measure all gene activity in a tissue sample and to map where that gene activity is occurring.

“It helps us to understand and visualize molecules and their unique context within individual cells and tissues,” Dr. Myasoedova explained.

With advanced molecular analyses already available, Dr. Perlman is adamant that synovial tissue remains the key to unlocking precision medicine.

“The tissue is the golden ticket,” he said, “but it’s how you analyze it.”

And it’s clear that older analytic methods – such as histology – are not enough, he said.

A larger study of a size similar to that of STRAP that incorporates multiple sources of patient information, from gene expression to clinical symptoms, to create a predictive model would be key to understanding how to move the field of precision treatment for RA forward, he added.

“Precision medicine for RA is close,” he said. “We still have to get the numbers.”

The STRAP and STRAP-EU trials were jointly funded by the UK Medical Research Council and Versus Arthritis. Pfizer and Roche donated the study drugs through an investigator-sponsored research grant. Many authors, including Dr. Pitzalis, have multiple financial relationships with pharmaceutical companies. Dr. Van der Helm-van Mil and Dr. Myasoedova have disclosed no relevant financial relationships. Dr. Perlman consults for AbbVie, AnaptysBio, Exagen, Janssen, and Kiniksa.
 

A version of this article first appeared on Medscape.com.

Researchers have yet to crack how to analyze synovial tissue biopsy specimens to predict treatment responses for patients with rheumatoid arthritis.

According to new research, classifying patients by synovial fluid B-cell status was not reliable in predicting treatment response to etanercept, tocilizumab, or rituximab. More comprehensive molecular analyses may hold promise in developing models to predict treatment of a disease as heterogeneous as RA, wrote the authors, led by chief investigator Costantino Pitzalis, MD, head of the Centre for Experimental Medicine and Rheumatology at Queen Mary University of London.

The article was published in the November 2023 issue of The Lancet Rheumatology..
 

Trial-and-error treatment

Because clinicians do not have a way to reliably predict how patients may respond to certain medications, the current RA treatments involve trial and error.

Courtesy Dr. Arthur Mandelin, Northwestern University

“Both with regard to the first conventional synthetic disease-modifying antirheumatic drug (DMARD) for all patients and the first biologic DMARD for the subgroup of patients requiring these drugs, the choice of a drug is based on pragmatic arguments rather than on individual patient characteristics,” Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at the Leiden University Medical Center, the Netherlands, wrote in an accompanying editorial.

Most research on predicting treatment response has used clinical features and blood biomarkers, but neither approach is reliably predictive. “Precision medicine, therefore, remains elusive,” she said. Newer research has focused on synovial tissue biopsy to inform research decisions.
 

The STRAP studies

In this newest study, researchers combined data from two clinical studies with identical design: the Stratification of Biological Therapies by Pathobiology in Biologic-Naive Patients With Rheumatoid Arthritis (STRAP) trial, taking place in the United Kingdom, and STRAP-EU, which recruited patients from the European Union. The trials are the largest biopsy-driven trials to date, according to the researchers.

In total, researchers recruited 223 biologic-naive adult patients from 26 universities in the United Kingdom and Europe. Participants underwent ultrasound-guided synovial tissue biopsy and were then randomly assigned to receive etanercept (72 patients), tocilizumab (73 patients), or rituximab (78 patients). In a histologic analysis, 121 patients were characterized as B-cell poor (BCP), 100 patients were classified as B-cell rich (BCR), and two patients were classified as undetermined.

“We hypothesized that patients with a low synovial histological or molecular B-cell score would have a lower response to rituximab than to etanercept or tocilizumab,” the authors wrote.

However, among the BCP patients, there were no significant differences between responses to treatment at week 16 in the rituximab group compared with the etanercept and tocilizumab groups put together. In both groups, around 60% of patients achieved the primary endpoint of at least 20% improvement in American College of Rheumatology response criteria.

The results suggest that “a dichotomic classification into synovial B cell poor versus rich is unable to predict treatment response in patients treated with rituximab compared with etanercept or tocilizumab,” the authors wrote.

The findings echo work from the same group of researchers in 2021. This study – the R4RA trial – enrolled 164 patients who previously had an inadequate response to tumor necrosis factor blockers. Researchers then used a similar histologic approach to compare patients’ responses to tocilizumab or rituximab.

Among patients classified as BCP, there was not a significant difference in treatment response between the tocilizumab group and the rituximab group. However, classifying patients as BCP with RNA sequencing did make a difference. In this subgroup, patients given tocilizumab demonstrated a significantly higher response rate than those treated with rituximab.
 

Molecular-level analyses needed

This 2021 study showed – and this most recent study further confirmed – that “histology is not the way to understand what’s going on with or be predictive with tissue,” said Harris R. Perlman, PhD, chief of rheumatology at Northwestern University in Chicago. He was not involved with the research.

Dr. Perlman

“Most people now believe that you really have to understand the tissue on a single-cell basis – using the gene expression of each individual cell – to really give you an idea of what’s happening in tissue,” he noted.

“RA continues to tell us that it is more complex than just something dichotomous,” added Elena Myasoedova, MD, PhD, director of the Inflammatory Arthritis Subspecialty Group at the Mayo Clinic in Rochester, Minn. She was not involved with the work.

Dr. Myasoedova

“Understanding more about the heterogeneity using different ‘-omics’ approaches and introducing a two- or three-dimensional approach with spatial biology can be helpful,” she said.

Spatial transcriptomics, for example, allows scientists to measure all gene activity in a tissue sample and to map where that gene activity is occurring.

“It helps us to understand and visualize molecules and their unique context within individual cells and tissues,” Dr. Myasoedova explained.

With advanced molecular analyses already available, Dr. Perlman is adamant that synovial tissue remains the key to unlocking precision medicine.

“The tissue is the golden ticket,” he said, “but it’s how you analyze it.”

And it’s clear that older analytic methods – such as histology – are not enough, he said.

A larger study of a size similar to that of STRAP that incorporates multiple sources of patient information, from gene expression to clinical symptoms, to create a predictive model would be key to understanding how to move the field of precision treatment for RA forward, he added.

“Precision medicine for RA is close,” he said. “We still have to get the numbers.”

The STRAP and STRAP-EU trials were jointly funded by the UK Medical Research Council and Versus Arthritis. Pfizer and Roche donated the study drugs through an investigator-sponsored research grant. Many authors, including Dr. Pitzalis, have multiple financial relationships with pharmaceutical companies. Dr. Van der Helm-van Mil and Dr. Myasoedova have disclosed no relevant financial relationships. Dr. Perlman consults for AbbVie, AnaptysBio, Exagen, Janssen, and Kiniksa.
 

A version of this article first appeared on Medscape.com.

Researchers have yet to crack how to analyze synovial tissue biopsy specimens to predict treatment responses for patients with rheumatoid arthritis.

According to new research, classifying patients by synovial fluid B-cell status was not reliable in predicting treatment response to etanercept, tocilizumab, or rituximab. More comprehensive molecular analyses may hold promise in developing models to predict treatment of a disease as heterogeneous as RA, wrote the authors, led by chief investigator Costantino Pitzalis, MD, head of the Centre for Experimental Medicine and Rheumatology at Queen Mary University of London.

The article was published in the November 2023 issue of The Lancet Rheumatology..
 

Trial-and-error treatment

Because clinicians do not have a way to reliably predict how patients may respond to certain medications, the current RA treatments involve trial and error.

Courtesy Dr. Arthur Mandelin, Northwestern University

“Both with regard to the first conventional synthetic disease-modifying antirheumatic drug (DMARD) for all patients and the first biologic DMARD for the subgroup of patients requiring these drugs, the choice of a drug is based on pragmatic arguments rather than on individual patient characteristics,” Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at the Leiden University Medical Center, the Netherlands, wrote in an accompanying editorial.

Most research on predicting treatment response has used clinical features and blood biomarkers, but neither approach is reliably predictive. “Precision medicine, therefore, remains elusive,” she said. Newer research has focused on synovial tissue biopsy to inform research decisions.
 

The STRAP studies

In this newest study, researchers combined data from two clinical studies with identical design: the Stratification of Biological Therapies by Pathobiology in Biologic-Naive Patients With Rheumatoid Arthritis (STRAP) trial, taking place in the United Kingdom, and STRAP-EU, which recruited patients from the European Union. The trials are the largest biopsy-driven trials to date, according to the researchers.

In total, researchers recruited 223 biologic-naive adult patients from 26 universities in the United Kingdom and Europe. Participants underwent ultrasound-guided synovial tissue biopsy and were then randomly assigned to receive etanercept (72 patients), tocilizumab (73 patients), or rituximab (78 patients). In a histologic analysis, 121 patients were characterized as B-cell poor (BCP), 100 patients were classified as B-cell rich (BCR), and two patients were classified as undetermined.

“We hypothesized that patients with a low synovial histological or molecular B-cell score would have a lower response to rituximab than to etanercept or tocilizumab,” the authors wrote.

However, among the BCP patients, there were no significant differences between responses to treatment at week 16 in the rituximab group compared with the etanercept and tocilizumab groups put together. In both groups, around 60% of patients achieved the primary endpoint of at least 20% improvement in American College of Rheumatology response criteria.

The results suggest that “a dichotomic classification into synovial B cell poor versus rich is unable to predict treatment response in patients treated with rituximab compared with etanercept or tocilizumab,” the authors wrote.

The findings echo work from the same group of researchers in 2021. This study – the R4RA trial – enrolled 164 patients who previously had an inadequate response to tumor necrosis factor blockers. Researchers then used a similar histologic approach to compare patients’ responses to tocilizumab or rituximab.

Among patients classified as BCP, there was not a significant difference in treatment response between the tocilizumab group and the rituximab group. However, classifying patients as BCP with RNA sequencing did make a difference. In this subgroup, patients given tocilizumab demonstrated a significantly higher response rate than those treated with rituximab.
 

Molecular-level analyses needed

This 2021 study showed – and this most recent study further confirmed – that “histology is not the way to understand what’s going on with or be predictive with tissue,” said Harris R. Perlman, PhD, chief of rheumatology at Northwestern University in Chicago. He was not involved with the research.

Dr. Perlman

“Most people now believe that you really have to understand the tissue on a single-cell basis – using the gene expression of each individual cell – to really give you an idea of what’s happening in tissue,” he noted.

“RA continues to tell us that it is more complex than just something dichotomous,” added Elena Myasoedova, MD, PhD, director of the Inflammatory Arthritis Subspecialty Group at the Mayo Clinic in Rochester, Minn. She was not involved with the work.

Dr. Myasoedova

“Understanding more about the heterogeneity using different ‘-omics’ approaches and introducing a two- or three-dimensional approach with spatial biology can be helpful,” she said.

Spatial transcriptomics, for example, allows scientists to measure all gene activity in a tissue sample and to map where that gene activity is occurring.

“It helps us to understand and visualize molecules and their unique context within individual cells and tissues,” Dr. Myasoedova explained.

With advanced molecular analyses already available, Dr. Perlman is adamant that synovial tissue remains the key to unlocking precision medicine.

“The tissue is the golden ticket,” he said, “but it’s how you analyze it.”

And it’s clear that older analytic methods – such as histology – are not enough, he said.

A larger study of a size similar to that of STRAP that incorporates multiple sources of patient information, from gene expression to clinical symptoms, to create a predictive model would be key to understanding how to move the field of precision treatment for RA forward, he added.

“Precision medicine for RA is close,” he said. “We still have to get the numbers.”

The STRAP and STRAP-EU trials were jointly funded by the UK Medical Research Council and Versus Arthritis. Pfizer and Roche donated the study drugs through an investigator-sponsored research grant. Many authors, including Dr. Pitzalis, have multiple financial relationships with pharmaceutical companies. Dr. Van der Helm-van Mil and Dr. Myasoedova have disclosed no relevant financial relationships. Dr. Perlman consults for AbbVie, AnaptysBio, Exagen, Janssen, and Kiniksa.
 

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – An everolimus-eluting stent with a resorbable scaffold showed superior efficacy in a randomized multicenter trial when compared with angioplasty for the treatment of patients with chronic limb threatening ischemia (CLTI) resulting from infrapopliteal artery disease.

The stent (Esprit BTK, Abbott Vascular) was also noninferior to angioplasty in terms of safety.

Presenting results of the LIFE-BTK trial at the Transcatheter Cardiovascular Therapeutics annual meeting, Ramon Varcoe, MBBS, MS, PhD, MMed, of Prince of Wales Hospital, Sydney, said that peripheral artery disease is a global epidemic, the most serious manifestation of which is CTLI.

“If not treated expeditiously, this could lead to high rates of amputation, which, as we all know, has a severe impact on patients’ quality of life and even worse impact on their life prognosis, with prognosis rates worse than most cancers.”

He said that for infrapopliteal or below-the-knee (BTK) arterial disease, treatment with angioplasty has proven superior to bypass graft surgery, but some limitations of angioplasty are elastic recoil, dissection, and restenosis, thus limiting its durability. Coronary drug-eluting stents showed promise in BTK procedures but can interfere with reintervention. Thus, LIFE-BTK compared a drug-eluting stent with resorbable scaffolding to surgery.

Esprit BTK is a drug-eluting resorbable scaffold consisting of a temporary scaffold backbone of poly(L-lactide) and a strut thickness of 99 μm. It is coated with everolimus and bioresorbable poly(D,L-lactide). Two platinum markers at each end provide radiopacity.

LIFE-BTK enrolled patients aged 18 years or older with CLTI associated with ischemic rest pain or minor tissue loss and who had infrapopliteal artery stenosis or occlusion. The trial was prospective, international multicenter, and single-blind and randomly assigned 261 patients aged 18 years or older in the ratio of 2:1 to Esprit BTK (n = 173) or to angioplasty (n = 88). Treatment of up to two target lesions was allowed with a total scaffold length less than 170 mm.

The primary efficacy endpoint was superiority of Esprit BTK over angioplasty in terms of freedom of above-ankle amputation in the index limb, binary restenosis of the target lesion, and clinically driven target lesion revascularization evaluated at 1 year.

The primary safety endpoint, evaluated at 6 months, consisted of freedom from above-ankle amputation, major reintervention at 6 months, and perioperative mortality at 30 days.

An independent committee adjudicated clinical events, and core laboratories with assessors blinded to trial group assignment adjudicated imaging results and wound assessments.
 

Superior efficacy, noninferior safety

Participants were about two-thirds men, largely White, with about 15% of participants being Black/African American, and more than 90% of patients in each arm had hypertension. Lesion lengths were approximately 44 mm in each group with reference vessel diameters averaging 2.82-2.94 mm before intervention. Less than 4% in each group had severe lesion calcification.

Clinical follow-up rate at 1 year in the Esprit BTK arm was 90.2% and in the angioplasty arm 90.9%. Six patients in the former arm died versus five in the latter.

At the meeting, sponsored by the Cardiovascular Research Foundation, Dr. Varcoe showed a graph of the primary efficacy results at 453 days, the extra time being allowed to achieve a diagnostic ultrasound. In the Esprit BTK group, 74.2% of participants achieved the efficacy endpoint versus 47.9% of the angioplasty subjects (P < .0001).

“As you can see, those bars start to diverge in about 5 months and continue to separate over time, showing clear superiority of the scaffold over angioplasty, absolute risk difference of 30.8% and a highly statistically significant P value,” he said. Very similar primary efficacy outcomes were seen at 393 days.

At 1 year, the secondary efficacy endpoint of binary restenosis of the target lesion occurred in 24.2% of scaffold patients versus 46.5% of the angioplasty group (P < .0001). Another secondary endpoint, freedom from above-ankle amputation, 100% total occlusion of the target vessel, or clinically driven target lesion revascularization, occurred in 82.5% of the scaffold group versus 70.4% in the angioplasty group (P = .0081).

The primary safety endpoint of freedom from a major adverse limb event plus perioperative death was 100% for angioplasty and 96.9% for Esprit BTK (P = .0019)

All subgroup analyses assessing interaction by sex, race, geographic region, or age showed Esprit BTK was superior to angioplasty, with relative risks ranging from 0.27 to 0.61.

“If this technology is approved by the FDA, it will provide a new option for our patients with very difficult-to-treat disease, which will provide them additional durability and fewer reinterventions,” Dr. Varcoe concluded. “And I think we all know deep down that’s going to translate to improved clinical outcomes and few amputations.”

David Kandzari, MD, of Peidmont Heart Institute, Atlanta, was asked to comment on the study. He said that as with other vascular interventions, the ideal technology “would be first to provide a safe and effective antiproliferative therapy that would mitigate against restenosis and for scaffolding to prevent elastic recoil and reocclusion ... and ultimately fulfill these two promises without the requisite of a permanent implant.

“Despite their common use in femoral popliteal disease, drug-coated balloons had at best demonstrated inconsistent results below the knee, and drug-coated balloons, therefore, are not approved for such indications.”

He said that drug-eluting stents have demonstrated efficacy in this indication but that these studies have been limited to fairly discrete proximal disease.

“LIFE-BTK therefore represents one of the most rigorous trials in the space of endovascular interventions as a single line and randomized trial,” Dr. Kandzari said, “showing a primary composite endpoint of both safety and effectiveness relative to conventional angioplasty.”

Dr. Kandzari pointed to strengths of the study in that it used standardization of technique with independent adjudication of both imaging and wound healing assessments. “And the study population, too, was relevant to clinical practice, representing oftentimes underrepresented groups, including those with extensive disease burden [and] clinical severity,” he said. “Importantly, in this study, nearly one-third of the population will be women.”

Panelist Jennifer Rymer, MD, of Duke University Medical Center, Durham, N.C., commented that she treats a lot of African American patients with CTLI and applauded the researchers for including those patients. “I think that this will be a groundbreaking new change in our practice,” she said.

The trial results were published simultaneously with the presentation at TCT 2023 in the New England Journal of Medicine.

Dr. Varcoe reported receiving consulting fees/honoraria from Boston Scientific Corporation, Medtronic, Abbott, BD, Intervene, Surmodics, Philips, Nectero, Alucent, W.L. Gore, Vesteck, Bard Medical, Cook Medical, and R3 Vascular. He has equity, stock, or stock options in EBR Systems and has an executive role or ownership interest in Provisio Medical and Vesteck. Dr. Kandzari received grant support/research contract from Medtronic, Teleflex, Biotronik, and CSI; consultant fees/honoraria from and is on the speaker’s bureau of CSI and Medtronic; and has equity, stock, or options in Biostar Ventures. Dr. Rymer receives grant support/research contract from Chiesi, Abbott Vascular, Abiomed, and Pfizer. The study was funded by Abbott.

A version of this article appeared on Medscape.com.

SAN FRANCISCO – An everolimus-eluting stent with a resorbable scaffold showed superior efficacy in a randomized multicenter trial when compared with angioplasty for the treatment of patients with chronic limb threatening ischemia (CLTI) resulting from infrapopliteal artery disease.

The stent (Esprit BTK, Abbott Vascular) was also noninferior to angioplasty in terms of safety.

Presenting results of the LIFE-BTK trial at the Transcatheter Cardiovascular Therapeutics annual meeting, Ramon Varcoe, MBBS, MS, PhD, MMed, of Prince of Wales Hospital, Sydney, said that peripheral artery disease is a global epidemic, the most serious manifestation of which is CTLI.

“If not treated expeditiously, this could lead to high rates of amputation, which, as we all know, has a severe impact on patients’ quality of life and even worse impact on their life prognosis, with prognosis rates worse than most cancers.”

He said that for infrapopliteal or below-the-knee (BTK) arterial disease, treatment with angioplasty has proven superior to bypass graft surgery, but some limitations of angioplasty are elastic recoil, dissection, and restenosis, thus limiting its durability. Coronary drug-eluting stents showed promise in BTK procedures but can interfere with reintervention. Thus, LIFE-BTK compared a drug-eluting stent with resorbable scaffolding to surgery.

Esprit BTK is a drug-eluting resorbable scaffold consisting of a temporary scaffold backbone of poly(L-lactide) and a strut thickness of 99 μm. It is coated with everolimus and bioresorbable poly(D,L-lactide). Two platinum markers at each end provide radiopacity.

LIFE-BTK enrolled patients aged 18 years or older with CLTI associated with ischemic rest pain or minor tissue loss and who had infrapopliteal artery stenosis or occlusion. The trial was prospective, international multicenter, and single-blind and randomly assigned 261 patients aged 18 years or older in the ratio of 2:1 to Esprit BTK (n = 173) or to angioplasty (n = 88). Treatment of up to two target lesions was allowed with a total scaffold length less than 170 mm.

The primary efficacy endpoint was superiority of Esprit BTK over angioplasty in terms of freedom of above-ankle amputation in the index limb, binary restenosis of the target lesion, and clinically driven target lesion revascularization evaluated at 1 year.

The primary safety endpoint, evaluated at 6 months, consisted of freedom from above-ankle amputation, major reintervention at 6 months, and perioperative mortality at 30 days.

An independent committee adjudicated clinical events, and core laboratories with assessors blinded to trial group assignment adjudicated imaging results and wound assessments.
 

Superior efficacy, noninferior safety

Participants were about two-thirds men, largely White, with about 15% of participants being Black/African American, and more than 90% of patients in each arm had hypertension. Lesion lengths were approximately 44 mm in each group with reference vessel diameters averaging 2.82-2.94 mm before intervention. Less than 4% in each group had severe lesion calcification.

Clinical follow-up rate at 1 year in the Esprit BTK arm was 90.2% and in the angioplasty arm 90.9%. Six patients in the former arm died versus five in the latter.

At the meeting, sponsored by the Cardiovascular Research Foundation, Dr. Varcoe showed a graph of the primary efficacy results at 453 days, the extra time being allowed to achieve a diagnostic ultrasound. In the Esprit BTK group, 74.2% of participants achieved the efficacy endpoint versus 47.9% of the angioplasty subjects (P < .0001).

“As you can see, those bars start to diverge in about 5 months and continue to separate over time, showing clear superiority of the scaffold over angioplasty, absolute risk difference of 30.8% and a highly statistically significant P value,” he said. Very similar primary efficacy outcomes were seen at 393 days.

At 1 year, the secondary efficacy endpoint of binary restenosis of the target lesion occurred in 24.2% of scaffold patients versus 46.5% of the angioplasty group (P < .0001). Another secondary endpoint, freedom from above-ankle amputation, 100% total occlusion of the target vessel, or clinically driven target lesion revascularization, occurred in 82.5% of the scaffold group versus 70.4% in the angioplasty group (P = .0081).

The primary safety endpoint of freedom from a major adverse limb event plus perioperative death was 100% for angioplasty and 96.9% for Esprit BTK (P = .0019)

All subgroup analyses assessing interaction by sex, race, geographic region, or age showed Esprit BTK was superior to angioplasty, with relative risks ranging from 0.27 to 0.61.

“If this technology is approved by the FDA, it will provide a new option for our patients with very difficult-to-treat disease, which will provide them additional durability and fewer reinterventions,” Dr. Varcoe concluded. “And I think we all know deep down that’s going to translate to improved clinical outcomes and few amputations.”

David Kandzari, MD, of Peidmont Heart Institute, Atlanta, was asked to comment on the study. He said that as with other vascular interventions, the ideal technology “would be first to provide a safe and effective antiproliferative therapy that would mitigate against restenosis and for scaffolding to prevent elastic recoil and reocclusion ... and ultimately fulfill these two promises without the requisite of a permanent implant.

“Despite their common use in femoral popliteal disease, drug-coated balloons had at best demonstrated inconsistent results below the knee, and drug-coated balloons, therefore, are not approved for such indications.”

He said that drug-eluting stents have demonstrated efficacy in this indication but that these studies have been limited to fairly discrete proximal disease.

“LIFE-BTK therefore represents one of the most rigorous trials in the space of endovascular interventions as a single line and randomized trial,” Dr. Kandzari said, “showing a primary composite endpoint of both safety and effectiveness relative to conventional angioplasty.”

Dr. Kandzari pointed to strengths of the study in that it used standardization of technique with independent adjudication of both imaging and wound healing assessments. “And the study population, too, was relevant to clinical practice, representing oftentimes underrepresented groups, including those with extensive disease burden [and] clinical severity,” he said. “Importantly, in this study, nearly one-third of the population will be women.”

Panelist Jennifer Rymer, MD, of Duke University Medical Center, Durham, N.C., commented that she treats a lot of African American patients with CTLI and applauded the researchers for including those patients. “I think that this will be a groundbreaking new change in our practice,” she said.

The trial results were published simultaneously with the presentation at TCT 2023 in the New England Journal of Medicine.

Dr. Varcoe reported receiving consulting fees/honoraria from Boston Scientific Corporation, Medtronic, Abbott, BD, Intervene, Surmodics, Philips, Nectero, Alucent, W.L. Gore, Vesteck, Bard Medical, Cook Medical, and R3 Vascular. He has equity, stock, or stock options in EBR Systems and has an executive role or ownership interest in Provisio Medical and Vesteck. Dr. Kandzari received grant support/research contract from Medtronic, Teleflex, Biotronik, and CSI; consultant fees/honoraria from and is on the speaker’s bureau of CSI and Medtronic; and has equity, stock, or options in Biostar Ventures. Dr. Rymer receives grant support/research contract from Chiesi, Abbott Vascular, Abiomed, and Pfizer. The study was funded by Abbott.

A version of this article appeared on Medscape.com.

SAN FRANCISCO – An everolimus-eluting stent with a resorbable scaffold showed superior efficacy in a randomized multicenter trial when compared with angioplasty for the treatment of patients with chronic limb threatening ischemia (CLTI) resulting from infrapopliteal artery disease.

The stent (Esprit BTK, Abbott Vascular) was also noninferior to angioplasty in terms of safety.

Presenting results of the LIFE-BTK trial at the Transcatheter Cardiovascular Therapeutics annual meeting, Ramon Varcoe, MBBS, MS, PhD, MMed, of Prince of Wales Hospital, Sydney, said that peripheral artery disease is a global epidemic, the most serious manifestation of which is CTLI.

“If not treated expeditiously, this could lead to high rates of amputation, which, as we all know, has a severe impact on patients’ quality of life and even worse impact on their life prognosis, with prognosis rates worse than most cancers.”

He said that for infrapopliteal or below-the-knee (BTK) arterial disease, treatment with angioplasty has proven superior to bypass graft surgery, but some limitations of angioplasty are elastic recoil, dissection, and restenosis, thus limiting its durability. Coronary drug-eluting stents showed promise in BTK procedures but can interfere with reintervention. Thus, LIFE-BTK compared a drug-eluting stent with resorbable scaffolding to surgery.

Esprit BTK is a drug-eluting resorbable scaffold consisting of a temporary scaffold backbone of poly(L-lactide) and a strut thickness of 99 μm. It is coated with everolimus and bioresorbable poly(D,L-lactide). Two platinum markers at each end provide radiopacity.

LIFE-BTK enrolled patients aged 18 years or older with CLTI associated with ischemic rest pain or minor tissue loss and who had infrapopliteal artery stenosis or occlusion. The trial was prospective, international multicenter, and single-blind and randomly assigned 261 patients aged 18 years or older in the ratio of 2:1 to Esprit BTK (n = 173) or to angioplasty (n = 88). Treatment of up to two target lesions was allowed with a total scaffold length less than 170 mm.

The primary efficacy endpoint was superiority of Esprit BTK over angioplasty in terms of freedom of above-ankle amputation in the index limb, binary restenosis of the target lesion, and clinically driven target lesion revascularization evaluated at 1 year.

The primary safety endpoint, evaluated at 6 months, consisted of freedom from above-ankle amputation, major reintervention at 6 months, and perioperative mortality at 30 days.

An independent committee adjudicated clinical events, and core laboratories with assessors blinded to trial group assignment adjudicated imaging results and wound assessments.
 

Superior efficacy, noninferior safety

Participants were about two-thirds men, largely White, with about 15% of participants being Black/African American, and more than 90% of patients in each arm had hypertension. Lesion lengths were approximately 44 mm in each group with reference vessel diameters averaging 2.82-2.94 mm before intervention. Less than 4% in each group had severe lesion calcification.

Clinical follow-up rate at 1 year in the Esprit BTK arm was 90.2% and in the angioplasty arm 90.9%. Six patients in the former arm died versus five in the latter.

At the meeting, sponsored by the Cardiovascular Research Foundation, Dr. Varcoe showed a graph of the primary efficacy results at 453 days, the extra time being allowed to achieve a diagnostic ultrasound. In the Esprit BTK group, 74.2% of participants achieved the efficacy endpoint versus 47.9% of the angioplasty subjects (P < .0001).

“As you can see, those bars start to diverge in about 5 months and continue to separate over time, showing clear superiority of the scaffold over angioplasty, absolute risk difference of 30.8% and a highly statistically significant P value,” he said. Very similar primary efficacy outcomes were seen at 393 days.

At 1 year, the secondary efficacy endpoint of binary restenosis of the target lesion occurred in 24.2% of scaffold patients versus 46.5% of the angioplasty group (P < .0001). Another secondary endpoint, freedom from above-ankle amputation, 100% total occlusion of the target vessel, or clinically driven target lesion revascularization, occurred in 82.5% of the scaffold group versus 70.4% in the angioplasty group (P = .0081).

The primary safety endpoint of freedom from a major adverse limb event plus perioperative death was 100% for angioplasty and 96.9% for Esprit BTK (P = .0019)

All subgroup analyses assessing interaction by sex, race, geographic region, or age showed Esprit BTK was superior to angioplasty, with relative risks ranging from 0.27 to 0.61.

“If this technology is approved by the FDA, it will provide a new option for our patients with very difficult-to-treat disease, which will provide them additional durability and fewer reinterventions,” Dr. Varcoe concluded. “And I think we all know deep down that’s going to translate to improved clinical outcomes and few amputations.”

David Kandzari, MD, of Peidmont Heart Institute, Atlanta, was asked to comment on the study. He said that as with other vascular interventions, the ideal technology “would be first to provide a safe and effective antiproliferative therapy that would mitigate against restenosis and for scaffolding to prevent elastic recoil and reocclusion ... and ultimately fulfill these two promises without the requisite of a permanent implant.

“Despite their common use in femoral popliteal disease, drug-coated balloons had at best demonstrated inconsistent results below the knee, and drug-coated balloons, therefore, are not approved for such indications.”

He said that drug-eluting stents have demonstrated efficacy in this indication but that these studies have been limited to fairly discrete proximal disease.

“LIFE-BTK therefore represents one of the most rigorous trials in the space of endovascular interventions as a single line and randomized trial,” Dr. Kandzari said, “showing a primary composite endpoint of both safety and effectiveness relative to conventional angioplasty.”

Dr. Kandzari pointed to strengths of the study in that it used standardization of technique with independent adjudication of both imaging and wound healing assessments. “And the study population, too, was relevant to clinical practice, representing oftentimes underrepresented groups, including those with extensive disease burden [and] clinical severity,” he said. “Importantly, in this study, nearly one-third of the population will be women.”

Panelist Jennifer Rymer, MD, of Duke University Medical Center, Durham, N.C., commented that she treats a lot of African American patients with CTLI and applauded the researchers for including those patients. “I think that this will be a groundbreaking new change in our practice,” she said.

The trial results were published simultaneously with the presentation at TCT 2023 in the New England Journal of Medicine.

Dr. Varcoe reported receiving consulting fees/honoraria from Boston Scientific Corporation, Medtronic, Abbott, BD, Intervene, Surmodics, Philips, Nectero, Alucent, W.L. Gore, Vesteck, Bard Medical, Cook Medical, and R3 Vascular. He has equity, stock, or stock options in EBR Systems and has an executive role or ownership interest in Provisio Medical and Vesteck. Dr. Kandzari received grant support/research contract from Medtronic, Teleflex, Biotronik, and CSI; consultant fees/honoraria from and is on the speaker’s bureau of CSI and Medtronic; and has equity, stock, or options in Biostar Ventures. Dr. Rymer receives grant support/research contract from Chiesi, Abbott Vascular, Abiomed, and Pfizer. The study was funded by Abbott.

A version of this article appeared on Medscape.com.

TOPLINE:

Childhood trauma increases the risk of developing a primary headache disorder in adulthood, with more early adverse experiences raising the risk even more, a new study found.

METHODOLOGY:

• The meta-analysis included 28 observational studies with 154,739 persons in 19 countries that assessed the relationship between at least one adverse childhood experience (ACE) and primary headache (including migraine, tension-type headache, cluster headache, and chronic/severe headache) at age 21 years or older.
• From each study, researchers extracted outcome point estimates and corresponding 95% confidence intervals, number of events in each group, and covariates included in the model. They subcategorized ACEs according to those involving threat (for example, physical, emotional, or sexual abuse) and deprivation (for example, neglect, household substance misuse).
• For the primary analysis, the researchers calculated the odds ratios and hazard ratios of headache among persons with at least one ACE, compared with those with no ACEs.
• They also tested an underlying biological theory that threat and deprivation ACEs may manifest differently in neurodevelopment, with distinct impacts on primary headaches.
•  

TAKEAWAY:

• The most commonly reported ACEs were physical abuse (77%), sexual abuse (73%), and exposure to family violence (38%).
• Compared with having experienced no ACEs, experiencing at least one was associated with primary headaches (pooled OR, 1.48; 95% confidence interval, 1.36-1.61).
• As the number of ACEs increased, the strength of the association with primary headaches increased in a dose-response relationship (P for trend < .0001).
• Both threat and deprivation were independently associated with primary headaches; the pooled main effect was consistent for threat (OR, 1.46; 95% CI, 1.32-1.60) and for deprivation (OR, 1.35; 95% CI, 1.23-1.49), suggesting possible distinct pathways of early adversity.
•  

IN PRACTICE:

Clinicians who treat primary headaches in adults “should routinely screen for ACEs, educate patients on the connection between ACEs and health, and provide referrals for treatment strategies,” the investigators write. Strategies such as trauma-informed or attachment-based therapy may help rewire parts of the brain that have been dysregulated, they add.

SOURCE:

The study was led by Claudia Sikorski, department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont. It was published online in Neurology.

LIMITATIONS:

The findings reflect a conservative estimate of the true impact of ACEs on primary headaches, because ACEs are commonly underreported. The analysis could not statistically disentangle younger adults with developing brains (age 21-26 years) from older adults. Not all included studies adjusted for age and sex, which are known risk factors for headaches. The study did not explore the relationship between ACEs and primary headache disorders in childhood and adolescence. Owing to the inherent nature of studies investigating ACEs, causation cannot be inferred.

DISCLOSURES:

The authors report no targeted funding and no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Childhood trauma increases the risk of developing a primary headache disorder in adulthood, with more early adverse experiences raising the risk even more, a new study found.

METHODOLOGY:

• The meta-analysis included 28 observational studies with 154,739 persons in 19 countries that assessed the relationship between at least one adverse childhood experience (ACE) and primary headache (including migraine, tension-type headache, cluster headache, and chronic/severe headache) at age 21 years or older.
• From each study, researchers extracted outcome point estimates and corresponding 95% confidence intervals, number of events in each group, and covariates included in the model. They subcategorized ACEs according to those involving threat (for example, physical, emotional, or sexual abuse) and deprivation (for example, neglect, household substance misuse).
• For the primary analysis, the researchers calculated the odds ratios and hazard ratios of headache among persons with at least one ACE, compared with those with no ACEs.
• They also tested an underlying biological theory that threat and deprivation ACEs may manifest differently in neurodevelopment, with distinct impacts on primary headaches.
•  

TAKEAWAY:

• The most commonly reported ACEs were physical abuse (77%), sexual abuse (73%), and exposure to family violence (38%).
• Compared with having experienced no ACEs, experiencing at least one was associated with primary headaches (pooled OR, 1.48; 95% confidence interval, 1.36-1.61).
• As the number of ACEs increased, the strength of the association with primary headaches increased in a dose-response relationship (P for trend < .0001).
• Both threat and deprivation were independently associated with primary headaches; the pooled main effect was consistent for threat (OR, 1.46; 95% CI, 1.32-1.60) and for deprivation (OR, 1.35; 95% CI, 1.23-1.49), suggesting possible distinct pathways of early adversity.
•  

IN PRACTICE:

Clinicians who treat primary headaches in adults “should routinely screen for ACEs, educate patients on the connection between ACEs and health, and provide referrals for treatment strategies,” the investigators write. Strategies such as trauma-informed or attachment-based therapy may help rewire parts of the brain that have been dysregulated, they add.

SOURCE:

The study was led by Claudia Sikorski, department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont. It was published online in Neurology.

LIMITATIONS:

The findings reflect a conservative estimate of the true impact of ACEs on primary headaches, because ACEs are commonly underreported. The analysis could not statistically disentangle younger adults with developing brains (age 21-26 years) from older adults. Not all included studies adjusted for age and sex, which are known risk factors for headaches. The study did not explore the relationship between ACEs and primary headache disorders in childhood and adolescence. Owing to the inherent nature of studies investigating ACEs, causation cannot be inferred.

DISCLOSURES:

The authors report no targeted funding and no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Childhood trauma increases the risk of developing a primary headache disorder in adulthood, with more early adverse experiences raising the risk even more, a new study found.

METHODOLOGY:

• The meta-analysis included 28 observational studies with 154,739 persons in 19 countries that assessed the relationship between at least one adverse childhood experience (ACE) and primary headache (including migraine, tension-type headache, cluster headache, and chronic/severe headache) at age 21 years or older.
• From each study, researchers extracted outcome point estimates and corresponding 95% confidence intervals, number of events in each group, and covariates included in the model. They subcategorized ACEs according to those involving threat (for example, physical, emotional, or sexual abuse) and deprivation (for example, neglect, household substance misuse).
• For the primary analysis, the researchers calculated the odds ratios and hazard ratios of headache among persons with at least one ACE, compared with those with no ACEs.
• They also tested an underlying biological theory that threat and deprivation ACEs may manifest differently in neurodevelopment, with distinct impacts on primary headaches.
•  

TAKEAWAY:

• The most commonly reported ACEs were physical abuse (77%), sexual abuse (73%), and exposure to family violence (38%).
• Compared with having experienced no ACEs, experiencing at least one was associated with primary headaches (pooled OR, 1.48; 95% confidence interval, 1.36-1.61).
• As the number of ACEs increased, the strength of the association with primary headaches increased in a dose-response relationship (P for trend < .0001).
• Both threat and deprivation were independently associated with primary headaches; the pooled main effect was consistent for threat (OR, 1.46; 95% CI, 1.32-1.60) and for deprivation (OR, 1.35; 95% CI, 1.23-1.49), suggesting possible distinct pathways of early adversity.
•  

IN PRACTICE:

Clinicians who treat primary headaches in adults “should routinely screen for ACEs, educate patients on the connection between ACEs and health, and provide referrals for treatment strategies,” the investigators write. Strategies such as trauma-informed or attachment-based therapy may help rewire parts of the brain that have been dysregulated, they add.

SOURCE:

The study was led by Claudia Sikorski, department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont. It was published online in Neurology.

LIMITATIONS:

The findings reflect a conservative estimate of the true impact of ACEs on primary headaches, because ACEs are commonly underreported. The analysis could not statistically disentangle younger adults with developing brains (age 21-26 years) from older adults. Not all included studies adjusted for age and sex, which are known risk factors for headaches. The study did not explore the relationship between ACEs and primary headache disorders in childhood and adolescence. Owing to the inherent nature of studies investigating ACEs, causation cannot be inferred.

DISCLOSURES:

The authors report no targeted funding and no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

A version of this article first appeared on Medscape.com.

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

A version of this article first appeared on Medscape.com.

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

A version of this article first appeared on Medscape.com.

CARLSBAD, CALIF. – For the estimated 10 million wounds that clinicians treat in the United States each year resulting from surgical procedures, trauma, burns, and other causes, the best outcome is a scar, a fibrotic dermis with a flattened epidermis that contains no sweat glands, no pilosebaceous units, and impaired nerve function.

But what if the outcome was skin regeneration instead of scar formation? At the annual symposium of the California Society of Dermatology & Dermatologic Surgery, Philip O. Scumpia, MD, PhD, described the development of a biomaterial known as microporous annealed particle (MAP) hydrogel, which in preclinical studies has been shown to trigger the immune system leading to improved tissue repair and healthier, stronger skin.

“We’re preprogrammed to undergo scarring,” said Dr. Scumpia, associate professor of dermatology at the University of California, Los Angeles. “Tissue fibrosis is an evolutionary process” where a fibrotic matrix is deposited “as quickly as possible to close the gap caused by an injury,” he noted. “All of the cues in the normal wound healing process result in fibrosis, but we want to move from scarring to tissue regeneration. The goal is to make something that can shift from this evolutionary process, and it’s proven to be inherently difficult.”

Dr. Scumpia

Common approaches to wound treatment include simple and advanced dressings, negative pressure, and hyperbaric oxygen. For wounds that persist beyond 30 days, advanced treatment options include decellularized grafts such as placental membranes, amniotic membranes, and acellular dermal matrices. “There are also cellularized grafts such as dressings that contain neonatal dermal fibroblasts,” which are expensive, said Dr. Scumpia, director of dermatopathology at the West Los Angeles VA Medical Center. “There are also semi-synthetic grafts such as single or double layer dermal replacement templates and synthetic dermal substitutes in the form of sheets or foam. All of these can help with wound coverage and help chronic wounds close on their own.”

Meanwhile, tissue regeneration – or efforts to restore tissue to its original functionality – include growth factors, stem cells, or replacement extracellular matrix (skin substitutes), or a combination. “Bioengineered dressings and bioengineered skin substitutes have shown modest improvement in wound healing but not tissue regeneration,” Dr. Scumpia said. “At best, we can accelerate scar formation and close the wound quicker, but nothing has been shown to regenerate tissue.”

Approaches to skin regeneration

Studies from the embryology literature have helped researchers develop better approaches to skin regeneration. For example, fetal skin heals without scarring when injured. “Hairs form from placodes, then sebaceous glands form, and fibroblasts that are part of the papillary mesenchymal body expressing special factors such as engrailed or CRABP1 drive hair follicle formation,” he said. “Many studies have shown that sonic hedgehog signaling, and Wnt/beta-catenin signaling can play a role in the development of new hair follicles. Also, fibroblasts in the dermis can drive hair follicle formation.”

Researchers are also learning about tissue regeneration from mouse models. For example, African spiny mice have been shown to heal regeneratively. “If you make wounds large enough on lab mice, the center heals regeneratively,” Dr. Scumpia said. “What’s interesting is that these same signals are present in embryonic hair follicle development. Why is this important? Who wants a hairy scar? It’s an organized structure that develops in the wound. That can help us understand what we need to put in so that our body regenerates on its own. In mouse models, the immune system has been shown to play a role in regeneration.”

Expanding on initial work conducted at UCLA, Dr. Scumpia and his colleagues founded San Diego-based Tempo Therapeutics, which is commercializing the MAP hydrogel to mimic the natural porosity and stiffness of skin. They sought to develop a new biomaterial, he said, noting that “the skin is porous on a microscale level, allowing cells to infiltrate different areas.” And the problem with existing biomaterials “is that they don’t incorporate into the skin very well,” he explained. “They’re usually stiff and rubbery and can cause a foreign body reaction, which can result in fibrous encapsulation and inflammation.”

The MAP hydrogel is composed of randomly packed “microsphere building blocks,” including an amino acid that promotes an immune response. When injected into a wound, the hydrogel forms a porous matrix in the tissue. Surface annealing locks in porosity and tissue grows into porous spaces, which avoids scar formation pathways and enables critical organs to regain function.

During in vivo tests, researchers observed decreases in inflammation compared with traditional hydrogels in the first 48 hours. “In mouse models, we found that if you inject in a hydrogel that has no porosity, the body tries to spit it out, and you have an immune reaction,” Dr. Scumpia said. “But when we used the MAP hydrogel, we found that cells can migrate through it, which allows wounds to heal quicker. When we added an antigen in the hydrogel trying to allow the hydrogel to degrade slower, it actually degraded more rapidly, but we found that new hair follicles formed in the center of these wounds, a hallmark of skin regeneration. My lab has been studying why this occurs and trying to use this to our advantage in other models.”

In an unpublished mouse burn wound model study, he and his colleagues excised a wound, but it never healed with regeneration in the center. “We don’t understand why,” he said. But when the researchers used the MAP gel in wounds of hairless mice, they observed the formation of sebaceous glands and hair follicles over the wound beds. “It’s an exciting finding to see hair follicles develop in the center of a wound,” Dr. Scumpia said. He noted that to date, use of the MAP hydrogel has demonstrated tissue regeneration in some of the 27 veterinary cases that have been performed, including for wounds following traumatic injuries or following tumor resections on paws that allowed the pets to avoid amputation.

Clinical trials planned

The first clinical trials of the MAP hydrogel are planned for treating complex diabetic wounds in early 2024 but will likely expand to other difficult-to-treat wounds, including venous stasis ulcers, decubitus ulcers, and use following large surgical resections. Dr. Scumpia and colleagues will also examine the regenerative biomaterial for tissue aesthetics, including dermal and deep tissue filler applications. The next steps in his laboratory, he said, are to combine biomaterials with stem cells, immune factors, or small molecular activators/inhibitors to improve sweat gland, nerve, or hair follicle regeneration.

Dr. Scumpia disclosed that he is a cofounder and shareholder in Tempo Therapeutics. He has also received grant support from the National Institutes of Health, Department of Veteran Affairs, and the LEO Foundation.

CARLSBAD, CALIF. – For the estimated 10 million wounds that clinicians treat in the United States each year resulting from surgical procedures, trauma, burns, and other causes, the best outcome is a scar, a fibrotic dermis with a flattened epidermis that contains no sweat glands, no pilosebaceous units, and impaired nerve function.

But what if the outcome was skin regeneration instead of scar formation? At the annual symposium of the California Society of Dermatology & Dermatologic Surgery, Philip O. Scumpia, MD, PhD, described the development of a biomaterial known as microporous annealed particle (MAP) hydrogel, which in preclinical studies has been shown to trigger the immune system leading to improved tissue repair and healthier, stronger skin.

“We’re preprogrammed to undergo scarring,” said Dr. Scumpia, associate professor of dermatology at the University of California, Los Angeles. “Tissue fibrosis is an evolutionary process” where a fibrotic matrix is deposited “as quickly as possible to close the gap caused by an injury,” he noted. “All of the cues in the normal wound healing process result in fibrosis, but we want to move from scarring to tissue regeneration. The goal is to make something that can shift from this evolutionary process, and it’s proven to be inherently difficult.”

Dr. Scumpia

Common approaches to wound treatment include simple and advanced dressings, negative pressure, and hyperbaric oxygen. For wounds that persist beyond 30 days, advanced treatment options include decellularized grafts such as placental membranes, amniotic membranes, and acellular dermal matrices. “There are also cellularized grafts such as dressings that contain neonatal dermal fibroblasts,” which are expensive, said Dr. Scumpia, director of dermatopathology at the West Los Angeles VA Medical Center. “There are also semi-synthetic grafts such as single or double layer dermal replacement templates and synthetic dermal substitutes in the form of sheets or foam. All of these can help with wound coverage and help chronic wounds close on their own.”

Meanwhile, tissue regeneration – or efforts to restore tissue to its original functionality – include growth factors, stem cells, or replacement extracellular matrix (skin substitutes), or a combination. “Bioengineered dressings and bioengineered skin substitutes have shown modest improvement in wound healing but not tissue regeneration,” Dr. Scumpia said. “At best, we can accelerate scar formation and close the wound quicker, but nothing has been shown to regenerate tissue.”

Approaches to skin regeneration

Studies from the embryology literature have helped researchers develop better approaches to skin regeneration. For example, fetal skin heals without scarring when injured. “Hairs form from placodes, then sebaceous glands form, and fibroblasts that are part of the papillary mesenchymal body expressing special factors such as engrailed or CRABP1 drive hair follicle formation,” he said. “Many studies have shown that sonic hedgehog signaling, and Wnt/beta-catenin signaling can play a role in the development of new hair follicles. Also, fibroblasts in the dermis can drive hair follicle formation.”

Researchers are also learning about tissue regeneration from mouse models. For example, African spiny mice have been shown to heal regeneratively. “If you make wounds large enough on lab mice, the center heals regeneratively,” Dr. Scumpia said. “What’s interesting is that these same signals are present in embryonic hair follicle development. Why is this important? Who wants a hairy scar? It’s an organized structure that develops in the wound. That can help us understand what we need to put in so that our body regenerates on its own. In mouse models, the immune system has been shown to play a role in regeneration.”

Expanding on initial work conducted at UCLA, Dr. Scumpia and his colleagues founded San Diego-based Tempo Therapeutics, which is commercializing the MAP hydrogel to mimic the natural porosity and stiffness of skin. They sought to develop a new biomaterial, he said, noting that “the skin is porous on a microscale level, allowing cells to infiltrate different areas.” And the problem with existing biomaterials “is that they don’t incorporate into the skin very well,” he explained. “They’re usually stiff and rubbery and can cause a foreign body reaction, which can result in fibrous encapsulation and inflammation.”

The MAP hydrogel is composed of randomly packed “microsphere building blocks,” including an amino acid that promotes an immune response. When injected into a wound, the hydrogel forms a porous matrix in the tissue. Surface annealing locks in porosity and tissue grows into porous spaces, which avoids scar formation pathways and enables critical organs to regain function.

During in vivo tests, researchers observed decreases in inflammation compared with traditional hydrogels in the first 48 hours. “In mouse models, we found that if you inject in a hydrogel that has no porosity, the body tries to spit it out, and you have an immune reaction,” Dr. Scumpia said. “But when we used the MAP hydrogel, we found that cells can migrate through it, which allows wounds to heal quicker. When we added an antigen in the hydrogel trying to allow the hydrogel to degrade slower, it actually degraded more rapidly, but we found that new hair follicles formed in the center of these wounds, a hallmark of skin regeneration. My lab has been studying why this occurs and trying to use this to our advantage in other models.”

In an unpublished mouse burn wound model study, he and his colleagues excised a wound, but it never healed with regeneration in the center. “We don’t understand why,” he said. But when the researchers used the MAP gel in wounds of hairless mice, they observed the formation of sebaceous glands and hair follicles over the wound beds. “It’s an exciting finding to see hair follicles develop in the center of a wound,” Dr. Scumpia said. He noted that to date, use of the MAP hydrogel has demonstrated tissue regeneration in some of the 27 veterinary cases that have been performed, including for wounds following traumatic injuries or following tumor resections on paws that allowed the pets to avoid amputation.

Clinical trials planned

The first clinical trials of the MAP hydrogel are planned for treating complex diabetic wounds in early 2024 but will likely expand to other difficult-to-treat wounds, including venous stasis ulcers, decubitus ulcers, and use following large surgical resections. Dr. Scumpia and colleagues will also examine the regenerative biomaterial for tissue aesthetics, including dermal and deep tissue filler applications. The next steps in his laboratory, he said, are to combine biomaterials with stem cells, immune factors, or small molecular activators/inhibitors to improve sweat gland, nerve, or hair follicle regeneration.

Dr. Scumpia disclosed that he is a cofounder and shareholder in Tempo Therapeutics. He has also received grant support from the National Institutes of Health, Department of Veteran Affairs, and the LEO Foundation.

CARLSBAD, CALIF. – For the estimated 10 million wounds that clinicians treat in the United States each year resulting from surgical procedures, trauma, burns, and other causes, the best outcome is a scar, a fibrotic dermis with a flattened epidermis that contains no sweat glands, no pilosebaceous units, and impaired nerve function.

But what if the outcome was skin regeneration instead of scar formation? At the annual symposium of the California Society of Dermatology & Dermatologic Surgery, Philip O. Scumpia, MD, PhD, described the development of a biomaterial known as microporous annealed particle (MAP) hydrogel, which in preclinical studies has been shown to trigger the immune system leading to improved tissue repair and healthier, stronger skin.

“We’re preprogrammed to undergo scarring,” said Dr. Scumpia, associate professor of dermatology at the University of California, Los Angeles. “Tissue fibrosis is an evolutionary process” where a fibrotic matrix is deposited “as quickly as possible to close the gap caused by an injury,” he noted. “All of the cues in the normal wound healing process result in fibrosis, but we want to move from scarring to tissue regeneration. The goal is to make something that can shift from this evolutionary process, and it’s proven to be inherently difficult.”

Dr. Scumpia

Common approaches to wound treatment include simple and advanced dressings, negative pressure, and hyperbaric oxygen. For wounds that persist beyond 30 days, advanced treatment options include decellularized grafts such as placental membranes, amniotic membranes, and acellular dermal matrices. “There are also cellularized grafts such as dressings that contain neonatal dermal fibroblasts,” which are expensive, said Dr. Scumpia, director of dermatopathology at the West Los Angeles VA Medical Center. “There are also semi-synthetic grafts such as single or double layer dermal replacement templates and synthetic dermal substitutes in the form of sheets or foam. All of these can help with wound coverage and help chronic wounds close on their own.”

Meanwhile, tissue regeneration – or efforts to restore tissue to its original functionality – include growth factors, stem cells, or replacement extracellular matrix (skin substitutes), or a combination. “Bioengineered dressings and bioengineered skin substitutes have shown modest improvement in wound healing but not tissue regeneration,” Dr. Scumpia said. “At best, we can accelerate scar formation and close the wound quicker, but nothing has been shown to regenerate tissue.”

Approaches to skin regeneration

Studies from the embryology literature have helped researchers develop better approaches to skin regeneration. For example, fetal skin heals without scarring when injured. “Hairs form from placodes, then sebaceous glands form, and fibroblasts that are part of the papillary mesenchymal body expressing special factors such as engrailed or CRABP1 drive hair follicle formation,” he said. “Many studies have shown that sonic hedgehog signaling, and Wnt/beta-catenin signaling can play a role in the development of new hair follicles. Also, fibroblasts in the dermis can drive hair follicle formation.”

Researchers are also learning about tissue regeneration from mouse models. For example, African spiny mice have been shown to heal regeneratively. “If you make wounds large enough on lab mice, the center heals regeneratively,” Dr. Scumpia said. “What’s interesting is that these same signals are present in embryonic hair follicle development. Why is this important? Who wants a hairy scar? It’s an organized structure that develops in the wound. That can help us understand what we need to put in so that our body regenerates on its own. In mouse models, the immune system has been shown to play a role in regeneration.”

Expanding on initial work conducted at UCLA, Dr. Scumpia and his colleagues founded San Diego-based Tempo Therapeutics, which is commercializing the MAP hydrogel to mimic the natural porosity and stiffness of skin. They sought to develop a new biomaterial, he said, noting that “the skin is porous on a microscale level, allowing cells to infiltrate different areas.” And the problem with existing biomaterials “is that they don’t incorporate into the skin very well,” he explained. “They’re usually stiff and rubbery and can cause a foreign body reaction, which can result in fibrous encapsulation and inflammation.”

The MAP hydrogel is composed of randomly packed “microsphere building blocks,” including an amino acid that promotes an immune response. When injected into a wound, the hydrogel forms a porous matrix in the tissue. Surface annealing locks in porosity and tissue grows into porous spaces, which avoids scar formation pathways and enables critical organs to regain function.

During in vivo tests, researchers observed decreases in inflammation compared with traditional hydrogels in the first 48 hours. “In mouse models, we found that if you inject in a hydrogel that has no porosity, the body tries to spit it out, and you have an immune reaction,” Dr. Scumpia said. “But when we used the MAP hydrogel, we found that cells can migrate through it, which allows wounds to heal quicker. When we added an antigen in the hydrogel trying to allow the hydrogel to degrade slower, it actually degraded more rapidly, but we found that new hair follicles formed in the center of these wounds, a hallmark of skin regeneration. My lab has been studying why this occurs and trying to use this to our advantage in other models.”

In an unpublished mouse burn wound model study, he and his colleagues excised a wound, but it never healed with regeneration in the center. “We don’t understand why,” he said. But when the researchers used the MAP gel in wounds of hairless mice, they observed the formation of sebaceous glands and hair follicles over the wound beds. “It’s an exciting finding to see hair follicles develop in the center of a wound,” Dr. Scumpia said. He noted that to date, use of the MAP hydrogel has demonstrated tissue regeneration in some of the 27 veterinary cases that have been performed, including for wounds following traumatic injuries or following tumor resections on paws that allowed the pets to avoid amputation.

Clinical trials planned

The first clinical trials of the MAP hydrogel are planned for treating complex diabetic wounds in early 2024 but will likely expand to other difficult-to-treat wounds, including venous stasis ulcers, decubitus ulcers, and use following large surgical resections. Dr. Scumpia and colleagues will also examine the regenerative biomaterial for tissue aesthetics, including dermal and deep tissue filler applications. The next steps in his laboratory, he said, are to combine biomaterials with stem cells, immune factors, or small molecular activators/inhibitors to improve sweat gland, nerve, or hair follicle regeneration.

Dr. Scumpia disclosed that he is a cofounder and shareholder in Tempo Therapeutics. He has also received grant support from the National Institutes of Health, Department of Veteran Affairs, and the LEO Foundation.