Rare Diseases

Switching from one biosimilar medication to another is safe and effective, a new systematic review indicates, even though this clinical practice is not governed by current health authority regulations or guidance.

“No reduction in effectiveness or increase in adverse events was detected in biosimilar-to-biosimilar switching studies conducted to date,” the review’s authors noted in their study, published online in BioDrugs.

“The possibility of multiple switches between biosimilars of the same reference biologic is already a reality, and these types of switches are expected to become more common in the future. ... Although it is not covered by current health authority regulations or guidance,” added the authors, led by Hillel P. Cohen, PhD, executive director of scientific affairs at Sandoz, a division of Novartis.

The researchers searched electronic databases through December 2021 and found 23 observational studies that met their search criteria, of which 13 were published in peer-reviewed journals; the remainder appeared in abstract form. The studies totaled 3,657 patients. The researchers did not identify any randomized clinical trials.

“The studies were heterogeneous in size, design, and endpoints, providing data on safety, effectiveness, immunogenicity, pharmacokinetics, patient retention, patient and physician perceptions, and drug-use patterns,” the authors wrote.

The authors found that the majority of studies evaluated switches between biosimilars of infliximab, but they also identified switches between biosimilars of adalimumab, etanercept, and rituximab.

“Some health care providers are hesitant to switch patients from one biosimilar to another biosimilar because of a perceived lack of clinical data on such switches,” Dr. Cohen said in an interview.

The review’s findings – that there were no clinically relevant differences when switching patients from one biosimilar to another – are consistent with the science, Dr. Cohen said. “Physicians should have confidence that the data demonstrate that safety and effectiveness are not impacted if patients switch from one biosimilar to another biosimilar of the same reference biologic,” he said.

Currently, the published data include biosimilars to only four reference biologics. “However, I anticipate additional biosimilar-to-biosimilar switching data will become available in the future,” Dr. Cohen said. “In fact, several new studies have been published in recent months, after the cut-off date for inclusion in our systematic review.”

Switching common in rheumatology, dermatology, and gastroenterology

Biosimilar-to-biosimilar switching was observed most commonly in rheumatology practice, but also was seen in the specialties of dermatology and gastroenterology.

Jeffrey Weinberg, MD, clinical professor of dermatology, Icahn School of Medicine at Mount Sinai, New York City, said in an interview that the study is among the best to date showing that switching biosimilars does not compromise efficacy or safety. 

“I would hypothesize that the interchangeability would apply to psoriasis patients,” Dr. Weinberg said. However, “over the next few years, we will have an increasing number of biosimilars for an increasing number of different molecules. We will need to be vigilant to observe if similar behavior is observed with the biosimilars yet to come.”

Keith Choate, MD, PhD, professor of dermatology, pathology, and genetics, and associate dean for physician-scientist development at Yale University, New Haven, Conn., said that biosimilars have comparable efficacy to the branded medication they replace. “If response is lost to an individual agent, we would not typically then switch to a biosimilar, but would favor another class of therapy or a distinct therapeutic which targets the same pathway.”

When physicians prescribe a biosimilar for rheumatoid arthritis or psoriatic arthritis, in 9 out 10 people, “it’s going to work as well, and it’s not going to cause any more side effects,” said Stanford Shoor, MD, clinical professor of medicine and rheumatology, Stanford (Calif.) University.

The systematic review, even within its limitations, reinforces confidence in the antitumor necrosis factor biosimilars, said Jean-Frederic Colombel, MD, codirector of the Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai, New York, and professor of medicine, division of gastroenterology, Icahn School of Medicine at Mount Sinai.

“Still, studies with longer follow-up are needed,” Dr. Colombel said, adding that the remaining questions relate to the efficacy and safety of switching multiple times, which will likely occur in the near future. There will be a “need to provide information to the patient regarding what originator or biosimilar(s) he has been exposed to during the course of his disease.”

Switching will increasingly become the norm, said Miguel Regueiro, MD, chair of the Digestive Disease & Surgery Institute, Cleveland Clinic. In his clinical practice, he has the most experience with Crohn’s disease and ulcerative colitis, and biosimilar-to-biosimilar infliximab switches. “Unless there are data that emerge, I have no concerns with this.” 

He added that it’s an “interesting study that affirms my findings in clinical practice – that one can switch from a biosimilar to biosimilar (of the same reference product).”

The review’s results also make sense from an economic standpoint, said Rajat Bhatt, MD, owner of Prime Rheumatology in Richmond, Tex., and an adjunct faculty member at Caribbean Medical University, Willemstad, Curaçao. “Switching to biosimilars will result in cost savings for the health care system.” Patients on certain insurances also will save by switching to a biosimilar with a lower copay.

However, the review is limited by a relatively small number of studies that have provided primary data on this topic, and most of these were switching from infliximab to a biosimilar for inflammatory bowel disease, said Alfred Kim, MD, PhD, an adult rheumatologist at Barnes-Jewish Hospital, St. Louis, and assistant professor of medicine at Washington University in St. Louis.

As with any meta-analysis evaluating a small number of studies, “broad applicability to all conditions and reference/biosimilar pair can only be assumed. Also, many of the studies used for this meta-analysis are observational, which can introduce a variety of biases that can be difficult to adjust for,” Dr. Kim said. “Nevertheless, these analyses are an important first step in validating the [Food and Drug Administration’s] approach to evaluating biosimilars, as the clinical outcomes are consistent between different biosimilars.”

This systematic review is not enough to prove that all patients will do fine when switching from one biosimilar to another, said Florence Aslinia, MD, a gastroenterologist at the University of Kansas Health System in Kansas City. It’s possible that some patients may not do as well, she said, noting that, in one study of patients with inflammatory bowel disease, 10% of patients on a biosimilar infliximab needed to switch back to the originator infliximab (Remicade, Janssen) because of side effects attributed to the biosimilar. The same thing may or may not happen with biosimilar-to-biosimilar switching, and it requires further study.

The authors did not receive any funding for writing this review. Dr. Cohen is an employee of Sandoz, a division of Novartis. He may own stock in Novartis. Two coauthors are also employees of Sandoz. The other three coauthors reported having financial relationships with numerous pharmaceutical companies, including Sandoz and/or Novartis. Dr. Colombel reported financial relationships with many pharmaceutical companies, including Novartis and other manufacturers of biosimilars. Dr. Regueiro reports financial relationships with numerous pharmaceutical companies, including some manufacturers of biosimilars. Dr. Weinberg reported financial relationships with Celgene, AbbVie, Eli Lilly, and Novartis. Kim reports financial relationships with GlaxoSmithKline, Pfizer, and AstraZeneca. Dr. Aslinia, Dr. Shoor, Dr. Choate, and Dr. Bhatt reported no relevant financial relationships.

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

Switching from one biosimilar medication to another is safe and effective, a new systematic review indicates, even though this clinical practice is not governed by current health authority regulations or guidance.

“No reduction in effectiveness or increase in adverse events was detected in biosimilar-to-biosimilar switching studies conducted to date,” the review’s authors noted in their study, published online in BioDrugs.

“The possibility of multiple switches between biosimilars of the same reference biologic is already a reality, and these types of switches are expected to become more common in the future. ... Although it is not covered by current health authority regulations or guidance,” added the authors, led by Hillel P. Cohen, PhD, executive director of scientific affairs at Sandoz, a division of Novartis.

The researchers searched electronic databases through December 2021 and found 23 observational studies that met their search criteria, of which 13 were published in peer-reviewed journals; the remainder appeared in abstract form. The studies totaled 3,657 patients. The researchers did not identify any randomized clinical trials.

“The studies were heterogeneous in size, design, and endpoints, providing data on safety, effectiveness, immunogenicity, pharmacokinetics, patient retention, patient and physician perceptions, and drug-use patterns,” the authors wrote.

The authors found that the majority of studies evaluated switches between biosimilars of infliximab, but they also identified switches between biosimilars of adalimumab, etanercept, and rituximab.

“Some health care providers are hesitant to switch patients from one biosimilar to another biosimilar because of a perceived lack of clinical data on such switches,” Dr. Cohen said in an interview.

The review’s findings – that there were no clinically relevant differences when switching patients from one biosimilar to another – are consistent with the science, Dr. Cohen said. “Physicians should have confidence that the data demonstrate that safety and effectiveness are not impacted if patients switch from one biosimilar to another biosimilar of the same reference biologic,” he said.

Currently, the published data include biosimilars to only four reference biologics. “However, I anticipate additional biosimilar-to-biosimilar switching data will become available in the future,” Dr. Cohen said. “In fact, several new studies have been published in recent months, after the cut-off date for inclusion in our systematic review.”

Switching common in rheumatology, dermatology, and gastroenterology

Biosimilar-to-biosimilar switching was observed most commonly in rheumatology practice, but also was seen in the specialties of dermatology and gastroenterology.

Jeffrey Weinberg, MD, clinical professor of dermatology, Icahn School of Medicine at Mount Sinai, New York City, said in an interview that the study is among the best to date showing that switching biosimilars does not compromise efficacy or safety. 

“I would hypothesize that the interchangeability would apply to psoriasis patients,” Dr. Weinberg said. However, “over the next few years, we will have an increasing number of biosimilars for an increasing number of different molecules. We will need to be vigilant to observe if similar behavior is observed with the biosimilars yet to come.”

Keith Choate, MD, PhD, professor of dermatology, pathology, and genetics, and associate dean for physician-scientist development at Yale University, New Haven, Conn., said that biosimilars have comparable efficacy to the branded medication they replace. “If response is lost to an individual agent, we would not typically then switch to a biosimilar, but would favor another class of therapy or a distinct therapeutic which targets the same pathway.”

When physicians prescribe a biosimilar for rheumatoid arthritis or psoriatic arthritis, in 9 out 10 people, “it’s going to work as well, and it’s not going to cause any more side effects,” said Stanford Shoor, MD, clinical professor of medicine and rheumatology, Stanford (Calif.) University.

The systematic review, even within its limitations, reinforces confidence in the antitumor necrosis factor biosimilars, said Jean-Frederic Colombel, MD, codirector of the Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai, New York, and professor of medicine, division of gastroenterology, Icahn School of Medicine at Mount Sinai.

“Still, studies with longer follow-up are needed,” Dr. Colombel said, adding that the remaining questions relate to the efficacy and safety of switching multiple times, which will likely occur in the near future. There will be a “need to provide information to the patient regarding what originator or biosimilar(s) he has been exposed to during the course of his disease.”

Switching will increasingly become the norm, said Miguel Regueiro, MD, chair of the Digestive Disease & Surgery Institute, Cleveland Clinic. In his clinical practice, he has the most experience with Crohn’s disease and ulcerative colitis, and biosimilar-to-biosimilar infliximab switches. “Unless there are data that emerge, I have no concerns with this.” 

He added that it’s an “interesting study that affirms my findings in clinical practice – that one can switch from a biosimilar to biosimilar (of the same reference product).”

The review’s results also make sense from an economic standpoint, said Rajat Bhatt, MD, owner of Prime Rheumatology in Richmond, Tex., and an adjunct faculty member at Caribbean Medical University, Willemstad, Curaçao. “Switching to biosimilars will result in cost savings for the health care system.” Patients on certain insurances also will save by switching to a biosimilar with a lower copay.

However, the review is limited by a relatively small number of studies that have provided primary data on this topic, and most of these were switching from infliximab to a biosimilar for inflammatory bowel disease, said Alfred Kim, MD, PhD, an adult rheumatologist at Barnes-Jewish Hospital, St. Louis, and assistant professor of medicine at Washington University in St. Louis.

As with any meta-analysis evaluating a small number of studies, “broad applicability to all conditions and reference/biosimilar pair can only be assumed. Also, many of the studies used for this meta-analysis are observational, which can introduce a variety of biases that can be difficult to adjust for,” Dr. Kim said. “Nevertheless, these analyses are an important first step in validating the [Food and Drug Administration’s] approach to evaluating biosimilars, as the clinical outcomes are consistent between different biosimilars.”

This systematic review is not enough to prove that all patients will do fine when switching from one biosimilar to another, said Florence Aslinia, MD, a gastroenterologist at the University of Kansas Health System in Kansas City. It’s possible that some patients may not do as well, she said, noting that, in one study of patients with inflammatory bowel disease, 10% of patients on a biosimilar infliximab needed to switch back to the originator infliximab (Remicade, Janssen) because of side effects attributed to the biosimilar. The same thing may or may not happen with biosimilar-to-biosimilar switching, and it requires further study.

The authors did not receive any funding for writing this review. Dr. Cohen is an employee of Sandoz, a division of Novartis. He may own stock in Novartis. Two coauthors are also employees of Sandoz. The other three coauthors reported having financial relationships with numerous pharmaceutical companies, including Sandoz and/or Novartis. Dr. Colombel reported financial relationships with many pharmaceutical companies, including Novartis and other manufacturers of biosimilars. Dr. Regueiro reports financial relationships with numerous pharmaceutical companies, including some manufacturers of biosimilars. Dr. Weinberg reported financial relationships with Celgene, AbbVie, Eli Lilly, and Novartis. Kim reports financial relationships with GlaxoSmithKline, Pfizer, and AstraZeneca. Dr. Aslinia, Dr. Shoor, Dr. Choate, and Dr. Bhatt reported no relevant financial relationships.

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

Switching from one biosimilar medication to another is safe and effective, a new systematic review indicates, even though this clinical practice is not governed by current health authority regulations or guidance.

“No reduction in effectiveness or increase in adverse events was detected in biosimilar-to-biosimilar switching studies conducted to date,” the review’s authors noted in their study, published online in BioDrugs.

“The possibility of multiple switches between biosimilars of the same reference biologic is already a reality, and these types of switches are expected to become more common in the future. ... Although it is not covered by current health authority regulations or guidance,” added the authors, led by Hillel P. Cohen, PhD, executive director of scientific affairs at Sandoz, a division of Novartis.

The researchers searched electronic databases through December 2021 and found 23 observational studies that met their search criteria, of which 13 were published in peer-reviewed journals; the remainder appeared in abstract form. The studies totaled 3,657 patients. The researchers did not identify any randomized clinical trials.

“The studies were heterogeneous in size, design, and endpoints, providing data on safety, effectiveness, immunogenicity, pharmacokinetics, patient retention, patient and physician perceptions, and drug-use patterns,” the authors wrote.

The authors found that the majority of studies evaluated switches between biosimilars of infliximab, but they also identified switches between biosimilars of adalimumab, etanercept, and rituximab.

“Some health care providers are hesitant to switch patients from one biosimilar to another biosimilar because of a perceived lack of clinical data on such switches,” Dr. Cohen said in an interview.

The review’s findings – that there were no clinically relevant differences when switching patients from one biosimilar to another – are consistent with the science, Dr. Cohen said. “Physicians should have confidence that the data demonstrate that safety and effectiveness are not impacted if patients switch from one biosimilar to another biosimilar of the same reference biologic,” he said.

Currently, the published data include biosimilars to only four reference biologics. “However, I anticipate additional biosimilar-to-biosimilar switching data will become available in the future,” Dr. Cohen said. “In fact, several new studies have been published in recent months, after the cut-off date for inclusion in our systematic review.”

Switching common in rheumatology, dermatology, and gastroenterology

Biosimilar-to-biosimilar switching was observed most commonly in rheumatology practice, but also was seen in the specialties of dermatology and gastroenterology.

Jeffrey Weinberg, MD, clinical professor of dermatology, Icahn School of Medicine at Mount Sinai, New York City, said in an interview that the study is among the best to date showing that switching biosimilars does not compromise efficacy or safety. 

“I would hypothesize that the interchangeability would apply to psoriasis patients,” Dr. Weinberg said. However, “over the next few years, we will have an increasing number of biosimilars for an increasing number of different molecules. We will need to be vigilant to observe if similar behavior is observed with the biosimilars yet to come.”

Keith Choate, MD, PhD, professor of dermatology, pathology, and genetics, and associate dean for physician-scientist development at Yale University, New Haven, Conn., said that biosimilars have comparable efficacy to the branded medication they replace. “If response is lost to an individual agent, we would not typically then switch to a biosimilar, but would favor another class of therapy or a distinct therapeutic which targets the same pathway.”

When physicians prescribe a biosimilar for rheumatoid arthritis or psoriatic arthritis, in 9 out 10 people, “it’s going to work as well, and it’s not going to cause any more side effects,” said Stanford Shoor, MD, clinical professor of medicine and rheumatology, Stanford (Calif.) University.

The systematic review, even within its limitations, reinforces confidence in the antitumor necrosis factor biosimilars, said Jean-Frederic Colombel, MD, codirector of the Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai, New York, and professor of medicine, division of gastroenterology, Icahn School of Medicine at Mount Sinai.

“Still, studies with longer follow-up are needed,” Dr. Colombel said, adding that the remaining questions relate to the efficacy and safety of switching multiple times, which will likely occur in the near future. There will be a “need to provide information to the patient regarding what originator or biosimilar(s) he has been exposed to during the course of his disease.”

Switching will increasingly become the norm, said Miguel Regueiro, MD, chair of the Digestive Disease & Surgery Institute, Cleveland Clinic. In his clinical practice, he has the most experience with Crohn’s disease and ulcerative colitis, and biosimilar-to-biosimilar infliximab switches. “Unless there are data that emerge, I have no concerns with this.” 

He added that it’s an “interesting study that affirms my findings in clinical practice – that one can switch from a biosimilar to biosimilar (of the same reference product).”

The review’s results also make sense from an economic standpoint, said Rajat Bhatt, MD, owner of Prime Rheumatology in Richmond, Tex., and an adjunct faculty member at Caribbean Medical University, Willemstad, Curaçao. “Switching to biosimilars will result in cost savings for the health care system.” Patients on certain insurances also will save by switching to a biosimilar with a lower copay.

However, the review is limited by a relatively small number of studies that have provided primary data on this topic, and most of these were switching from infliximab to a biosimilar for inflammatory bowel disease, said Alfred Kim, MD, PhD, an adult rheumatologist at Barnes-Jewish Hospital, St. Louis, and assistant professor of medicine at Washington University in St. Louis.

As with any meta-analysis evaluating a small number of studies, “broad applicability to all conditions and reference/biosimilar pair can only be assumed. Also, many of the studies used for this meta-analysis are observational, which can introduce a variety of biases that can be difficult to adjust for,” Dr. Kim said. “Nevertheless, these analyses are an important first step in validating the [Food and Drug Administration’s] approach to evaluating biosimilars, as the clinical outcomes are consistent between different biosimilars.”

This systematic review is not enough to prove that all patients will do fine when switching from one biosimilar to another, said Florence Aslinia, MD, a gastroenterologist at the University of Kansas Health System in Kansas City. It’s possible that some patients may not do as well, she said, noting that, in one study of patients with inflammatory bowel disease, 10% of patients on a biosimilar infliximab needed to switch back to the originator infliximab (Remicade, Janssen) because of side effects attributed to the biosimilar. The same thing may or may not happen with biosimilar-to-biosimilar switching, and it requires further study.

The authors did not receive any funding for writing this review. Dr. Cohen is an employee of Sandoz, a division of Novartis. He may own stock in Novartis. Two coauthors are also employees of Sandoz. The other three coauthors reported having financial relationships with numerous pharmaceutical companies, including Sandoz and/or Novartis. Dr. Colombel reported financial relationships with many pharmaceutical companies, including Novartis and other manufacturers of biosimilars. Dr. Regueiro reports financial relationships with numerous pharmaceutical companies, including some manufacturers of biosimilars. Dr. Weinberg reported financial relationships with Celgene, AbbVie, Eli Lilly, and Novartis. Kim reports financial relationships with GlaxoSmithKline, Pfizer, and AstraZeneca. Dr. Aslinia, Dr. Shoor, Dr. Choate, and Dr. Bhatt reported no relevant financial relationships.

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

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug›s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment›s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.

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

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug›s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment›s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.

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

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug›s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment›s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.

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

About two-thirds of children with juvenile idiopathic arthritis (JIA) were able to return to an inactive disease state within 12 months after a flare occurred when they took a break from medication, and slightly more than half – 55% – reached this state within 6 months, according to findings from registry data examined in a study published in Arthritis Care & Research.

Sarah Ringold, MD, MS, of the Seattle Children’s Hospital, and coauthors used data from participants in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry to track what happened to patients when they took a break from antirheumatic drugs. They described their paper as being the first to use a large multicenter database such as the CARRA Registry to focus on JIA outcomes after medication discontinuation and flare, to describe flare severity after medication discontinuation, and to report patterns of medication use for flares.

“To date, JIA studies have established that flares after medication discontinuation are common but have generated conflicting data regarding flare risk factors,” Dr. Ringold and coauthors wrote. “Since it is not yet possible to predict reliably which children will successfully discontinue medication, families and physicians face uncertainty when deciding to stop medications, and there is significant variation in approach.”

The study will be “very helpful” to physicians working with parents and patients to make decisions about discontinuing medications, said Grant Schulert, MD, PhD, of Cincinnati Children’s Hospital, who was not involved with the study.

“It gives some numbers to help us have those conversations,” he said in an interview.

But interpreting those numbers still will present parents with a challenge, Dr. Schulert said.

“You can say: ‘The glass is half full; 55% of them could go back into remission in 6 months, a little bit higher in a year,’ ” he said. “Or the glass is half empty; some of them, even at a year, are still not back in remission.”

But “patients aren’t a statistic. They’re each one person,” he said. “They’re going to be in one of those two situations.”

There are many challenges in explaining the potential advantages and disadvantages of medication breaks to patients and families, said the study’s senior author, Daniel B. Horton, MD, MSCE, of Rutgers Robert Wood Johnson Medical School and the Rutgers Center for Pharmacoepidemiology and Treatment Science, both in New Brunswick, N.J., and the department of biostatistics and epidemiology at Rutgers School of Public Health, Piscataway, N.J.

“One of the challenges of explaining the pros and cons about stopping medicines is the uncertainty – not knowing if and when a flare will occur, if and when a flare would be well controlled, and, for treatments that are continued, if and when complications of that treatment could occur,” Dr. Horton said in an interview. “Many patients and families are afraid about what the medicines might do long-term and want to stop treatment as soon as possible, despite the risks of stopping. Another challenge is that we do not yet have accurate, widely available tests that help us predict these various outcomes. Still, it is important for clinicians to explain the risks of continuing treatment and of stopping treatment, and to give patients and families time to ask questions and share their own values and preferences. If these conversations don’t happen, patients or families may just stop the medicines even if stopping is not warranted or is likely to lead to a poor outcome.”
 

Study details

Of the 367 patients studied, 270 (74%) were female. Half of all patients in the study had extended oligoarticular/rheumatoid factor (RF)–negative polyarticular JIA, and the second most common category was persistent oligoarthritis at 25%.The median age at disease onset was 4, with a range of 2-9 years.

The median age at disease flare was 11.3, with a range of 7.5-15.7 years. At the time of flare, children had a median disease duration of 5.1 years and had been off systemic disease-modifying antirheumatic drugs (DMARDs) for a median of 205 days. In addition, at the time of flare, the median active joint count was 1 and the maximum active joint count was 33, and approximately 13% of children had 5 or more active joints.

Conventional synthetic DMARDs were the most commonly stopped medications (48%), and tumor necrosis factor inhibitors (TNFi) were second (42%), Dr. Ringold and coauthors wrote.

Independent predictors of successful recapture of inactive disease included TNFi as recapture medication and history of a non-TNFi biologic use.

Dr. Ringold and coauthors noted limitations of the registry-based study. This is “a convenience sample of patients who are cared for and consented at academic sites, and additional study may be needed to understand how these results generalize to other countries and health systems,” they wrote.

And there may have been misclassification and inclusion of patients who stopped medications for self-perceived well-controlled disease, they wrote.

“Although the intent was to include children who stopped their medications at their physician’s direction due to physician-confirmed inactive disease, patients who had been previously enrolled in the registry were included if inactive disease was listed as the reason for medication discontinuation,” they said.

Still, these results should serve as a “benchmark for future studies of medication discontinuation” in JIA, the researchers wrote.
 

‘Fortunate challenge’

In an accompanying editorial, Melissa L. Mannion, MD, MSPH, and Randy Q. Cron, MD, PhD, of the University of Alabama at Birmingham noted that pediatric rheumatologists now face what they call the “fortunate challenge” of helping patients and parents decide whether treatments can be stopped in cases where there’s been a sustained period of inactive disease.

“Once a patient has reached the goal of inactive disease, why would patients or providers want to stop medications?” Dr. Mannion and Dr. Cron wrote. “We tell our patients that we want them to be like everyone else and have no limitations on their goals. However, the burden of chronic medication to achieve that goal is a constant reminder that they are different from their peers.”

In their article, Dr. Mannion and Dr. Cron noted what they called “interesting” results observed among children with different forms of JIA in the study.

Children with “systemic JIA had the highest recapture rates at 6 or 12 months, perhaps reflecting the high percentage use of [biologic] DMARDs targeting interleukin-1 and IL-6, or maybe the timeliness of recognition (e.g., fever, rash) of disease flare,” Dr. Mannion and Dr. Cron wrote. “Conversely, children with JIA enthesitis-related arthritis (ERA) had the lowest recapture rate at 6 months (27.6%, even lower than RF-positive polyarticular JIA, 42.9%).”

Still, the editorial authors said that “additional well-controlled studies are needed to move pediatric rheumatology deeper into the realm of precision medicine and the ability to decide whether or not to wean DMARD therapy for those with clinically inactive disease.”

Pamela Weiss, MD, of Children’s Hospital of Philadelphia, said in a comment that the study by Dr. Ringold and colleagues, as well as others that address similar questions, “are critically needed to move our field towards a personalized medicine approach.” But she added that while the paper from Dr. Ringold and colleagues addresses an important question, it “should be interpreted with some caution.”

She noted, for example, that “disease flare,” which prompted reinitiation of treatment and study entry, was not always aligned with a registry visit, which makes determination of the primary exposure less stringent. The rate of recapture across JIA categories differed by as much as 20% depending upon which inactive disease assessment outcome was used – either the study’s novel but unvalidated primary outcome or the validated secondary outcome of using the clinical Juvenile Arthritis Disease Activity Score based on 10 joints. The resulting difference was marked for some JIA categories and minimal for others.

“The flare and recapture rates are likely to be vastly different for JIA categories with distinct pathophysiology – namely systemic JIA, psoriatic arthritis, and enthesitis-related arthritis,” Dr. Weiss said. “While numbers for these categories were too small to make meaningful conclusions, grouping them with the other JIA categories has limitations.”

The research was funded by a Rheumatology Research Foundation Innovative Research Award.

Dr. Ringold’s current employment is through Janssen Research & Development. She changed primary employment from Seattle Children’s to Janssen during completion of the analyses and preparation of the manuscript. She has maintained her affiliation with Seattle Children’s. Dr. Schulert has consulting for Novartis. Dr. Cron reported speaker fees, consulting fees, and grant support from Sobi, consulting fees from Sironax and Novartis, speaker fees from Lilly, and support from Pfizer for working on a committee adjudicating clinical trial side effects.

* This article was updated on 8/11/2022.

About two-thirds of children with juvenile idiopathic arthritis (JIA) were able to return to an inactive disease state within 12 months after a flare occurred when they took a break from medication, and slightly more than half – 55% – reached this state within 6 months, according to findings from registry data examined in a study published in Arthritis Care & Research.

Sarah Ringold, MD, MS, of the Seattle Children’s Hospital, and coauthors used data from participants in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry to track what happened to patients when they took a break from antirheumatic drugs. They described their paper as being the first to use a large multicenter database such as the CARRA Registry to focus on JIA outcomes after medication discontinuation and flare, to describe flare severity after medication discontinuation, and to report patterns of medication use for flares.

“To date, JIA studies have established that flares after medication discontinuation are common but have generated conflicting data regarding flare risk factors,” Dr. Ringold and coauthors wrote. “Since it is not yet possible to predict reliably which children will successfully discontinue medication, families and physicians face uncertainty when deciding to stop medications, and there is significant variation in approach.”

The study will be “very helpful” to physicians working with parents and patients to make decisions about discontinuing medications, said Grant Schulert, MD, PhD, of Cincinnati Children’s Hospital, who was not involved with the study.

“It gives some numbers to help us have those conversations,” he said in an interview.

But interpreting those numbers still will present parents with a challenge, Dr. Schulert said.

“You can say: ‘The glass is half full; 55% of them could go back into remission in 6 months, a little bit higher in a year,’ ” he said. “Or the glass is half empty; some of them, even at a year, are still not back in remission.”

But “patients aren’t a statistic. They’re each one person,” he said. “They’re going to be in one of those two situations.”

There are many challenges in explaining the potential advantages and disadvantages of medication breaks to patients and families, said the study’s senior author, Daniel B. Horton, MD, MSCE, of Rutgers Robert Wood Johnson Medical School and the Rutgers Center for Pharmacoepidemiology and Treatment Science, both in New Brunswick, N.J., and the department of biostatistics and epidemiology at Rutgers School of Public Health, Piscataway, N.J.

“One of the challenges of explaining the pros and cons about stopping medicines is the uncertainty – not knowing if and when a flare will occur, if and when a flare would be well controlled, and, for treatments that are continued, if and when complications of that treatment could occur,” Dr. Horton said in an interview. “Many patients and families are afraid about what the medicines might do long-term and want to stop treatment as soon as possible, despite the risks of stopping. Another challenge is that we do not yet have accurate, widely available tests that help us predict these various outcomes. Still, it is important for clinicians to explain the risks of continuing treatment and of stopping treatment, and to give patients and families time to ask questions and share their own values and preferences. If these conversations don’t happen, patients or families may just stop the medicines even if stopping is not warranted or is likely to lead to a poor outcome.”
 

Study details

Of the 367 patients studied, 270 (74%) were female. Half of all patients in the study had extended oligoarticular/rheumatoid factor (RF)–negative polyarticular JIA, and the second most common category was persistent oligoarthritis at 25%.The median age at disease onset was 4, with a range of 2-9 years.

The median age at disease flare was 11.3, with a range of 7.5-15.7 years. At the time of flare, children had a median disease duration of 5.1 years and had been off systemic disease-modifying antirheumatic drugs (DMARDs) for a median of 205 days. In addition, at the time of flare, the median active joint count was 1 and the maximum active joint count was 33, and approximately 13% of children had 5 or more active joints.

Conventional synthetic DMARDs were the most commonly stopped medications (48%), and tumor necrosis factor inhibitors (TNFi) were second (42%), Dr. Ringold and coauthors wrote.

Independent predictors of successful recapture of inactive disease included TNFi as recapture medication and history of a non-TNFi biologic use.

Dr. Ringold and coauthors noted limitations of the registry-based study. This is “a convenience sample of patients who are cared for and consented at academic sites, and additional study may be needed to understand how these results generalize to other countries and health systems,” they wrote.

And there may have been misclassification and inclusion of patients who stopped medications for self-perceived well-controlled disease, they wrote.

“Although the intent was to include children who stopped their medications at their physician’s direction due to physician-confirmed inactive disease, patients who had been previously enrolled in the registry were included if inactive disease was listed as the reason for medication discontinuation,” they said.

Still, these results should serve as a “benchmark for future studies of medication discontinuation” in JIA, the researchers wrote.
 

‘Fortunate challenge’

In an accompanying editorial, Melissa L. Mannion, MD, MSPH, and Randy Q. Cron, MD, PhD, of the University of Alabama at Birmingham noted that pediatric rheumatologists now face what they call the “fortunate challenge” of helping patients and parents decide whether treatments can be stopped in cases where there’s been a sustained period of inactive disease.

“Once a patient has reached the goal of inactive disease, why would patients or providers want to stop medications?” Dr. Mannion and Dr. Cron wrote. “We tell our patients that we want them to be like everyone else and have no limitations on their goals. However, the burden of chronic medication to achieve that goal is a constant reminder that they are different from their peers.”

In their article, Dr. Mannion and Dr. Cron noted what they called “interesting” results observed among children with different forms of JIA in the study.

Children with “systemic JIA had the highest recapture rates at 6 or 12 months, perhaps reflecting the high percentage use of [biologic] DMARDs targeting interleukin-1 and IL-6, or maybe the timeliness of recognition (e.g., fever, rash) of disease flare,” Dr. Mannion and Dr. Cron wrote. “Conversely, children with JIA enthesitis-related arthritis (ERA) had the lowest recapture rate at 6 months (27.6%, even lower than RF-positive polyarticular JIA, 42.9%).”

Still, the editorial authors said that “additional well-controlled studies are needed to move pediatric rheumatology deeper into the realm of precision medicine and the ability to decide whether or not to wean DMARD therapy for those with clinically inactive disease.”

Pamela Weiss, MD, of Children’s Hospital of Philadelphia, said in a comment that the study by Dr. Ringold and colleagues, as well as others that address similar questions, “are critically needed to move our field towards a personalized medicine approach.” But she added that while the paper from Dr. Ringold and colleagues addresses an important question, it “should be interpreted with some caution.”

She noted, for example, that “disease flare,” which prompted reinitiation of treatment and study entry, was not always aligned with a registry visit, which makes determination of the primary exposure less stringent. The rate of recapture across JIA categories differed by as much as 20% depending upon which inactive disease assessment outcome was used – either the study’s novel but unvalidated primary outcome or the validated secondary outcome of using the clinical Juvenile Arthritis Disease Activity Score based on 10 joints. The resulting difference was marked for some JIA categories and minimal for others.

“The flare and recapture rates are likely to be vastly different for JIA categories with distinct pathophysiology – namely systemic JIA, psoriatic arthritis, and enthesitis-related arthritis,” Dr. Weiss said. “While numbers for these categories were too small to make meaningful conclusions, grouping them with the other JIA categories has limitations.”

The research was funded by a Rheumatology Research Foundation Innovative Research Award.

Dr. Ringold’s current employment is through Janssen Research & Development. She changed primary employment from Seattle Children’s to Janssen during completion of the analyses and preparation of the manuscript. She has maintained her affiliation with Seattle Children’s. Dr. Schulert has consulting for Novartis. Dr. Cron reported speaker fees, consulting fees, and grant support from Sobi, consulting fees from Sironax and Novartis, speaker fees from Lilly, and support from Pfizer for working on a committee adjudicating clinical trial side effects.

* This article was updated on 8/11/2022.

About two-thirds of children with juvenile idiopathic arthritis (JIA) were able to return to an inactive disease state within 12 months after a flare occurred when they took a break from medication, and slightly more than half – 55% – reached this state within 6 months, according to findings from registry data examined in a study published in Arthritis Care & Research.

Sarah Ringold, MD, MS, of the Seattle Children’s Hospital, and coauthors used data from participants in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry to track what happened to patients when they took a break from antirheumatic drugs. They described their paper as being the first to use a large multicenter database such as the CARRA Registry to focus on JIA outcomes after medication discontinuation and flare, to describe flare severity after medication discontinuation, and to report patterns of medication use for flares.

“To date, JIA studies have established that flares after medication discontinuation are common but have generated conflicting data regarding flare risk factors,” Dr. Ringold and coauthors wrote. “Since it is not yet possible to predict reliably which children will successfully discontinue medication, families and physicians face uncertainty when deciding to stop medications, and there is significant variation in approach.”

The study will be “very helpful” to physicians working with parents and patients to make decisions about discontinuing medications, said Grant Schulert, MD, PhD, of Cincinnati Children’s Hospital, who was not involved with the study.

“It gives some numbers to help us have those conversations,” he said in an interview.

But interpreting those numbers still will present parents with a challenge, Dr. Schulert said.

“You can say: ‘The glass is half full; 55% of them could go back into remission in 6 months, a little bit higher in a year,’ ” he said. “Or the glass is half empty; some of them, even at a year, are still not back in remission.”

But “patients aren’t a statistic. They’re each one person,” he said. “They’re going to be in one of those two situations.”

There are many challenges in explaining the potential advantages and disadvantages of medication breaks to patients and families, said the study’s senior author, Daniel B. Horton, MD, MSCE, of Rutgers Robert Wood Johnson Medical School and the Rutgers Center for Pharmacoepidemiology and Treatment Science, both in New Brunswick, N.J., and the department of biostatistics and epidemiology at Rutgers School of Public Health, Piscataway, N.J.

“One of the challenges of explaining the pros and cons about stopping medicines is the uncertainty – not knowing if and when a flare will occur, if and when a flare would be well controlled, and, for treatments that are continued, if and when complications of that treatment could occur,” Dr. Horton said in an interview. “Many patients and families are afraid about what the medicines might do long-term and want to stop treatment as soon as possible, despite the risks of stopping. Another challenge is that we do not yet have accurate, widely available tests that help us predict these various outcomes. Still, it is important for clinicians to explain the risks of continuing treatment and of stopping treatment, and to give patients and families time to ask questions and share their own values and preferences. If these conversations don’t happen, patients or families may just stop the medicines even if stopping is not warranted or is likely to lead to a poor outcome.”
 

Study details

Of the 367 patients studied, 270 (74%) were female. Half of all patients in the study had extended oligoarticular/rheumatoid factor (RF)–negative polyarticular JIA, and the second most common category was persistent oligoarthritis at 25%.The median age at disease onset was 4, with a range of 2-9 years.

The median age at disease flare was 11.3, with a range of 7.5-15.7 years. At the time of flare, children had a median disease duration of 5.1 years and had been off systemic disease-modifying antirheumatic drugs (DMARDs) for a median of 205 days. In addition, at the time of flare, the median active joint count was 1 and the maximum active joint count was 33, and approximately 13% of children had 5 or more active joints.

Conventional synthetic DMARDs were the most commonly stopped medications (48%), and tumor necrosis factor inhibitors (TNFi) were second (42%), Dr. Ringold and coauthors wrote.

Independent predictors of successful recapture of inactive disease included TNFi as recapture medication and history of a non-TNFi biologic use.

Dr. Ringold and coauthors noted limitations of the registry-based study. This is “a convenience sample of patients who are cared for and consented at academic sites, and additional study may be needed to understand how these results generalize to other countries and health systems,” they wrote.

And there may have been misclassification and inclusion of patients who stopped medications for self-perceived well-controlled disease, they wrote.

“Although the intent was to include children who stopped their medications at their physician’s direction due to physician-confirmed inactive disease, patients who had been previously enrolled in the registry were included if inactive disease was listed as the reason for medication discontinuation,” they said.

Still, these results should serve as a “benchmark for future studies of medication discontinuation” in JIA, the researchers wrote.
 

‘Fortunate challenge’

In an accompanying editorial, Melissa L. Mannion, MD, MSPH, and Randy Q. Cron, MD, PhD, of the University of Alabama at Birmingham noted that pediatric rheumatologists now face what they call the “fortunate challenge” of helping patients and parents decide whether treatments can be stopped in cases where there’s been a sustained period of inactive disease.

“Once a patient has reached the goal of inactive disease, why would patients or providers want to stop medications?” Dr. Mannion and Dr. Cron wrote. “We tell our patients that we want them to be like everyone else and have no limitations on their goals. However, the burden of chronic medication to achieve that goal is a constant reminder that they are different from their peers.”

In their article, Dr. Mannion and Dr. Cron noted what they called “interesting” results observed among children with different forms of JIA in the study.

Children with “systemic JIA had the highest recapture rates at 6 or 12 months, perhaps reflecting the high percentage use of [biologic] DMARDs targeting interleukin-1 and IL-6, or maybe the timeliness of recognition (e.g., fever, rash) of disease flare,” Dr. Mannion and Dr. Cron wrote. “Conversely, children with JIA enthesitis-related arthritis (ERA) had the lowest recapture rate at 6 months (27.6%, even lower than RF-positive polyarticular JIA, 42.9%).”

Still, the editorial authors said that “additional well-controlled studies are needed to move pediatric rheumatology deeper into the realm of precision medicine and the ability to decide whether or not to wean DMARD therapy for those with clinically inactive disease.”

Pamela Weiss, MD, of Children’s Hospital of Philadelphia, said in a comment that the study by Dr. Ringold and colleagues, as well as others that address similar questions, “are critically needed to move our field towards a personalized medicine approach.” But she added that while the paper from Dr. Ringold and colleagues addresses an important question, it “should be interpreted with some caution.”

She noted, for example, that “disease flare,” which prompted reinitiation of treatment and study entry, was not always aligned with a registry visit, which makes determination of the primary exposure less stringent. The rate of recapture across JIA categories differed by as much as 20% depending upon which inactive disease assessment outcome was used – either the study’s novel but unvalidated primary outcome or the validated secondary outcome of using the clinical Juvenile Arthritis Disease Activity Score based on 10 joints. The resulting difference was marked for some JIA categories and minimal for others.

“The flare and recapture rates are likely to be vastly different for JIA categories with distinct pathophysiology – namely systemic JIA, psoriatic arthritis, and enthesitis-related arthritis,” Dr. Weiss said. “While numbers for these categories were too small to make meaningful conclusions, grouping them with the other JIA categories has limitations.”

The research was funded by a Rheumatology Research Foundation Innovative Research Award.

Dr. Ringold’s current employment is through Janssen Research & Development. She changed primary employment from Seattle Children’s to Janssen during completion of the analyses and preparation of the manuscript. She has maintained her affiliation with Seattle Children’s. Dr. Schulert has consulting for Novartis. Dr. Cron reported speaker fees, consulting fees, and grant support from Sobi, consulting fees from Sironax and Novartis, speaker fees from Lilly, and support from Pfizer for working on a committee adjudicating clinical trial side effects.

* This article was updated on 8/11/2022.

The Food and Drug Administration has approved the dual interleukin-12 and IL-23 inhibitor ustekinumab (Stelara) for the treatment of juvenile psoriatic arthritis (jPsA) in patients aged 6 years and older, according to an Aug. 1 announcement from its manufacturer, Janssen.

The approval makes jPsA the sixth approved indication for ustekinumab, which include active psoriatic arthritis in adults, moderate to severe plaque psoriasis in both adults and children aged 6 years or older who are candidates for phototherapy or systemic therapy, moderately to severely active Crohn’s disease in adults, and moderately to severely active ulcerative colitis in adults.

In addition, ustekinumab is now the second biologic to be approved for jPsA, following the agency’s December 2021 approval of secukinumab (Cosentyx) to treat jPsA in children and adolescents aged 2 years and older as well as enthesitis-related arthritis in children and adolescents aged 4 years and older.

In pediatric patients, ustekinumab is administered as a subcutaneous injection dosed four times per year after two starter doses.

Ustekinumab’s approval is based on “an extrapolation of the established data and existing safety profile” of ustekinumab in multiple phase 3 studies in adult and pediatric patients with moderate to severe plaque psoriasis and adult patients with active PsA, according to Janssen.

“With the limited availability of pediatric patients for clinical trial inclusion, researchers can extrapolate data from trials with adults to determine the potential efficacy and tolerability of a treatment for a pediatric population,” according to the October 2021 announcement from the company that the Biologics License Application had been submitted to the FDA.

Juvenile arthritis occurs in an estimated 20-45 children per 100,000 in the United States, with about 5% of those children having jPsA, according to the National Psoriasis Foundation.

The prescribing information for ustekinumab includes specific warnings and areas of concern. The drug should not be administered to individuals with known hypersensitivity to ustekinumab. The drug may lower the ability of the immune system to fight infections and may increase risk of infections, sometimes serious, and a test for tuberculosis infection should be given before administration.

Patients taking ustekinumab should not be given a live vaccine, and their doctors should be informed if anyone in their household needs a live vaccine. They also should not receive the BCG vaccine during the 1 year before receiving the drug or 1 year after they stop taking it, according to Johnson & Johnson.

The most common adverse effects include nasal congestion, sore throat, runny nose, upper respiratory infections, fever, headache, tiredness, itching, nausea and vomiting, redness at the injection site, vaginal yeast infections, urinary tract infections, sinus infection, bronchitis, diarrhea, stomach pain, and joint pain.

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

The Food and Drug Administration has approved the dual interleukin-12 and IL-23 inhibitor ustekinumab (Stelara) for the treatment of juvenile psoriatic arthritis (jPsA) in patients aged 6 years and older, according to an Aug. 1 announcement from its manufacturer, Janssen.

The approval makes jPsA the sixth approved indication for ustekinumab, which include active psoriatic arthritis in adults, moderate to severe plaque psoriasis in both adults and children aged 6 years or older who are candidates for phototherapy or systemic therapy, moderately to severely active Crohn’s disease in adults, and moderately to severely active ulcerative colitis in adults.

In addition, ustekinumab is now the second biologic to be approved for jPsA, following the agency’s December 2021 approval of secukinumab (Cosentyx) to treat jPsA in children and adolescents aged 2 years and older as well as enthesitis-related arthritis in children and adolescents aged 4 years and older.

In pediatric patients, ustekinumab is administered as a subcutaneous injection dosed four times per year after two starter doses.

Ustekinumab’s approval is based on “an extrapolation of the established data and existing safety profile” of ustekinumab in multiple phase 3 studies in adult and pediatric patients with moderate to severe plaque psoriasis and adult patients with active PsA, according to Janssen.

“With the limited availability of pediatric patients for clinical trial inclusion, researchers can extrapolate data from trials with adults to determine the potential efficacy and tolerability of a treatment for a pediatric population,” according to the October 2021 announcement from the company that the Biologics License Application had been submitted to the FDA.

Juvenile arthritis occurs in an estimated 20-45 children per 100,000 in the United States, with about 5% of those children having jPsA, according to the National Psoriasis Foundation.

The prescribing information for ustekinumab includes specific warnings and areas of concern. The drug should not be administered to individuals with known hypersensitivity to ustekinumab. The drug may lower the ability of the immune system to fight infections and may increase risk of infections, sometimes serious, and a test for tuberculosis infection should be given before administration.

Patients taking ustekinumab should not be given a live vaccine, and their doctors should be informed if anyone in their household needs a live vaccine. They also should not receive the BCG vaccine during the 1 year before receiving the drug or 1 year after they stop taking it, according to Johnson & Johnson.

The most common adverse effects include nasal congestion, sore throat, runny nose, upper respiratory infections, fever, headache, tiredness, itching, nausea and vomiting, redness at the injection site, vaginal yeast infections, urinary tract infections, sinus infection, bronchitis, diarrhea, stomach pain, and joint pain.

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

The Food and Drug Administration has approved the dual interleukin-12 and IL-23 inhibitor ustekinumab (Stelara) for the treatment of juvenile psoriatic arthritis (jPsA) in patients aged 6 years and older, according to an Aug. 1 announcement from its manufacturer, Janssen.

The approval makes jPsA the sixth approved indication for ustekinumab, which include active psoriatic arthritis in adults, moderate to severe plaque psoriasis in both adults and children aged 6 years or older who are candidates for phototherapy or systemic therapy, moderately to severely active Crohn’s disease in adults, and moderately to severely active ulcerative colitis in adults.

In addition, ustekinumab is now the second biologic to be approved for jPsA, following the agency’s December 2021 approval of secukinumab (Cosentyx) to treat jPsA in children and adolescents aged 2 years and older as well as enthesitis-related arthritis in children and adolescents aged 4 years and older.

In pediatric patients, ustekinumab is administered as a subcutaneous injection dosed four times per year after two starter doses.

Ustekinumab’s approval is based on “an extrapolation of the established data and existing safety profile” of ustekinumab in multiple phase 3 studies in adult and pediatric patients with moderate to severe plaque psoriasis and adult patients with active PsA, according to Janssen.

“With the limited availability of pediatric patients for clinical trial inclusion, researchers can extrapolate data from trials with adults to determine the potential efficacy and tolerability of a treatment for a pediatric population,” according to the October 2021 announcement from the company that the Biologics License Application had been submitted to the FDA.

Juvenile arthritis occurs in an estimated 20-45 children per 100,000 in the United States, with about 5% of those children having jPsA, according to the National Psoriasis Foundation.

The prescribing information for ustekinumab includes specific warnings and areas of concern. The drug should not be administered to individuals with known hypersensitivity to ustekinumab. The drug may lower the ability of the immune system to fight infections and may increase risk of infections, sometimes serious, and a test for tuberculosis infection should be given before administration.

Patients taking ustekinumab should not be given a live vaccine, and their doctors should be informed if anyone in their household needs a live vaccine. They also should not receive the BCG vaccine during the 1 year before receiving the drug or 1 year after they stop taking it, according to Johnson & Johnson.

The most common adverse effects include nasal congestion, sore throat, runny nose, upper respiratory infections, fever, headache, tiredness, itching, nausea and vomiting, redness at the injection site, vaginal yeast infections, urinary tract infections, sinus infection, bronchitis, diarrhea, stomach pain, and joint pain.

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

Psittacosis, a rare disease, has been underdiagnosed or misdiagnosed during the COVID-19 pandemic, likely because the symptoms of the disease are similar to COVID-19 symptoms, researchers suggest on the basis of data from 32 individuals.

Diagnosis of and screening for COVID-19 continues to increase; however, cases of atypical pneumonia caused by uncommon pathogens, which presents with similar symptoms, may be missed, wrote Qiaoqiao Yin, MS, of Zhejiang Provincial People’s Hospital, China, and colleagues.

“The clinical manifestations of human psittacosis can present as rapidly progressing severe pneumonia, acute respiratory distress syndrome, sepsis, and multiple organ failure,” but human cases have not been well studied, they say.

In a study  published in the International Journal of Infectious Diseases, the researchers reviewed data from 32 adults diagnosed with Chlamydia psittaci pneumonia during the COVID-19 pandemic between April 2020 and June 2021 in China. The median age of the patients was 63 years, 20 were men, and 20 had underlying diseases.

A total of 17 patients presented with fever, cough, and expectoration of yellow-white sputum. At the time of hospital admission, three patients had myalgia, two had headache, and two had hypertension. The patients were originally suspected of having COVID-19.

“All patients showed atypical pneumonia, including inflammatory infiltration, pleural effusion, multiple inflammatory exudative lesions with interstitial edema, lung abscesses, and white lung,” all of which could be observed in COVID-19 patients as well, the researchers wrote.

Reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) testing were used to rule out COVID-19. The researchers then used metagenomic next-generation sequencing (mNGS) to identify the disease-causing pathogens. They collected 18 bronchoalveolar lavage fluid (BALF) samples, 9 peripheral blood samples, and 5 sputum samples. The mNGS identified C. psittaci as the suspected pathogen within 48 hours. Suspected C. psittaci infections were confirmed by endpoint PCR for the BALF and sputum samples and six of nine blood samples, “indicating a lower sensitivity of PCR compared to mNGS for blood samples,” the researchers say. No other potential pathogens were identified.

Psittacosis is common in birds but is rare in humans. C. psittaci is responsible for 1%-8% of cases involving community-acquired pneumonia in China, the researchers note. Although poultry is a source of infection, 25 of the patients in the study did not report a history of exposure to poultry or pigeons at the time of their initial hospital admission. Many patients may be unaware of exposures to poultry, which further complicates the C. psittaci diagnosis, they note.

All patients were treated with doxycycline-based regimens and showed improvement.

The findings were limited by several factors, including the lack of a definitive diagnostic tool for C. psittaci and the lack of convalescent serum samples to confirm cases, the researchers note. In addition, molecular detections for PCR are unavailable in most hospitals in China, they say. The results represent the largest known collection of suspected C. psittaci pneumonia cases and highlight the need for clinician vigilance and awareness of this rare condition, especially in light of the potential for misdiagnosis during the ongoing COVID-19 pandemic, they conclude.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.

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

Psittacosis, a rare disease, has been underdiagnosed or misdiagnosed during the COVID-19 pandemic, likely because the symptoms of the disease are similar to COVID-19 symptoms, researchers suggest on the basis of data from 32 individuals.

Diagnosis of and screening for COVID-19 continues to increase; however, cases of atypical pneumonia caused by uncommon pathogens, which presents with similar symptoms, may be missed, wrote Qiaoqiao Yin, MS, of Zhejiang Provincial People’s Hospital, China, and colleagues.

“The clinical manifestations of human psittacosis can present as rapidly progressing severe pneumonia, acute respiratory distress syndrome, sepsis, and multiple organ failure,” but human cases have not been well studied, they say.

In a study  published in the International Journal of Infectious Diseases, the researchers reviewed data from 32 adults diagnosed with Chlamydia psittaci pneumonia during the COVID-19 pandemic between April 2020 and June 2021 in China. The median age of the patients was 63 years, 20 were men, and 20 had underlying diseases.

A total of 17 patients presented with fever, cough, and expectoration of yellow-white sputum. At the time of hospital admission, three patients had myalgia, two had headache, and two had hypertension. The patients were originally suspected of having COVID-19.

“All patients showed atypical pneumonia, including inflammatory infiltration, pleural effusion, multiple inflammatory exudative lesions with interstitial edema, lung abscesses, and white lung,” all of which could be observed in COVID-19 patients as well, the researchers wrote.

Reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) testing were used to rule out COVID-19. The researchers then used metagenomic next-generation sequencing (mNGS) to identify the disease-causing pathogens. They collected 18 bronchoalveolar lavage fluid (BALF) samples, 9 peripheral blood samples, and 5 sputum samples. The mNGS identified C. psittaci as the suspected pathogen within 48 hours. Suspected C. psittaci infections were confirmed by endpoint PCR for the BALF and sputum samples and six of nine blood samples, “indicating a lower sensitivity of PCR compared to mNGS for blood samples,” the researchers say. No other potential pathogens were identified.

Psittacosis is common in birds but is rare in humans. C. psittaci is responsible for 1%-8% of cases involving community-acquired pneumonia in China, the researchers note. Although poultry is a source of infection, 25 of the patients in the study did not report a history of exposure to poultry or pigeons at the time of their initial hospital admission. Many patients may be unaware of exposures to poultry, which further complicates the C. psittaci diagnosis, they note.

All patients were treated with doxycycline-based regimens and showed improvement.

The findings were limited by several factors, including the lack of a definitive diagnostic tool for C. psittaci and the lack of convalescent serum samples to confirm cases, the researchers note. In addition, molecular detections for PCR are unavailable in most hospitals in China, they say. The results represent the largest known collection of suspected C. psittaci pneumonia cases and highlight the need for clinician vigilance and awareness of this rare condition, especially in light of the potential for misdiagnosis during the ongoing COVID-19 pandemic, they conclude.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.

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

Psittacosis, a rare disease, has been underdiagnosed or misdiagnosed during the COVID-19 pandemic, likely because the symptoms of the disease are similar to COVID-19 symptoms, researchers suggest on the basis of data from 32 individuals.

Diagnosis of and screening for COVID-19 continues to increase; however, cases of atypical pneumonia caused by uncommon pathogens, which presents with similar symptoms, may be missed, wrote Qiaoqiao Yin, MS, of Zhejiang Provincial People’s Hospital, China, and colleagues.

“The clinical manifestations of human psittacosis can present as rapidly progressing severe pneumonia, acute respiratory distress syndrome, sepsis, and multiple organ failure,” but human cases have not been well studied, they say.

In a study  published in the International Journal of Infectious Diseases, the researchers reviewed data from 32 adults diagnosed with Chlamydia psittaci pneumonia during the COVID-19 pandemic between April 2020 and June 2021 in China. The median age of the patients was 63 years, 20 were men, and 20 had underlying diseases.

A total of 17 patients presented with fever, cough, and expectoration of yellow-white sputum. At the time of hospital admission, three patients had myalgia, two had headache, and two had hypertension. The patients were originally suspected of having COVID-19.

“All patients showed atypical pneumonia, including inflammatory infiltration, pleural effusion, multiple inflammatory exudative lesions with interstitial edema, lung abscesses, and white lung,” all of which could be observed in COVID-19 patients as well, the researchers wrote.

Reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) testing were used to rule out COVID-19. The researchers then used metagenomic next-generation sequencing (mNGS) to identify the disease-causing pathogens. They collected 18 bronchoalveolar lavage fluid (BALF) samples, 9 peripheral blood samples, and 5 sputum samples. The mNGS identified C. psittaci as the suspected pathogen within 48 hours. Suspected C. psittaci infections were confirmed by endpoint PCR for the BALF and sputum samples and six of nine blood samples, “indicating a lower sensitivity of PCR compared to mNGS for blood samples,” the researchers say. No other potential pathogens were identified.

Psittacosis is common in birds but is rare in humans. C. psittaci is responsible for 1%-8% of cases involving community-acquired pneumonia in China, the researchers note. Although poultry is a source of infection, 25 of the patients in the study did not report a history of exposure to poultry or pigeons at the time of their initial hospital admission. Many patients may be unaware of exposures to poultry, which further complicates the C. psittaci diagnosis, they note.

All patients were treated with doxycycline-based regimens and showed improvement.

The findings were limited by several factors, including the lack of a definitive diagnostic tool for C. psittaci and the lack of convalescent serum samples to confirm cases, the researchers note. In addition, molecular detections for PCR are unavailable in most hospitals in China, they say. The results represent the largest known collection of suspected C. psittaci pneumonia cases and highlight the need for clinician vigilance and awareness of this rare condition, especially in light of the potential for misdiagnosis during the ongoing COVID-19 pandemic, they conclude.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved belimumab (Benlysta) for treating active lupus nephritis (LN) in children aged 5-17 years. The drug can now be used to treat adult and pediatric patients with systemic lupus erythematosus (SLE) and LN. The decision expands therapeutic options for the estimated 1.5 million Americans currently living with lupus.

“This approval marks a significant step forward in providing treatment options to these children at risk of incurring kidney damage early on in life,” Stevan W. Gibson, president and CEO of the Lupus Foundation of America, said in a press release issued by the manufacturer, GlaxoSmithKline. LN is a condition that sometimes develops in people with lupus. In LN, the autoimmune cells produced by the disease attack the kidney. Roughly 40% of people with SLE experience LN.

Olivier Le Moal/Getty Images

Damage to the kidneys causes the body to have difficulty processing waste and toxins. This can create a host of problems, including end-stage kidney disease, which may be treated only with dialysis or kidney transplant. These situations significantly increase mortality among people with lupus, especially children.

Prior to the approval, the only treatment pathway for children with active LN included immunosuppressants and corticosteroids. While they may be effective, use of these classes of drugs may come with many side effects, including susceptibility to other diseases and infections. Belimumab, by contrast, is a B-lymphocyte stimulator protein inhibitor. It inhibits the survival of B cells, which are thought to play a role in the disease’s pathophysiology.

Belimumab was first approved to treat patients with SLE in 2011. It was approved for children with SLE 8 years later. The drug’s indications were expanded to include adults with LN in 2020.

Organizations within the lupus research community have communicated their support of the FDA’s decision. “Our community has much to celebrate with the approval of the first and much-needed treatment for children with lupus nephritis,” Lupus Research Alliance President and CEO Kenneth M. Farber said in a release from the organization.

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

The Food and Drug Administration has approved belimumab (Benlysta) for treating active lupus nephritis (LN) in children aged 5-17 years. The drug can now be used to treat adult and pediatric patients with systemic lupus erythematosus (SLE) and LN. The decision expands therapeutic options for the estimated 1.5 million Americans currently living with lupus.

“This approval marks a significant step forward in providing treatment options to these children at risk of incurring kidney damage early on in life,” Stevan W. Gibson, president and CEO of the Lupus Foundation of America, said in a press release issued by the manufacturer, GlaxoSmithKline. LN is a condition that sometimes develops in people with lupus. In LN, the autoimmune cells produced by the disease attack the kidney. Roughly 40% of people with SLE experience LN.

Olivier Le Moal/Getty Images

Damage to the kidneys causes the body to have difficulty processing waste and toxins. This can create a host of problems, including end-stage kidney disease, which may be treated only with dialysis or kidney transplant. These situations significantly increase mortality among people with lupus, especially children.

Prior to the approval, the only treatment pathway for children with active LN included immunosuppressants and corticosteroids. While they may be effective, use of these classes of drugs may come with many side effects, including susceptibility to other diseases and infections. Belimumab, by contrast, is a B-lymphocyte stimulator protein inhibitor. It inhibits the survival of B cells, which are thought to play a role in the disease’s pathophysiology.

Belimumab was first approved to treat patients with SLE in 2011. It was approved for children with SLE 8 years later. The drug’s indications were expanded to include adults with LN in 2020.

Organizations within the lupus research community have communicated their support of the FDA’s decision. “Our community has much to celebrate with the approval of the first and much-needed treatment for children with lupus nephritis,” Lupus Research Alliance President and CEO Kenneth M. Farber said in a release from the organization.

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

The Food and Drug Administration has approved belimumab (Benlysta) for treating active lupus nephritis (LN) in children aged 5-17 years. The drug can now be used to treat adult and pediatric patients with systemic lupus erythematosus (SLE) and LN. The decision expands therapeutic options for the estimated 1.5 million Americans currently living with lupus.

“This approval marks a significant step forward in providing treatment options to these children at risk of incurring kidney damage early on in life,” Stevan W. Gibson, president and CEO of the Lupus Foundation of America, said in a press release issued by the manufacturer, GlaxoSmithKline. LN is a condition that sometimes develops in people with lupus. In LN, the autoimmune cells produced by the disease attack the kidney. Roughly 40% of people with SLE experience LN.

Olivier Le Moal/Getty Images

Damage to the kidneys causes the body to have difficulty processing waste and toxins. This can create a host of problems, including end-stage kidney disease, which may be treated only with dialysis or kidney transplant. These situations significantly increase mortality among people with lupus, especially children.

Prior to the approval, the only treatment pathway for children with active LN included immunosuppressants and corticosteroids. While they may be effective, use of these classes of drugs may come with many side effects, including susceptibility to other diseases and infections. Belimumab, by contrast, is a B-lymphocyte stimulator protein inhibitor. It inhibits the survival of B cells, which are thought to play a role in the disease’s pathophysiology.

Belimumab was first approved to treat patients with SLE in 2011. It was approved for children with SLE 8 years later. The drug’s indications were expanded to include adults with LN in 2020.

Organizations within the lupus research community have communicated their support of the FDA’s decision. “Our community has much to celebrate with the approval of the first and much-needed treatment for children with lupus nephritis,” Lupus Research Alliance President and CEO Kenneth M. Farber said in a release from the organization.

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

To the Editor:

Peristomal pyoderma gangrenosum (PPG) is a rare entity first described in 1984.¹ Lesions usually begin as pustules that coalesce into an erythematous skin ulceration that contains purulent material. The lesion appears on the skin that surrounds an abdominal stoma. Peristomal pyoderma gangrenosum typically is associated with Crohn disease and ulcerative colitis, cancer, blood dyscrasia, diabetes mellitus, and hepatitis.² We describe a case of PPG following an ileostomy in a patient with colon cancer and a related history of Crohn disease.

A 32-year-old woman presented to a dermatology office with a spontaneously painful, 3.2-cm ulceration that was extremely tender to palpation, located immediately adjacent to the site of an ileostomy (Figure). The patient had a history of refractory constipation that failed to respond to standard conservative measures 4 years prior. She underwent a colonoscopy, which revealed a 6.5-cm, irregularly shaped, exophytic mass in the rectosigmoid portion of the colon. Histopathologic examination of several biopsies confirmed the diagnosis of moderately well-differentiated adenocarcinoma, and additional evaluation determined the cancer to be stage IIB. She had a medical history of pancolonic Crohn disease since high school that was treated with periodic infusions of infliximab at the standard dose of 5 mg/kg. Colon cancer treatment consisted of preoperative radiotherapy, complete colectomy with ileoanal anastomosis, and creation of a J-pouch and formation of a temporary ileostomy, along with postoperative capecitabine chemotherapy.

The ileostomy eventually was reversed, and the patient did well for 3 years. When the patient developed severe abdominal pain, the J-pouch was examined and found to be remarkably involved with Crohn disease. However, during the colonoscopy, the J-pouch was inadvertently punctured, leading to the formation of a large pelvic abscess. The latter necessitated diversion of stool, and the patient had the original ileostomy recreated.

Prior to presentation to dermatology, various consultants suspected the ulceration was possibly a deep fungal infection, cutaneous Crohn disease, a factitious ulceration, or acute allergic contact dermatitis related to some element of ostomy care. However, dermatologic consultation suggested that the troublesome lesion was classic PPG and recommended administration of a tumor necrosis factor (TNF) α–blocking agent and concomitant intralesional injections of dilute triamcinolone acetonide.

The patient was treated with subcutaneous adalimumab 40 mg once weekly, and received near weekly subcutaneous injections of triamcinolone acetonide 10 mg/mL. After 2 months, the discomfort subsided, and the ulceration gradually resolved into a depressed scar. Eighteen months later, the scar was barely perceptible as a minimally erythematous depression. Adalimumab ultimately was discontinued, as the residual J-pouch was removed, and the biologic drug was associated with extensive alopecia areata–like hair loss. There has been no recurrence of PPG in the 40 months since clinical resolution.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum, which is characterized by chronic, persistent, or recurrent painful ulceration(s) close to an abdominal stoma. In total, fewer than 100 cases of PPG have been reported thus far in the readily available medical literature.³ Inflammatory bowel disease (IBD) is the most frequently diagnosed systemic condition associated with PPG, though other associated conditions include diverticular disease, abdominal malignancy, and neurologic dysfunction. Approximately 2% to 4.3% of all patients who have stoma creation surgery related to underlying IBD develop PPG. It is estimated that the yearly incidence rate of PPG in all abdominal stomas is quite low (approximately 0.6%).⁴

Peristomal pyoderma gangrenosum can occur at any age, but it tends to predominate in young to middle-aged adults, with a slight female predilection. The etiology and pathogenesis of PPG are largely unknown, though studies have shown that an abnormal immune response may be critical to its development. Risk factors for PPG are not well defined but potentially include autoimmune disorders, a high body mass index, and females or African Americans with IBD.⁴ Because PPG does not have characteristic histopathologic features, it is a diagnosis of exclusion that is based on the clinical examination and histologic findings that rule out other potential disorders.

There are 4 types of PPG based on the clinical and histopathologic characteristics: ulcerative, pustular, bullous, and vegetative. Peristomal pyoderma gangrenosum tends to be either ulcerative or vegetative, with ulcerative being by far the predominant type. The onset of PPG is quite variable, occurring a few weeks to several years after stoma formation.⁵ Ulcer size can range from less than 3 cm to 30 cm.⁴ Lesions begin as deep painful nodules or as superficial hemorrhagic pustules, either idiopathic or following ostensibly minimal trauma. Subsequently, they become necrotic and form an ulceration. The ulcers can be single or multiple lesions, typically with erythematous raised borders and purulent discharge. The ulcers are extremely painful and rapidly progressive. After the ulcers heal, they often leave a characteristic weblike atrophic scar that can break down further following any form of irritation or trauma.⁵

A prompt diagnosis of PPG is important. A diagnosis of PPG should be considered when dealing with a noninfectious ulcer surrounding a stoma in patients with IBD or other autoimmune conditions.⁶ Because PPG is a rare skin disorder, it is likely to be missed and lead to unnecessary diagnostic workup and a delay in proper therapy. In our patient, a diagnosis of PPG was overlooked for other infectious and autoimmune causes. The diagnostic evaluation of a patient with PPG is based on 3 principles: (1) ruling out other causes of a peristomal ulcer, such as an abscess, contact dermatitis, or wound infection; (2) determining whether there is an underlying intestinal bowel disease in the stoma; and (3) identifying associated systemic disorders such as vasculitis, erythema nodosum, or similar processes.⁴ The differential diagnosis depends on the type and stage of PPG and can include malignancy, vasculitis, extraintestinal IBD, infectious disease, and insect bites. A review of the history of the ulcer is helpful in ruling out other diseases, and a colonoscopy or ileoscopy can identify if patients have an underlying active IBD. Swabs for smear and both bacterial and fungal cultures should be taken from the exudate and directly from the ulcer base. Biopsy of the ulcer also helps to exclude alternative diagnoses.⁶

The primary goals of treating PPG include to reduce pain and the risk for secondary infection, increase pouch adherence, and decrease purulent exudate.⁷ Although there is not one well-defined optimal therapeutic intervention, there are a variety of effective approaches that may be considered and used. In mild cases, management methods such as dressings, topical agents, or intralesional steroids may be capable of controlling the disease. Daily wound care is important. Moisture-retentive dressings can control pain, induce collagen formation, promote angiogenesis, and prevent contamination. Cleaning the wound with sterile saline and applying an anti-infective agent also may be effective. Application of ultrapotent topical steroids and tacrolimus ointment 0.3% can be used in patients without concomitant secondary infection. In patients who are in remission, human platelet-derived growth factor may be used. Intralesional injections of dilute triamcinolone acetonide or cyclosporine solution also can be helpful. Cyclosporin A was used as a systemic monotherapy to treat a 48-year-old man and 50-year-old woman with the idiopathic form of PPG. After 3 months of treatment, PPG had completely resolved and there were no major side effects.⁸ Other potential topical therapies that control inflammation and promote wound healing include benzoyl peroxide, chlormethine (topical alkylating agent and nitrogen mustard that has anti-inflammatory properties), nicotine, and 5-aminosalicylic acid. If an ulcer becomes infected, empiric antibiotic therapy should be given immediately and adjusted based on culture and sensitivity results.⁴

Systemic therapy should be considered in patients who do not respond to topical or local interventions, have a rapid and severe course, or have an active underlying bowel disease. Oral prednisone (1 mg/kg/d) has proved to be one of the most successful drugs used to treat PPG. Treatment should be continued until complete lesion healing, and low-dose maintenance therapy should be administered in recurrent cases. Intravenous corticosteroid therapy—hydrocortisone 100 mg 4 times daily or pulse therapy with intravenous methylprednisolone 1 g/d)—can be used for up to 5 days and may be effective. Oral minocycline 100 mg twice daily may be helpful as an adjunctive therapy to corticosteroids. When corticosteroids fail, oral cyclosporine 3 to 5 mg/kg/d often is prescribed. Studies have shown that patients demonstrate clinical improvement within 3 weeks of cyclosporine initiation, and it has been shown further to be more effective than either azathioprine or methotrexate.^4,8

Infliximab, a chimeric antibody that binds both circulating and tissue-bound TNF-α, has been shown to effectively treat PPG. A clinical trial conducted by Brooklyn et al⁹ found that 46% of patients (6/13) treated with infliximab responded compared with only 6% in a placebo control group (1/17). Although infliximab may result in sepsis, the benefits far outweigh the risks, especially for patients with steroid-refractory PPG.⁴ Adalimumab is a human monoclonal IgG1 antibody to TNF-α that neutralizes its function by blocking the interaction between the molecule and its receptor. Many clinical studies have shown that adalimumab induces and maintains a clinical response in patients with active Crohn disease. The biologic proved to be effective in our patient, but it is associated with potential side effects that should be monitored including injection-site reactions, pruritus, leukopenia, urticaria, and rare instances of alopecia.¹⁰ Etanercept is another potentially effective biologic agent.⁷ Plasma exchange, immunoglobulin infusion, and interferon-alfa therapy also can be used in refractory PPG cases, though data on these treatments are very limited.⁴

Unlike routine pyoderma gangrenosum—for which surgical intervention is contraindicated—surgical intervention may be appropriate for the peristomal variant. Surgical treatment options include stoma revision and/or relocation; however, both of these procedures are accompanied by failure rates ranging from 40% to 100%.⁵ Removal of a diseased intestinal segment, especially one with active IBD, may result in healing of the skin lesion. In our patient, removal of the residual and diseased J-pouch was part of the management plan. However,it generally is recommended that any surgical intervention be accompanied by medical therapy including oral metronidazole 500 mg/d and concomitant administration of an immunosuppressant.^1,3

Because PPG tends to recur, long-term maintenance therapy should always be considered. Pain reduction, anemia correction, proper nutrition, and management of associated and underlying diseases should be performed. Meticulous care of the stoma and prevention of leaks also should be emphasized. Overall, if PPG is detected and diagnosed early as well as treated appropriately and aggressively, the patient likely will have a good prognosis.⁴

To the Editor:

Peristomal pyoderma gangrenosum (PPG) is a rare entity first described in 1984.¹ Lesions usually begin as pustules that coalesce into an erythematous skin ulceration that contains purulent material. The lesion appears on the skin that surrounds an abdominal stoma. Peristomal pyoderma gangrenosum typically is associated with Crohn disease and ulcerative colitis, cancer, blood dyscrasia, diabetes mellitus, and hepatitis.² We describe a case of PPG following an ileostomy in a patient with colon cancer and a related history of Crohn disease.

A 32-year-old woman presented to a dermatology office with a spontaneously painful, 3.2-cm ulceration that was extremely tender to palpation, located immediately adjacent to the site of an ileostomy (Figure). The patient had a history of refractory constipation that failed to respond to standard conservative measures 4 years prior. She underwent a colonoscopy, which revealed a 6.5-cm, irregularly shaped, exophytic mass in the rectosigmoid portion of the colon. Histopathologic examination of several biopsies confirmed the diagnosis of moderately well-differentiated adenocarcinoma, and additional evaluation determined the cancer to be stage IIB. She had a medical history of pancolonic Crohn disease since high school that was treated with periodic infusions of infliximab at the standard dose of 5 mg/kg. Colon cancer treatment consisted of preoperative radiotherapy, complete colectomy with ileoanal anastomosis, and creation of a J-pouch and formation of a temporary ileostomy, along with postoperative capecitabine chemotherapy.

The ileostomy eventually was reversed, and the patient did well for 3 years. When the patient developed severe abdominal pain, the J-pouch was examined and found to be remarkably involved with Crohn disease. However, during the colonoscopy, the J-pouch was inadvertently punctured, leading to the formation of a large pelvic abscess. The latter necessitated diversion of stool, and the patient had the original ileostomy recreated.

Prior to presentation to dermatology, various consultants suspected the ulceration was possibly a deep fungal infection, cutaneous Crohn disease, a factitious ulceration, or acute allergic contact dermatitis related to some element of ostomy care. However, dermatologic consultation suggested that the troublesome lesion was classic PPG and recommended administration of a tumor necrosis factor (TNF) α–blocking agent and concomitant intralesional injections of dilute triamcinolone acetonide.

The patient was treated with subcutaneous adalimumab 40 mg once weekly, and received near weekly subcutaneous injections of triamcinolone acetonide 10 mg/mL. After 2 months, the discomfort subsided, and the ulceration gradually resolved into a depressed scar. Eighteen months later, the scar was barely perceptible as a minimally erythematous depression. Adalimumab ultimately was discontinued, as the residual J-pouch was removed, and the biologic drug was associated with extensive alopecia areata–like hair loss. There has been no recurrence of PPG in the 40 months since clinical resolution.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum, which is characterized by chronic, persistent, or recurrent painful ulceration(s) close to an abdominal stoma. In total, fewer than 100 cases of PPG have been reported thus far in the readily available medical literature.³ Inflammatory bowel disease (IBD) is the most frequently diagnosed systemic condition associated with PPG, though other associated conditions include diverticular disease, abdominal malignancy, and neurologic dysfunction. Approximately 2% to 4.3% of all patients who have stoma creation surgery related to underlying IBD develop PPG. It is estimated that the yearly incidence rate of PPG in all abdominal stomas is quite low (approximately 0.6%).⁴

Peristomal pyoderma gangrenosum can occur at any age, but it tends to predominate in young to middle-aged adults, with a slight female predilection. The etiology and pathogenesis of PPG are largely unknown, though studies have shown that an abnormal immune response may be critical to its development. Risk factors for PPG are not well defined but potentially include autoimmune disorders, a high body mass index, and females or African Americans with IBD.⁴ Because PPG does not have characteristic histopathologic features, it is a diagnosis of exclusion that is based on the clinical examination and histologic findings that rule out other potential disorders.

There are 4 types of PPG based on the clinical and histopathologic characteristics: ulcerative, pustular, bullous, and vegetative. Peristomal pyoderma gangrenosum tends to be either ulcerative or vegetative, with ulcerative being by far the predominant type. The onset of PPG is quite variable, occurring a few weeks to several years after stoma formation.⁵ Ulcer size can range from less than 3 cm to 30 cm.⁴ Lesions begin as deep painful nodules or as superficial hemorrhagic pustules, either idiopathic or following ostensibly minimal trauma. Subsequently, they become necrotic and form an ulceration. The ulcers can be single or multiple lesions, typically with erythematous raised borders and purulent discharge. The ulcers are extremely painful and rapidly progressive. After the ulcers heal, they often leave a characteristic weblike atrophic scar that can break down further following any form of irritation or trauma.⁵

A prompt diagnosis of PPG is important. A diagnosis of PPG should be considered when dealing with a noninfectious ulcer surrounding a stoma in patients with IBD or other autoimmune conditions.⁶ Because PPG is a rare skin disorder, it is likely to be missed and lead to unnecessary diagnostic workup and a delay in proper therapy. In our patient, a diagnosis of PPG was overlooked for other infectious and autoimmune causes. The diagnostic evaluation of a patient with PPG is based on 3 principles: (1) ruling out other causes of a peristomal ulcer, such as an abscess, contact dermatitis, or wound infection; (2) determining whether there is an underlying intestinal bowel disease in the stoma; and (3) identifying associated systemic disorders such as vasculitis, erythema nodosum, or similar processes.⁴ The differential diagnosis depends on the type and stage of PPG and can include malignancy, vasculitis, extraintestinal IBD, infectious disease, and insect bites. A review of the history of the ulcer is helpful in ruling out other diseases, and a colonoscopy or ileoscopy can identify if patients have an underlying active IBD. Swabs for smear and both bacterial and fungal cultures should be taken from the exudate and directly from the ulcer base. Biopsy of the ulcer also helps to exclude alternative diagnoses.⁶

The primary goals of treating PPG include to reduce pain and the risk for secondary infection, increase pouch adherence, and decrease purulent exudate.⁷ Although there is not one well-defined optimal therapeutic intervention, there are a variety of effective approaches that may be considered and used. In mild cases, management methods such as dressings, topical agents, or intralesional steroids may be capable of controlling the disease. Daily wound care is important. Moisture-retentive dressings can control pain, induce collagen formation, promote angiogenesis, and prevent contamination. Cleaning the wound with sterile saline and applying an anti-infective agent also may be effective. Application of ultrapotent topical steroids and tacrolimus ointment 0.3% can be used in patients without concomitant secondary infection. In patients who are in remission, human platelet-derived growth factor may be used. Intralesional injections of dilute triamcinolone acetonide or cyclosporine solution also can be helpful. Cyclosporin A was used as a systemic monotherapy to treat a 48-year-old man and 50-year-old woman with the idiopathic form of PPG. After 3 months of treatment, PPG had completely resolved and there were no major side effects.⁸ Other potential topical therapies that control inflammation and promote wound healing include benzoyl peroxide, chlormethine (topical alkylating agent and nitrogen mustard that has anti-inflammatory properties), nicotine, and 5-aminosalicylic acid. If an ulcer becomes infected, empiric antibiotic therapy should be given immediately and adjusted based on culture and sensitivity results.⁴

Systemic therapy should be considered in patients who do not respond to topical or local interventions, have a rapid and severe course, or have an active underlying bowel disease. Oral prednisone (1 mg/kg/d) has proved to be one of the most successful drugs used to treat PPG. Treatment should be continued until complete lesion healing, and low-dose maintenance therapy should be administered in recurrent cases. Intravenous corticosteroid therapy—hydrocortisone 100 mg 4 times daily or pulse therapy with intravenous methylprednisolone 1 g/d)—can be used for up to 5 days and may be effective. Oral minocycline 100 mg twice daily may be helpful as an adjunctive therapy to corticosteroids. When corticosteroids fail, oral cyclosporine 3 to 5 mg/kg/d often is prescribed. Studies have shown that patients demonstrate clinical improvement within 3 weeks of cyclosporine initiation, and it has been shown further to be more effective than either azathioprine or methotrexate.^4,8

Infliximab, a chimeric antibody that binds both circulating and tissue-bound TNF-α, has been shown to effectively treat PPG. A clinical trial conducted by Brooklyn et al⁹ found that 46% of patients (6/13) treated with infliximab responded compared with only 6% in a placebo control group (1/17). Although infliximab may result in sepsis, the benefits far outweigh the risks, especially for patients with steroid-refractory PPG.⁴ Adalimumab is a human monoclonal IgG1 antibody to TNF-α that neutralizes its function by blocking the interaction between the molecule and its receptor. Many clinical studies have shown that adalimumab induces and maintains a clinical response in patients with active Crohn disease. The biologic proved to be effective in our patient, but it is associated with potential side effects that should be monitored including injection-site reactions, pruritus, leukopenia, urticaria, and rare instances of alopecia.¹⁰ Etanercept is another potentially effective biologic agent.⁷ Plasma exchange, immunoglobulin infusion, and interferon-alfa therapy also can be used in refractory PPG cases, though data on these treatments are very limited.⁴

Unlike routine pyoderma gangrenosum—for which surgical intervention is contraindicated—surgical intervention may be appropriate for the peristomal variant. Surgical treatment options include stoma revision and/or relocation; however, both of these procedures are accompanied by failure rates ranging from 40% to 100%.⁵ Removal of a diseased intestinal segment, especially one with active IBD, may result in healing of the skin lesion. In our patient, removal of the residual and diseased J-pouch was part of the management plan. However,it generally is recommended that any surgical intervention be accompanied by medical therapy including oral metronidazole 500 mg/d and concomitant administration of an immunosuppressant.^1,3

Because PPG tends to recur, long-term maintenance therapy should always be considered. Pain reduction, anemia correction, proper nutrition, and management of associated and underlying diseases should be performed. Meticulous care of the stoma and prevention of leaks also should be emphasized. Overall, if PPG is detected and diagnosed early as well as treated appropriately and aggressively, the patient likely will have a good prognosis.⁴

To the Editor:

Peristomal pyoderma gangrenosum (PPG) is a rare entity first described in 1984.¹ Lesions usually begin as pustules that coalesce into an erythematous skin ulceration that contains purulent material. The lesion appears on the skin that surrounds an abdominal stoma. Peristomal pyoderma gangrenosum typically is associated with Crohn disease and ulcerative colitis, cancer, blood dyscrasia, diabetes mellitus, and hepatitis.² We describe a case of PPG following an ileostomy in a patient with colon cancer and a related history of Crohn disease.

A 32-year-old woman presented to a dermatology office with a spontaneously painful, 3.2-cm ulceration that was extremely tender to palpation, located immediately adjacent to the site of an ileostomy (Figure). The patient had a history of refractory constipation that failed to respond to standard conservative measures 4 years prior. She underwent a colonoscopy, which revealed a 6.5-cm, irregularly shaped, exophytic mass in the rectosigmoid portion of the colon. Histopathologic examination of several biopsies confirmed the diagnosis of moderately well-differentiated adenocarcinoma, and additional evaluation determined the cancer to be stage IIB. She had a medical history of pancolonic Crohn disease since high school that was treated with periodic infusions of infliximab at the standard dose of 5 mg/kg. Colon cancer treatment consisted of preoperative radiotherapy, complete colectomy with ileoanal anastomosis, and creation of a J-pouch and formation of a temporary ileostomy, along with postoperative capecitabine chemotherapy.

The ileostomy eventually was reversed, and the patient did well for 3 years. When the patient developed severe abdominal pain, the J-pouch was examined and found to be remarkably involved with Crohn disease. However, during the colonoscopy, the J-pouch was inadvertently punctured, leading to the formation of a large pelvic abscess. The latter necessitated diversion of stool, and the patient had the original ileostomy recreated.

Prior to presentation to dermatology, various consultants suspected the ulceration was possibly a deep fungal infection, cutaneous Crohn disease, a factitious ulceration, or acute allergic contact dermatitis related to some element of ostomy care. However, dermatologic consultation suggested that the troublesome lesion was classic PPG and recommended administration of a tumor necrosis factor (TNF) α–blocking agent and concomitant intralesional injections of dilute triamcinolone acetonide.

The patient was treated with subcutaneous adalimumab 40 mg once weekly, and received near weekly subcutaneous injections of triamcinolone acetonide 10 mg/mL. After 2 months, the discomfort subsided, and the ulceration gradually resolved into a depressed scar. Eighteen months later, the scar was barely perceptible as a minimally erythematous depression. Adalimumab ultimately was discontinued, as the residual J-pouch was removed, and the biologic drug was associated with extensive alopecia areata–like hair loss. There has been no recurrence of PPG in the 40 months since clinical resolution.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum, which is characterized by chronic, persistent, or recurrent painful ulceration(s) close to an abdominal stoma. In total, fewer than 100 cases of PPG have been reported thus far in the readily available medical literature.³ Inflammatory bowel disease (IBD) is the most frequently diagnosed systemic condition associated with PPG, though other associated conditions include diverticular disease, abdominal malignancy, and neurologic dysfunction. Approximately 2% to 4.3% of all patients who have stoma creation surgery related to underlying IBD develop PPG. It is estimated that the yearly incidence rate of PPG in all abdominal stomas is quite low (approximately 0.6%).⁴

Peristomal pyoderma gangrenosum can occur at any age, but it tends to predominate in young to middle-aged adults, with a slight female predilection. The etiology and pathogenesis of PPG are largely unknown, though studies have shown that an abnormal immune response may be critical to its development. Risk factors for PPG are not well defined but potentially include autoimmune disorders, a high body mass index, and females or African Americans with IBD.⁴ Because PPG does not have characteristic histopathologic features, it is a diagnosis of exclusion that is based on the clinical examination and histologic findings that rule out other potential disorders.

There are 4 types of PPG based on the clinical and histopathologic characteristics: ulcerative, pustular, bullous, and vegetative. Peristomal pyoderma gangrenosum tends to be either ulcerative or vegetative, with ulcerative being by far the predominant type. The onset of PPG is quite variable, occurring a few weeks to several years after stoma formation.⁵ Ulcer size can range from less than 3 cm to 30 cm.⁴ Lesions begin as deep painful nodules or as superficial hemorrhagic pustules, either idiopathic or following ostensibly minimal trauma. Subsequently, they become necrotic and form an ulceration. The ulcers can be single or multiple lesions, typically with erythematous raised borders and purulent discharge. The ulcers are extremely painful and rapidly progressive. After the ulcers heal, they often leave a characteristic weblike atrophic scar that can break down further following any form of irritation or trauma.⁵

A prompt diagnosis of PPG is important. A diagnosis of PPG should be considered when dealing with a noninfectious ulcer surrounding a stoma in patients with IBD or other autoimmune conditions.⁶ Because PPG is a rare skin disorder, it is likely to be missed and lead to unnecessary diagnostic workup and a delay in proper therapy. In our patient, a diagnosis of PPG was overlooked for other infectious and autoimmune causes. The diagnostic evaluation of a patient with PPG is based on 3 principles: (1) ruling out other causes of a peristomal ulcer, such as an abscess, contact dermatitis, or wound infection; (2) determining whether there is an underlying intestinal bowel disease in the stoma; and (3) identifying associated systemic disorders such as vasculitis, erythema nodosum, or similar processes.⁴ The differential diagnosis depends on the type and stage of PPG and can include malignancy, vasculitis, extraintestinal IBD, infectious disease, and insect bites. A review of the history of the ulcer is helpful in ruling out other diseases, and a colonoscopy or ileoscopy can identify if patients have an underlying active IBD. Swabs for smear and both bacterial and fungal cultures should be taken from the exudate and directly from the ulcer base. Biopsy of the ulcer also helps to exclude alternative diagnoses.⁶

The primary goals of treating PPG include to reduce pain and the risk for secondary infection, increase pouch adherence, and decrease purulent exudate.⁷ Although there is not one well-defined optimal therapeutic intervention, there are a variety of effective approaches that may be considered and used. In mild cases, management methods such as dressings, topical agents, or intralesional steroids may be capable of controlling the disease. Daily wound care is important. Moisture-retentive dressings can control pain, induce collagen formation, promote angiogenesis, and prevent contamination. Cleaning the wound with sterile saline and applying an anti-infective agent also may be effective. Application of ultrapotent topical steroids and tacrolimus ointment 0.3% can be used in patients without concomitant secondary infection. In patients who are in remission, human platelet-derived growth factor may be used. Intralesional injections of dilute triamcinolone acetonide or cyclosporine solution also can be helpful. Cyclosporin A was used as a systemic monotherapy to treat a 48-year-old man and 50-year-old woman with the idiopathic form of PPG. After 3 months of treatment, PPG had completely resolved and there were no major side effects.⁸ Other potential topical therapies that control inflammation and promote wound healing include benzoyl peroxide, chlormethine (topical alkylating agent and nitrogen mustard that has anti-inflammatory properties), nicotine, and 5-aminosalicylic acid. If an ulcer becomes infected, empiric antibiotic therapy should be given immediately and adjusted based on culture and sensitivity results.⁴

Systemic therapy should be considered in patients who do not respond to topical or local interventions, have a rapid and severe course, or have an active underlying bowel disease. Oral prednisone (1 mg/kg/d) has proved to be one of the most successful drugs used to treat PPG. Treatment should be continued until complete lesion healing, and low-dose maintenance therapy should be administered in recurrent cases. Intravenous corticosteroid therapy—hydrocortisone 100 mg 4 times daily or pulse therapy with intravenous methylprednisolone 1 g/d)—can be used for up to 5 days and may be effective. Oral minocycline 100 mg twice daily may be helpful as an adjunctive therapy to corticosteroids. When corticosteroids fail, oral cyclosporine 3 to 5 mg/kg/d often is prescribed. Studies have shown that patients demonstrate clinical improvement within 3 weeks of cyclosporine initiation, and it has been shown further to be more effective than either azathioprine or methotrexate.^4,8

Infliximab, a chimeric antibody that binds both circulating and tissue-bound TNF-α, has been shown to effectively treat PPG. A clinical trial conducted by Brooklyn et al⁹ found that 46% of patients (6/13) treated with infliximab responded compared with only 6% in a placebo control group (1/17). Although infliximab may result in sepsis, the benefits far outweigh the risks, especially for patients with steroid-refractory PPG.⁴ Adalimumab is a human monoclonal IgG1 antibody to TNF-α that neutralizes its function by blocking the interaction between the molecule and its receptor. Many clinical studies have shown that adalimumab induces and maintains a clinical response in patients with active Crohn disease. The biologic proved to be effective in our patient, but it is associated with potential side effects that should be monitored including injection-site reactions, pruritus, leukopenia, urticaria, and rare instances of alopecia.¹⁰ Etanercept is another potentially effective biologic agent.⁷ Plasma exchange, immunoglobulin infusion, and interferon-alfa therapy also can be used in refractory PPG cases, though data on these treatments are very limited.⁴

Unlike routine pyoderma gangrenosum—for which surgical intervention is contraindicated—surgical intervention may be appropriate for the peristomal variant. Surgical treatment options include stoma revision and/or relocation; however, both of these procedures are accompanied by failure rates ranging from 40% to 100%.⁵ Removal of a diseased intestinal segment, especially one with active IBD, may result in healing of the skin lesion. In our patient, removal of the residual and diseased J-pouch was part of the management plan. However,it generally is recommended that any surgical intervention be accompanied by medical therapy including oral metronidazole 500 mg/d and concomitant administration of an immunosuppressant.^1,3

Because PPG tends to recur, long-term maintenance therapy should always be considered. Pain reduction, anemia correction, proper nutrition, and management of associated and underlying diseases should be performed. Meticulous care of the stoma and prevention of leaks also should be emphasized. Overall, if PPG is detected and diagnosed early as well as treated appropriately and aggressively, the patient likely will have a good prognosis.⁴

INDIANAPOLIS – An investigational topical treatment for dystrophic epidermolysis bullosa (DEB) known as beremagene geperpavec (B-VEC) showed durable and statistically significant improvement in complete wound healing at 3 and 6 months compared with placebo, according to results from a small phase 3 study.

DEB is a serious, ultra-rare genetic blistering disease caused by mutations in the COL7A1 gene, encoding for type VII collagen and leading to skin fragility and wounds. No approved therapies are currently available. In the study, treatment was generally well tolerated.

Doug Brunk/MDedge News

“B-VEC is the first treatment that has not only been shown to be effective, but the first to directly target the defect through topical application,” the study’s principal investigator, Shireen V. Guide, MD, said in an interview during a poster session at the annual meeting of the Society for Pediatric Dermatology. “It delivers type VII collagen gene therapy to these patients, which allows healing in areas that they may have had open since birth. It’s been life-changing for them.”

B-VEC is a herpes simplex virus (HSV-1)-based topical, redosable gene therapy being developed by Krystal Biotech that is designed to restore functional COL7 protein by delivering the COL7A1 gene. For the phase 3, multicenter, double-blind, placebo-controlled study known GEM-3, Dr. Guide, who practices dermatology in Rancho Santa Margarita, Calif., and her colleagues, including Peter Marinkovich, MD, from Stanford (Calif.) University, and Mercedes Gonzalez, MD, from the University of Miami, enrolled 31 patients aged 6 months and older with genetically confirmed DEB. Each patient had one wound treated randomized 1:1 to treatment with B-VEC once a week or placebo for 6 months. The mean age of the 31 study participants was 17 years, 65% were male, 65% were White, and 19% were Asian.

The primary endpoint was complete wound healing (defined as 100% wound closure from exact wound area at baseline, specified as skin re-epithelialization without drainage) at 6 months. Additional endpoints included complete wound healing at 3 months and change in pain associated with wound dressing changes.

At 3 months, 70% of wounds treated with B-VEC met the endpoint of complete wound healing, compared with 20% of wounds treated with placebo (P < .005). At 6 months, 67% of wounds treated with B-VEC met the endpoint of complete wound healing compared with 22% of those treated with placebo (P < .005).

Of the total wounds that closed at 3 months, 67% of wounds treated with B-VEC were also closed at 6 months, compared with 33% of those treated with placebo (P = .02). In other findings, a trend toward decreased pain was observed in wounds treated with B-VEC vs. those treated with placebo.

B-VEC was well tolerated with no treatment-related serious adverse events or discontinuations. Three patients experienced a total of five serious adverse events during the study: anemia (two events), and cellulitis, diarrhea, and positive blood culture (one event each). None were considered related to the study drug.

Dr. Guide, who is on staff at Children’s Health of Orange County, Orange, Calif., characterized B-VEC as “very novel because it’s very practical.”

To date, all treatments for DEB “have been extremely labor intensive, including skin grafting and hospitalizations. It’s a topical application that can be done in the office and potentially applied at home in the future. It’s also durable. Not only are the [treated] areas closing, but they are staying closed.”

Kalyani S. Marathe, MD, MPH, director of the dermatology division at Cincinnati Children’s Hospital, who was asked to comment on the study, said that topical application of B-VEC “allows the side effect profile to be very favorable. The results are remarkable in the amount of wound healing and reduction in pain.”

The tolerability of this medication “is crucial,” she added. “EB patients have a lot of pain from their wounds and so any treatment needs to be as painless as possible for it to be usable. I’m very excited about the next phase of studies for this medication and hopeful that it heralds new treatments for our EB patients.”

In June 2022, the manufacturer announced that it had submitted a biologics license application to the Food and Drug Administration for approval of B-VEC for the treatment of DEB, and that it anticipates submitting an application for marketing authorization with the European Medical Agency (EMA) in the second half of 2022.

Dr. Guide disclosed that she has served as an investigator for Krystal Biotech, Innovaderm Research, Arcutis, Premier Research, Paidion, and Castle Biosciences. Dr. Marathe disclosed that she has served as an adviser for Verrica, and that Cincinnati Children’s Hospital is a site for the next phase studies for B-VEC.

*This story was updated on July 25. 

INDIANAPOLIS – An investigational topical treatment for dystrophic epidermolysis bullosa (DEB) known as beremagene geperpavec (B-VEC) showed durable and statistically significant improvement in complete wound healing at 3 and 6 months compared with placebo, according to results from a small phase 3 study.

DEB is a serious, ultra-rare genetic blistering disease caused by mutations in the COL7A1 gene, encoding for type VII collagen and leading to skin fragility and wounds. No approved therapies are currently available. In the study, treatment was generally well tolerated.

Doug Brunk/MDedge News

“B-VEC is the first treatment that has not only been shown to be effective, but the first to directly target the defect through topical application,” the study’s principal investigator, Shireen V. Guide, MD, said in an interview during a poster session at the annual meeting of the Society for Pediatric Dermatology. “It delivers type VII collagen gene therapy to these patients, which allows healing in areas that they may have had open since birth. It’s been life-changing for them.”

B-VEC is a herpes simplex virus (HSV-1)-based topical, redosable gene therapy being developed by Krystal Biotech that is designed to restore functional COL7 protein by delivering the COL7A1 gene. For the phase 3, multicenter, double-blind, placebo-controlled study known GEM-3, Dr. Guide, who practices dermatology in Rancho Santa Margarita, Calif., and her colleagues, including Peter Marinkovich, MD, from Stanford (Calif.) University, and Mercedes Gonzalez, MD, from the University of Miami, enrolled 31 patients aged 6 months and older with genetically confirmed DEB. Each patient had one wound treated randomized 1:1 to treatment with B-VEC once a week or placebo for 6 months. The mean age of the 31 study participants was 17 years, 65% were male, 65% were White, and 19% were Asian.

The primary endpoint was complete wound healing (defined as 100% wound closure from exact wound area at baseline, specified as skin re-epithelialization without drainage) at 6 months. Additional endpoints included complete wound healing at 3 months and change in pain associated with wound dressing changes.

At 3 months, 70% of wounds treated with B-VEC met the endpoint of complete wound healing, compared with 20% of wounds treated with placebo (P < .005). At 6 months, 67% of wounds treated with B-VEC met the endpoint of complete wound healing compared with 22% of those treated with placebo (P < .005).

Of the total wounds that closed at 3 months, 67% of wounds treated with B-VEC were also closed at 6 months, compared with 33% of those treated with placebo (P = .02). In other findings, a trend toward decreased pain was observed in wounds treated with B-VEC vs. those treated with placebo.

B-VEC was well tolerated with no treatment-related serious adverse events or discontinuations. Three patients experienced a total of five serious adverse events during the study: anemia (two events), and cellulitis, diarrhea, and positive blood culture (one event each). None were considered related to the study drug.

Dr. Guide, who is on staff at Children’s Health of Orange County, Orange, Calif., characterized B-VEC as “very novel because it’s very practical.”

To date, all treatments for DEB “have been extremely labor intensive, including skin grafting and hospitalizations. It’s a topical application that can be done in the office and potentially applied at home in the future. It’s also durable. Not only are the [treated] areas closing, but they are staying closed.”

Kalyani S. Marathe, MD, MPH, director of the dermatology division at Cincinnati Children’s Hospital, who was asked to comment on the study, said that topical application of B-VEC “allows the side effect profile to be very favorable. The results are remarkable in the amount of wound healing and reduction in pain.”

The tolerability of this medication “is crucial,” she added. “EB patients have a lot of pain from their wounds and so any treatment needs to be as painless as possible for it to be usable. I’m very excited about the next phase of studies for this medication and hopeful that it heralds new treatments for our EB patients.”

In June 2022, the manufacturer announced that it had submitted a biologics license application to the Food and Drug Administration for approval of B-VEC for the treatment of DEB, and that it anticipates submitting an application for marketing authorization with the European Medical Agency (EMA) in the second half of 2022.

Dr. Guide disclosed that she has served as an investigator for Krystal Biotech, Innovaderm Research, Arcutis, Premier Research, Paidion, and Castle Biosciences. Dr. Marathe disclosed that she has served as an adviser for Verrica, and that Cincinnati Children’s Hospital is a site for the next phase studies for B-VEC.

*This story was updated on July 25. 

INDIANAPOLIS – An investigational topical treatment for dystrophic epidermolysis bullosa (DEB) known as beremagene geperpavec (B-VEC) showed durable and statistically significant improvement in complete wound healing at 3 and 6 months compared with placebo, according to results from a small phase 3 study.

DEB is a serious, ultra-rare genetic blistering disease caused by mutations in the COL7A1 gene, encoding for type VII collagen and leading to skin fragility and wounds. No approved therapies are currently available. In the study, treatment was generally well tolerated.

Doug Brunk/MDedge News

“B-VEC is the first treatment that has not only been shown to be effective, but the first to directly target the defect through topical application,” the study’s principal investigator, Shireen V. Guide, MD, said in an interview during a poster session at the annual meeting of the Society for Pediatric Dermatology. “It delivers type VII collagen gene therapy to these patients, which allows healing in areas that they may have had open since birth. It’s been life-changing for them.”

B-VEC is a herpes simplex virus (HSV-1)-based topical, redosable gene therapy being developed by Krystal Biotech that is designed to restore functional COL7 protein by delivering the COL7A1 gene. For the phase 3, multicenter, double-blind, placebo-controlled study known GEM-3, Dr. Guide, who practices dermatology in Rancho Santa Margarita, Calif., and her colleagues, including Peter Marinkovich, MD, from Stanford (Calif.) University, and Mercedes Gonzalez, MD, from the University of Miami, enrolled 31 patients aged 6 months and older with genetically confirmed DEB. Each patient had one wound treated randomized 1:1 to treatment with B-VEC once a week or placebo for 6 months. The mean age of the 31 study participants was 17 years, 65% were male, 65% were White, and 19% were Asian.

The primary endpoint was complete wound healing (defined as 100% wound closure from exact wound area at baseline, specified as skin re-epithelialization without drainage) at 6 months. Additional endpoints included complete wound healing at 3 months and change in pain associated with wound dressing changes.

At 3 months, 70% of wounds treated with B-VEC met the endpoint of complete wound healing, compared with 20% of wounds treated with placebo (P < .005). At 6 months, 67% of wounds treated with B-VEC met the endpoint of complete wound healing compared with 22% of those treated with placebo (P < .005).

Of the total wounds that closed at 3 months, 67% of wounds treated with B-VEC were also closed at 6 months, compared with 33% of those treated with placebo (P = .02). In other findings, a trend toward decreased pain was observed in wounds treated with B-VEC vs. those treated with placebo.

B-VEC was well tolerated with no treatment-related serious adverse events or discontinuations. Three patients experienced a total of five serious adverse events during the study: anemia (two events), and cellulitis, diarrhea, and positive blood culture (one event each). None were considered related to the study drug.

Dr. Guide, who is on staff at Children’s Health of Orange County, Orange, Calif., characterized B-VEC as “very novel because it’s very practical.”

To date, all treatments for DEB “have been extremely labor intensive, including skin grafting and hospitalizations. It’s a topical application that can be done in the office and potentially applied at home in the future. It’s also durable. Not only are the [treated] areas closing, but they are staying closed.”

Kalyani S. Marathe, MD, MPH, director of the dermatology division at Cincinnati Children’s Hospital, who was asked to comment on the study, said that topical application of B-VEC “allows the side effect profile to be very favorable. The results are remarkable in the amount of wound healing and reduction in pain.”

The tolerability of this medication “is crucial,” she added. “EB patients have a lot of pain from their wounds and so any treatment needs to be as painless as possible for it to be usable. I’m very excited about the next phase of studies for this medication and hopeful that it heralds new treatments for our EB patients.”

In June 2022, the manufacturer announced that it had submitted a biologics license application to the Food and Drug Administration for approval of B-VEC for the treatment of DEB, and that it anticipates submitting an application for marketing authorization with the European Medical Agency (EMA) in the second half of 2022.

Dr. Guide disclosed that she has served as an investigator for Krystal Biotech, Innovaderm Research, Arcutis, Premier Research, Paidion, and Castle Biosciences. Dr. Marathe disclosed that she has served as an adviser for Verrica, and that Cincinnati Children’s Hospital is a site for the next phase studies for B-VEC.

*This story was updated on July 25. 

To the Editor:

Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin¹ in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.²

Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.

Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as Papillon-Lefèvre syndrome (OMIM 245000) and Olmsted syndrome (OMIM 614594). Papillon-Lefèvre syndrome is a rare autosomal-recessive disorder caused by mutations in the cathepsin C, CTSC, gene that exhibits erythematous, diffuse, transgradient PPK and early severe periodontitis. Olmsted syndrome is caused by autosomal-dominant gene mutations in transient receptor potential cation channel, subfamily V, member 3, TRPV3, and is characterized by severe bilateral transgradient PPK with leukoplakia of the tongue and buccal mucosa but also usually exhibits marked periorificial keratotic plaques, which facilitate exclusion of other phenotypically similar syndromes.³

Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.

The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.

Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.

Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.⁴KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.⁵ Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.⁶

Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.² This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.

Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.⁷ These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.

We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.

To the Editor:

Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin¹ in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.²

Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.

Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as Papillon-Lefèvre syndrome (OMIM 245000) and Olmsted syndrome (OMIM 614594). Papillon-Lefèvre syndrome is a rare autosomal-recessive disorder caused by mutations in the cathepsin C, CTSC, gene that exhibits erythematous, diffuse, transgradient PPK and early severe periodontitis. Olmsted syndrome is caused by autosomal-dominant gene mutations in transient receptor potential cation channel, subfamily V, member 3, TRPV3, and is characterized by severe bilateral transgradient PPK with leukoplakia of the tongue and buccal mucosa but also usually exhibits marked periorificial keratotic plaques, which facilitate exclusion of other phenotypically similar syndromes.³

Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.

The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.

Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.

Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.⁴KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.⁵ Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.⁶

Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.² This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.

Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.⁷ These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.

We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.

To the Editor:

Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin¹ in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.²

Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.

Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as Papillon-Lefèvre syndrome (OMIM 245000) and Olmsted syndrome (OMIM 614594). Papillon-Lefèvre syndrome is a rare autosomal-recessive disorder caused by mutations in the cathepsin C, CTSC, gene that exhibits erythematous, diffuse, transgradient PPK and early severe periodontitis. Olmsted syndrome is caused by autosomal-dominant gene mutations in transient receptor potential cation channel, subfamily V, member 3, TRPV3, and is characterized by severe bilateral transgradient PPK with leukoplakia of the tongue and buccal mucosa but also usually exhibits marked periorificial keratotic plaques, which facilitate exclusion of other phenotypically similar syndromes.³

Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.

The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.

Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.

Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.⁴KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.⁵ Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.⁶

Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.² This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.

Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.⁷ These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.

We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.

GLASGOW, Scotland – The wound-healing benefits seen with a topical agent containing the bark derivative oleogel-S10 (Filsuvez) for patients with epidermolysis bullosa (EB) continue to accrue with continued use, suggests data from an open-label extension of EASE, the phase 3 safety and efficacy study of the treatment.

Over 200 patients from the trial, including 105 who began treatment with a control gel, continued taking oleogel-S10 after 90 days. The current interim analysis at 12 months indicates there was a 55% reduction in the proportion of the body affected, compared with baseline.

Moreover, reductions in skin activity scores seen in the double-blind phase of the trial were maintained during the open-label extension. About 6% of patients experienced adverse events that led to withdrawal from the study.

The results show that oleogel-S10 was associated with “accelerated wound healing,” said study presenter Tracey Cunningham, MD, chief medical officer, Amryt Pharmaceuticals DAC, Dublin, which is developing the topical agent. “There were no new safety signals with this longer exposure to oleogel-S10, and patients had sustained improvement in wound burden,” she added.

The research was presented at the British Association of Dermatologists (BAD) 2022 Annual Meeting on July 6.

In April, European Medicines Agency recommended approval of oleogel-S10 for the treatment of partial-thickness skin wounds associated with dystrophic and junctional EB for patients aged 6 months and older.

However, just a month earlier, the U.S. Food and Drug Administration declined to approve the topical agent for use in EB, even after it extended its review by 3 months to include additional analyses of data previously submitted by the company.

In the post-presentation discussion, Dr. Cunningham said that the FDA had “not been satisfied at this point with the information that we have given them,” adding, “We don’t agree with the decision, and we will be appealing.”

Raman K. Madan, MD, a dermatologist at Northwell Health, Huntington, New York, who was not involved in the study, said that the reductions in wound healing seen in the study are “meaningful” and that the numbers represent a “big breakthrough.”

He told this news organization that there are “very few products on the market” for EB and that having an option for patients “would be amazing.”

“The big issue here would be cost and coverage for patients,” he said. If approved, “hopefully” it will be affordable, he added.

Dr. Madan noted that from his perspective, the majority of the reactions to the topical gel were “mild,” and there are “a lot of confounding factors” underlying the number of serious adverse events. “These patients with epidermolysis are prone to some of these issues regardless of treatment,” he said.

During her presentation, Dr. Cunningham noted that EB is a rare, debilitating condition that is characterized by varying degrees of skin fragility, blisters, and impaired wound healing that in turn lead to serious complications that affect quality of life.

While wound management is a “fundamental priority” for patients living with EB, she said, there is a “high, unmet” clinical need.

To those ends, EASE was the largest randomized controlled phase 3 efficacy and safety study in EB. In the study, 252 patients were allocated to receive oleogel-S10 or control gel plus standard-of-care nonadhesive wound dressing.

The double-blind phase of the trial met its primary endpoint: A higher proportion of patients who were given oleogel-S10 achieved first complete closure of the EB target wound by day 45, compared with patients who were given control gel, at 41.3% versus 28.9%. This equated to a relative risk of wound closure by day 45 of 1.44, or an odds ratio of 1.84 (P = .013).

However, as reported at the time by this news organization, the difference in time to wound healing by day 90 between the two patient groups was not statistically significant (P = .302), with 50.5% of oleogel-S10 patients achieving wound closure, versus 43.9% of those in the control group.

Dr. Cunningham discussed the open-label extension, which involved 205 patients from the double-blind phase (mean age, of 16.3 years) treated with oleogel-S10 or control gel plus standard-of-care nonadhesive wound dressing for 24 months.

In presenting the results of the first 12 months of the open-label extension, she said that oleogel-S10 led to “consistent” reductions in the body surface area percentage (BSAP) affected by EB. The overall reduction from baseline was 55% after receiving treatment for 15 months.

Between day 90 and month 12 of the open-label extension, the absolute BSAP was reduced from 7.4% to 5.4% for patients who had received oleogel-S10 from the start of the study. For those who started in the control group and then switched to the oleogel-S10 arm during the open-label extension, the reduction was from 8.3% to 6.4%.

Dr. Cunningham pointed out that a 1% reduction in BSAP equates approximately to the palmar surface of the hand.

Scores on the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Skin activity subscale indicated that the reductions achieved in the double-blind phase of the trial were maintained.

Among patients who received oleogel-S10 from the start of the trial, EBDASI Skin scores were reduced from 19.6 at baseline to 13.5 at 12 months’ follow-up in the open-label extension. The reduction was from 19.6 to 13.5 for those who began the trial taking control gel.

Dr. Cunningham showed that adverse events of any grade were seen in 72.0% of patients who began taking oleogel-S10 at the start of the trial and in 69.5% of those who began the trial taking control gel.

Serious adverse events were recorded in 23.0% and 20.0% of patients, respectively, while 6.0% of those who initially received oleogel-S10 and 6.7% of those initially assigned to control gel experienced adverse events that led to study withdrawal during the open-label phase.

The most frequently reported adverse events in the open-label extension were wound complications, seen in 39.5% of patients; anemia, seen in 14.1%; wound infection, seen in 9.3%; pyrexia, seen in 8.3%; and pruritus, seen in 5.9%. No more details regarding adverse events were provided.

The study was funded by Amryt Pharmaceuticals DAC. Dr. Cunningham is an employee of Amryt Pharmaceuticals. No other relevant financial relationships have been disclosed.

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

GLASGOW, Scotland – The wound-healing benefits seen with a topical agent containing the bark derivative oleogel-S10 (Filsuvez) for patients with epidermolysis bullosa (EB) continue to accrue with continued use, suggests data from an open-label extension of EASE, the phase 3 safety and efficacy study of the treatment.

Over 200 patients from the trial, including 105 who began treatment with a control gel, continued taking oleogel-S10 after 90 days. The current interim analysis at 12 months indicates there was a 55% reduction in the proportion of the body affected, compared with baseline.

Moreover, reductions in skin activity scores seen in the double-blind phase of the trial were maintained during the open-label extension. About 6% of patients experienced adverse events that led to withdrawal from the study.

The results show that oleogel-S10 was associated with “accelerated wound healing,” said study presenter Tracey Cunningham, MD, chief medical officer, Amryt Pharmaceuticals DAC, Dublin, which is developing the topical agent. “There were no new safety signals with this longer exposure to oleogel-S10, and patients had sustained improvement in wound burden,” she added.

The research was presented at the British Association of Dermatologists (BAD) 2022 Annual Meeting on July 6.

In April, European Medicines Agency recommended approval of oleogel-S10 for the treatment of partial-thickness skin wounds associated with dystrophic and junctional EB for patients aged 6 months and older.

However, just a month earlier, the U.S. Food and Drug Administration declined to approve the topical agent for use in EB, even after it extended its review by 3 months to include additional analyses of data previously submitted by the company.

In the post-presentation discussion, Dr. Cunningham said that the FDA had “not been satisfied at this point with the information that we have given them,” adding, “We don’t agree with the decision, and we will be appealing.”

Raman K. Madan, MD, a dermatologist at Northwell Health, Huntington, New York, who was not involved in the study, said that the reductions in wound healing seen in the study are “meaningful” and that the numbers represent a “big breakthrough.”

He told this news organization that there are “very few products on the market” for EB and that having an option for patients “would be amazing.”

“The big issue here would be cost and coverage for patients,” he said. If approved, “hopefully” it will be affordable, he added.

Dr. Madan noted that from his perspective, the majority of the reactions to the topical gel were “mild,” and there are “a lot of confounding factors” underlying the number of serious adverse events. “These patients with epidermolysis are prone to some of these issues regardless of treatment,” he said.

During her presentation, Dr. Cunningham noted that EB is a rare, debilitating condition that is characterized by varying degrees of skin fragility, blisters, and impaired wound healing that in turn lead to serious complications that affect quality of life.

While wound management is a “fundamental priority” for patients living with EB, she said, there is a “high, unmet” clinical need.

To those ends, EASE was the largest randomized controlled phase 3 efficacy and safety study in EB. In the study, 252 patients were allocated to receive oleogel-S10 or control gel plus standard-of-care nonadhesive wound dressing.

The double-blind phase of the trial met its primary endpoint: A higher proportion of patients who were given oleogel-S10 achieved first complete closure of the EB target wound by day 45, compared with patients who were given control gel, at 41.3% versus 28.9%. This equated to a relative risk of wound closure by day 45 of 1.44, or an odds ratio of 1.84 (P = .013).

However, as reported at the time by this news organization, the difference in time to wound healing by day 90 between the two patient groups was not statistically significant (P = .302), with 50.5% of oleogel-S10 patients achieving wound closure, versus 43.9% of those in the control group.

Dr. Cunningham discussed the open-label extension, which involved 205 patients from the double-blind phase (mean age, of 16.3 years) treated with oleogel-S10 or control gel plus standard-of-care nonadhesive wound dressing for 24 months.

In presenting the results of the first 12 months of the open-label extension, she said that oleogel-S10 led to “consistent” reductions in the body surface area percentage (BSAP) affected by EB. The overall reduction from baseline was 55% after receiving treatment for 15 months.

Between day 90 and month 12 of the open-label extension, the absolute BSAP was reduced from 7.4% to 5.4% for patients who had received oleogel-S10 from the start of the study. For those who started in the control group and then switched to the oleogel-S10 arm during the open-label extension, the reduction was from 8.3% to 6.4%.

Dr. Cunningham pointed out that a 1% reduction in BSAP equates approximately to the palmar surface of the hand.

Scores on the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Skin activity subscale indicated that the reductions achieved in the double-blind phase of the trial were maintained.

Among patients who received oleogel-S10 from the start of the trial, EBDASI Skin scores were reduced from 19.6 at baseline to 13.5 at 12 months’ follow-up in the open-label extension. The reduction was from 19.6 to 13.5 for those who began the trial taking control gel.

Dr. Cunningham showed that adverse events of any grade were seen in 72.0% of patients who began taking oleogel-S10 at the start of the trial and in 69.5% of those who began the trial taking control gel.

Serious adverse events were recorded in 23.0% and 20.0% of patients, respectively, while 6.0% of those who initially received oleogel-S10 and 6.7% of those initially assigned to control gel experienced adverse events that led to study withdrawal during the open-label phase.

The most frequently reported adverse events in the open-label extension were wound complications, seen in 39.5% of patients; anemia, seen in 14.1%; wound infection, seen in 9.3%; pyrexia, seen in 8.3%; and pruritus, seen in 5.9%. No more details regarding adverse events were provided.

The study was funded by Amryt Pharmaceuticals DAC. Dr. Cunningham is an employee of Amryt Pharmaceuticals. No other relevant financial relationships have been disclosed.

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

GLASGOW, Scotland – The wound-healing benefits seen with a topical agent containing the bark derivative oleogel-S10 (Filsuvez) for patients with epidermolysis bullosa (EB) continue to accrue with continued use, suggests data from an open-label extension of EASE, the phase 3 safety and efficacy study of the treatment.

Over 200 patients from the trial, including 105 who began treatment with a control gel, continued taking oleogel-S10 after 90 days. The current interim analysis at 12 months indicates there was a 55% reduction in the proportion of the body affected, compared with baseline.

Moreover, reductions in skin activity scores seen in the double-blind phase of the trial were maintained during the open-label extension. About 6% of patients experienced adverse events that led to withdrawal from the study.

The results show that oleogel-S10 was associated with “accelerated wound healing,” said study presenter Tracey Cunningham, MD, chief medical officer, Amryt Pharmaceuticals DAC, Dublin, which is developing the topical agent. “There were no new safety signals with this longer exposure to oleogel-S10, and patients had sustained improvement in wound burden,” she added.

The research was presented at the British Association of Dermatologists (BAD) 2022 Annual Meeting on July 6.

In April, European Medicines Agency recommended approval of oleogel-S10 for the treatment of partial-thickness skin wounds associated with dystrophic and junctional EB for patients aged 6 months and older.

However, just a month earlier, the U.S. Food and Drug Administration declined to approve the topical agent for use in EB, even after it extended its review by 3 months to include additional analyses of data previously submitted by the company.

In the post-presentation discussion, Dr. Cunningham said that the FDA had “not been satisfied at this point with the information that we have given them,” adding, “We don’t agree with the decision, and we will be appealing.”

Raman K. Madan, MD, a dermatologist at Northwell Health, Huntington, New York, who was not involved in the study, said that the reductions in wound healing seen in the study are “meaningful” and that the numbers represent a “big breakthrough.”

He told this news organization that there are “very few products on the market” for EB and that having an option for patients “would be amazing.”

“The big issue here would be cost and coverage for patients,” he said. If approved, “hopefully” it will be affordable, he added.

Dr. Madan noted that from his perspective, the majority of the reactions to the topical gel were “mild,” and there are “a lot of confounding factors” underlying the number of serious adverse events. “These patients with epidermolysis are prone to some of these issues regardless of treatment,” he said.

During her presentation, Dr. Cunningham noted that EB is a rare, debilitating condition that is characterized by varying degrees of skin fragility, blisters, and impaired wound healing that in turn lead to serious complications that affect quality of life.

While wound management is a “fundamental priority” for patients living with EB, she said, there is a “high, unmet” clinical need.

To those ends, EASE was the largest randomized controlled phase 3 efficacy and safety study in EB. In the study, 252 patients were allocated to receive oleogel-S10 or control gel plus standard-of-care nonadhesive wound dressing.

The double-blind phase of the trial met its primary endpoint: A higher proportion of patients who were given oleogel-S10 achieved first complete closure of the EB target wound by day 45, compared with patients who were given control gel, at 41.3% versus 28.9%. This equated to a relative risk of wound closure by day 45 of 1.44, or an odds ratio of 1.84 (P = .013).

However, as reported at the time by this news organization, the difference in time to wound healing by day 90 between the two patient groups was not statistically significant (P = .302), with 50.5% of oleogel-S10 patients achieving wound closure, versus 43.9% of those in the control group.

Dr. Cunningham discussed the open-label extension, which involved 205 patients from the double-blind phase (mean age, of 16.3 years) treated with oleogel-S10 or control gel plus standard-of-care nonadhesive wound dressing for 24 months.

In presenting the results of the first 12 months of the open-label extension, she said that oleogel-S10 led to “consistent” reductions in the body surface area percentage (BSAP) affected by EB. The overall reduction from baseline was 55% after receiving treatment for 15 months.

Between day 90 and month 12 of the open-label extension, the absolute BSAP was reduced from 7.4% to 5.4% for patients who had received oleogel-S10 from the start of the study. For those who started in the control group and then switched to the oleogel-S10 arm during the open-label extension, the reduction was from 8.3% to 6.4%.

Dr. Cunningham pointed out that a 1% reduction in BSAP equates approximately to the palmar surface of the hand.

Scores on the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) Skin activity subscale indicated that the reductions achieved in the double-blind phase of the trial were maintained.

Among patients who received oleogel-S10 from the start of the trial, EBDASI Skin scores were reduced from 19.6 at baseline to 13.5 at 12 months’ follow-up in the open-label extension. The reduction was from 19.6 to 13.5 for those who began the trial taking control gel.

Dr. Cunningham showed that adverse events of any grade were seen in 72.0% of patients who began taking oleogel-S10 at the start of the trial and in 69.5% of those who began the trial taking control gel.

Serious adverse events were recorded in 23.0% and 20.0% of patients, respectively, while 6.0% of those who initially received oleogel-S10 and 6.7% of those initially assigned to control gel experienced adverse events that led to study withdrawal during the open-label phase.

The most frequently reported adverse events in the open-label extension were wound complications, seen in 39.5% of patients; anemia, seen in 14.1%; wound infection, seen in 9.3%; pyrexia, seen in 8.3%; and pruritus, seen in 5.9%. No more details regarding adverse events were provided.

The study was funded by Amryt Pharmaceuticals DAC. Dr. Cunningham is an employee of Amryt Pharmaceuticals. No other relevant financial relationships have been disclosed.

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