Conference Coverage

AMSTERDAM — Prurigo nodularis (PN), an itchy, highly symptomatic disease that can cause severe impairments in quality of life, may gain a third therapy if promising data on povorcitinib presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress are further validated.

“We now have a pipeline of clinical studies in PN. Who would have even thought that a few years ago,” said Shawn Kwatra, MD, professor and chair, Department of Dermatology, University of Maryland School of Medicine, Baltimore. That is a remarkable turn of events for a difficult disease, he added.

Dr. Kwatra

Dupilumab, a monoclonal antibody that inhibits the activity of interleukin (IL)–4 and IL-13, was the first treatment approved for PN by the Food and Drug Administration 2 years ago. Approval of nemolizumab, a monoclonal antibody that targets IL-31, a cytokine strongly implicated in the itch response, followed in August 2024. Povorcitinib, which targets Janus kinase 1 (JAK1), is on track to be the third.

New data on both nemolizumab and povorcitinib were presented in late breaking news sessions at EADV.

For povorcitinib, a JAK inhibitor, Dr. Kwatra presented extended phase 2 results through 40 weeks at a late-breaker session at the EADV meeting. They follow 16-week data from a randomized study presented earlier this year.

Of the 146 patients followed in the original 16-week randomized trial, which compared 15, 45, and 75 mg of oral povorcitinib once daily against placebo, 126 entered an extension in which all patients were treated with active therapy. In this single-blind phase, those who were responders at 16 weeks received 45 mg povorcitinib, and those who were nonresponders received 75 mg povorcitinib.

At 16 weeks, all doses were superior to placebo in achieving at least a 4-point reduction on the Itch Numerical Rating Scale (NRS4) and the Investigator Global Assessment (IGA) score 0 or 1 (clear or almost clear), as well as in a composite endpoint of both. However, even though the lowest dose of povorcitinib was active, there was a “very clear dose response” demonstrated in speed of response and proportion of responders, according to Dr. Kwatra.

On the 75-mg dose, the time to improvement was a median of 19 days, while the median times to improvement were 35 days on the 45-mg dose and 58 days on the 15-mg dose.

Among povorcitinib responders, 96% had met the NRS4 response at the time they entered the extension study. During the extension study, the proportion of responders who maintained this level of itch control hovered around 90% for the duration. The proportion was 89% at week 40.

The proportion of responders at 16 weeks achieving IGA 0/1, signifying clear or almost clear, was 93%. Again, the rate hovered around 90% for the full 40 weeks. At week 40, the proportion at this outcome was also 89%. The composite outcome among responders persisted at about 80% for most of the follow-up but fell to 63% at the last follow-up.

Among nonresponders who transitioned to 75 mg povorcitinib for the extension period, the NSR4 response rates climbed within 4 weeks to approximately 60% and reached 70% at week 40. For the endpoint of IGA 0/1, rates rose incrementally among the nonresponders over time, reaching 51% at week 40. The composite endpoint was reached at 40 weeks by 41% of nonresponders switched to 75 mg during the 24-week extension.

The results at 40 weeks were highly encouraging, according to Dr. Kwatra, who reported there were no surprises in regard to safety during the extension period. He reported some transient reductions in hemoglobin and infections that resolved, but there were no cardiac events or other more serious events that have been previously associated with JAK inhibitors during the 40-week study period.

When asked if there might be an advantage for povorcitinib relative to the monoclonal antibodies in regard to speed of onset, Dr. Kwatra said that there are no comparative data. Like previous experience with dupilumab, some patients responded rapidly with povorcitinib, but others took longer to achieve benefit.

This variability in response is consistent with the growing evidence that PN is a heterogeneous disease, according to Dr. Kwatra. With multiple up-regulated cytokines implicated in the pathogenesis of PN, he suggested that more treatment options would be useful. When it comes to the multiple molecular pathways involved in the pathogenesis of PN, he said, “patients can be at a different edge of a spectrum.”

In other evidence suggesting that more options are needed, another late-breaking news study at the 2024 EADV congress underlined the fact that PN is a chronic disease. Presented by Franz J. Legat, MD, professor of dermatology at the Medical University of Graz, Graz, Austria, the data involved a withdrawal evaluation nested in a long-term extension (LTE) of the OLYMPIA pivotal trials with nemolizumab.

After 52 weeks in the LTE, 34 patients entered the OLYMPIA DURABILITY study, in which they were randomized to withdrawal or to continue on nemolizumab on an every 4-week dosing schedule.

The relapse rate over 24 weeks was 16.7% (3 of 18 patients) in the continuous nemolizumab arm and 75% (12 of 16 patients) in the withdrawal arm. The median time to relapse was 112.5 days for those in the withdrawal arm and was not reached during follow-up in the nemolizumab arm.

Praising the patients who were willing to risk PN relapse by entering this randomized trial, Dr. Legat said that the study shows a relatively high risk for relapse within months of treatment withdrawal even after good PN control over a period of 52 weeks.

“These data clearly support continuous nemolizumab beyond 52 weeks,” he said.

Dr. Kwatra reported financial relationships with AbbVie, Arcutis, Biotherapeutics, Aslan, Celldex, Galderma, Genzada, Johnson & Johnson, Novartis, Pfizer, Regeneron, Sanofi, and Incyte, which is developing povorcitinib for PN. Dr. Legat reported financial relationships with Almirall, Celgene, Eli Lilly, Menlo Therapeutics, Novartis, Pfizer, Trevi, Vifor, and Galderma, which provided funding for the nemolizumab studies.

A version of this article appeared on Medscape.com.

AMSTERDAM — Prurigo nodularis (PN), an itchy, highly symptomatic disease that can cause severe impairments in quality of life, may gain a third therapy if promising data on povorcitinib presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress are further validated.

“We now have a pipeline of clinical studies in PN. Who would have even thought that a few years ago,” said Shawn Kwatra, MD, professor and chair, Department of Dermatology, University of Maryland School of Medicine, Baltimore. That is a remarkable turn of events for a difficult disease, he added.

Dr. Kwatra

Dupilumab, a monoclonal antibody that inhibits the activity of interleukin (IL)–4 and IL-13, was the first treatment approved for PN by the Food and Drug Administration 2 years ago. Approval of nemolizumab, a monoclonal antibody that targets IL-31, a cytokine strongly implicated in the itch response, followed in August 2024. Povorcitinib, which targets Janus kinase 1 (JAK1), is on track to be the third.

New data on both nemolizumab and povorcitinib were presented in late breaking news sessions at EADV.

For povorcitinib, a JAK inhibitor, Dr. Kwatra presented extended phase 2 results through 40 weeks at a late-breaker session at the EADV meeting. They follow 16-week data from a randomized study presented earlier this year.

Of the 146 patients followed in the original 16-week randomized trial, which compared 15, 45, and 75 mg of oral povorcitinib once daily against placebo, 126 entered an extension in which all patients were treated with active therapy. In this single-blind phase, those who were responders at 16 weeks received 45 mg povorcitinib, and those who were nonresponders received 75 mg povorcitinib.

At 16 weeks, all doses were superior to placebo in achieving at least a 4-point reduction on the Itch Numerical Rating Scale (NRS4) and the Investigator Global Assessment (IGA) score 0 or 1 (clear or almost clear), as well as in a composite endpoint of both. However, even though the lowest dose of povorcitinib was active, there was a “very clear dose response” demonstrated in speed of response and proportion of responders, according to Dr. Kwatra.

On the 75-mg dose, the time to improvement was a median of 19 days, while the median times to improvement were 35 days on the 45-mg dose and 58 days on the 15-mg dose.

Among povorcitinib responders, 96% had met the NRS4 response at the time they entered the extension study. During the extension study, the proportion of responders who maintained this level of itch control hovered around 90% for the duration. The proportion was 89% at week 40.

The proportion of responders at 16 weeks achieving IGA 0/1, signifying clear or almost clear, was 93%. Again, the rate hovered around 90% for the full 40 weeks. At week 40, the proportion at this outcome was also 89%. The composite outcome among responders persisted at about 80% for most of the follow-up but fell to 63% at the last follow-up.

Among nonresponders who transitioned to 75 mg povorcitinib for the extension period, the NSR4 response rates climbed within 4 weeks to approximately 60% and reached 70% at week 40. For the endpoint of IGA 0/1, rates rose incrementally among the nonresponders over time, reaching 51% at week 40. The composite endpoint was reached at 40 weeks by 41% of nonresponders switched to 75 mg during the 24-week extension.

The results at 40 weeks were highly encouraging, according to Dr. Kwatra, who reported there were no surprises in regard to safety during the extension period. He reported some transient reductions in hemoglobin and infections that resolved, but there were no cardiac events or other more serious events that have been previously associated with JAK inhibitors during the 40-week study period.

When asked if there might be an advantage for povorcitinib relative to the monoclonal antibodies in regard to speed of onset, Dr. Kwatra said that there are no comparative data. Like previous experience with dupilumab, some patients responded rapidly with povorcitinib, but others took longer to achieve benefit.

This variability in response is consistent with the growing evidence that PN is a heterogeneous disease, according to Dr. Kwatra. With multiple up-regulated cytokines implicated in the pathogenesis of PN, he suggested that more treatment options would be useful. When it comes to the multiple molecular pathways involved in the pathogenesis of PN, he said, “patients can be at a different edge of a spectrum.”

In other evidence suggesting that more options are needed, another late-breaking news study at the 2024 EADV congress underlined the fact that PN is a chronic disease. Presented by Franz J. Legat, MD, professor of dermatology at the Medical University of Graz, Graz, Austria, the data involved a withdrawal evaluation nested in a long-term extension (LTE) of the OLYMPIA pivotal trials with nemolizumab.

After 52 weeks in the LTE, 34 patients entered the OLYMPIA DURABILITY study, in which they were randomized to withdrawal or to continue on nemolizumab on an every 4-week dosing schedule.

The relapse rate over 24 weeks was 16.7% (3 of 18 patients) in the continuous nemolizumab arm and 75% (12 of 16 patients) in the withdrawal arm. The median time to relapse was 112.5 days for those in the withdrawal arm and was not reached during follow-up in the nemolizumab arm.

Praising the patients who were willing to risk PN relapse by entering this randomized trial, Dr. Legat said that the study shows a relatively high risk for relapse within months of treatment withdrawal even after good PN control over a period of 52 weeks.

“These data clearly support continuous nemolizumab beyond 52 weeks,” he said.

Dr. Kwatra reported financial relationships with AbbVie, Arcutis, Biotherapeutics, Aslan, Celldex, Galderma, Genzada, Johnson & Johnson, Novartis, Pfizer, Regeneron, Sanofi, and Incyte, which is developing povorcitinib for PN. Dr. Legat reported financial relationships with Almirall, Celgene, Eli Lilly, Menlo Therapeutics, Novartis, Pfizer, Trevi, Vifor, and Galderma, which provided funding for the nemolizumab studies.

A version of this article appeared on Medscape.com.

AMSTERDAM — Prurigo nodularis (PN), an itchy, highly symptomatic disease that can cause severe impairments in quality of life, may gain a third therapy if promising data on povorcitinib presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress are further validated.

“We now have a pipeline of clinical studies in PN. Who would have even thought that a few years ago,” said Shawn Kwatra, MD, professor and chair, Department of Dermatology, University of Maryland School of Medicine, Baltimore. That is a remarkable turn of events for a difficult disease, he added.

Dr. Kwatra

Dupilumab, a monoclonal antibody that inhibits the activity of interleukin (IL)–4 and IL-13, was the first treatment approved for PN by the Food and Drug Administration 2 years ago. Approval of nemolizumab, a monoclonal antibody that targets IL-31, a cytokine strongly implicated in the itch response, followed in August 2024. Povorcitinib, which targets Janus kinase 1 (JAK1), is on track to be the third.

New data on both nemolizumab and povorcitinib were presented in late breaking news sessions at EADV.

For povorcitinib, a JAK inhibitor, Dr. Kwatra presented extended phase 2 results through 40 weeks at a late-breaker session at the EADV meeting. They follow 16-week data from a randomized study presented earlier this year.

Of the 146 patients followed in the original 16-week randomized trial, which compared 15, 45, and 75 mg of oral povorcitinib once daily against placebo, 126 entered an extension in which all patients were treated with active therapy. In this single-blind phase, those who were responders at 16 weeks received 45 mg povorcitinib, and those who were nonresponders received 75 mg povorcitinib.

At 16 weeks, all doses were superior to placebo in achieving at least a 4-point reduction on the Itch Numerical Rating Scale (NRS4) and the Investigator Global Assessment (IGA) score 0 or 1 (clear or almost clear), as well as in a composite endpoint of both. However, even though the lowest dose of povorcitinib was active, there was a “very clear dose response” demonstrated in speed of response and proportion of responders, according to Dr. Kwatra.

On the 75-mg dose, the time to improvement was a median of 19 days, while the median times to improvement were 35 days on the 45-mg dose and 58 days on the 15-mg dose.

Among povorcitinib responders, 96% had met the NRS4 response at the time they entered the extension study. During the extension study, the proportion of responders who maintained this level of itch control hovered around 90% for the duration. The proportion was 89% at week 40.

The proportion of responders at 16 weeks achieving IGA 0/1, signifying clear or almost clear, was 93%. Again, the rate hovered around 90% for the full 40 weeks. At week 40, the proportion at this outcome was also 89%. The composite outcome among responders persisted at about 80% for most of the follow-up but fell to 63% at the last follow-up.

Among nonresponders who transitioned to 75 mg povorcitinib for the extension period, the NSR4 response rates climbed within 4 weeks to approximately 60% and reached 70% at week 40. For the endpoint of IGA 0/1, rates rose incrementally among the nonresponders over time, reaching 51% at week 40. The composite endpoint was reached at 40 weeks by 41% of nonresponders switched to 75 mg during the 24-week extension.

The results at 40 weeks were highly encouraging, according to Dr. Kwatra, who reported there were no surprises in regard to safety during the extension period. He reported some transient reductions in hemoglobin and infections that resolved, but there were no cardiac events or other more serious events that have been previously associated with JAK inhibitors during the 40-week study period.

When asked if there might be an advantage for povorcitinib relative to the monoclonal antibodies in regard to speed of onset, Dr. Kwatra said that there are no comparative data. Like previous experience with dupilumab, some patients responded rapidly with povorcitinib, but others took longer to achieve benefit.

This variability in response is consistent with the growing evidence that PN is a heterogeneous disease, according to Dr. Kwatra. With multiple up-regulated cytokines implicated in the pathogenesis of PN, he suggested that more treatment options would be useful. When it comes to the multiple molecular pathways involved in the pathogenesis of PN, he said, “patients can be at a different edge of a spectrum.”

In other evidence suggesting that more options are needed, another late-breaking news study at the 2024 EADV congress underlined the fact that PN is a chronic disease. Presented by Franz J. Legat, MD, professor of dermatology at the Medical University of Graz, Graz, Austria, the data involved a withdrawal evaluation nested in a long-term extension (LTE) of the OLYMPIA pivotal trials with nemolizumab.

After 52 weeks in the LTE, 34 patients entered the OLYMPIA DURABILITY study, in which they were randomized to withdrawal or to continue on nemolizumab on an every 4-week dosing schedule.

The relapse rate over 24 weeks was 16.7% (3 of 18 patients) in the continuous nemolizumab arm and 75% (12 of 16 patients) in the withdrawal arm. The median time to relapse was 112.5 days for those in the withdrawal arm and was not reached during follow-up in the nemolizumab arm.

Praising the patients who were willing to risk PN relapse by entering this randomized trial, Dr. Legat said that the study shows a relatively high risk for relapse within months of treatment withdrawal even after good PN control over a period of 52 weeks.

“These data clearly support continuous nemolizumab beyond 52 weeks,” he said.

Dr. Kwatra reported financial relationships with AbbVie, Arcutis, Biotherapeutics, Aslan, Celldex, Galderma, Genzada, Johnson & Johnson, Novartis, Pfizer, Regeneron, Sanofi, and Incyte, which is developing povorcitinib for PN. Dr. Legat reported financial relationships with Almirall, Celgene, Eli Lilly, Menlo Therapeutics, Novartis, Pfizer, Trevi, Vifor, and Galderma, which provided funding for the nemolizumab studies.

A version of this article appeared on Medscape.com.

AMSTERDAM — For patients with atopic dermatitis (AD) who responded to the anti–interleukin (IL)–13 monoclonal antibody lebrikizumab in the pivotal trials, the level of response, including 90% skin clearance, has generally remained unchanged among those followed up for an additional 2 years, according to the latest data from an extension study. 

At the end of the maintenance phase of the pivotal trials at 12 months, 84% of the patients enrolled into the extension had clear or almost clear skin, as per the Investigator Global Assessment (IGA). This overall figure as well as the proportion with even better responses have persisted unchanged, reported Diamant Thaçi, MD, PhD, professor and head of the Comprehensive Center for Inflammatory Medicine, University of Lübeck in Germany. 
 

Responses at 3 Years Maintained

“This is really quite remarkable,” Dr. Thaçi said. “Roughly all the patients maintained their response.” These results became even more remarkable when patients were assessed for their use of adjunctive therapy to control flares. 

“Over the whole follow-up, 90% had no need for topical corticosteroids or any other rescue therapy,” Dr. Thaçi reported, providing data from the ADjoin lebrikizumab extension study during a late-breaking news session at the annual meeting of the European Academy of Dermatology and Venereology. 

The patients in ADjoin were enrolled from the pivotal phase 3 ADvocate 1 and 2 trials completed almost 2 years ago and published together in March 2023. Lebrikizumab was approved in the United States in September 2024 for moderate to severe AD in patients aged ≥ 12 years, following previous approvals in Europe in 2023 and in Japan in January 2024.

In these two identical trials with a total of 564 patients, the primary endpoint was an IGA of 0 or 1, signifying clear or almost clear skin. At nearly 40%, the proportion of patients reaching this outcome at 16 weeks was about threefold greater (P < .001) on lebrikizumab than on placebo. The benefit was similar on secondary endpoints, such as 75% improvement in the Eczema Area and Severity Index (EASI75) score. 

At the end of the double-blind, placebo-controlled 16-week phase of the ADvocate 1 and 2 trials, which enrolled adults and adolescents aged ≥ 12 years, responders were enrolled into a maintenance phase in which they were rerandomized to 250 mg lebrikizumab every 2 weeks (Q2W) or every 4 weeks (Q4W). The latter is the approved maintenance dose. 

At the end of the maintenance phase, which lasted another 32 weeks (total exposure of 52 weeks for those initially randomized to lebrikizumab), patients were invited into the ADjoin extension. The only exclusions from the extension were serious adverse events related to lebrikizumab and noncompliance. 
 

Response Curves Appear as Straight Lines

Over the next 2 years of ADjoin, response curves appeared as straight lines not only for the overall response but when patients were stratified for different levels of response at the extension study entry. Specifically, 81.5% and 83.3% had an IGA score of 0 or 1 in the Q2W and Q4W arms at completion of the ADvocate 16-week double-blind phase. At 3 years, the rates were 84.0% and 82.9%, respectively. 

For the subgroup who entered ADjoin with an EASI75 or an EASI90 response, the persistence of this level of response over 2 years was similar, although there was some gain observed among those who entered the trial with an EASI75 response. 

“Not only did these patients maintain their response, but the response on average slowly improved, so that there were more patients with an EASI90 response at the 3-year timepoint,” Dr. Thaçi said.

Of the 181 patients in the ADjoin extension, 82 patients were maintained on Q2W dosing and 99 were maintained on Q4W lebrikizumab. Their mean age was about 35 years, more than half were women, and nearly 40% had severe AD at the time they enrolled in the ADvocate trials. There was essentially no difference in response rates among those in the Q2W and Q4W arms over time in ADjoin. 
 

Side Effect Profile Essentially Unchanged

The side effect and tolerability profiles, which were favorable in the original 16-week placebo-controlled study, have remained unchanged over the subsequent maintenance phase and through the additional 2 years of the ADjoin extension.

“There continued to be reports of conjunctivitis, which is very specific for anti–IL-13 therapies,” Dr. Thaçi said. However, he said that the incidence did not increase over time, and because it was easy to treat, “most patients do not discontinue lebrikizumab for this reason.” Moreover, he said the impression was that “the number of patients experiencing adverse effects has been decreasing over time.” 

Calling these long-term results “very exciting,” Dr. Thaçi called lebrikizumab “a very valuable option for long-term AD care.” 

Asked for his perspective on the results, Jonathan I. Silverberg, MD, PhD, Director of Clinical Research, Department of Dermatology, George Washington University, Washington, DC, said that it is important to study long-term efficacy, and these results are positive. Without direct comparisons to other biologics available for AD, nothing can be implied about the relative efficacy of monoclonal antibodies approved for AD. 

“These data are important both from an efficacy and safety perspective” for those advising patients who need chronic AD treatment, said Dr. Silverberg, who was the principal investigator of the ADvocate trials. 

Earlier this year, 5-year follow-up data were published for dupilumab. Of 326 patients who remained on therapy this long, 220 (67%) maintained an IGA of 0 or 1 at the end of the study. There were no unexpected adverse events, which were generally stable or declined throughout the study. 

Dr. Thaçi has financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Galderma, Leo Pharma, L’Oreal, Janssen-Cilag, New Bridge, Novartis, Pfizer, Regeneron, Roche, Sanofi, Sun Pharma, UCB, and Vichy. Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies including those that make drugs for AD.

A version of this article appeared on Medscape.com.

AMSTERDAM — For patients with atopic dermatitis (AD) who responded to the anti–interleukin (IL)–13 monoclonal antibody lebrikizumab in the pivotal trials, the level of response, including 90% skin clearance, has generally remained unchanged among those followed up for an additional 2 years, according to the latest data from an extension study. 

At the end of the maintenance phase of the pivotal trials at 12 months, 84% of the patients enrolled into the extension had clear or almost clear skin, as per the Investigator Global Assessment (IGA). This overall figure as well as the proportion with even better responses have persisted unchanged, reported Diamant Thaçi, MD, PhD, professor and head of the Comprehensive Center for Inflammatory Medicine, University of Lübeck in Germany. 
 

Responses at 3 Years Maintained

“This is really quite remarkable,” Dr. Thaçi said. “Roughly all the patients maintained their response.” These results became even more remarkable when patients were assessed for their use of adjunctive therapy to control flares. 

“Over the whole follow-up, 90% had no need for topical corticosteroids or any other rescue therapy,” Dr. Thaçi reported, providing data from the ADjoin lebrikizumab extension study during a late-breaking news session at the annual meeting of the European Academy of Dermatology and Venereology. 

The patients in ADjoin were enrolled from the pivotal phase 3 ADvocate 1 and 2 trials completed almost 2 years ago and published together in March 2023. Lebrikizumab was approved in the United States in September 2024 for moderate to severe AD in patients aged ≥ 12 years, following previous approvals in Europe in 2023 and in Japan in January 2024.

In these two identical trials with a total of 564 patients, the primary endpoint was an IGA of 0 or 1, signifying clear or almost clear skin. At nearly 40%, the proportion of patients reaching this outcome at 16 weeks was about threefold greater (P < .001) on lebrikizumab than on placebo. The benefit was similar on secondary endpoints, such as 75% improvement in the Eczema Area and Severity Index (EASI75) score. 

At the end of the double-blind, placebo-controlled 16-week phase of the ADvocate 1 and 2 trials, which enrolled adults and adolescents aged ≥ 12 years, responders were enrolled into a maintenance phase in which they were rerandomized to 250 mg lebrikizumab every 2 weeks (Q2W) or every 4 weeks (Q4W). The latter is the approved maintenance dose. 

At the end of the maintenance phase, which lasted another 32 weeks (total exposure of 52 weeks for those initially randomized to lebrikizumab), patients were invited into the ADjoin extension. The only exclusions from the extension were serious adverse events related to lebrikizumab and noncompliance. 
 

Response Curves Appear as Straight Lines

Over the next 2 years of ADjoin, response curves appeared as straight lines not only for the overall response but when patients were stratified for different levels of response at the extension study entry. Specifically, 81.5% and 83.3% had an IGA score of 0 or 1 in the Q2W and Q4W arms at completion of the ADvocate 16-week double-blind phase. At 3 years, the rates were 84.0% and 82.9%, respectively. 

For the subgroup who entered ADjoin with an EASI75 or an EASI90 response, the persistence of this level of response over 2 years was similar, although there was some gain observed among those who entered the trial with an EASI75 response. 

“Not only did these patients maintain their response, but the response on average slowly improved, so that there were more patients with an EASI90 response at the 3-year timepoint,” Dr. Thaçi said.

Of the 181 patients in the ADjoin extension, 82 patients were maintained on Q2W dosing and 99 were maintained on Q4W lebrikizumab. Their mean age was about 35 years, more than half were women, and nearly 40% had severe AD at the time they enrolled in the ADvocate trials. There was essentially no difference in response rates among those in the Q2W and Q4W arms over time in ADjoin. 
 

Side Effect Profile Essentially Unchanged

The side effect and tolerability profiles, which were favorable in the original 16-week placebo-controlled study, have remained unchanged over the subsequent maintenance phase and through the additional 2 years of the ADjoin extension.

“There continued to be reports of conjunctivitis, which is very specific for anti–IL-13 therapies,” Dr. Thaçi said. However, he said that the incidence did not increase over time, and because it was easy to treat, “most patients do not discontinue lebrikizumab for this reason.” Moreover, he said the impression was that “the number of patients experiencing adverse effects has been decreasing over time.” 

Calling these long-term results “very exciting,” Dr. Thaçi called lebrikizumab “a very valuable option for long-term AD care.” 

Asked for his perspective on the results, Jonathan I. Silverberg, MD, PhD, Director of Clinical Research, Department of Dermatology, George Washington University, Washington, DC, said that it is important to study long-term efficacy, and these results are positive. Without direct comparisons to other biologics available for AD, nothing can be implied about the relative efficacy of monoclonal antibodies approved for AD. 

“These data are important both from an efficacy and safety perspective” for those advising patients who need chronic AD treatment, said Dr. Silverberg, who was the principal investigator of the ADvocate trials. 

Earlier this year, 5-year follow-up data were published for dupilumab. Of 326 patients who remained on therapy this long, 220 (67%) maintained an IGA of 0 or 1 at the end of the study. There were no unexpected adverse events, which were generally stable or declined throughout the study. 

Dr. Thaçi has financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Galderma, Leo Pharma, L’Oreal, Janssen-Cilag, New Bridge, Novartis, Pfizer, Regeneron, Roche, Sanofi, Sun Pharma, UCB, and Vichy. Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies including those that make drugs for AD.

A version of this article appeared on Medscape.com.

AMSTERDAM — For patients with atopic dermatitis (AD) who responded to the anti–interleukin (IL)–13 monoclonal antibody lebrikizumab in the pivotal trials, the level of response, including 90% skin clearance, has generally remained unchanged among those followed up for an additional 2 years, according to the latest data from an extension study. 

At the end of the maintenance phase of the pivotal trials at 12 months, 84% of the patients enrolled into the extension had clear or almost clear skin, as per the Investigator Global Assessment (IGA). This overall figure as well as the proportion with even better responses have persisted unchanged, reported Diamant Thaçi, MD, PhD, professor and head of the Comprehensive Center for Inflammatory Medicine, University of Lübeck in Germany. 
 

Responses at 3 Years Maintained

“This is really quite remarkable,” Dr. Thaçi said. “Roughly all the patients maintained their response.” These results became even more remarkable when patients were assessed for their use of adjunctive therapy to control flares. 

“Over the whole follow-up, 90% had no need for topical corticosteroids or any other rescue therapy,” Dr. Thaçi reported, providing data from the ADjoin lebrikizumab extension study during a late-breaking news session at the annual meeting of the European Academy of Dermatology and Venereology. 

The patients in ADjoin were enrolled from the pivotal phase 3 ADvocate 1 and 2 trials completed almost 2 years ago and published together in March 2023. Lebrikizumab was approved in the United States in September 2024 for moderate to severe AD in patients aged ≥ 12 years, following previous approvals in Europe in 2023 and in Japan in January 2024.

In these two identical trials with a total of 564 patients, the primary endpoint was an IGA of 0 or 1, signifying clear or almost clear skin. At nearly 40%, the proportion of patients reaching this outcome at 16 weeks was about threefold greater (P < .001) on lebrikizumab than on placebo. The benefit was similar on secondary endpoints, such as 75% improvement in the Eczema Area and Severity Index (EASI75) score. 

At the end of the double-blind, placebo-controlled 16-week phase of the ADvocate 1 and 2 trials, which enrolled adults and adolescents aged ≥ 12 years, responders were enrolled into a maintenance phase in which they were rerandomized to 250 mg lebrikizumab every 2 weeks (Q2W) or every 4 weeks (Q4W). The latter is the approved maintenance dose. 

At the end of the maintenance phase, which lasted another 32 weeks (total exposure of 52 weeks for those initially randomized to lebrikizumab), patients were invited into the ADjoin extension. The only exclusions from the extension were serious adverse events related to lebrikizumab and noncompliance. 
 

Response Curves Appear as Straight Lines

Over the next 2 years of ADjoin, response curves appeared as straight lines not only for the overall response but when patients were stratified for different levels of response at the extension study entry. Specifically, 81.5% and 83.3% had an IGA score of 0 or 1 in the Q2W and Q4W arms at completion of the ADvocate 16-week double-blind phase. At 3 years, the rates were 84.0% and 82.9%, respectively. 

For the subgroup who entered ADjoin with an EASI75 or an EASI90 response, the persistence of this level of response over 2 years was similar, although there was some gain observed among those who entered the trial with an EASI75 response. 

“Not only did these patients maintain their response, but the response on average slowly improved, so that there were more patients with an EASI90 response at the 3-year timepoint,” Dr. Thaçi said.

Of the 181 patients in the ADjoin extension, 82 patients were maintained on Q2W dosing and 99 were maintained on Q4W lebrikizumab. Their mean age was about 35 years, more than half were women, and nearly 40% had severe AD at the time they enrolled in the ADvocate trials. There was essentially no difference in response rates among those in the Q2W and Q4W arms over time in ADjoin. 
 

Side Effect Profile Essentially Unchanged

The side effect and tolerability profiles, which were favorable in the original 16-week placebo-controlled study, have remained unchanged over the subsequent maintenance phase and through the additional 2 years of the ADjoin extension.

“There continued to be reports of conjunctivitis, which is very specific for anti–IL-13 therapies,” Dr. Thaçi said. However, he said that the incidence did not increase over time, and because it was easy to treat, “most patients do not discontinue lebrikizumab for this reason.” Moreover, he said the impression was that “the number of patients experiencing adverse effects has been decreasing over time.” 

Calling these long-term results “very exciting,” Dr. Thaçi called lebrikizumab “a very valuable option for long-term AD care.” 

Asked for his perspective on the results, Jonathan I. Silverberg, MD, PhD, Director of Clinical Research, Department of Dermatology, George Washington University, Washington, DC, said that it is important to study long-term efficacy, and these results are positive. Without direct comparisons to other biologics available for AD, nothing can be implied about the relative efficacy of monoclonal antibodies approved for AD. 

“These data are important both from an efficacy and safety perspective” for those advising patients who need chronic AD treatment, said Dr. Silverberg, who was the principal investigator of the ADvocate trials. 

Earlier this year, 5-year follow-up data were published for dupilumab. Of 326 patients who remained on therapy this long, 220 (67%) maintained an IGA of 0 or 1 at the end of the study. There were no unexpected adverse events, which were generally stable or declined throughout the study. 

Dr. Thaçi has financial relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Galderma, Leo Pharma, L’Oreal, Janssen-Cilag, New Bridge, Novartis, Pfizer, Regeneron, Roche, Sanofi, Sun Pharma, UCB, and Vichy. Dr. Silverberg reported financial relationships with more than 40 pharmaceutical companies including those that make drugs for AD.

A version of this article appeared on Medscape.com.

AMSTERDAM — For frontal fibrosing alopecia (FFA), a disease with no approved therapies, topical delgocitinib attenuated inflammation and generated hair regrowth in women in a controlled phase 2a trial.

“This is an exciting avenue for FFA if the data are recapitulated in a larger population. It could be an important new treatment option,” said Maryanne Senna, MD, director at Lahey Hospital & Medical Center’s Hair Loss Center of Excellence, Burlington, Massachusetts, and assistant dermatology professor at Harvard Medical School, Boston, Massachusetts.

In a design characterized as “exploratory,” the trial had two parts: a randomized, double-blind, vehicle-controlled intervention for 12 weeks, followed by an open-label extension of topical delgocitinib for all participants for another 12 weeks. 

The primary efficacy endpoint was change in the molecular signature of FFA inflammation at 12 weeks. Clinical improvement was monitored with both trichoscopic images capturing the numbers of hairs and follicular units at 12 weeks and clinical severity scores through week 24. In a topical cream formulation, the Janus kinase inhibitor (JAKi) delgocitinib was associated with favorable activity for both. 
 

Some Hair Regrowth for All

“At 24 weeks, all patients achieved some degree of hair regrowth and a stabilization of disease based on hairline measurements,” Senna reported in a late-breaking news session at the 2024 European Academy of Dermatology and Venereology (EADV) Congress. 

On the clinical endpoints, Senna noted an upward trajectory in clinical improvement at the completion of the study.

The 30 participants were randomly assigned in a 1:1 ratio to receive delgocitinib cream in a concentration of 20 mg/g or vehicle cream applied twice daily for 12 weeks. At the end of this double-blind period, patients on vehicle were crossed over to the active therapy, and all patients were monitored for another 12 weeks in an open-label extension. 

The change from baseline in FFA biomarkers was selected as the primary endpoint based on previous work showing up-regulation in the expression of the Th1 biomarkers CXCL9, CXCL10, and interferon gamma in lesional vs nonlesional scalp in patients with FFA. 

When biopsies at the end of 12 weeks in the double-blind phase of the study were compared with the baseline biopsies, researchers found a decrease in expression of the three local inflammation markers in all patients receiving the JAKi, but not in those receiving the vehicle cream. In this small patient sample, only the reduction in expression of CXCL9, a cytokine known for differentiation and promotion of leukocytes, reached statistical significance (P < .05).

But in an analysis involving the expression of multiple genes, “lesions treated with delgocitinib had a 4% improvement in normalization toward a nonlesional transcriptomic profile, while patients treated with vehicle had a 33% worsening,” Senna reported. The difference was highly significant (P < .001).

Furthermore, the decrease in total Lichen Planopilaris Activity Index and FFA severity scores were numerically and statistically greater (P = .023) in the active-treatment arm than in the vehicle arm by the end of the double-blind part of the trial, she said.

On trichoscopy, there was an increased number of hairs and follicular units at 12 weeks relative to baseline among those treated with topical delgocitinib but a reduction in those treated with vehicle.
 

JAKi Patients Gained Hair, Vehicle Patients Lost Hair

On the basis of hair count per square centimeter from baseline, delgocitinib-treated patients gained on average of seven hairs whereas vehicle recipients lost an average of 11 hairs at 24 weeks, Senna reported.

Patients originally treated with vehicle did improve in most outcome measures in the open-label extension of the experimental treatment after crossover, but they did not catch up to those initially randomized to delgocitinib because of further accrual of favorable changes in the active-treatment group over time.

“There were no adverse events associated with active therapy or vehicle, including application-site reactions,” Senna said. The one between-group difference was a higher rate of COVID-19, but this was greater in the control arm.

All 30 of the participants in this study were women, and all had moderate to severe disease at enrollment. The median age was 64 years. Because of the predominant population at the hair loss center, all but one of the participants were White, and one participant was Asian. 

Characterizing FFA as “devastating and disfiguring,” Senna, who specializes in the care of alopecia, noted that this a difficult disease to control with the off-label strategies that are now used. The slow progress to identify treatments for FFA is illustrated by the fact that only one other double-blind and randomized trial has ever been conducted in FFA, she said.
 

Exploratory Study Supports Anecdotal Experience

On the basis of prior anecdotal experience with JAKi treatment for FFA, Senna said, “I do think that it is possible to get largely clear skin with this therapy.” However, she is now hoping for definitive trials to better characterize the efficacy and safety of oral and topical therapies, perhaps used sequentially to maintain clinical improvement.

In light of the limited current options, Menno de Rie, MD, PhD, professor of dermatology at the University of Amsterdam in the Netherlands, called these data “very inspiring and hopeful.” He suggested the promise of this therapy was reinforced by the upward trajectory of the biomarkers and clinical improvement over the study period. 

“Any improvement in treatment options would be welcome, because we do not [have] any reliable therapies for this condition,” de Rie, who was not an investigator, said in an interview after the presentation. 

Ultimately, Senna said, once effective therapy is established, the goal will be to start as early as possible in the disease process. She noted that there is evidence that prompt therapy can reverse the disorder, not just prevent progression.

“If you can get to the hair follicles before the point of no return, there is [a] chance [of] follicular rescue,” she said.

Delgocitinib cream (Anzupgo) was approved in Europe for treating chronic hand eczema in late September and is under review for the same indication in the United States. 

Senna has financial relationships with Arena, Concert, Eli Lilly, Pfizer, and Leo Pharma, which provided funding for this study. de Rie reported no potential conflicts of interest.

A version of this article appeared on Medscape.com.

AMSTERDAM — For frontal fibrosing alopecia (FFA), a disease with no approved therapies, topical delgocitinib attenuated inflammation and generated hair regrowth in women in a controlled phase 2a trial.

“This is an exciting avenue for FFA if the data are recapitulated in a larger population. It could be an important new treatment option,” said Maryanne Senna, MD, director at Lahey Hospital & Medical Center’s Hair Loss Center of Excellence, Burlington, Massachusetts, and assistant dermatology professor at Harvard Medical School, Boston, Massachusetts.

In a design characterized as “exploratory,” the trial had two parts: a randomized, double-blind, vehicle-controlled intervention for 12 weeks, followed by an open-label extension of topical delgocitinib for all participants for another 12 weeks. 

The primary efficacy endpoint was change in the molecular signature of FFA inflammation at 12 weeks. Clinical improvement was monitored with both trichoscopic images capturing the numbers of hairs and follicular units at 12 weeks and clinical severity scores through week 24. In a topical cream formulation, the Janus kinase inhibitor (JAKi) delgocitinib was associated with favorable activity for both. 
 

Some Hair Regrowth for All

“At 24 weeks, all patients achieved some degree of hair regrowth and a stabilization of disease based on hairline measurements,” Senna reported in a late-breaking news session at the 2024 European Academy of Dermatology and Venereology (EADV) Congress. 

On the clinical endpoints, Senna noted an upward trajectory in clinical improvement at the completion of the study.

The 30 participants were randomly assigned in a 1:1 ratio to receive delgocitinib cream in a concentration of 20 mg/g or vehicle cream applied twice daily for 12 weeks. At the end of this double-blind period, patients on vehicle were crossed over to the active therapy, and all patients were monitored for another 12 weeks in an open-label extension. 

The change from baseline in FFA biomarkers was selected as the primary endpoint based on previous work showing up-regulation in the expression of the Th1 biomarkers CXCL9, CXCL10, and interferon gamma in lesional vs nonlesional scalp in patients with FFA. 

When biopsies at the end of 12 weeks in the double-blind phase of the study were compared with the baseline biopsies, researchers found a decrease in expression of the three local inflammation markers in all patients receiving the JAKi, but not in those receiving the vehicle cream. In this small patient sample, only the reduction in expression of CXCL9, a cytokine known for differentiation and promotion of leukocytes, reached statistical significance (P < .05).

But in an analysis involving the expression of multiple genes, “lesions treated with delgocitinib had a 4% improvement in normalization toward a nonlesional transcriptomic profile, while patients treated with vehicle had a 33% worsening,” Senna reported. The difference was highly significant (P < .001).

Furthermore, the decrease in total Lichen Planopilaris Activity Index and FFA severity scores were numerically and statistically greater (P = .023) in the active-treatment arm than in the vehicle arm by the end of the double-blind part of the trial, she said.

On trichoscopy, there was an increased number of hairs and follicular units at 12 weeks relative to baseline among those treated with topical delgocitinib but a reduction in those treated with vehicle.
 

JAKi Patients Gained Hair, Vehicle Patients Lost Hair

On the basis of hair count per square centimeter from baseline, delgocitinib-treated patients gained on average of seven hairs whereas vehicle recipients lost an average of 11 hairs at 24 weeks, Senna reported.

Patients originally treated with vehicle did improve in most outcome measures in the open-label extension of the experimental treatment after crossover, but they did not catch up to those initially randomized to delgocitinib because of further accrual of favorable changes in the active-treatment group over time.

“There were no adverse events associated with active therapy or vehicle, including application-site reactions,” Senna said. The one between-group difference was a higher rate of COVID-19, but this was greater in the control arm.

All 30 of the participants in this study were women, and all had moderate to severe disease at enrollment. The median age was 64 years. Because of the predominant population at the hair loss center, all but one of the participants were White, and one participant was Asian. 

Characterizing FFA as “devastating and disfiguring,” Senna, who specializes in the care of alopecia, noted that this a difficult disease to control with the off-label strategies that are now used. The slow progress to identify treatments for FFA is illustrated by the fact that only one other double-blind and randomized trial has ever been conducted in FFA, she said.
 

Exploratory Study Supports Anecdotal Experience

On the basis of prior anecdotal experience with JAKi treatment for FFA, Senna said, “I do think that it is possible to get largely clear skin with this therapy.” However, she is now hoping for definitive trials to better characterize the efficacy and safety of oral and topical therapies, perhaps used sequentially to maintain clinical improvement.

In light of the limited current options, Menno de Rie, MD, PhD, professor of dermatology at the University of Amsterdam in the Netherlands, called these data “very inspiring and hopeful.” He suggested the promise of this therapy was reinforced by the upward trajectory of the biomarkers and clinical improvement over the study period. 

“Any improvement in treatment options would be welcome, because we do not [have] any reliable therapies for this condition,” de Rie, who was not an investigator, said in an interview after the presentation. 

Ultimately, Senna said, once effective therapy is established, the goal will be to start as early as possible in the disease process. She noted that there is evidence that prompt therapy can reverse the disorder, not just prevent progression.

“If you can get to the hair follicles before the point of no return, there is [a] chance [of] follicular rescue,” she said.

Delgocitinib cream (Anzupgo) was approved in Europe for treating chronic hand eczema in late September and is under review for the same indication in the United States. 

Senna has financial relationships with Arena, Concert, Eli Lilly, Pfizer, and Leo Pharma, which provided funding for this study. de Rie reported no potential conflicts of interest.

A version of this article appeared on Medscape.com.

AMSTERDAM — For frontal fibrosing alopecia (FFA), a disease with no approved therapies, topical delgocitinib attenuated inflammation and generated hair regrowth in women in a controlled phase 2a trial.

“This is an exciting avenue for FFA if the data are recapitulated in a larger population. It could be an important new treatment option,” said Maryanne Senna, MD, director at Lahey Hospital & Medical Center’s Hair Loss Center of Excellence, Burlington, Massachusetts, and assistant dermatology professor at Harvard Medical School, Boston, Massachusetts.

In a design characterized as “exploratory,” the trial had two parts: a randomized, double-blind, vehicle-controlled intervention for 12 weeks, followed by an open-label extension of topical delgocitinib for all participants for another 12 weeks. 

The primary efficacy endpoint was change in the molecular signature of FFA inflammation at 12 weeks. Clinical improvement was monitored with both trichoscopic images capturing the numbers of hairs and follicular units at 12 weeks and clinical severity scores through week 24. In a topical cream formulation, the Janus kinase inhibitor (JAKi) delgocitinib was associated with favorable activity for both. 
 

Some Hair Regrowth for All

“At 24 weeks, all patients achieved some degree of hair regrowth and a stabilization of disease based on hairline measurements,” Senna reported in a late-breaking news session at the 2024 European Academy of Dermatology and Venereology (EADV) Congress. 

On the clinical endpoints, Senna noted an upward trajectory in clinical improvement at the completion of the study.

The 30 participants were randomly assigned in a 1:1 ratio to receive delgocitinib cream in a concentration of 20 mg/g or vehicle cream applied twice daily for 12 weeks. At the end of this double-blind period, patients on vehicle were crossed over to the active therapy, and all patients were monitored for another 12 weeks in an open-label extension. 

The change from baseline in FFA biomarkers was selected as the primary endpoint based on previous work showing up-regulation in the expression of the Th1 biomarkers CXCL9, CXCL10, and interferon gamma in lesional vs nonlesional scalp in patients with FFA. 

When biopsies at the end of 12 weeks in the double-blind phase of the study were compared with the baseline biopsies, researchers found a decrease in expression of the three local inflammation markers in all patients receiving the JAKi, but not in those receiving the vehicle cream. In this small patient sample, only the reduction in expression of CXCL9, a cytokine known for differentiation and promotion of leukocytes, reached statistical significance (P < .05).

But in an analysis involving the expression of multiple genes, “lesions treated with delgocitinib had a 4% improvement in normalization toward a nonlesional transcriptomic profile, while patients treated with vehicle had a 33% worsening,” Senna reported. The difference was highly significant (P < .001).

Furthermore, the decrease in total Lichen Planopilaris Activity Index and FFA severity scores were numerically and statistically greater (P = .023) in the active-treatment arm than in the vehicle arm by the end of the double-blind part of the trial, she said.

On trichoscopy, there was an increased number of hairs and follicular units at 12 weeks relative to baseline among those treated with topical delgocitinib but a reduction in those treated with vehicle.
 

JAKi Patients Gained Hair, Vehicle Patients Lost Hair

On the basis of hair count per square centimeter from baseline, delgocitinib-treated patients gained on average of seven hairs whereas vehicle recipients lost an average of 11 hairs at 24 weeks, Senna reported.

Patients originally treated with vehicle did improve in most outcome measures in the open-label extension of the experimental treatment after crossover, but they did not catch up to those initially randomized to delgocitinib because of further accrual of favorable changes in the active-treatment group over time.

“There were no adverse events associated with active therapy or vehicle, including application-site reactions,” Senna said. The one between-group difference was a higher rate of COVID-19, but this was greater in the control arm.

All 30 of the participants in this study were women, and all had moderate to severe disease at enrollment. The median age was 64 years. Because of the predominant population at the hair loss center, all but one of the participants were White, and one participant was Asian. 

Characterizing FFA as “devastating and disfiguring,” Senna, who specializes in the care of alopecia, noted that this a difficult disease to control with the off-label strategies that are now used. The slow progress to identify treatments for FFA is illustrated by the fact that only one other double-blind and randomized trial has ever been conducted in FFA, she said.
 

Exploratory Study Supports Anecdotal Experience

On the basis of prior anecdotal experience with JAKi treatment for FFA, Senna said, “I do think that it is possible to get largely clear skin with this therapy.” However, she is now hoping for definitive trials to better characterize the efficacy and safety of oral and topical therapies, perhaps used sequentially to maintain clinical improvement.

In light of the limited current options, Menno de Rie, MD, PhD, professor of dermatology at the University of Amsterdam in the Netherlands, called these data “very inspiring and hopeful.” He suggested the promise of this therapy was reinforced by the upward trajectory of the biomarkers and clinical improvement over the study period. 

“Any improvement in treatment options would be welcome, because we do not [have] any reliable therapies for this condition,” de Rie, who was not an investigator, said in an interview after the presentation. 

Ultimately, Senna said, once effective therapy is established, the goal will be to start as early as possible in the disease process. She noted that there is evidence that prompt therapy can reverse the disorder, not just prevent progression.

“If you can get to the hair follicles before the point of no return, there is [a] chance [of] follicular rescue,” she said.

Delgocitinib cream (Anzupgo) was approved in Europe for treating chronic hand eczema in late September and is under review for the same indication in the United States. 

Senna has financial relationships with Arena, Concert, Eli Lilly, Pfizer, and Leo Pharma, which provided funding for this study. de Rie reported no potential conflicts of interest.

A version of this article appeared on Medscape.com.

AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.

A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.

The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.

The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.

“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Of the 67 patients with AD, 39 were early responders, 11 were late responders, and 17 were nonresponders.

The differences in proteomics were marked. For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.

In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.

In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.

“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.

To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.

When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.

“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.

Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.

The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.

This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.

When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.

This is an important missing piece of this investigation, according to Dréno.

“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”

This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.

The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.

A version of this article appeared on Medscape.com.

AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.

A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.

The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.

The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.

“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Of the 67 patients with AD, 39 were early responders, 11 were late responders, and 17 were nonresponders.

The differences in proteomics were marked. For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.

In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.

In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.

“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.

To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.

When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.

“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.

Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.

The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.

This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.

When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.

This is an important missing piece of this investigation, according to Dréno.

“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”

This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.

The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.

A version of this article appeared on Medscape.com.

AMSTERDAM — A proteomics study designed to determine why some patients with atopic dermatitis (AD) respond quickly to dupilumab, others respond more slowly, and the remainder do not respond at all demonstrated that molecular responses in these three groups are very different.

A discovery that could lead to personalizing therapies, the data identified “distinct systemic biomarker profiles,” according to Ester Del Duca, MD, an instructor in the Laboratory of Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai, New York City.

The study was conducted with 67 patients with AD and 16 healthy controls. Serum was collected at two timepoints: An average of 20 weeks after starting dupilumab, then at a mean interval of about 9 months later. At these timepoints, called follow-up 1 and 2, a panel of more than 600 proteins, including unique markers for immunologic, cardiovascular, and neurologic activity, were evaluated.

The criterion for differentiating the three response groups was an Investigator Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (or at least a 2-point IGA reduction from baseline). Early responders were those who met the criterion at both follow-ups, late responders were those who met this criterion only at the second follow-up, and nonresponders never met the criterion.

“There were no significant differences at baseline in clinical severity, past medical history, or patient characteristics,” said Del Duca, who presented these data in a late breaking news session at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Of the 67 patients with AD, 39 were early responders, 11 were late responders, and 17 were nonresponders.

The differences in proteomics were marked. For early responders, there was an early normalization of the proteome, reported Del Duca, illustrating the differences in the proteome of the three groups with a color-coded chart of protein up-regulation and down-regulation relative to healthy controls. The normalization of the proteome persisted in early responders when assessed at the second follow-up.

In the late responders, the proteome dysregulation was substantial relative to healthy controls at the first follow-up, but there was considerable improvement by the second follow-up. Although the change at the second follow-up was still not as robust as that seen in the early responders at either follow-up, Del Duca described the proteomic profile as a 45% improvement from the first follow-up.

In contrast, nonresponders showed worsening in their blood proteome from follow-up 1 to 2. Nonresponders at first follow-up showed up-regulation relative to healthy controls for many proteins associated with the Th1 response, such as interferon gamma, CXCL9, and CXCL10, and Th2 response, such as interleukin-4 and Th17/22, and these did not normalize or worsen by the second follow-up.

“Uniquely to nonresponders, key Th1 biomarkers remained significantly up-regulated relative to controls at both follow-up 1 and 2,” with a P value < .05, Del Duca reported.

To achieve normalization of the proteome as defined by healthy controls, both up-regulation and down-regulation of protein activity were required, although more up-regulations than down-regulations were observed.

When evaluating the proteome changes most implicated in immunoregulation, the investigators were able to show a correlation between worsening in the proteome and greater severity of AD as defined by IGA, Eczema Area and Severity Index, and body surface area involvement.

“Spearman analysis revealed strong and positive correlations between improvements in biomarkers at follow-up 1 and 2 with improvements in clinical markers,” Del Duca said. As examples, she noted favorable changes in biomarkers specifically associated with T cells, dendritic cells, and natural killer cells as clinical outcomes improved.

Conversely, the worsening in T-cell activation among nonresponders, particularly Th1 biomarkers, also tracked with increasing AD symptoms over time.

The implications of the research are broad, and most importantly, it shows that therapeutic targets are likely to differ between patients with AD, according to Del Duca. Although proteomic studies have not yet been conducted with other treatments, these might provide further insight about how patients with AD differ in response across other drugs.

This is important work, according to Brigitte Dréno, MD, PhD, head of the Department of Dermatology, Nantes University Hospital in France. As moderator of the late-breaking news session, she suggested that there are many potential messages from these data, not least that treatment of AD likely involves targeting cytokines beyond those affected by dupilumab in at least some patients.

When Dréno asked Del Duca about what could be surmised about changes from baseline before treatment to the first follow-up, Del Duca said that the study was retrospective, so baseline data were not available.

This is an important missing piece of this investigation, according to Dréno.

“As you move this work forward,” she said that it would be “very important” to determine “if there are predictive markers for evaluating which patients will respond.”

This is a small study with many additional variables to consider in order to develop a clinically useful tool, Del Duca noted. However, this work not only has the potential to guide treatment selection but the biomarkers up-regulated in nonresponders are already “suggesting potential targets for refining therapeutic strategies,” she said.

The study received funding from Bristol-Myers Squibb. Del Duca reported no financial relationships with industry. Dréno reported financial relationships with La Roche–Posay, Pierre Fabré, and Galderma.

A version of this article appeared on Medscape.com.

AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in patients with mild to moderate hidradenitis suppurativa (HS), an open-label extension showed that 16 more weeks of treatment on as-needed basis provided complete or near complete clearance of lesions in up to 38.5% of patients.

“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
 

Over 80% Meet Primary Endpoint at 32 Weeks

Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4. 

In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.

The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.

The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.

This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said. 

For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).

AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.

One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively. 

The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively. 
 

Patients in the Study Mostly Women, 42% Black Individuals

Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m². A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.

“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.

The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low. 

Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.

Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.

Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.

“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment. 

Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years. 

Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.

A version of this article appeared on Medscape.com.

AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in patients with mild to moderate hidradenitis suppurativa (HS), an open-label extension showed that 16 more weeks of treatment on as-needed basis provided complete or near complete clearance of lesions in up to 38.5% of patients.

“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
 

Over 80% Meet Primary Endpoint at 32 Weeks

Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4. 

In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.

The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.

The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.

This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said. 

For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).

AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.

One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively. 

The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively. 
 

Patients in the Study Mostly Women, 42% Black Individuals

Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m². A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.

“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.

The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low. 

Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.

Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.

Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.

“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment. 

Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years. 

Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.

A version of this article appeared on Medscape.com.

AMSTERDAM — Following the report of results from a randomized trial in which a topically applied Janus kinase (JAK) inhibitor was highly active in patients with mild to moderate hidradenitis suppurativa (HS), an open-label extension showed that 16 more weeks of treatment on as-needed basis provided complete or near complete clearance of lesions in up to 38.5% of patients.

“Ruxolitinib cream may be a novel approach to address an unmet medical need in the treatment of milder HS for which there are no currently approved treatments,” reported Martina L. Porter, MD, assistant professor of dermatology, Harvard Medical School, and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

In the earlier 16-week, double-blind, randomized period of this phase 2b study, 69 adults with mild to moderate HS were randomized to 1.5% ruxolitinib cream or vehicle, applied twice daily for 16 weeks. The new results are from the open-label extension period, where those on the vehicle were crossed over to topical ruxolitinib and treatment was continued for another 16 weeks.
 

Over 80% Meet Primary Endpoint at 32 Weeks

Entry criteria for the study included Hurley stage I or II HS with no draining tunnels. Hurley stage III patients were not eligible. Patients had to have an abscess or inflammatory nodule (AN) count of 3 lesions concentrated in a single anatomic area or up to 10 lesions if disseminated. The median AN count of those enrolled was 5.4. 

In the randomized portion of the study and in the open-label extension, the recommendation for application was to apply the medication to nodules and a 1-cm area of surrounding skin. As-needed treatment was only recommended in the extension portion of the study and rescue medication was not allowed.

The goal of the open-label extension was to evaluate how long the improvements were sustained, according to Dr. Porter, who presented the results at the 2024 European Academy of Dermatology and Venereology (EADV) meeting.

The primary endpoints of AN50, signaling at least a 50% reduction in AN count from baseline, among those initially randomized to ruxolitinib cream climbed slightly from 79.2% at the end of 16 weeks to 81.0% at the end of 32 weeks.

This shows that the benefits recorded in the randomized phase of the trial were sustained during the open-label extension, Dr. Porter said. 

For those randomized to vehicle, there was a substantial response of 56.3% for AN50 during the randomized portion of the study, but catchup in the vehicle group to those on active therapy occurred rapidly over the open-label extension. By the end of 32 weeks, the score among the crossover patients slightly exceeded that of those on continuous therapy (88.5% vs 81.0%).

AN75 responses at week 32 were 66.7% and 61.5% in the continuous arm and crossover arm, respectively. The proportion of patients reaching an AN90 or AN100 response, meaning clear or almost clear, were 19% and 38.5%, in continuous treatment and crossover arms, respectively.

One of the secondary endpoints was the HS Clinical Response 50, indicating at least a 50% reduction in the AN count with no increase in abscesses or draining fistulae. At 32 weeks, the proportions of patients who met this endpoint were 81.0% and 88.5% in the continuous treatment and crossover arms, respectively. 

The mean reduction in International HS Severity Scoring System scores from baseline were 4.1 and 4.5 in the continuous treatment and crossover arms, respectively. 
 

Patients in the Study Mostly Women, 42% Black Individuals

Most (94%) of the participants were women; about 45% and 42% were White and Black individuals, respectively. Most of the remaining patients were Asian individuals. The median age at entry was 29 years, and the mean body mass index was approximately 34 kg/m². A substantial proportion of patients had systemic comorbidities, according to Dr. Porter, who noted that about 25% had anxiety, depression, or both.

“This phenotype — a high proportion of women with nodules but no draining tunnels and a substantial number of comorbidities — is one we often see in patients with mild HS,” Dr. Porter said.

The safety and tolerability profile of ruxolitinib cream was quite good, according to Dr. Porter, who noted that there were fewer treatment-related adverse events in the open-label extension. Overall, the number of treatment-related adverse events (3.6%), including application site reactions leading to discontinuation (1.8%) was low. 

Although there is a growing list of therapies now approved for HS, Dr. Porter emphasized that all have been developed for moderate to severe disease. She suggested that there is a sizable group of patients with mild disease for whom such therapies as biologics might not be warranted even if symptom relief is needed.

Given this unmet need, she said phase 3 trials are warranted to confirm the benefits and the safety of a topical therapy that can be used as needed to control intermittent HS flares.

Asked to comment, the lead author of a recently published review article on the “evolving treatment landscape” of HS, James G. Krueger, MD, professor in clinical investigation at Rockefeller University, New York City, agreed that there is an unmet need for effective and safe therapies in milder HS.

“I agree with the premise,” said Dr. Krueger, indicating that phase 3 data will be essential to confirm the promise of this approach. Dr. Krueger, who did not hear the results presented at the EADV meeting, listed several JAK inhibitors in his review that have shown promising efficacy as oral agents and support JAK signaling as a target of HS treatment. 

Topical ruxolitinib (Opzelura) is currently approved in the United States for treating nonsegmental vitiligo in patients aged ≥ 12 years and for mild to moderate atopic dermatitis in patients aged ≥ 12 years. In Europe, it is approved for treatment of nonsegmental vitiligo with facial involvement in patients aged ≥ 12 years. 

Dr. Porter reported no potential conflicts of interest. Dr. Krueger reported financial relationships with more than 25 pharmaceutical companies not including Incyte, which is developing ruxolitinib cream.

A version of this article appeared on Medscape.com.

VIENNA, AUSTRIA — The appropriate dose of pancreatic enzyme replacement therapy (PERT) for exocrine pancreatic insufficiency (EPI) depends on the root cause of the insufficiency, according to results of a prospective study using European registry data. 

Specifically, patients with EPI caused by pancreatic cancer or pancreatectomy need significantly more enzyme replacement than patients with insufficiency caused by chronic pancreatitis and acute pancreatitis. The need to add a proton pump inhibitor (PPI) to achieve the therapeutic goal also varies by condition, the study showed. 

World Pancreatic Cancer Coalition

One of the main symptoms of EPI is malnutrition, and successful PERT is defined as the resolution of nutritional deficiencies and relief of symptoms and signs associated with insufficiency, said study lead Enrique Domínguez Muñoz, MD, director of the department of gastroenterology and hepatology at University Hospital of Santiago de Compostela, Spain. 

Our findings show that, “in order to achieve this, enzyme dose escalation and sometimes additional treatment with a [PPI] should be applied as required by the individual”, he reported in a presentation at the United European Gastroenterology (UEG) Week 2024.

Therefore, having dose recommendations for PERT for different causes of EPI is very helpful, said Domínguez Muñoz.

Pancreatic enzyme preparations, specifically pancreatin, are the recommended first-line treatment for EPI, but the initial doses of PERT vary depending on the patient’s age (whether adult or child), the severity of the insufficiency, and the fat content of the meal eaten. 

Domínguez Muñoz and colleagues wanted to explore whether — and how — the severity of EPI varied with different diseases, therefore varying the optimal dose of PERT. 
 

Optimal Dosing to Achieve Therapeutic Goal 

The prospective study drew on data from a European multicenter registry of patients diagnosed with EPI being treated with PERT in expert centers. 

The researchers evaluated the dose of PERT required to achieve symptom relief and normalization of the nutritional status in adult patients with EPI secondary to different pancreatic diseases and conditions. The percentage of patients who required the addition of a PPI to PERT to achieve the therapeutic goal was also determined. 

Decisions on the initial enzyme dose (including the addition of a PPI) and any necessary adjustments during follow-up to achieve the therapeutic goal were made by the participants’ clinicians.

A total of 678 patients (mean age, 61.2 ± 13.8 years; 63.6% male) were stratified according to disease: 50% had chronic pancreatitis, 10% had acute pancreatitis, 17% had undergone pancreaticoduodenectomy, 15% had pancreatic cancer, and 8% had another pancreatic condition. 

To achieve the therapeutic goal, the median optimal enzyme doses with the main meal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy, were 40,000, 50,000, 70,000, and 75,000 Ph.U, respectively. The respective optimal daily enzyme doses were 100,000, 150,000, 210,000, and 225,000 Ph.U. 

The highest enzyme doses required with the main meal to achieve the therapeutic goal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy were 125,000, 210,000, 175,000, and 210,000 Ph.U, respectively. The respective highest daily enzyme doses were 400,000, 625,000, 675,000, and 750,000 Ph.U. 

The need for additional therapy with twice-daily PPI to achieve the therapeutic goal also varied according to the underlying disease. It was administered to 44.1% of patients with acute pancreatitis, 37.2% of patients with chronic pancreatitis, 78.8% of patients with pancreatic cancer, and 74.1% of patients who had undergone pancreaticoduodenectomy. 

“This shows us that sometimes we really do need to significantly increase the dose of pancreatic enzyme replacement therapy,” reported Domínguez Muñoz. 
 

Clear Direction on Where to Start

Comoderator Kasper Overbeek, MD, from the department of gastroenterology and hepatology, Erasmus MC Cancer Institute, University Medical Center, the Netherlands, commented: “It’s a useful study because it gives us practical advice on what to do in specific cases.”

Dr. Overbeek

Until now, we’ve done the same thing for everyone, he said, “but these data clearly show that this is not optimal.” 

In addition, “it is often the case with enzyme replacement therapy that doctors under-dose so it is necessary to increase the dose,” he said.

“This work gives us a clearer direction on where to start,” Overbeek said. “For example, with patients who have cancer, because they do not have time to start low and titrate up, they need a higher dose than patients with chronic pancreatitis.”

This pragmatic and novel guidance will “help us in our clinical practice,” he added.

Domínguez Muñoz reports receiving speaking and consultancy fees from Viatris, Abbott Pharmaceuticals, and Boston Scientific. Overbeek reports no relevant disclosures.

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

VIENNA, AUSTRIA — The appropriate dose of pancreatic enzyme replacement therapy (PERT) for exocrine pancreatic insufficiency (EPI) depends on the root cause of the insufficiency, according to results of a prospective study using European registry data. 

Specifically, patients with EPI caused by pancreatic cancer or pancreatectomy need significantly more enzyme replacement than patients with insufficiency caused by chronic pancreatitis and acute pancreatitis. The need to add a proton pump inhibitor (PPI) to achieve the therapeutic goal also varies by condition, the study showed. 

World Pancreatic Cancer Coalition

One of the main symptoms of EPI is malnutrition, and successful PERT is defined as the resolution of nutritional deficiencies and relief of symptoms and signs associated with insufficiency, said study lead Enrique Domínguez Muñoz, MD, director of the department of gastroenterology and hepatology at University Hospital of Santiago de Compostela, Spain. 

Our findings show that, “in order to achieve this, enzyme dose escalation and sometimes additional treatment with a [PPI] should be applied as required by the individual”, he reported in a presentation at the United European Gastroenterology (UEG) Week 2024.

Therefore, having dose recommendations for PERT for different causes of EPI is very helpful, said Domínguez Muñoz.

Pancreatic enzyme preparations, specifically pancreatin, are the recommended first-line treatment for EPI, but the initial doses of PERT vary depending on the patient’s age (whether adult or child), the severity of the insufficiency, and the fat content of the meal eaten. 

Domínguez Muñoz and colleagues wanted to explore whether — and how — the severity of EPI varied with different diseases, therefore varying the optimal dose of PERT. 
 

Optimal Dosing to Achieve Therapeutic Goal 

The prospective study drew on data from a European multicenter registry of patients diagnosed with EPI being treated with PERT in expert centers. 

The researchers evaluated the dose of PERT required to achieve symptom relief and normalization of the nutritional status in adult patients with EPI secondary to different pancreatic diseases and conditions. The percentage of patients who required the addition of a PPI to PERT to achieve the therapeutic goal was also determined. 

Decisions on the initial enzyme dose (including the addition of a PPI) and any necessary adjustments during follow-up to achieve the therapeutic goal were made by the participants’ clinicians.

A total of 678 patients (mean age, 61.2 ± 13.8 years; 63.6% male) were stratified according to disease: 50% had chronic pancreatitis, 10% had acute pancreatitis, 17% had undergone pancreaticoduodenectomy, 15% had pancreatic cancer, and 8% had another pancreatic condition. 

To achieve the therapeutic goal, the median optimal enzyme doses with the main meal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy, were 40,000, 50,000, 70,000, and 75,000 Ph.U, respectively. The respective optimal daily enzyme doses were 100,000, 150,000, 210,000, and 225,000 Ph.U. 

The highest enzyme doses required with the main meal to achieve the therapeutic goal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy were 125,000, 210,000, 175,000, and 210,000 Ph.U, respectively. The respective highest daily enzyme doses were 400,000, 625,000, 675,000, and 750,000 Ph.U. 

The need for additional therapy with twice-daily PPI to achieve the therapeutic goal also varied according to the underlying disease. It was administered to 44.1% of patients with acute pancreatitis, 37.2% of patients with chronic pancreatitis, 78.8% of patients with pancreatic cancer, and 74.1% of patients who had undergone pancreaticoduodenectomy. 

“This shows us that sometimes we really do need to significantly increase the dose of pancreatic enzyme replacement therapy,” reported Domínguez Muñoz. 
 

Clear Direction on Where to Start

Comoderator Kasper Overbeek, MD, from the department of gastroenterology and hepatology, Erasmus MC Cancer Institute, University Medical Center, the Netherlands, commented: “It’s a useful study because it gives us practical advice on what to do in specific cases.”

Dr. Overbeek

Until now, we’ve done the same thing for everyone, he said, “but these data clearly show that this is not optimal.” 

In addition, “it is often the case with enzyme replacement therapy that doctors under-dose so it is necessary to increase the dose,” he said.

“This work gives us a clearer direction on where to start,” Overbeek said. “For example, with patients who have cancer, because they do not have time to start low and titrate up, they need a higher dose than patients with chronic pancreatitis.”

This pragmatic and novel guidance will “help us in our clinical practice,” he added.

Domínguez Muñoz reports receiving speaking and consultancy fees from Viatris, Abbott Pharmaceuticals, and Boston Scientific. Overbeek reports no relevant disclosures.

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

VIENNA, AUSTRIA — The appropriate dose of pancreatic enzyme replacement therapy (PERT) for exocrine pancreatic insufficiency (EPI) depends on the root cause of the insufficiency, according to results of a prospective study using European registry data. 

Specifically, patients with EPI caused by pancreatic cancer or pancreatectomy need significantly more enzyme replacement than patients with insufficiency caused by chronic pancreatitis and acute pancreatitis. The need to add a proton pump inhibitor (PPI) to achieve the therapeutic goal also varies by condition, the study showed. 

World Pancreatic Cancer Coalition

One of the main symptoms of EPI is malnutrition, and successful PERT is defined as the resolution of nutritional deficiencies and relief of symptoms and signs associated with insufficiency, said study lead Enrique Domínguez Muñoz, MD, director of the department of gastroenterology and hepatology at University Hospital of Santiago de Compostela, Spain. 

Our findings show that, “in order to achieve this, enzyme dose escalation and sometimes additional treatment with a [PPI] should be applied as required by the individual”, he reported in a presentation at the United European Gastroenterology (UEG) Week 2024.

Therefore, having dose recommendations for PERT for different causes of EPI is very helpful, said Domínguez Muñoz.

Pancreatic enzyme preparations, specifically pancreatin, are the recommended first-line treatment for EPI, but the initial doses of PERT vary depending on the patient’s age (whether adult or child), the severity of the insufficiency, and the fat content of the meal eaten. 

Domínguez Muñoz and colleagues wanted to explore whether — and how — the severity of EPI varied with different diseases, therefore varying the optimal dose of PERT. 
 

Optimal Dosing to Achieve Therapeutic Goal 

The prospective study drew on data from a European multicenter registry of patients diagnosed with EPI being treated with PERT in expert centers. 

The researchers evaluated the dose of PERT required to achieve symptom relief and normalization of the nutritional status in adult patients with EPI secondary to different pancreatic diseases and conditions. The percentage of patients who required the addition of a PPI to PERT to achieve the therapeutic goal was also determined. 

Decisions on the initial enzyme dose (including the addition of a PPI) and any necessary adjustments during follow-up to achieve the therapeutic goal were made by the participants’ clinicians.

A total of 678 patients (mean age, 61.2 ± 13.8 years; 63.6% male) were stratified according to disease: 50% had chronic pancreatitis, 10% had acute pancreatitis, 17% had undergone pancreaticoduodenectomy, 15% had pancreatic cancer, and 8% had another pancreatic condition. 

To achieve the therapeutic goal, the median optimal enzyme doses with the main meal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy, were 40,000, 50,000, 70,000, and 75,000 Ph.U, respectively. The respective optimal daily enzyme doses were 100,000, 150,000, 210,000, and 225,000 Ph.U. 

The highest enzyme doses required with the main meal to achieve the therapeutic goal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy were 125,000, 210,000, 175,000, and 210,000 Ph.U, respectively. The respective highest daily enzyme doses were 400,000, 625,000, 675,000, and 750,000 Ph.U. 

The need for additional therapy with twice-daily PPI to achieve the therapeutic goal also varied according to the underlying disease. It was administered to 44.1% of patients with acute pancreatitis, 37.2% of patients with chronic pancreatitis, 78.8% of patients with pancreatic cancer, and 74.1% of patients who had undergone pancreaticoduodenectomy. 

“This shows us that sometimes we really do need to significantly increase the dose of pancreatic enzyme replacement therapy,” reported Domínguez Muñoz. 
 

Clear Direction on Where to Start

Comoderator Kasper Overbeek, MD, from the department of gastroenterology and hepatology, Erasmus MC Cancer Institute, University Medical Center, the Netherlands, commented: “It’s a useful study because it gives us practical advice on what to do in specific cases.”

Dr. Overbeek

Until now, we’ve done the same thing for everyone, he said, “but these data clearly show that this is not optimal.” 

In addition, “it is often the case with enzyme replacement therapy that doctors under-dose so it is necessary to increase the dose,” he said.

“This work gives us a clearer direction on where to start,” Overbeek said. “For example, with patients who have cancer, because they do not have time to start low and titrate up, they need a higher dose than patients with chronic pancreatitis.”

This pragmatic and novel guidance will “help us in our clinical practice,” he added.

Domínguez Muñoz reports receiving speaking and consultancy fees from Viatris, Abbott Pharmaceuticals, and Boston Scientific. Overbeek reports no relevant disclosures.

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

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

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

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

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

SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.

Genetic-based therapies for CMT are currently in preclinical research phases, and an experimental small-molecule drug has reached phase 3 in humans, neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
 

A Common Genetic Neuromuscular Disorder

As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”

Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”

As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
 

Genetic Therapy

In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.

“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”

A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.

Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.

Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.

“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
 

Preclinical Treatment Approaches

However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”

Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.

One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.

The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.

Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”

Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.

Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.

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

TOPLINE:

VIENNA — Individuals with ulcerative colitis (UC) who carry the HLA-DRB1*01:03 allele are at increased risk of having a more severe disease course requiring major surgery, hospitalization, and high-dose systemic corticosteroids within 3 years of diagnosis, according to a Danish study.

METHODOLOGY:

• Reliable biomarkers are lacking to identify patients with inflammatory bowel disease at greater risk for severe disease and who therefore might require intensified monitoring and treatment.
• Researchers explored genetic variants associated with severe UC in patients from two Danish cohorts, whose DNA was extracted from dried blood spots and full blood, with genotyping then performed to assess the presence of human leukocyte antigen (HLA) alleles and single-nucleotide variants.
• Severe UC was defined as having at least one major UC-related operation, at least two UC-related hospitalizations exceeding 2 days, and/or use of at least 5000 mg of systemic corticosteroids within 3 years of diagnosis. Patients not meeting these criteria were considered to have less severe UC and included as the comparison group.
• A genome-wide association study was conducted comparing severe vs less severe UC.

TAKEAWAY:

• Researchers analyzed 4491 patients with UC (mean age at diagnosis, 23 years; 53% women; 27% with severe UC) and determined that carriers of the HLA-DRB1*01:03 allele had a significantly higher risk for severe UC (odds ratio, 3.32).
• Compared with noncarriers, those with this allele had an approximately sixfold increased risk of needing major surgery, a fivefold increased risk of requiring at least two hospitalizations, and a twofold increased risk for use of over 5000 mg of systemic corticosteroids within 3 years of diagnosis.
• Time-to-event analysis showed that the association between carriers and disease severity extended beyond 3 years after diagnosis.
• Compared with noncarriers, those with the HLA-DRB1*01:03 allele had a higher hazard ratio for time to hospitalization, major surgery, and first treatment with systemic corticosteroids.

IN PRACTICE:

“Although HLA-DRB1*01:03 is a low-frequency allele, carriers have a significantly higher risk of severe ulcerative colitis. Given the low cost of typing a single HLA allele, HLA-DRB1*01:03 could be a valuable tool for risk assessment of patients with ulcerative colitis at diagnosis,” the authors concluded.

SOURCE:

The study, with first author Marie Vibeke Vestergaard, MSc, Aalborg University, Aalborg, Denmark, was published online on October 15 in JAMA, to coincide with its presentation at United European Gastroenterology (UEG) Week 2024 in Vienna, Austria. 

LIMITATIONS:

The findings are based on a Danish population of European genetic ancestry and require validation in diverse patient cohorts with UC.

DISCLOSURES:

The study was funded by the Danish National Research Foundation, the Lundbeck Foundation, and the Novo Nordisk Foundation. The authors reported no relevant disclosures related to the study.
 

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

TOPLINE:

VIENNA — Individuals with ulcerative colitis (UC) who carry the HLA-DRB1*01:03 allele are at increased risk of having a more severe disease course requiring major surgery, hospitalization, and high-dose systemic corticosteroids within 3 years of diagnosis, according to a Danish study.

METHODOLOGY:

• Reliable biomarkers are lacking to identify patients with inflammatory bowel disease at greater risk for severe disease and who therefore might require intensified monitoring and treatment.
• Researchers explored genetic variants associated with severe UC in patients from two Danish cohorts, whose DNA was extracted from dried blood spots and full blood, with genotyping then performed to assess the presence of human leukocyte antigen (HLA) alleles and single-nucleotide variants.
• Severe UC was defined as having at least one major UC-related operation, at least two UC-related hospitalizations exceeding 2 days, and/or use of at least 5000 mg of systemic corticosteroids within 3 years of diagnosis. Patients not meeting these criteria were considered to have less severe UC and included as the comparison group.
• A genome-wide association study was conducted comparing severe vs less severe UC.

TAKEAWAY:

• Researchers analyzed 4491 patients with UC (mean age at diagnosis, 23 years; 53% women; 27% with severe UC) and determined that carriers of the HLA-DRB1*01:03 allele had a significantly higher risk for severe UC (odds ratio, 3.32).
• Compared with noncarriers, those with this allele had an approximately sixfold increased risk of needing major surgery, a fivefold increased risk of requiring at least two hospitalizations, and a twofold increased risk for use of over 5000 mg of systemic corticosteroids within 3 years of diagnosis.
• Time-to-event analysis showed that the association between carriers and disease severity extended beyond 3 years after diagnosis.
• Compared with noncarriers, those with the HLA-DRB1*01:03 allele had a higher hazard ratio for time to hospitalization, major surgery, and first treatment with systemic corticosteroids.

IN PRACTICE:

“Although HLA-DRB1*01:03 is a low-frequency allele, carriers have a significantly higher risk of severe ulcerative colitis. Given the low cost of typing a single HLA allele, HLA-DRB1*01:03 could be a valuable tool for risk assessment of patients with ulcerative colitis at diagnosis,” the authors concluded.

SOURCE:

The study, with first author Marie Vibeke Vestergaard, MSc, Aalborg University, Aalborg, Denmark, was published online on October 15 in JAMA, to coincide with its presentation at United European Gastroenterology (UEG) Week 2024 in Vienna, Austria. 

LIMITATIONS:

The findings are based on a Danish population of European genetic ancestry and require validation in diverse patient cohorts with UC.

DISCLOSURES:

The study was funded by the Danish National Research Foundation, the Lundbeck Foundation, and the Novo Nordisk Foundation. The authors reported no relevant disclosures related to the study.
 

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

TOPLINE:

VIENNA — Individuals with ulcerative colitis (UC) who carry the HLA-DRB1*01:03 allele are at increased risk of having a more severe disease course requiring major surgery, hospitalization, and high-dose systemic corticosteroids within 3 years of diagnosis, according to a Danish study.

METHODOLOGY:

• Reliable biomarkers are lacking to identify patients with inflammatory bowel disease at greater risk for severe disease and who therefore might require intensified monitoring and treatment.
• Researchers explored genetic variants associated with severe UC in patients from two Danish cohorts, whose DNA was extracted from dried blood spots and full blood, with genotyping then performed to assess the presence of human leukocyte antigen (HLA) alleles and single-nucleotide variants.
• Severe UC was defined as having at least one major UC-related operation, at least two UC-related hospitalizations exceeding 2 days, and/or use of at least 5000 mg of systemic corticosteroids within 3 years of diagnosis. Patients not meeting these criteria were considered to have less severe UC and included as the comparison group.
• A genome-wide association study was conducted comparing severe vs less severe UC.

TAKEAWAY:

• Researchers analyzed 4491 patients with UC (mean age at diagnosis, 23 years; 53% women; 27% with severe UC) and determined that carriers of the HLA-DRB1*01:03 allele had a significantly higher risk for severe UC (odds ratio, 3.32).
• Compared with noncarriers, those with this allele had an approximately sixfold increased risk of needing major surgery, a fivefold increased risk of requiring at least two hospitalizations, and a twofold increased risk for use of over 5000 mg of systemic corticosteroids within 3 years of diagnosis.
• Time-to-event analysis showed that the association between carriers and disease severity extended beyond 3 years after diagnosis.
• Compared with noncarriers, those with the HLA-DRB1*01:03 allele had a higher hazard ratio for time to hospitalization, major surgery, and first treatment with systemic corticosteroids.

IN PRACTICE:

“Although HLA-DRB1*01:03 is a low-frequency allele, carriers have a significantly higher risk of severe ulcerative colitis. Given the low cost of typing a single HLA allele, HLA-DRB1*01:03 could be a valuable tool for risk assessment of patients with ulcerative colitis at diagnosis,” the authors concluded.

SOURCE:

The study, with first author Marie Vibeke Vestergaard, MSc, Aalborg University, Aalborg, Denmark, was published online on October 15 in JAMA, to coincide with its presentation at United European Gastroenterology (UEG) Week 2024 in Vienna, Austria. 

LIMITATIONS:

The findings are based on a Danish population of European genetic ancestry and require validation in diverse patient cohorts with UC.

DISCLOSURES:

The study was funded by the Danish National Research Foundation, the Lundbeck Foundation, and the Novo Nordisk Foundation. The authors reported no relevant disclosures related to the study.
 

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

Postoperative chronic pain (POCP) is common and is expected to become increasingly prevalent. This type of pain, however, which specifically arises following surgery, independent of any infection or surgical failure, remains poorly understood. Facilities dedicated to treating it are nearly nonexistent.

At the 2024 congress of the French Society of Anesthesia and Resuscitation, anesthesiologists specializing in pain management advocated for improved management of POCP. They put themselves forward as essential interlocutors and actors in this effort. The anesthesiologists also called for better recognition of postoperative pain by patients, general practitioners, and surgeons to enable early intervention and reduce the risk for chronicity.
 

Underrecognized, Poorly Managed

POCP is defined as persistent pain lasting more than 3 months after surgery, unrelated to preoperative pain, and not associated with surgical complications. It can manifest in various forms, but the most typical scenario involves a patient complaining of persistent pain that developed following a surgical procedure. Normal radiological and biologic assessments rule out infectious complications. The persistence of pain long after surgery contrasts with what is often considered a successful surgical outcome by the surgeon.

“Of the 10 million patients operated on each year in France, it is estimated that about 10% will develop POCP, equating to 1.2 million patients,” explained Cyril Quémeneur, a specialist in anesthesiology and pain management at Pitié-Salpêtrière Hospital in Paris, France.

Because of the increasing number of surgical interventions in recent years, POCP has become a major concern. “Currently, there are 275 facilities dedicated to chronic pain across the country, capable of accommodating between 300,000 and 400,000 patients. Given that knee replacement surgery — the incidence of which is rising sharply — results in postoperative pain for 20%-30% of operated patients, the question of managing this type of pain will become even more pressing in the future,” said Quémeneur.

Moreover, specialized facilities for transitional pain management are not widespread in France, unlike in Canada, which has been developing them for about a decade, he noted.

France’s pain treatment centers “are overwhelmed,” said Gilles Lebuffe, a specialist in anesthesiology and pain management at Lille University Hospital in Lille, France. “Thus, the time between when the patient is operated on and when we discuss chronic pain allows the painful condition to establish itself, leading to central sensitization at the neurological level.” Once established, this pain is difficult to treat. “The later a patient arrives at a pain center, the more challenging the situation is to manage,” said Lebuffe.
 

Risk Factors

It is therefore crucial to identify patients at higher risk for postoperative pain during the anesthesia consultation, thus allowing for monitoring during the postoperative period. These pains can be highly debilitating because of their intensity, chronicity, and impact on quality of life.

To target these patients, it is essential to understand which surgeries and patient types constitute risk factors, as well as the characteristics of the pain experienced.

While all surgeries can lead to POCP, certain procedures are more likely to result in chronic pain. They include breast surgery with mastectomy, thoracic and spinal surgery, amputations, and knee replacement surgery. Notably, surgical repair of inguinal hernias, considered routine surgery, is emblematic of the risk for POCP. Its incidence after this procedure is 10% or more in the literature.

In addition, POCP often has neuropathic characteristics. Patients frequently describe their pain using terms like “burning” or “electric shock.” These pains are often associated with strange sensations such as tingling, prickling, itching, or numbness. “This describes neuropathic pain, which increases the risk of chronicity,” said Lebuffe.
 

Preoperative Opioid Use

Another warning sign for healthcare professionals is that patients with chronic pain may have factors associated with vulnerability. Women, who have a higher incidence of chronic pain syndrome, are at greater risk of developing postoperative chronic pain than men.

It has also been shown that preoperative opioid use leads to higher postoperative pain intensities for several days. This is a factor to consider, even though opioid consumption rates in France are far lower than those in the United States, where as much as 35% of patients use opioids preoperatively, said Frédéric Aubrun, head of the Anesthesia and Intensive Care Department and a pain management specialist at the Hospices Civils de Lyon in Lyon, France. Finally, significant literature indicates that psychological fragility is a risk factor for more intense acute pain and for POCP. “Patients with chronic pain frequently have depressive symptoms and anxiety,” said Lebuffe.
 

Involving General Practitioners

Because one responsibility of general practitioners is to identify patients with abnormal postoperative pain trajectories, the anesthesiologists at the press conference advocated for greater patient awareness and increased involvement of general practitioners in this identification process.

“If there is an expected duration of postoperative pain at varying intensities, since it all depends on the patient’s journey (the number of reoperations, history of opioid use, etc.), it is necessary to make patients aware that it is not normal to suffer long after a surgical intervention,” said Aubrun. In addition, it is important to “connect with primary care” and mobilize general practitioners to “detect patients sliding toward opioid overconsumption” and refer them to the appropriate care structure, he said.

Although dedicated facilities for this type of pain — like transitional pain clinics in Canada or northern Europe — do not exist in France, some hospitals, like Lille University Hospital, have established “intermediate consultations targeting patients with specific pain or chronicity characteristics. In these consultations, patients are systematically reviewed 4-6 weeks after surgery by the surgeon, who has been trained to identify neuropathic pain,” said Lebuffe. When a patient with such pain is identified, he or she is referred to an intermediate consultation and seen by a fellow anesthesiologist. The advantage of this consultation is that it is linked to a chronic pain structure. Consequently, frequent exchanges occur with the pain specialists involved in this structure, thus allowing for immediate optimization of pain treatments. The goal is to halt the process of central sensitization.

“We strongly believe in this type of transitional structure, even though it requires significant human resources,” said Lebuffe. He also called for a “societal reflection” on this issue because patients with chronic pain represent a significant cost to society, in terms of medications and work stoppages. Moreover, patients who are forced to stop working see their lives disrupted.
 

Managing POCP

When POCP with neuropathic characteristics has been diagnosed, specific treatments and techniques for chronic pain can be prescribed earlier than they currently are. “Systemic drug treatments for neuropathic POCP rely on various therapeutic classes (opioids, antidepressants, antiepileptics), which are not without side effects for the patient,” said Violaine D’ans, an anesthesiologist and pain management specialist at Polyclinique du Parc in Caen, France. Hence, the idea is to prescribe a minimal dose while providing the patient with techniques available to anesthesiologists. “We have a good range of management options that we use in perioperative pain management, and we have a role to play in radio- or CT-guided perinerve infiltrations, with continuous peripheral nerve blocks and possibly later with electrostimulation to help restore movement and avoid kinesiophobia.”

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Postoperative chronic pain (POCP) is common and is expected to become increasingly prevalent. This type of pain, however, which specifically arises following surgery, independent of any infection or surgical failure, remains poorly understood. Facilities dedicated to treating it are nearly nonexistent.

At the 2024 congress of the French Society of Anesthesia and Resuscitation, anesthesiologists specializing in pain management advocated for improved management of POCP. They put themselves forward as essential interlocutors and actors in this effort. The anesthesiologists also called for better recognition of postoperative pain by patients, general practitioners, and surgeons to enable early intervention and reduce the risk for chronicity.
 

Underrecognized, Poorly Managed

POCP is defined as persistent pain lasting more than 3 months after surgery, unrelated to preoperative pain, and not associated with surgical complications. It can manifest in various forms, but the most typical scenario involves a patient complaining of persistent pain that developed following a surgical procedure. Normal radiological and biologic assessments rule out infectious complications. The persistence of pain long after surgery contrasts with what is often considered a successful surgical outcome by the surgeon.

“Of the 10 million patients operated on each year in France, it is estimated that about 10% will develop POCP, equating to 1.2 million patients,” explained Cyril Quémeneur, a specialist in anesthesiology and pain management at Pitié-Salpêtrière Hospital in Paris, France.

Because of the increasing number of surgical interventions in recent years, POCP has become a major concern. “Currently, there are 275 facilities dedicated to chronic pain across the country, capable of accommodating between 300,000 and 400,000 patients. Given that knee replacement surgery — the incidence of which is rising sharply — results in postoperative pain for 20%-30% of operated patients, the question of managing this type of pain will become even more pressing in the future,” said Quémeneur.

Moreover, specialized facilities for transitional pain management are not widespread in France, unlike in Canada, which has been developing them for about a decade, he noted.

France’s pain treatment centers “are overwhelmed,” said Gilles Lebuffe, a specialist in anesthesiology and pain management at Lille University Hospital in Lille, France. “Thus, the time between when the patient is operated on and when we discuss chronic pain allows the painful condition to establish itself, leading to central sensitization at the neurological level.” Once established, this pain is difficult to treat. “The later a patient arrives at a pain center, the more challenging the situation is to manage,” said Lebuffe.
 

Risk Factors

It is therefore crucial to identify patients at higher risk for postoperative pain during the anesthesia consultation, thus allowing for monitoring during the postoperative period. These pains can be highly debilitating because of their intensity, chronicity, and impact on quality of life.

To target these patients, it is essential to understand which surgeries and patient types constitute risk factors, as well as the characteristics of the pain experienced.

While all surgeries can lead to POCP, certain procedures are more likely to result in chronic pain. They include breast surgery with mastectomy, thoracic and spinal surgery, amputations, and knee replacement surgery. Notably, surgical repair of inguinal hernias, considered routine surgery, is emblematic of the risk for POCP. Its incidence after this procedure is 10% or more in the literature.

In addition, POCP often has neuropathic characteristics. Patients frequently describe their pain using terms like “burning” or “electric shock.” These pains are often associated with strange sensations such as tingling, prickling, itching, or numbness. “This describes neuropathic pain, which increases the risk of chronicity,” said Lebuffe.
 

Preoperative Opioid Use

Another warning sign for healthcare professionals is that patients with chronic pain may have factors associated with vulnerability. Women, who have a higher incidence of chronic pain syndrome, are at greater risk of developing postoperative chronic pain than men.

It has also been shown that preoperative opioid use leads to higher postoperative pain intensities for several days. This is a factor to consider, even though opioid consumption rates in France are far lower than those in the United States, where as much as 35% of patients use opioids preoperatively, said Frédéric Aubrun, head of the Anesthesia and Intensive Care Department and a pain management specialist at the Hospices Civils de Lyon in Lyon, France. Finally, significant literature indicates that psychological fragility is a risk factor for more intense acute pain and for POCP. “Patients with chronic pain frequently have depressive symptoms and anxiety,” said Lebuffe.
 

Involving General Practitioners

Because one responsibility of general practitioners is to identify patients with abnormal postoperative pain trajectories, the anesthesiologists at the press conference advocated for greater patient awareness and increased involvement of general practitioners in this identification process.

“If there is an expected duration of postoperative pain at varying intensities, since it all depends on the patient’s journey (the number of reoperations, history of opioid use, etc.), it is necessary to make patients aware that it is not normal to suffer long after a surgical intervention,” said Aubrun. In addition, it is important to “connect with primary care” and mobilize general practitioners to “detect patients sliding toward opioid overconsumption” and refer them to the appropriate care structure, he said.

Although dedicated facilities for this type of pain — like transitional pain clinics in Canada or northern Europe — do not exist in France, some hospitals, like Lille University Hospital, have established “intermediate consultations targeting patients with specific pain or chronicity characteristics. In these consultations, patients are systematically reviewed 4-6 weeks after surgery by the surgeon, who has been trained to identify neuropathic pain,” said Lebuffe. When a patient with such pain is identified, he or she is referred to an intermediate consultation and seen by a fellow anesthesiologist. The advantage of this consultation is that it is linked to a chronic pain structure. Consequently, frequent exchanges occur with the pain specialists involved in this structure, thus allowing for immediate optimization of pain treatments. The goal is to halt the process of central sensitization.

“We strongly believe in this type of transitional structure, even though it requires significant human resources,” said Lebuffe. He also called for a “societal reflection” on this issue because patients with chronic pain represent a significant cost to society, in terms of medications and work stoppages. Moreover, patients who are forced to stop working see their lives disrupted.
 

Managing POCP

When POCP with neuropathic characteristics has been diagnosed, specific treatments and techniques for chronic pain can be prescribed earlier than they currently are. “Systemic drug treatments for neuropathic POCP rely on various therapeutic classes (opioids, antidepressants, antiepileptics), which are not without side effects for the patient,” said Violaine D’ans, an anesthesiologist and pain management specialist at Polyclinique du Parc in Caen, France. Hence, the idea is to prescribe a minimal dose while providing the patient with techniques available to anesthesiologists. “We have a good range of management options that we use in perioperative pain management, and we have a role to play in radio- or CT-guided perinerve infiltrations, with continuous peripheral nerve blocks and possibly later with electrostimulation to help restore movement and avoid kinesiophobia.”

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Postoperative chronic pain (POCP) is common and is expected to become increasingly prevalent. This type of pain, however, which specifically arises following surgery, independent of any infection or surgical failure, remains poorly understood. Facilities dedicated to treating it are nearly nonexistent.

At the 2024 congress of the French Society of Anesthesia and Resuscitation, anesthesiologists specializing in pain management advocated for improved management of POCP. They put themselves forward as essential interlocutors and actors in this effort. The anesthesiologists also called for better recognition of postoperative pain by patients, general practitioners, and surgeons to enable early intervention and reduce the risk for chronicity.
 

Underrecognized, Poorly Managed

POCP is defined as persistent pain lasting more than 3 months after surgery, unrelated to preoperative pain, and not associated with surgical complications. It can manifest in various forms, but the most typical scenario involves a patient complaining of persistent pain that developed following a surgical procedure. Normal radiological and biologic assessments rule out infectious complications. The persistence of pain long after surgery contrasts with what is often considered a successful surgical outcome by the surgeon.

“Of the 10 million patients operated on each year in France, it is estimated that about 10% will develop POCP, equating to 1.2 million patients,” explained Cyril Quémeneur, a specialist in anesthesiology and pain management at Pitié-Salpêtrière Hospital in Paris, France.

Because of the increasing number of surgical interventions in recent years, POCP has become a major concern. “Currently, there are 275 facilities dedicated to chronic pain across the country, capable of accommodating between 300,000 and 400,000 patients. Given that knee replacement surgery — the incidence of which is rising sharply — results in postoperative pain for 20%-30% of operated patients, the question of managing this type of pain will become even more pressing in the future,” said Quémeneur.

Moreover, specialized facilities for transitional pain management are not widespread in France, unlike in Canada, which has been developing them for about a decade, he noted.

France’s pain treatment centers “are overwhelmed,” said Gilles Lebuffe, a specialist in anesthesiology and pain management at Lille University Hospital in Lille, France. “Thus, the time between when the patient is operated on and when we discuss chronic pain allows the painful condition to establish itself, leading to central sensitization at the neurological level.” Once established, this pain is difficult to treat. “The later a patient arrives at a pain center, the more challenging the situation is to manage,” said Lebuffe.
 

Risk Factors

It is therefore crucial to identify patients at higher risk for postoperative pain during the anesthesia consultation, thus allowing for monitoring during the postoperative period. These pains can be highly debilitating because of their intensity, chronicity, and impact on quality of life.

To target these patients, it is essential to understand which surgeries and patient types constitute risk factors, as well as the characteristics of the pain experienced.

While all surgeries can lead to POCP, certain procedures are more likely to result in chronic pain. They include breast surgery with mastectomy, thoracic and spinal surgery, amputations, and knee replacement surgery. Notably, surgical repair of inguinal hernias, considered routine surgery, is emblematic of the risk for POCP. Its incidence after this procedure is 10% or more in the literature.

In addition, POCP often has neuropathic characteristics. Patients frequently describe their pain using terms like “burning” or “electric shock.” These pains are often associated with strange sensations such as tingling, prickling, itching, or numbness. “This describes neuropathic pain, which increases the risk of chronicity,” said Lebuffe.
 

Preoperative Opioid Use

Another warning sign for healthcare professionals is that patients with chronic pain may have factors associated with vulnerability. Women, who have a higher incidence of chronic pain syndrome, are at greater risk of developing postoperative chronic pain than men.

It has also been shown that preoperative opioid use leads to higher postoperative pain intensities for several days. This is a factor to consider, even though opioid consumption rates in France are far lower than those in the United States, where as much as 35% of patients use opioids preoperatively, said Frédéric Aubrun, head of the Anesthesia and Intensive Care Department and a pain management specialist at the Hospices Civils de Lyon in Lyon, France. Finally, significant literature indicates that psychological fragility is a risk factor for more intense acute pain and for POCP. “Patients with chronic pain frequently have depressive symptoms and anxiety,” said Lebuffe.
 

Involving General Practitioners

Because one responsibility of general practitioners is to identify patients with abnormal postoperative pain trajectories, the anesthesiologists at the press conference advocated for greater patient awareness and increased involvement of general practitioners in this identification process.

“If there is an expected duration of postoperative pain at varying intensities, since it all depends on the patient’s journey (the number of reoperations, history of opioid use, etc.), it is necessary to make patients aware that it is not normal to suffer long after a surgical intervention,” said Aubrun. In addition, it is important to “connect with primary care” and mobilize general practitioners to “detect patients sliding toward opioid overconsumption” and refer them to the appropriate care structure, he said.

Although dedicated facilities for this type of pain — like transitional pain clinics in Canada or northern Europe — do not exist in France, some hospitals, like Lille University Hospital, have established “intermediate consultations targeting patients with specific pain or chronicity characteristics. In these consultations, patients are systematically reviewed 4-6 weeks after surgery by the surgeon, who has been trained to identify neuropathic pain,” said Lebuffe. When a patient with such pain is identified, he or she is referred to an intermediate consultation and seen by a fellow anesthesiologist. The advantage of this consultation is that it is linked to a chronic pain structure. Consequently, frequent exchanges occur with the pain specialists involved in this structure, thus allowing for immediate optimization of pain treatments. The goal is to halt the process of central sensitization.

“We strongly believe in this type of transitional structure, even though it requires significant human resources,” said Lebuffe. He also called for a “societal reflection” on this issue because patients with chronic pain represent a significant cost to society, in terms of medications and work stoppages. Moreover, patients who are forced to stop working see their lives disrupted.
 

Managing POCP

When POCP with neuropathic characteristics has been diagnosed, specific treatments and techniques for chronic pain can be prescribed earlier than they currently are. “Systemic drug treatments for neuropathic POCP rely on various therapeutic classes (opioids, antidepressants, antiepileptics), which are not without side effects for the patient,” said Violaine D’ans, an anesthesiologist and pain management specialist at Polyclinique du Parc in Caen, France. Hence, the idea is to prescribe a minimal dose while providing the patient with techniques available to anesthesiologists. “We have a good range of management options that we use in perioperative pain management, and we have a role to play in radio- or CT-guided perinerve infiltrations, with continuous peripheral nerve blocks and possibly later with electrostimulation to help restore movement and avoid kinesiophobia.”

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In several countries, including China, Mexico, and the United States, the incidence of type 2 diabetes now exceeds that of type 1 diabetes among patients younger than 20 years.

“This is an emerging epidemic,” said Orit Pinhas-Hamiel, MD, director of the Pediatric Endocrinology and Diabetes Unit at Sheba Medical Center in Ramat Gan, Israel, at the annual meeting of the European Association for the Study of Diabetes, noting that these young patients, most with obesity, exhibit a significantly higher incidence of complications than adults with type 2 diabetes or young people with type 1 diabetes.

In 2017-2018, the incidence of type 2 diabetes among patients aged 15-19 years (19.7 per 100,000) surpassed that of type 1 diabetes (14.6 per 100,000), according to data from the United States.

“This is the first time that the incidence of type 2 diabetes has exceeded that of type 1 among youth,” said Pinhas-Hamiel. A review of 2021 published a few months ago highlighted this surge, with countries like China, India, the United States, Brazil, and Mexico leading the way.
 

SEARCH and TODAY

The SEARCH for Diabetes in Youth study, which was launched in 2000, is a multicenter observational study in the United States aimed at estimating the prevalence, incidence, and complications of types 1 and 2 diabetes among young patients. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is an interventional study focusing on adolescents with type 2 diabetes to evaluate the effectiveness of various treatment options.

“Diabesity” — the dual global epidemic of obesity and type 2 diabetes — has visible consequences from the moment of diagnosis, including hypertension. In the TODAY study, 11.6% adolescents had hypertension at diagnosis. A study conducted in Hong Kong involving 391 children younger than 18 years revealed that 22.5% had hypertension. In SEARCH, 27% young patients diagnosed with type 2 diabetes for 1.5 years had hypertension.

In addition, the SEARCH study found that 27% young individuals had low levels of high-density lipoprotein cholesterol, while 25% had high triglyceride levels, at 1.5 years after diagnosis.

Overall, the cumulative incidence of long-term diabetic complications was assessed in 500 adolescents participating in TODAY (mean age, 26.4 ± 2.8 years; mean time since diagnosis, 13.3 ± 1.8 years). The initial prevalence was 19.2%, while the cumulative incidence rose to 67.5% after 15 years of follow-up.

For dyslipidemia, the initial prevalence was 20.8%, with a cumulative incidence of 51.6%. The incidence of diabetic nephropathy was 54.8% and neuropathies was 32.4%. The prevalence of retinopathy was 13.7% for the period 2010-2011 and 51% for 2017-2018.

At least one complication was observed in 60.1% participants and at least two in 28.4%. As expected, risk factors for developing complications included belonging to a racial or ethnic minority, hyperglycemia, hypertension, and dyslipidemia.

“Among those who developed type 2 diabetes in adolescence, the risk for complications, including microvascular complications, has continuously increased and affected most participants in young adulthood,” said Pinhas-Hamiel.

At the same time, the rate of treatment with lipid-lowering and antihypertensive medications remains low among young people with type 2 diabetes. The management of dyslipidemia is suboptimal, with only 5% young patients with diabetes and dyslipidemia receiving appropriate medications. Furthermore, treatment adherence is lacking. In the TODAY cohort, for example, only one third of participants with high levels of low-density lipoprotein cholesterol were on lipid-lowering medications, and only half of the young patients with hypertension were taking antihypertensives.
 

Focus on Diabetic Nephropathy

Diabetic kidney disease is the leading microvascular complication of type 2 diabetes in adolescents. It is associated with rapid progression and poor prognosis. The natural history begins with hyperfiltration: A consequence of obesity and impaired glucose tolerance. Structural renal changes can be detected as early as 1.5 years after diagnosis.

The second stage is characterized by a reduction in the glomerular filtration rate. At this stage, “the structural changes in the kidney are typical but often present,” said Pinhas-Hamiel, making this period critical for reducing risk factors.

In TODAY, the cumulative incidence of diabetic nephropathy was 54.8%. The prevalence at inclusion was 8%. In SEARCH, after 8 years, the prevalence of diabetic kidney disease was 19.9% among adolescents with type 2 diabetes vs 5.8% among those with type 1 diabetes. A pre-analysis revealed that the overall prevalence of macroalbuminuria among 730 children and adolescents with type 2 diabetes was 3.8%. The ages at diagnosis of type 2 diabetes ranged from 6.5 to 21 years, and the duration of the disease varied from diagnosis to 15 years after.

Diabetic retinopathy was present in 50% participants in the TODAY study at age 25 years (ie, after 12 years of disease). In SEARCH, 56% young patients had diabetic retinopathy after 12.5 years of diabetes. In addition, in the same study, the prevalence of peripheral neuropathy, assessed after 8 years, was 22% among adolescents with type 2 diabetes vs 7% among those with type 1 diabetes.
 

Cardiovascular Autonomic Neuropathy

A decrease in heart rate variability was observed in 47% young patients with type 2 diabetes after an average disease duration of only 1.7 years. In SEARCH, the prevalence of cardiovascular autonomic neuropathy, assessed after 8 years of disease, was 17% in adolescents with type 2 diabetes versus 12% in those with type 1 diabetes.

Overall, 7.1% participants had three complications: nephropathy, retinopathy, and neuropathy. The cumulative incidence of microvascular complications was 80%.

Moreover, A1c levels deteriorated progressively throughout the follow-up period. Approximately 45% participants had an A1c of at least 10%, and 20% were between 8% and 10%. Body mass index consistently remained between 35 and 37.5.

Young patients with type 2 diabetes exhibit endothelial dysfunction, increased carotid intima-media thickness, elevated arterial stiffness, left ventricular hypertrophy, diastolic dysfunction, and reduced maximal exercise capacity. All these factors predict cardiovascular morbidity and mortality.

In TODAY, 17 serious cardiovascular events were recorded, including four myocardial infarctions, six cases of congestive heart failure, three coronary events, and four strokes.

In an analysis of the TODAY and SEARCH studies, although the average duration of diabetes was similar, complications were more frequent among young patients with type 2 diabetes than among those with type 1 diabetes. Microvascular complications were 2.5 times more frequent, and macrovascular complications were four times more frequent.

In SEARCH, excessive mortality was observed among young adults for each type of diabetes. Differences in risk were associated with diabetes type, age, race/ethnicity, and sex. Mortality ratios were 1.5 and 2.3 for types 1 and 2 diabetes, respectively.

Women had higher mortality rates than men. Diabetes was the underlying cause of death in 9.1% cases, which was comparable to cardiovascular diseases or cancer (10.9%). According to a life expectancy model, young patients with type 2 diabetes lose about 15 years of life.
 

Eating Disorders and Depression

Beyond these complications, other issues are often present among adolescents with type 2 diabetes. Approximately 50% have eating disorders (compared with 21% among those with type 1 diabetes), 19.3% report depressive symptoms, and 18.9% have expressed thoughts of self-harm. In addition, 19.6% have polycystic ovary syndrome. Z-scores for bone mineral density at the femoral neck and lumbar spine were significantly lower in adolescents with type 2 diabetes than in healthy peers. The presence of metabolic dysfunction–associated fatty liver disease is also more pronounced.

“The recent approvals of new pharmacological interventions for weight loss and improved glycemic control in adolescents offer hope. We hope that, over the next decade, the prevalence of complications among these young patients with type 2 diabetes will decline. In the meantime, a proactive approach is essential to prevent complications related to type 2 diabetes in these youth,” Pinhas-Hamiel concluded.

For more information, see ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 Diabetes in Children and Adolescents.

Pinhas-Hamiel reported no relevant financial relationships.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In several countries, including China, Mexico, and the United States, the incidence of type 2 diabetes now exceeds that of type 1 diabetes among patients younger than 20 years.

“This is an emerging epidemic,” said Orit Pinhas-Hamiel, MD, director of the Pediatric Endocrinology and Diabetes Unit at Sheba Medical Center in Ramat Gan, Israel, at the annual meeting of the European Association for the Study of Diabetes, noting that these young patients, most with obesity, exhibit a significantly higher incidence of complications than adults with type 2 diabetes or young people with type 1 diabetes.

In 2017-2018, the incidence of type 2 diabetes among patients aged 15-19 years (19.7 per 100,000) surpassed that of type 1 diabetes (14.6 per 100,000), according to data from the United States.

“This is the first time that the incidence of type 2 diabetes has exceeded that of type 1 among youth,” said Pinhas-Hamiel. A review of 2021 published a few months ago highlighted this surge, with countries like China, India, the United States, Brazil, and Mexico leading the way.
 

SEARCH and TODAY

The SEARCH for Diabetes in Youth study, which was launched in 2000, is a multicenter observational study in the United States aimed at estimating the prevalence, incidence, and complications of types 1 and 2 diabetes among young patients. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is an interventional study focusing on adolescents with type 2 diabetes to evaluate the effectiveness of various treatment options.

“Diabesity” — the dual global epidemic of obesity and type 2 diabetes — has visible consequences from the moment of diagnosis, including hypertension. In the TODAY study, 11.6% adolescents had hypertension at diagnosis. A study conducted in Hong Kong involving 391 children younger than 18 years revealed that 22.5% had hypertension. In SEARCH, 27% young patients diagnosed with type 2 diabetes for 1.5 years had hypertension.

In addition, the SEARCH study found that 27% young individuals had low levels of high-density lipoprotein cholesterol, while 25% had high triglyceride levels, at 1.5 years after diagnosis.

Overall, the cumulative incidence of long-term diabetic complications was assessed in 500 adolescents participating in TODAY (mean age, 26.4 ± 2.8 years; mean time since diagnosis, 13.3 ± 1.8 years). The initial prevalence was 19.2%, while the cumulative incidence rose to 67.5% after 15 years of follow-up.

For dyslipidemia, the initial prevalence was 20.8%, with a cumulative incidence of 51.6%. The incidence of diabetic nephropathy was 54.8% and neuropathies was 32.4%. The prevalence of retinopathy was 13.7% for the period 2010-2011 and 51% for 2017-2018.

At least one complication was observed in 60.1% participants and at least two in 28.4%. As expected, risk factors for developing complications included belonging to a racial or ethnic minority, hyperglycemia, hypertension, and dyslipidemia.

“Among those who developed type 2 diabetes in adolescence, the risk for complications, including microvascular complications, has continuously increased and affected most participants in young adulthood,” said Pinhas-Hamiel.

At the same time, the rate of treatment with lipid-lowering and antihypertensive medications remains low among young people with type 2 diabetes. The management of dyslipidemia is suboptimal, with only 5% young patients with diabetes and dyslipidemia receiving appropriate medications. Furthermore, treatment adherence is lacking. In the TODAY cohort, for example, only one third of participants with high levels of low-density lipoprotein cholesterol were on lipid-lowering medications, and only half of the young patients with hypertension were taking antihypertensives.
 

Focus on Diabetic Nephropathy

Diabetic kidney disease is the leading microvascular complication of type 2 diabetes in adolescents. It is associated with rapid progression and poor prognosis. The natural history begins with hyperfiltration: A consequence of obesity and impaired glucose tolerance. Structural renal changes can be detected as early as 1.5 years after diagnosis.

The second stage is characterized by a reduction in the glomerular filtration rate. At this stage, “the structural changes in the kidney are typical but often present,” said Pinhas-Hamiel, making this period critical for reducing risk factors.

In TODAY, the cumulative incidence of diabetic nephropathy was 54.8%. The prevalence at inclusion was 8%. In SEARCH, after 8 years, the prevalence of diabetic kidney disease was 19.9% among adolescents with type 2 diabetes vs 5.8% among those with type 1 diabetes. A pre-analysis revealed that the overall prevalence of macroalbuminuria among 730 children and adolescents with type 2 diabetes was 3.8%. The ages at diagnosis of type 2 diabetes ranged from 6.5 to 21 years, and the duration of the disease varied from diagnosis to 15 years after.

Diabetic retinopathy was present in 50% participants in the TODAY study at age 25 years (ie, after 12 years of disease). In SEARCH, 56% young patients had diabetic retinopathy after 12.5 years of diabetes. In addition, in the same study, the prevalence of peripheral neuropathy, assessed after 8 years, was 22% among adolescents with type 2 diabetes vs 7% among those with type 1 diabetes.
 

Cardiovascular Autonomic Neuropathy

A decrease in heart rate variability was observed in 47% young patients with type 2 diabetes after an average disease duration of only 1.7 years. In SEARCH, the prevalence of cardiovascular autonomic neuropathy, assessed after 8 years of disease, was 17% in adolescents with type 2 diabetes versus 12% in those with type 1 diabetes.

Overall, 7.1% participants had three complications: nephropathy, retinopathy, and neuropathy. The cumulative incidence of microvascular complications was 80%.

Moreover, A1c levels deteriorated progressively throughout the follow-up period. Approximately 45% participants had an A1c of at least 10%, and 20% were between 8% and 10%. Body mass index consistently remained between 35 and 37.5.

Young patients with type 2 diabetes exhibit endothelial dysfunction, increased carotid intima-media thickness, elevated arterial stiffness, left ventricular hypertrophy, diastolic dysfunction, and reduced maximal exercise capacity. All these factors predict cardiovascular morbidity and mortality.

In TODAY, 17 serious cardiovascular events were recorded, including four myocardial infarctions, six cases of congestive heart failure, three coronary events, and four strokes.

In an analysis of the TODAY and SEARCH studies, although the average duration of diabetes was similar, complications were more frequent among young patients with type 2 diabetes than among those with type 1 diabetes. Microvascular complications were 2.5 times more frequent, and macrovascular complications were four times more frequent.

In SEARCH, excessive mortality was observed among young adults for each type of diabetes. Differences in risk were associated with diabetes type, age, race/ethnicity, and sex. Mortality ratios were 1.5 and 2.3 for types 1 and 2 diabetes, respectively.

Women had higher mortality rates than men. Diabetes was the underlying cause of death in 9.1% cases, which was comparable to cardiovascular diseases or cancer (10.9%). According to a life expectancy model, young patients with type 2 diabetes lose about 15 years of life.
 

Eating Disorders and Depression

Beyond these complications, other issues are often present among adolescents with type 2 diabetes. Approximately 50% have eating disorders (compared with 21% among those with type 1 diabetes), 19.3% report depressive symptoms, and 18.9% have expressed thoughts of self-harm. In addition, 19.6% have polycystic ovary syndrome. Z-scores for bone mineral density at the femoral neck and lumbar spine were significantly lower in adolescents with type 2 diabetes than in healthy peers. The presence of metabolic dysfunction–associated fatty liver disease is also more pronounced.

“The recent approvals of new pharmacological interventions for weight loss and improved glycemic control in adolescents offer hope. We hope that, over the next decade, the prevalence of complications among these young patients with type 2 diabetes will decline. In the meantime, a proactive approach is essential to prevent complications related to type 2 diabetes in these youth,” Pinhas-Hamiel concluded.

For more information, see ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 Diabetes in Children and Adolescents.

Pinhas-Hamiel reported no relevant financial relationships.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In several countries, including China, Mexico, and the United States, the incidence of type 2 diabetes now exceeds that of type 1 diabetes among patients younger than 20 years.

“This is an emerging epidemic,” said Orit Pinhas-Hamiel, MD, director of the Pediatric Endocrinology and Diabetes Unit at Sheba Medical Center in Ramat Gan, Israel, at the annual meeting of the European Association for the Study of Diabetes, noting that these young patients, most with obesity, exhibit a significantly higher incidence of complications than adults with type 2 diabetes or young people with type 1 diabetes.

In 2017-2018, the incidence of type 2 diabetes among patients aged 15-19 years (19.7 per 100,000) surpassed that of type 1 diabetes (14.6 per 100,000), according to data from the United States.

“This is the first time that the incidence of type 2 diabetes has exceeded that of type 1 among youth,” said Pinhas-Hamiel. A review of 2021 published a few months ago highlighted this surge, with countries like China, India, the United States, Brazil, and Mexico leading the way.
 

SEARCH and TODAY

The SEARCH for Diabetes in Youth study, which was launched in 2000, is a multicenter observational study in the United States aimed at estimating the prevalence, incidence, and complications of types 1 and 2 diabetes among young patients. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is an interventional study focusing on adolescents with type 2 diabetes to evaluate the effectiveness of various treatment options.

“Diabesity” — the dual global epidemic of obesity and type 2 diabetes — has visible consequences from the moment of diagnosis, including hypertension. In the TODAY study, 11.6% adolescents had hypertension at diagnosis. A study conducted in Hong Kong involving 391 children younger than 18 years revealed that 22.5% had hypertension. In SEARCH, 27% young patients diagnosed with type 2 diabetes for 1.5 years had hypertension.

In addition, the SEARCH study found that 27% young individuals had low levels of high-density lipoprotein cholesterol, while 25% had high triglyceride levels, at 1.5 years after diagnosis.

Overall, the cumulative incidence of long-term diabetic complications was assessed in 500 adolescents participating in TODAY (mean age, 26.4 ± 2.8 years; mean time since diagnosis, 13.3 ± 1.8 years). The initial prevalence was 19.2%, while the cumulative incidence rose to 67.5% after 15 years of follow-up.

For dyslipidemia, the initial prevalence was 20.8%, with a cumulative incidence of 51.6%. The incidence of diabetic nephropathy was 54.8% and neuropathies was 32.4%. The prevalence of retinopathy was 13.7% for the period 2010-2011 and 51% for 2017-2018.

At least one complication was observed in 60.1% participants and at least two in 28.4%. As expected, risk factors for developing complications included belonging to a racial or ethnic minority, hyperglycemia, hypertension, and dyslipidemia.

“Among those who developed type 2 diabetes in adolescence, the risk for complications, including microvascular complications, has continuously increased and affected most participants in young adulthood,” said Pinhas-Hamiel.

At the same time, the rate of treatment with lipid-lowering and antihypertensive medications remains low among young people with type 2 diabetes. The management of dyslipidemia is suboptimal, with only 5% young patients with diabetes and dyslipidemia receiving appropriate medications. Furthermore, treatment adherence is lacking. In the TODAY cohort, for example, only one third of participants with high levels of low-density lipoprotein cholesterol were on lipid-lowering medications, and only half of the young patients with hypertension were taking antihypertensives.
 

Focus on Diabetic Nephropathy

Diabetic kidney disease is the leading microvascular complication of type 2 diabetes in adolescents. It is associated with rapid progression and poor prognosis. The natural history begins with hyperfiltration: A consequence of obesity and impaired glucose tolerance. Structural renal changes can be detected as early as 1.5 years after diagnosis.

The second stage is characterized by a reduction in the glomerular filtration rate. At this stage, “the structural changes in the kidney are typical but often present,” said Pinhas-Hamiel, making this period critical for reducing risk factors.

In TODAY, the cumulative incidence of diabetic nephropathy was 54.8%. The prevalence at inclusion was 8%. In SEARCH, after 8 years, the prevalence of diabetic kidney disease was 19.9% among adolescents with type 2 diabetes vs 5.8% among those with type 1 diabetes. A pre-analysis revealed that the overall prevalence of macroalbuminuria among 730 children and adolescents with type 2 diabetes was 3.8%. The ages at diagnosis of type 2 diabetes ranged from 6.5 to 21 years, and the duration of the disease varied from diagnosis to 15 years after.

Diabetic retinopathy was present in 50% participants in the TODAY study at age 25 years (ie, after 12 years of disease). In SEARCH, 56% young patients had diabetic retinopathy after 12.5 years of diabetes. In addition, in the same study, the prevalence of peripheral neuropathy, assessed after 8 years, was 22% among adolescents with type 2 diabetes vs 7% among those with type 1 diabetes.
 

Cardiovascular Autonomic Neuropathy

A decrease in heart rate variability was observed in 47% young patients with type 2 diabetes after an average disease duration of only 1.7 years. In SEARCH, the prevalence of cardiovascular autonomic neuropathy, assessed after 8 years of disease, was 17% in adolescents with type 2 diabetes versus 12% in those with type 1 diabetes.

Overall, 7.1% participants had three complications: nephropathy, retinopathy, and neuropathy. The cumulative incidence of microvascular complications was 80%.

Moreover, A1c levels deteriorated progressively throughout the follow-up period. Approximately 45% participants had an A1c of at least 10%, and 20% were between 8% and 10%. Body mass index consistently remained between 35 and 37.5.

Young patients with type 2 diabetes exhibit endothelial dysfunction, increased carotid intima-media thickness, elevated arterial stiffness, left ventricular hypertrophy, diastolic dysfunction, and reduced maximal exercise capacity. All these factors predict cardiovascular morbidity and mortality.

In TODAY, 17 serious cardiovascular events were recorded, including four myocardial infarctions, six cases of congestive heart failure, three coronary events, and four strokes.

In an analysis of the TODAY and SEARCH studies, although the average duration of diabetes was similar, complications were more frequent among young patients with type 2 diabetes than among those with type 1 diabetes. Microvascular complications were 2.5 times more frequent, and macrovascular complications were four times more frequent.

In SEARCH, excessive mortality was observed among young adults for each type of diabetes. Differences in risk were associated with diabetes type, age, race/ethnicity, and sex. Mortality ratios were 1.5 and 2.3 for types 1 and 2 diabetes, respectively.

Women had higher mortality rates than men. Diabetes was the underlying cause of death in 9.1% cases, which was comparable to cardiovascular diseases or cancer (10.9%). According to a life expectancy model, young patients with type 2 diabetes lose about 15 years of life.
 

Eating Disorders and Depression

Beyond these complications, other issues are often present among adolescents with type 2 diabetes. Approximately 50% have eating disorders (compared with 21% among those with type 1 diabetes), 19.3% report depressive symptoms, and 18.9% have expressed thoughts of self-harm. In addition, 19.6% have polycystic ovary syndrome. Z-scores for bone mineral density at the femoral neck and lumbar spine were significantly lower in adolescents with type 2 diabetes than in healthy peers. The presence of metabolic dysfunction–associated fatty liver disease is also more pronounced.

“The recent approvals of new pharmacological interventions for weight loss and improved glycemic control in adolescents offer hope. We hope that, over the next decade, the prevalence of complications among these young patients with type 2 diabetes will decline. In the meantime, a proactive approach is essential to prevent complications related to type 2 diabetes in these youth,” Pinhas-Hamiel concluded.

For more information, see ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 Diabetes in Children and Adolescents.

Pinhas-Hamiel reported no relevant financial relationships.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.