Dermatology

Isotretinoin was not associated with a 1-year risk of incident inflammatory bowel disease (IBD) in a large population-based cohort study that also found no significant association of oral tetracycline-class antibiotics with IBD – and a small but statistically significant association of acne itself with the inflammatory disorders that make up IBD.

For the study, senior author John S. Barbieri, MD, MBA, of the department of dermatology, at Brigham and Women’s Hospital, Boston, and his colleagues used data from the TriNetX global research platform, which mines patient-level electronic medical record data from dozens of health care organizations, mainly in the United States. The network includes over 106 million patients. They looked at four cohorts: Patients without acne; those with acne but no current or prior use of systemic medications; those with acne managed with isotretinoin (and no prior use of oral tetracycline-class antibiotics); and those with acne managed with oral tetracycline-class antibiotics (and no exposure to isotretinoin).

Ocskay Bence/Fotolia.com

For the acne cohorts, the investigators captured first encounters with a diagnosis of acne and first prescriptions of interest. And studywide, they used propensity score matching to balance cohorts for age, sex, race, ethnicity, and combined oral contraceptive use.

“These data should provide more reassurance to patients and prescribers that isotretinoin does not appear to result in a meaningfully increased risk of inflammatory bowel disease,” they wrote in the study, published online in the Journal of the American Academy of Dermatology.

“These are important findings as isotretinoin is a valuable treatment for acne that can result in a durable remission of disease activity, prevent acne scarring, and reduce our overreliance on oral antibiotics for acne,” they added.

Indeed, dermatologist Jonathan S. Weiss, MD, who was not involved in the research and was asked to comment on the study, said that the findings “are reassuring given the large numbers of patients evaluated and treated.” The smallest cohort – the isotretinoin group – had over 11,000 patients, and the other cohorts had over 100,000 patients each, he said in an interview.

“At this point, I’m not sure we need any other immediate information to feel comfortable using isotretinoin with respect to a potential to cause IBD, but it would be nice to see some longitudinal follow-up data for longer-term reassurance,” added Dr. Weiss, who practices in Snellville, Georgia, and is on the board of the directors of the American Acne and Rosacea Society.

 

The findings: Risk with acne

To assess the potential association between acne and IBD, the researchers identified more than 350,000 patients with acne managed without systemic medications, and propensity score matched them with patients who did not have acne. Altogether, their mean age was 22; 32.1% were male, and 59.6% were White.

Compared with the controls who did not have acne, they found a statistically significant association between acne and risk of incident IBD (odds ratio, 1.42; 95% confidence interval, 1.23-1.65) and an absolute risk difference of .04%. Separated into Crohn’s disease (CD) and ulcerative colitis (UC), ORs were 1.56 and 1.62, respectively.
 

Tetracyclines

To assess the association of oral tetracycline use and IBD, they compared more than 144,000 patients whose acne was managed with antibiotics with patients whose acne was managed without systemic medications. The patients had a mean age of 24.4; 34.7% were male, and 68.2% were White.

Compared with the patients who were not on systemic medications, there were no significant associations among those on oral tetracyclines, with an OR for incident IBD of 1 (95% CI, 0.82-1.22), an OR for incident CD of 1.09 (95% CI, 0.86-1.38), and an OR for UC of 0.78 (95% CI, 0.61-1.00).
 

Isotretinoin

To evaluate the association of isotretinoin and IBD, the researchers compared more than 11,000 patients treated with isotretinoin with two matched groups: patients with acne managed without systemic medications, and patients with acne managed with oral tetracyclines. The latter comparison was made to minimize potential confounding by acne severity. These patients had a mean age of 21.1; 49.5% were male, and 75.3% were White.

In the first comparison, compared with patients not treated with systemic medications, the OR for 1-year incidence of IBD among patients treated with isotretinoin was 1.29 (95% CI, 0.64-2.59), with an absolute risk difference of .036%. The ORs for CD and UC were 1.00 (95% CI, 0.45-2.23) and 1.27 (95% CI, .58-2.80), respectively.

And compared with the antibiotic-managed group, the OR for incident IBD among those on isotretinoin was 1.13 (95% CI, 0.57-2.21), with an absolute risk difference of .018%. The OR for CD was 1.00 (95% CI, 0.45-2.23). The OR for UC could not be accurately estimated because of an insufficient number of events in the tetracycline-treated group.
 

‘Challenging’ area of research

Researching acne treatments and the potential risk of IBD has been a methodologically “challenging topic to study” because of possible confounding and surveillance bias depending on study designs, Dr. Barbieri, director of the Brigham and Women’s Advanced Acne Therapeutics Clinic, said in an interview.

Studies that have identified a potential association between isotretinoin and IBD often have not adequately controlled for prior antibiotic exposure, for instance. And other studies, including a retrospective cohort study also published recently in JAAD using the same TriNetX database, have found 6-month isotretinoin-related risks of IBD but no increased risk at 1 year or more of follow-up – a finding that suggests a role of surveillance bias, Dr. Barbieri said.

The follow-up period of 1 year in their new study was chosen to minimize the risk of such bias. “Since patients on isotretinoin are seen more often, and since there are historical concerns about isotretinoin and IBD, patients on isotretinoin may be more likely to be screened earlier and thus could be diagnosed sooner than those not on [the medication],” he said.

He and his coauthors considered similar potential bias in designing the no-acne cohort, choosing patients who had routine primary care visits without abnormal findings in order to “reduce potential for bias due to frequency of interaction with the health care system,” they noted in their paper. (Patients had no prior encounters for acne and no history of acne treatments.)
 

Antibiotics, acne itself

Research on antibiotic use for acne and risk of IBD is scant, and the few studies that have been published show conflicting findings, Dr. Barbieri noted. In the meantime, studies and meta-analyses in the general medical literature – not involving acne – have identified an association between lifetime oral antibiotic exposure and IBD, he said.

While the results of the new study “are reassuring that oral tetracycline-class exposure for acne may not be associated with a significant absolute risk of inflammatory bowel disease, given the potential for antibiotic resistance and other antibiotic-associated complications, it remains important to be judicious” with their use in acne management, he and his coauthors wrote in the study.

The potential association between antibiotics for acne and IBD needs further study, preferably with longer follow-up duration, Dr. Barbieri said in the interview, but researchers are challenged by the lack of datasets with high-quality longitudinal data “beyond a few years of follow-up.”

The extent to which acne itself is associated with IBD is another area ripe for more research. Thus far, it seems that IBD and acne – and other chronic inflammatory skin diseases such as psoriasis – involve similar pathogenic pathways. “We know that in IBD Th17 and TNF immunologic pathways are important, so it’s not surprising that there may be associations,” he said.

In their paper, Dr. Barbieri and his coauthors emphasize, however, that the absolute risk difference between acne and IBD is small. It’s “unlikely that population level screening is warranted among patients with acne,” they wrote.

A second new study

The other study, also published recently in JAAD, used the same TriNetX research platform to identify approximately 77,000 patients with acne starting isotretinoin and matched them with patients starting oral antibiotics.

The investigators, Khalaf Kridin MD, PhD, and Ralf J. Ludwig, MD, of the Lübeck Institute of Experimental Dermatology, University of Lübeck (Germany), found that the lifetime risks (greater than 6 months) for patients on isotretinoin were not significantly elevated, compared with those on oral antibiotics for either CD (hazard ratio 1.05; 95% CI, 0.89-1.24, P = .583) or UC (HR, 1.13; 95% CI, 0.95-1.34; P = .162) They also looked at the risk of irritable bowel syndrome (IBS) and found a lower lifetime risk in the isotretinoin group.

In the short term, during the first 6 months after drug initiation, there was a significant, but slight increase in UC in the isotretinoin group. But this risk decreased to the level of the antibiotic group with longer follow up. “The absolute incidence rates [of IBD] and the risk difference of UC within the first 6 months are of limited clinical significance,” they wrote.

It may be, Dr. Weiss said in commenting on this study, “that isotretinoin unmasks an already-existing genetic tendency to UC early on in the course of treatment, but that it does not truly cause an increased incidence of any type of IBD.”

Both studies, said Dr. Barbieri, “add to an extensive body of literature that supports that isotretinoin is not associated with IBD.”

Dr. Barbieri had no disclosures for the study, for which Matthew T. Taylor served as first author. Coauthor Shawn Kwatra, MD, disclosed that he is an advisory board member/consultant for numerous pharmaceutical companies and has served as an investigator for several. Both are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The other authors had no disclosures. Dr. Kridin and Dr. Ludwig had no disclosures for their study. Dr. Weiss had no disclosures.

Isotretinoin was not associated with a 1-year risk of incident inflammatory bowel disease (IBD) in a large population-based cohort study that also found no significant association of oral tetracycline-class antibiotics with IBD – and a small but statistically significant association of acne itself with the inflammatory disorders that make up IBD.

For the study, senior author John S. Barbieri, MD, MBA, of the department of dermatology, at Brigham and Women’s Hospital, Boston, and his colleagues used data from the TriNetX global research platform, which mines patient-level electronic medical record data from dozens of health care organizations, mainly in the United States. The network includes over 106 million patients. They looked at four cohorts: Patients without acne; those with acne but no current or prior use of systemic medications; those with acne managed with isotretinoin (and no prior use of oral tetracycline-class antibiotics); and those with acne managed with oral tetracycline-class antibiotics (and no exposure to isotretinoin).

Ocskay Bence/Fotolia.com

For the acne cohorts, the investigators captured first encounters with a diagnosis of acne and first prescriptions of interest. And studywide, they used propensity score matching to balance cohorts for age, sex, race, ethnicity, and combined oral contraceptive use.

“These data should provide more reassurance to patients and prescribers that isotretinoin does not appear to result in a meaningfully increased risk of inflammatory bowel disease,” they wrote in the study, published online in the Journal of the American Academy of Dermatology.

“These are important findings as isotretinoin is a valuable treatment for acne that can result in a durable remission of disease activity, prevent acne scarring, and reduce our overreliance on oral antibiotics for acne,” they added.

Indeed, dermatologist Jonathan S. Weiss, MD, who was not involved in the research and was asked to comment on the study, said that the findings “are reassuring given the large numbers of patients evaluated and treated.” The smallest cohort – the isotretinoin group – had over 11,000 patients, and the other cohorts had over 100,000 patients each, he said in an interview.

“At this point, I’m not sure we need any other immediate information to feel comfortable using isotretinoin with respect to a potential to cause IBD, but it would be nice to see some longitudinal follow-up data for longer-term reassurance,” added Dr. Weiss, who practices in Snellville, Georgia, and is on the board of the directors of the American Acne and Rosacea Society.

 

The findings: Risk with acne

To assess the potential association between acne and IBD, the researchers identified more than 350,000 patients with acne managed without systemic medications, and propensity score matched them with patients who did not have acne. Altogether, their mean age was 22; 32.1% were male, and 59.6% were White.

Compared with the controls who did not have acne, they found a statistically significant association between acne and risk of incident IBD (odds ratio, 1.42; 95% confidence interval, 1.23-1.65) and an absolute risk difference of .04%. Separated into Crohn’s disease (CD) and ulcerative colitis (UC), ORs were 1.56 and 1.62, respectively.
 

Tetracyclines

To assess the association of oral tetracycline use and IBD, they compared more than 144,000 patients whose acne was managed with antibiotics with patients whose acne was managed without systemic medications. The patients had a mean age of 24.4; 34.7% were male, and 68.2% were White.

Compared with the patients who were not on systemic medications, there were no significant associations among those on oral tetracyclines, with an OR for incident IBD of 1 (95% CI, 0.82-1.22), an OR for incident CD of 1.09 (95% CI, 0.86-1.38), and an OR for UC of 0.78 (95% CI, 0.61-1.00).
 

Isotretinoin

To evaluate the association of isotretinoin and IBD, the researchers compared more than 11,000 patients treated with isotretinoin with two matched groups: patients with acne managed without systemic medications, and patients with acne managed with oral tetracyclines. The latter comparison was made to minimize potential confounding by acne severity. These patients had a mean age of 21.1; 49.5% were male, and 75.3% were White.

In the first comparison, compared with patients not treated with systemic medications, the OR for 1-year incidence of IBD among patients treated with isotretinoin was 1.29 (95% CI, 0.64-2.59), with an absolute risk difference of .036%. The ORs for CD and UC were 1.00 (95% CI, 0.45-2.23) and 1.27 (95% CI, .58-2.80), respectively.

And compared with the antibiotic-managed group, the OR for incident IBD among those on isotretinoin was 1.13 (95% CI, 0.57-2.21), with an absolute risk difference of .018%. The OR for CD was 1.00 (95% CI, 0.45-2.23). The OR for UC could not be accurately estimated because of an insufficient number of events in the tetracycline-treated group.
 

‘Challenging’ area of research

Researching acne treatments and the potential risk of IBD has been a methodologically “challenging topic to study” because of possible confounding and surveillance bias depending on study designs, Dr. Barbieri, director of the Brigham and Women’s Advanced Acne Therapeutics Clinic, said in an interview.

Studies that have identified a potential association between isotretinoin and IBD often have not adequately controlled for prior antibiotic exposure, for instance. And other studies, including a retrospective cohort study also published recently in JAAD using the same TriNetX database, have found 6-month isotretinoin-related risks of IBD but no increased risk at 1 year or more of follow-up – a finding that suggests a role of surveillance bias, Dr. Barbieri said.

The follow-up period of 1 year in their new study was chosen to minimize the risk of such bias. “Since patients on isotretinoin are seen more often, and since there are historical concerns about isotretinoin and IBD, patients on isotretinoin may be more likely to be screened earlier and thus could be diagnosed sooner than those not on [the medication],” he said.

He and his coauthors considered similar potential bias in designing the no-acne cohort, choosing patients who had routine primary care visits without abnormal findings in order to “reduce potential for bias due to frequency of interaction with the health care system,” they noted in their paper. (Patients had no prior encounters for acne and no history of acne treatments.)
 

Antibiotics, acne itself

Research on antibiotic use for acne and risk of IBD is scant, and the few studies that have been published show conflicting findings, Dr. Barbieri noted. In the meantime, studies and meta-analyses in the general medical literature – not involving acne – have identified an association between lifetime oral antibiotic exposure and IBD, he said.

While the results of the new study “are reassuring that oral tetracycline-class exposure for acne may not be associated with a significant absolute risk of inflammatory bowel disease, given the potential for antibiotic resistance and other antibiotic-associated complications, it remains important to be judicious” with their use in acne management, he and his coauthors wrote in the study.

The potential association between antibiotics for acne and IBD needs further study, preferably with longer follow-up duration, Dr. Barbieri said in the interview, but researchers are challenged by the lack of datasets with high-quality longitudinal data “beyond a few years of follow-up.”

The extent to which acne itself is associated with IBD is another area ripe for more research. Thus far, it seems that IBD and acne – and other chronic inflammatory skin diseases such as psoriasis – involve similar pathogenic pathways. “We know that in IBD Th17 and TNF immunologic pathways are important, so it’s not surprising that there may be associations,” he said.

In their paper, Dr. Barbieri and his coauthors emphasize, however, that the absolute risk difference between acne and IBD is small. It’s “unlikely that population level screening is warranted among patients with acne,” they wrote.

A second new study

The other study, also published recently in JAAD, used the same TriNetX research platform to identify approximately 77,000 patients with acne starting isotretinoin and matched them with patients starting oral antibiotics.

The investigators, Khalaf Kridin MD, PhD, and Ralf J. Ludwig, MD, of the Lübeck Institute of Experimental Dermatology, University of Lübeck (Germany), found that the lifetime risks (greater than 6 months) for patients on isotretinoin were not significantly elevated, compared with those on oral antibiotics for either CD (hazard ratio 1.05; 95% CI, 0.89-1.24, P = .583) or UC (HR, 1.13; 95% CI, 0.95-1.34; P = .162) They also looked at the risk of irritable bowel syndrome (IBS) and found a lower lifetime risk in the isotretinoin group.

In the short term, during the first 6 months after drug initiation, there was a significant, but slight increase in UC in the isotretinoin group. But this risk decreased to the level of the antibiotic group with longer follow up. “The absolute incidence rates [of IBD] and the risk difference of UC within the first 6 months are of limited clinical significance,” they wrote.

It may be, Dr. Weiss said in commenting on this study, “that isotretinoin unmasks an already-existing genetic tendency to UC early on in the course of treatment, but that it does not truly cause an increased incidence of any type of IBD.”

Both studies, said Dr. Barbieri, “add to an extensive body of literature that supports that isotretinoin is not associated with IBD.”

Dr. Barbieri had no disclosures for the study, for which Matthew T. Taylor served as first author. Coauthor Shawn Kwatra, MD, disclosed that he is an advisory board member/consultant for numerous pharmaceutical companies and has served as an investigator for several. Both are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The other authors had no disclosures. Dr. Kridin and Dr. Ludwig had no disclosures for their study. Dr. Weiss had no disclosures.

Isotretinoin was not associated with a 1-year risk of incident inflammatory bowel disease (IBD) in a large population-based cohort study that also found no significant association of oral tetracycline-class antibiotics with IBD – and a small but statistically significant association of acne itself with the inflammatory disorders that make up IBD.

For the study, senior author John S. Barbieri, MD, MBA, of the department of dermatology, at Brigham and Women’s Hospital, Boston, and his colleagues used data from the TriNetX global research platform, which mines patient-level electronic medical record data from dozens of health care organizations, mainly in the United States. The network includes over 106 million patients. They looked at four cohorts: Patients without acne; those with acne but no current or prior use of systemic medications; those with acne managed with isotretinoin (and no prior use of oral tetracycline-class antibiotics); and those with acne managed with oral tetracycline-class antibiotics (and no exposure to isotretinoin).

Ocskay Bence/Fotolia.com

For the acne cohorts, the investigators captured first encounters with a diagnosis of acne and first prescriptions of interest. And studywide, they used propensity score matching to balance cohorts for age, sex, race, ethnicity, and combined oral contraceptive use.

“These data should provide more reassurance to patients and prescribers that isotretinoin does not appear to result in a meaningfully increased risk of inflammatory bowel disease,” they wrote in the study, published online in the Journal of the American Academy of Dermatology.

“These are important findings as isotretinoin is a valuable treatment for acne that can result in a durable remission of disease activity, prevent acne scarring, and reduce our overreliance on oral antibiotics for acne,” they added.

Indeed, dermatologist Jonathan S. Weiss, MD, who was not involved in the research and was asked to comment on the study, said that the findings “are reassuring given the large numbers of patients evaluated and treated.” The smallest cohort – the isotretinoin group – had over 11,000 patients, and the other cohorts had over 100,000 patients each, he said in an interview.

“At this point, I’m not sure we need any other immediate information to feel comfortable using isotretinoin with respect to a potential to cause IBD, but it would be nice to see some longitudinal follow-up data for longer-term reassurance,” added Dr. Weiss, who practices in Snellville, Georgia, and is on the board of the directors of the American Acne and Rosacea Society.

 

The findings: Risk with acne

To assess the potential association between acne and IBD, the researchers identified more than 350,000 patients with acne managed without systemic medications, and propensity score matched them with patients who did not have acne. Altogether, their mean age was 22; 32.1% were male, and 59.6% were White.

Compared with the controls who did not have acne, they found a statistically significant association between acne and risk of incident IBD (odds ratio, 1.42; 95% confidence interval, 1.23-1.65) and an absolute risk difference of .04%. Separated into Crohn’s disease (CD) and ulcerative colitis (UC), ORs were 1.56 and 1.62, respectively.
 

Tetracyclines

To assess the association of oral tetracycline use and IBD, they compared more than 144,000 patients whose acne was managed with antibiotics with patients whose acne was managed without systemic medications. The patients had a mean age of 24.4; 34.7% were male, and 68.2% were White.

Compared with the patients who were not on systemic medications, there were no significant associations among those on oral tetracyclines, with an OR for incident IBD of 1 (95% CI, 0.82-1.22), an OR for incident CD of 1.09 (95% CI, 0.86-1.38), and an OR for UC of 0.78 (95% CI, 0.61-1.00).
 

Isotretinoin

To evaluate the association of isotretinoin and IBD, the researchers compared more than 11,000 patients treated with isotretinoin with two matched groups: patients with acne managed without systemic medications, and patients with acne managed with oral tetracyclines. The latter comparison was made to minimize potential confounding by acne severity. These patients had a mean age of 21.1; 49.5% were male, and 75.3% were White.

In the first comparison, compared with patients not treated with systemic medications, the OR for 1-year incidence of IBD among patients treated with isotretinoin was 1.29 (95% CI, 0.64-2.59), with an absolute risk difference of .036%. The ORs for CD and UC were 1.00 (95% CI, 0.45-2.23) and 1.27 (95% CI, .58-2.80), respectively.

And compared with the antibiotic-managed group, the OR for incident IBD among those on isotretinoin was 1.13 (95% CI, 0.57-2.21), with an absolute risk difference of .018%. The OR for CD was 1.00 (95% CI, 0.45-2.23). The OR for UC could not be accurately estimated because of an insufficient number of events in the tetracycline-treated group.
 

‘Challenging’ area of research

Researching acne treatments and the potential risk of IBD has been a methodologically “challenging topic to study” because of possible confounding and surveillance bias depending on study designs, Dr. Barbieri, director of the Brigham and Women’s Advanced Acne Therapeutics Clinic, said in an interview.

Studies that have identified a potential association between isotretinoin and IBD often have not adequately controlled for prior antibiotic exposure, for instance. And other studies, including a retrospective cohort study also published recently in JAAD using the same TriNetX database, have found 6-month isotretinoin-related risks of IBD but no increased risk at 1 year or more of follow-up – a finding that suggests a role of surveillance bias, Dr. Barbieri said.

The follow-up period of 1 year in their new study was chosen to minimize the risk of such bias. “Since patients on isotretinoin are seen more often, and since there are historical concerns about isotretinoin and IBD, patients on isotretinoin may be more likely to be screened earlier and thus could be diagnosed sooner than those not on [the medication],” he said.

He and his coauthors considered similar potential bias in designing the no-acne cohort, choosing patients who had routine primary care visits without abnormal findings in order to “reduce potential for bias due to frequency of interaction with the health care system,” they noted in their paper. (Patients had no prior encounters for acne and no history of acne treatments.)
 

Antibiotics, acne itself

Research on antibiotic use for acne and risk of IBD is scant, and the few studies that have been published show conflicting findings, Dr. Barbieri noted. In the meantime, studies and meta-analyses in the general medical literature – not involving acne – have identified an association between lifetime oral antibiotic exposure and IBD, he said.

While the results of the new study “are reassuring that oral tetracycline-class exposure for acne may not be associated with a significant absolute risk of inflammatory bowel disease, given the potential for antibiotic resistance and other antibiotic-associated complications, it remains important to be judicious” with their use in acne management, he and his coauthors wrote in the study.

The potential association between antibiotics for acne and IBD needs further study, preferably with longer follow-up duration, Dr. Barbieri said in the interview, but researchers are challenged by the lack of datasets with high-quality longitudinal data “beyond a few years of follow-up.”

The extent to which acne itself is associated with IBD is another area ripe for more research. Thus far, it seems that IBD and acne – and other chronic inflammatory skin diseases such as psoriasis – involve similar pathogenic pathways. “We know that in IBD Th17 and TNF immunologic pathways are important, so it’s not surprising that there may be associations,” he said.

In their paper, Dr. Barbieri and his coauthors emphasize, however, that the absolute risk difference between acne and IBD is small. It’s “unlikely that population level screening is warranted among patients with acne,” they wrote.

A second new study

The other study, also published recently in JAAD, used the same TriNetX research platform to identify approximately 77,000 patients with acne starting isotretinoin and matched them with patients starting oral antibiotics.

The investigators, Khalaf Kridin MD, PhD, and Ralf J. Ludwig, MD, of the Lübeck Institute of Experimental Dermatology, University of Lübeck (Germany), found that the lifetime risks (greater than 6 months) for patients on isotretinoin were not significantly elevated, compared with those on oral antibiotics for either CD (hazard ratio 1.05; 95% CI, 0.89-1.24, P = .583) or UC (HR, 1.13; 95% CI, 0.95-1.34; P = .162) They also looked at the risk of irritable bowel syndrome (IBS) and found a lower lifetime risk in the isotretinoin group.

In the short term, during the first 6 months after drug initiation, there was a significant, but slight increase in UC in the isotretinoin group. But this risk decreased to the level of the antibiotic group with longer follow up. “The absolute incidence rates [of IBD] and the risk difference of UC within the first 6 months are of limited clinical significance,” they wrote.

It may be, Dr. Weiss said in commenting on this study, “that isotretinoin unmasks an already-existing genetic tendency to UC early on in the course of treatment, but that it does not truly cause an increased incidence of any type of IBD.”

Both studies, said Dr. Barbieri, “add to an extensive body of literature that supports that isotretinoin is not associated with IBD.”

Dr. Barbieri had no disclosures for the study, for which Matthew T. Taylor served as first author. Coauthor Shawn Kwatra, MD, disclosed that he is an advisory board member/consultant for numerous pharmaceutical companies and has served as an investigator for several. Both are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The other authors had no disclosures. Dr. Kridin and Dr. Ludwig had no disclosures for their study. Dr. Weiss had no disclosures.

Leprosy, also known as Hansen’s disease (HD), is a historically stigmatized infection caused by acid-fast bacilli Mycobacterium leprae, and M. lepromatosis. Paucibacillary tuberculoid leprosy is characterized by few anesthetic hypo- or hyperpigmented lesions and can be accompanied by palpable peripheral nerve enlargements.

Tuberculoid leprosy presents histologically with epithelioid histiocytes with lymphocytes and Langhans giant cells. Neurotropic granulomas are also characteristic of tuberculoid leprosy. Fite staining allows for the identification of the acid-fast bacilli of M. leprae, which in some cases are quite few in number. The standard mycobacterium stain, Ziehl-Neelsen, is a good option for M. tuberculosis, but because of the relative weak mycolic acid coat of M. leprae, the Fite stain is more appropriate for identifying M. leprae.

Clinically, other than the presence of fewer than five hypoesthetic lesions that are either hypopigmented or erythematous, tuberculoid leprosy often presents with additional peripheral nerve involvement that manifests as numbness and tingling in hands and feet.¹ This patient denied any tingling, weakness, or numbness, outside of the anesthetic lesion on his posterior upper arm.

The patient, born in the United States, had a remote history of military travel to Iraq, Kuwait, and the Philippines, but had not traveled internationally within the last 15 years, apart from a cruise to the Bahamas. He denied any known contact with individuals with similar lesions. He denied a history of contact with armadillos, but acknowledged that they are native to where he resides in central Florida, and that he had seen them in his yard.

Histopathological examination revealed an unremarkable epidermis with a superficial and deep perivascular, periadnexal, and perineural lymphohistiocytic infiltrate. Fite stain revealed rare rod-shaped organisms (Figure 2). These findings are consistent with a diagnosis of paucibacillary, tuberculoid leprosy.

The patient’s travel history to highly endemic areas (Middle East), as well as possible environmental contact with armadillos – including contact with soil that the armadillos occupied – could explain plausible modes of transmission. Following consultation with our infectious disease department and the National Hansen’s Disease Program, our patient began a planned course of therapy with 18 months of minocycline, rifampin, and moxifloxacin.

Human-to-human transmission of HD has been well documented; however, zoonotic transmission – specifically via the nine-banded armadillo (Dasypus novemcinctus) – serves as another suggested means of transmission, especially in the Southeastern United States.^2-6 Travel to highly-endemic areas increases the risk of contracting HD, which may take up to 20 years following contact with the bacteria to manifest clinically.

While central Florida was previously thought to be a nonendemic area of disease, the incidence of the disease in this region has increased in recent years.⁷ Human-to-human transmission, which remains a concern with immigration from highly-endemic regions^, occurs via long-term contact with nasal droplets of an infected person.^8,9

Many patients in regions with very few cases of leprosy deny travel to other endemic regions and contact with infected people. Thus, zoonotic transmission remains a legitimate concern in the Southeastern United States – accounting, at least in part, for many of the non–human-transmitted cases of leprosy.^2,10 We encourage clinicians to maintain a high level of clinical suspicion for leprosy when evaluating patients presenting with hypoesthetic cutaneous lesions and to obtain a travel history and to ask about armadillo exposure.

This case and the photos were submitted by Ms. Smith, from the University of South Florida, Tampa; Dr. Hatch and Dr. Sarriera-Lazaro, from the department of dermatology and cutaneous surgery, University of South Florida; and Dr. Turner and Dr. Beachkofsky, from the department of pathology and laboratory medicine at the James A. Haley Veterans’ Hospital, Tampa. Dr. Bilu Martin edited this case. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. Leprosy (Hansen’s Disease), in: “Goldman’s Cecil Medicine,” 24th ed. (Philadelphia: W.B. Saunders, 2012: pp. 1950-4.

2. Sharma R et al. Emerg Infect Dis. 2015 Dec;21(12):2127-34.

3. Lane JE et al. J Am Acad Dermatol. 2006 Oct;55(4):714-6.

4. Clark BM et al. Am J Trop Med Hyg. 2008 Jun;78(6):962-7.

5. Bruce S et al. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):223-8.

6. Loughry WJ et al. J Wildl Dis. 2009 Jan;45(1):144-52.

7. FDo H. Florida charts: Hansen’s Disease (Leprosy). Health FDo. 2019. https://www.flhealthcharts.gov/ChartsReports/rdPage.aspx?rdReport=NonVitalIndNoGrpCounts.DataViewer&cid=174.

8. Maymone MBC et al. J Am Acad Dermatol. 2020 Jul;83(1):1-14.

9. Scollard DM et al. Clin Microbiol Rev. 2006 Apr;19(2):338-81.

10. Domozych R et al. JAAD Case Rep. 2016 May 12;2(3):189-92.




 

Leprosy, also known as Hansen’s disease (HD), is a historically stigmatized infection caused by acid-fast bacilli Mycobacterium leprae, and M. lepromatosis. Paucibacillary tuberculoid leprosy is characterized by few anesthetic hypo- or hyperpigmented lesions and can be accompanied by palpable peripheral nerve enlargements.

Tuberculoid leprosy presents histologically with epithelioid histiocytes with lymphocytes and Langhans giant cells. Neurotropic granulomas are also characteristic of tuberculoid leprosy. Fite staining allows for the identification of the acid-fast bacilli of M. leprae, which in some cases are quite few in number. The standard mycobacterium stain, Ziehl-Neelsen, is a good option for M. tuberculosis, but because of the relative weak mycolic acid coat of M. leprae, the Fite stain is more appropriate for identifying M. leprae.

Clinically, other than the presence of fewer than five hypoesthetic lesions that are either hypopigmented or erythematous, tuberculoid leprosy often presents with additional peripheral nerve involvement that manifests as numbness and tingling in hands and feet.¹ This patient denied any tingling, weakness, or numbness, outside of the anesthetic lesion on his posterior upper arm.

The patient, born in the United States, had a remote history of military travel to Iraq, Kuwait, and the Philippines, but had not traveled internationally within the last 15 years, apart from a cruise to the Bahamas. He denied any known contact with individuals with similar lesions. He denied a history of contact with armadillos, but acknowledged that they are native to where he resides in central Florida, and that he had seen them in his yard.

Histopathological examination revealed an unremarkable epidermis with a superficial and deep perivascular, periadnexal, and perineural lymphohistiocytic infiltrate. Fite stain revealed rare rod-shaped organisms (Figure 2). These findings are consistent with a diagnosis of paucibacillary, tuberculoid leprosy.

The patient’s travel history to highly endemic areas (Middle East), as well as possible environmental contact with armadillos – including contact with soil that the armadillos occupied – could explain plausible modes of transmission. Following consultation with our infectious disease department and the National Hansen’s Disease Program, our patient began a planned course of therapy with 18 months of minocycline, rifampin, and moxifloxacin.

Human-to-human transmission of HD has been well documented; however, zoonotic transmission – specifically via the nine-banded armadillo (Dasypus novemcinctus) – serves as another suggested means of transmission, especially in the Southeastern United States.^2-6 Travel to highly-endemic areas increases the risk of contracting HD, which may take up to 20 years following contact with the bacteria to manifest clinically.

While central Florida was previously thought to be a nonendemic area of disease, the incidence of the disease in this region has increased in recent years.⁷ Human-to-human transmission, which remains a concern with immigration from highly-endemic regions^, occurs via long-term contact with nasal droplets of an infected person.^8,9

Many patients in regions with very few cases of leprosy deny travel to other endemic regions and contact with infected people. Thus, zoonotic transmission remains a legitimate concern in the Southeastern United States – accounting, at least in part, for many of the non–human-transmitted cases of leprosy.^2,10 We encourage clinicians to maintain a high level of clinical suspicion for leprosy when evaluating patients presenting with hypoesthetic cutaneous lesions and to obtain a travel history and to ask about armadillo exposure.

This case and the photos were submitted by Ms. Smith, from the University of South Florida, Tampa; Dr. Hatch and Dr. Sarriera-Lazaro, from the department of dermatology and cutaneous surgery, University of South Florida; and Dr. Turner and Dr. Beachkofsky, from the department of pathology and laboratory medicine at the James A. Haley Veterans’ Hospital, Tampa. Dr. Bilu Martin edited this case. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. Leprosy (Hansen’s Disease), in: “Goldman’s Cecil Medicine,” 24th ed. (Philadelphia: W.B. Saunders, 2012: pp. 1950-4.

2. Sharma R et al. Emerg Infect Dis. 2015 Dec;21(12):2127-34.

3. Lane JE et al. J Am Acad Dermatol. 2006 Oct;55(4):714-6.

4. Clark BM et al. Am J Trop Med Hyg. 2008 Jun;78(6):962-7.

5. Bruce S et al. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):223-8.

6. Loughry WJ et al. J Wildl Dis. 2009 Jan;45(1):144-52.

7. FDo H. Florida charts: Hansen’s Disease (Leprosy). Health FDo. 2019. https://www.flhealthcharts.gov/ChartsReports/rdPage.aspx?rdReport=NonVitalIndNoGrpCounts.DataViewer&cid=174.

8. Maymone MBC et al. J Am Acad Dermatol. 2020 Jul;83(1):1-14.

9. Scollard DM et al. Clin Microbiol Rev. 2006 Apr;19(2):338-81.

10. Domozych R et al. JAAD Case Rep. 2016 May 12;2(3):189-92.




 

Leprosy, also known as Hansen’s disease (HD), is a historically stigmatized infection caused by acid-fast bacilli Mycobacterium leprae, and M. lepromatosis. Paucibacillary tuberculoid leprosy is characterized by few anesthetic hypo- or hyperpigmented lesions and can be accompanied by palpable peripheral nerve enlargements.

Tuberculoid leprosy presents histologically with epithelioid histiocytes with lymphocytes and Langhans giant cells. Neurotropic granulomas are also characteristic of tuberculoid leprosy. Fite staining allows for the identification of the acid-fast bacilli of M. leprae, which in some cases are quite few in number. The standard mycobacterium stain, Ziehl-Neelsen, is a good option for M. tuberculosis, but because of the relative weak mycolic acid coat of M. leprae, the Fite stain is more appropriate for identifying M. leprae.

Clinically, other than the presence of fewer than five hypoesthetic lesions that are either hypopigmented or erythematous, tuberculoid leprosy often presents with additional peripheral nerve involvement that manifests as numbness and tingling in hands and feet.¹ This patient denied any tingling, weakness, or numbness, outside of the anesthetic lesion on his posterior upper arm.

The patient, born in the United States, had a remote history of military travel to Iraq, Kuwait, and the Philippines, but had not traveled internationally within the last 15 years, apart from a cruise to the Bahamas. He denied any known contact with individuals with similar lesions. He denied a history of contact with armadillos, but acknowledged that they are native to where he resides in central Florida, and that he had seen them in his yard.

Histopathological examination revealed an unremarkable epidermis with a superficial and deep perivascular, periadnexal, and perineural lymphohistiocytic infiltrate. Fite stain revealed rare rod-shaped organisms (Figure 2). These findings are consistent with a diagnosis of paucibacillary, tuberculoid leprosy.

The patient’s travel history to highly endemic areas (Middle East), as well as possible environmental contact with armadillos – including contact with soil that the armadillos occupied – could explain plausible modes of transmission. Following consultation with our infectious disease department and the National Hansen’s Disease Program, our patient began a planned course of therapy with 18 months of minocycline, rifampin, and moxifloxacin.

Human-to-human transmission of HD has been well documented; however, zoonotic transmission – specifically via the nine-banded armadillo (Dasypus novemcinctus) – serves as another suggested means of transmission, especially in the Southeastern United States.^2-6 Travel to highly-endemic areas increases the risk of contracting HD, which may take up to 20 years following contact with the bacteria to manifest clinically.

While central Florida was previously thought to be a nonendemic area of disease, the incidence of the disease in this region has increased in recent years.⁷ Human-to-human transmission, which remains a concern with immigration from highly-endemic regions^, occurs via long-term contact with nasal droplets of an infected person.^8,9

Many patients in regions with very few cases of leprosy deny travel to other endemic regions and contact with infected people. Thus, zoonotic transmission remains a legitimate concern in the Southeastern United States – accounting, at least in part, for many of the non–human-transmitted cases of leprosy.^2,10 We encourage clinicians to maintain a high level of clinical suspicion for leprosy when evaluating patients presenting with hypoesthetic cutaneous lesions and to obtain a travel history and to ask about armadillo exposure.

This case and the photos were submitted by Ms. Smith, from the University of South Florida, Tampa; Dr. Hatch and Dr. Sarriera-Lazaro, from the department of dermatology and cutaneous surgery, University of South Florida; and Dr. Turner and Dr. Beachkofsky, from the department of pathology and laboratory medicine at the James A. Haley Veterans’ Hospital, Tampa. Dr. Bilu Martin edited this case. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. Leprosy (Hansen’s Disease), in: “Goldman’s Cecil Medicine,” 24th ed. (Philadelphia: W.B. Saunders, 2012: pp. 1950-4.

2. Sharma R et al. Emerg Infect Dis. 2015 Dec;21(12):2127-34.

3. Lane JE et al. J Am Acad Dermatol. 2006 Oct;55(4):714-6.

4. Clark BM et al. Am J Trop Med Hyg. 2008 Jun;78(6):962-7.

5. Bruce S et al. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):223-8.

6. Loughry WJ et al. J Wildl Dis. 2009 Jan;45(1):144-52.

7. FDo H. Florida charts: Hansen’s Disease (Leprosy). Health FDo. 2019. https://www.flhealthcharts.gov/ChartsReports/rdPage.aspx?rdReport=NonVitalIndNoGrpCounts.DataViewer&cid=174.

8. Maymone MBC et al. J Am Acad Dermatol. 2020 Jul;83(1):1-14.

9. Scollard DM et al. Clin Microbiol Rev. 2006 Apr;19(2):338-81.

10. Domozych R et al. JAAD Case Rep. 2016 May 12;2(3):189-92.




 

People with untreatable dystrophic epidermolysis bullosa (DEB) may soon have access to an investigational gene therapy delivered in a topical gel that is currently under review by the Food and Drug Administration.

In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.

“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.

“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
 

Rare, life-threatening, genetic blistering disease

DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue.

COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
 

The first therapy for DEB, under FDA review

B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.

On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.

Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).

For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.

The results of the study included the following:

• Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
• Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
• The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
• Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.

“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.

The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.

“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.

Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.

“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.

Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”

In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.

B-VEC for treating other conditions

Dr. Marinkovich noted that an ongoing phase 1 clinical trial, also sponsored by Krystal Biotech, is using the HSV-1 vector to deliver a different biologic (KB105) to establish dose and safety in the treatment of ichthyosis. He added that he would like to explore the use of B-VEC to treat DEB at mucosal surfaces, including inside the mouth, the eye, and the esophagus.

Authors of two editorials that accompanied the study also referred to other conditions B-VEC might treat.

This study “highlights potential future investigations,” David V. Schaffer, PhD, professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California, Berkeley, wrotes in one of the editorials.

Important considerations he mentioned include the likelihood of the treatment becoming lifelong; the inability of HSV to penetrate intact skin, making B-VEC unsuitable for preventing the development of new wounds; and the inability of this treatment to treat EB lesions along the digestive tract. “This important trial builds on and extends gene-therapy successes to new targets and vectors, an advance for patients,” he added.

In the second editorial, Aimee S. Payne, MD, PhD, professor of dermatology at the University of Pennsylvania, Philadelphia, raised the question of whether B-VEC’s clinical success for treating DEB can translate to other genetic diseases.

“Formulations for ophthalmic, oral-gastrointestinal, or respiratory delivery would be of great value to address the extracutaneous manifestations of epidermolysis bullosa and other genetic diseases,” she wrote.

Referring to an ongoing trial of a topical gene therapy for cystic fibrosis that is delivered by a nebulizer, Dr. Payne noted, “Ultimately, the completion of clinical trials such as this one will be required to determine whether HSV-1–mediated gene delivery can go more than skin deep.”

Earlier data and more details of the study were presented in a poster at the annual meeting of the Society for Pediatric Dermatology in July 2022.

Dr. Marinkovich has disclosed no relevant financial relationships. Several coauthors are employees of or have other financial relationships with Krystal Biotech, the study’s sponsor and the developer of beremagene geperpavec. Dr. Schaffer and Dr. Payne have financial relationships with the pharmaceutical industry. Dr. Ebens, Dr. Holland, and Dr. Vakharia have disclosed no relevant financial relationships.

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

People with untreatable dystrophic epidermolysis bullosa (DEB) may soon have access to an investigational gene therapy delivered in a topical gel that is currently under review by the Food and Drug Administration.

In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.

“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.

“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
 

Rare, life-threatening, genetic blistering disease

DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue.

COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
 

The first therapy for DEB, under FDA review

B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.

On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.

Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).

For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.

The results of the study included the following:

• Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
• Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
• The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
• Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.

“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.

The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.

“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.

Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.

“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.

Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”

In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.

B-VEC for treating other conditions

Dr. Marinkovich noted that an ongoing phase 1 clinical trial, also sponsored by Krystal Biotech, is using the HSV-1 vector to deliver a different biologic (KB105) to establish dose and safety in the treatment of ichthyosis. He added that he would like to explore the use of B-VEC to treat DEB at mucosal surfaces, including inside the mouth, the eye, and the esophagus.

Authors of two editorials that accompanied the study also referred to other conditions B-VEC might treat.

This study “highlights potential future investigations,” David V. Schaffer, PhD, professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California, Berkeley, wrotes in one of the editorials.

Important considerations he mentioned include the likelihood of the treatment becoming lifelong; the inability of HSV to penetrate intact skin, making B-VEC unsuitable for preventing the development of new wounds; and the inability of this treatment to treat EB lesions along the digestive tract. “This important trial builds on and extends gene-therapy successes to new targets and vectors, an advance for patients,” he added.

In the second editorial, Aimee S. Payne, MD, PhD, professor of dermatology at the University of Pennsylvania, Philadelphia, raised the question of whether B-VEC’s clinical success for treating DEB can translate to other genetic diseases.

“Formulations for ophthalmic, oral-gastrointestinal, or respiratory delivery would be of great value to address the extracutaneous manifestations of epidermolysis bullosa and other genetic diseases,” she wrote.

Referring to an ongoing trial of a topical gene therapy for cystic fibrosis that is delivered by a nebulizer, Dr. Payne noted, “Ultimately, the completion of clinical trials such as this one will be required to determine whether HSV-1–mediated gene delivery can go more than skin deep.”

Earlier data and more details of the study were presented in a poster at the annual meeting of the Society for Pediatric Dermatology in July 2022.

Dr. Marinkovich has disclosed no relevant financial relationships. Several coauthors are employees of or have other financial relationships with Krystal Biotech, the study’s sponsor and the developer of beremagene geperpavec. Dr. Schaffer and Dr. Payne have financial relationships with the pharmaceutical industry. Dr. Ebens, Dr. Holland, and Dr. Vakharia have disclosed no relevant financial relationships.

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

People with untreatable dystrophic epidermolysis bullosa (DEB) may soon have access to an investigational gene therapy delivered in a topical gel that is currently under review by the Food and Drug Administration.

In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.

“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.

“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
 

Rare, life-threatening, genetic blistering disease

DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue.

COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
 

The first therapy for DEB, under FDA review

B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.

On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.

Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).

For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.

The results of the study included the following:

• Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
• Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
• The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
• Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.

“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.

The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.

“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.

Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.

“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.

Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”

In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.

B-VEC for treating other conditions

Dr. Marinkovich noted that an ongoing phase 1 clinical trial, also sponsored by Krystal Biotech, is using the HSV-1 vector to deliver a different biologic (KB105) to establish dose and safety in the treatment of ichthyosis. He added that he would like to explore the use of B-VEC to treat DEB at mucosal surfaces, including inside the mouth, the eye, and the esophagus.

Authors of two editorials that accompanied the study also referred to other conditions B-VEC might treat.

This study “highlights potential future investigations,” David V. Schaffer, PhD, professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California, Berkeley, wrotes in one of the editorials.

Important considerations he mentioned include the likelihood of the treatment becoming lifelong; the inability of HSV to penetrate intact skin, making B-VEC unsuitable for preventing the development of new wounds; and the inability of this treatment to treat EB lesions along the digestive tract. “This important trial builds on and extends gene-therapy successes to new targets and vectors, an advance for patients,” he added.

In the second editorial, Aimee S. Payne, MD, PhD, professor of dermatology at the University of Pennsylvania, Philadelphia, raised the question of whether B-VEC’s clinical success for treating DEB can translate to other genetic diseases.

“Formulations for ophthalmic, oral-gastrointestinal, or respiratory delivery would be of great value to address the extracutaneous manifestations of epidermolysis bullosa and other genetic diseases,” she wrote.

Referring to an ongoing trial of a topical gene therapy for cystic fibrosis that is delivered by a nebulizer, Dr. Payne noted, “Ultimately, the completion of clinical trials such as this one will be required to determine whether HSV-1–mediated gene delivery can go more than skin deep.”

Earlier data and more details of the study were presented in a poster at the annual meeting of the Society for Pediatric Dermatology in July 2022.

Dr. Marinkovich has disclosed no relevant financial relationships. Several coauthors are employees of or have other financial relationships with Krystal Biotech, the study’s sponsor and the developer of beremagene geperpavec. Dr. Schaffer and Dr. Payne have financial relationships with the pharmaceutical industry. Dr. Ebens, Dr. Holland, and Dr. Vakharia have disclosed no relevant financial relationships.

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

ORLANDO – From new tools for diagnosis to new treatment options, the science on wound care continues to advance, providing clinicians with better options for their patients, Hadar Lev-Tov, MD, said at the ODAC Dermatology, Aesthetic & Surgery Conference.

At the meeting, Dr. Lev-Tov, associate professor of dermatology at the University of Miami, reviewed some of the latest developments in several conditions involving wound care.

ORLANDO – From new tools for diagnosis to new treatment options, the science on wound care continues to advance, providing clinicians with better options for their patients, Hadar Lev-Tov, MD, said at the ODAC Dermatology, Aesthetic & Surgery Conference.

At the meeting, Dr. Lev-Tov, associate professor of dermatology at the University of Miami, reviewed some of the latest developments in several conditions involving wound care.

ORLANDO – From new tools for diagnosis to new treatment options, the science on wound care continues to advance, providing clinicians with better options for their patients, Hadar Lev-Tov, MD, said at the ODAC Dermatology, Aesthetic & Surgery Conference.

At the meeting, Dr. Lev-Tov, associate professor of dermatology at the University of Miami, reviewed some of the latest developments in several conditions involving wound care.

ORLANDO – While less frequently seen dermatologic diseases do not get a “ton of attention” in expert talks and discussions, even one to two patients presenting with these conditions a month warrants continuing education, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.

These semi-forsaken diseases are important not to miss and can “also be quite challenging when we think about their management,” he said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Dr. Friedman, also director of the GW dermatology residency program, reviewed several of these diseases – along with tips for management – during a session at the meeting.

Granuloma annulare (GA). This condition, Dr. Friedman said, can have “a lot of faces” – with a localized, general, perforating, subcutaneous, micropapular, or patchy appearance. It does not always have the classic ring pattern for which it is best known, he said. And in patients with darker skin tones, it is characterized by more of a brown or black color, rather than the pink-red color.

Dr. Friedman said that despite a kind of “Pavlovian response” linking GA with diabetes, this link might not be as strong as the field has come to believe, since the studies on which this belief was based included a patient population with narrow demographics. “Maybe GA and type 1 diabetes aren’t necessarily connected,” he said.

Dyslipidemia, on the other hand, has a strong connection with GA, he said. The disease is also linked to thyroid disease and is linked with malignancy, especially in older patients with generalized or atypical presentations of GA, he said.

Spontaneous resolution of the disease is seen within 2 years for 50% to 75% of patients, so “no treatment may be the best treatment,” but antimalarials can be effective, Dr. Friedman said. “I use antimalarials frequently in my practice,” he said. “The key is, they take time to work (4-5 months),” which should be explained to patients.

Antibiotics, he said, can be “somewhat effective,” but in the case of doxycycline at least, the disease can resolve within weeks but then may return when treatment is stopped.

There is some evidence to support using biologics and more recently, Janus kinase (JAK) inhibitors, off-label, to treat GA. Efficacy has been seen with the tumor necrosis factor (TNF) blocker infliximab and with the JAK inhibitor tofacitinib, he said.

 Lichen planus (LP). This is another common disease that can go off-script with its presentation. The disease is often described with the “six P’s” indicating the following characteristics: pruritic, polygonal, planar or flat-topped, purple papules, and plaques. But LP “didn’t read the textbook,” Dr. Friedman said.

“The clinical presentation of lichen planus can be quite broad,” he said. “The P’s aren’t always followed as there are a variety of colors and configurations which can be witnessed.”

With LP, there is a clear association with dyslipidemia and diabetes, so “asking the right questions is going to be important” when talking to the patient. There is also a higher risk of autoimmune diseases, especially of the thyroid type, associated with LP, he said.

No treatment has been Food and Drug Administration approved for LP, but some are expected in the future, he said.

For now, he emphasized creativity in the management of patients with LP. “I love oral retinoids for this,” he said. Antimalarials and methotrexate are also options.

In one case Dr. Friedman saw, nothing seemed to work: light therapy for a year; metronidazole; isotretinoin; halobetasol/tazarotene lotion; and the TNF-blocker adalimumab either weren’t effective or resulted in complications in the patient.

Knowing the recent implication of the interleukin (IL)-17 pathway in the pathophysiology of LP, he then tried the anti-IL17 antibody secukinumab. “This patient had a pretty robust response to treatment,” Dr. Friedman said. “He was very excited. The problem, as always, is access, especially for off-label therapies.”

Tumid lupus erythematosus. This disease is characterized by erythematous, edematous, nonscarring plaques on sun-exposed sites. For treatment, Dr. Friedman said antimalarials can be up to 90% effective, sometimes with rapid resolution of the lesions.

“You want to dose below that 5 mg per kg of true body weight to limit the small potential for ocular toxicity over time,” he said. And, he emphasized, “always combine treatment with good sun-protective measures.”

Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis, and other companies.

ORLANDO – While less frequently seen dermatologic diseases do not get a “ton of attention” in expert talks and discussions, even one to two patients presenting with these conditions a month warrants continuing education, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.

These semi-forsaken diseases are important not to miss and can “also be quite challenging when we think about their management,” he said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Dr. Friedman, also director of the GW dermatology residency program, reviewed several of these diseases – along with tips for management – during a session at the meeting.

Granuloma annulare (GA). This condition, Dr. Friedman said, can have “a lot of faces” – with a localized, general, perforating, subcutaneous, micropapular, or patchy appearance. It does not always have the classic ring pattern for which it is best known, he said. And in patients with darker skin tones, it is characterized by more of a brown or black color, rather than the pink-red color.

Dr. Friedman said that despite a kind of “Pavlovian response” linking GA with diabetes, this link might not be as strong as the field has come to believe, since the studies on which this belief was based included a patient population with narrow demographics. “Maybe GA and type 1 diabetes aren’t necessarily connected,” he said.

Dyslipidemia, on the other hand, has a strong connection with GA, he said. The disease is also linked to thyroid disease and is linked with malignancy, especially in older patients with generalized or atypical presentations of GA, he said.

Spontaneous resolution of the disease is seen within 2 years for 50% to 75% of patients, so “no treatment may be the best treatment,” but antimalarials can be effective, Dr. Friedman said. “I use antimalarials frequently in my practice,” he said. “The key is, they take time to work (4-5 months),” which should be explained to patients.

Antibiotics, he said, can be “somewhat effective,” but in the case of doxycycline at least, the disease can resolve within weeks but then may return when treatment is stopped.

There is some evidence to support using biologics and more recently, Janus kinase (JAK) inhibitors, off-label, to treat GA. Efficacy has been seen with the tumor necrosis factor (TNF) blocker infliximab and with the JAK inhibitor tofacitinib, he said.

 Lichen planus (LP). This is another common disease that can go off-script with its presentation. The disease is often described with the “six P’s” indicating the following characteristics: pruritic, polygonal, planar or flat-topped, purple papules, and plaques. But LP “didn’t read the textbook,” Dr. Friedman said.

“The clinical presentation of lichen planus can be quite broad,” he said. “The P’s aren’t always followed as there are a variety of colors and configurations which can be witnessed.”

With LP, there is a clear association with dyslipidemia and diabetes, so “asking the right questions is going to be important” when talking to the patient. There is also a higher risk of autoimmune diseases, especially of the thyroid type, associated with LP, he said.

No treatment has been Food and Drug Administration approved for LP, but some are expected in the future, he said.

For now, he emphasized creativity in the management of patients with LP. “I love oral retinoids for this,” he said. Antimalarials and methotrexate are also options.

In one case Dr. Friedman saw, nothing seemed to work: light therapy for a year; metronidazole; isotretinoin; halobetasol/tazarotene lotion; and the TNF-blocker adalimumab either weren’t effective or resulted in complications in the patient.

Knowing the recent implication of the interleukin (IL)-17 pathway in the pathophysiology of LP, he then tried the anti-IL17 antibody secukinumab. “This patient had a pretty robust response to treatment,” Dr. Friedman said. “He was very excited. The problem, as always, is access, especially for off-label therapies.”

Tumid lupus erythematosus. This disease is characterized by erythematous, edematous, nonscarring plaques on sun-exposed sites. For treatment, Dr. Friedman said antimalarials can be up to 90% effective, sometimes with rapid resolution of the lesions.

“You want to dose below that 5 mg per kg of true body weight to limit the small potential for ocular toxicity over time,” he said. And, he emphasized, “always combine treatment with good sun-protective measures.”

Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis, and other companies.

ORLANDO – While less frequently seen dermatologic diseases do not get a “ton of attention” in expert talks and discussions, even one to two patients presenting with these conditions a month warrants continuing education, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.

These semi-forsaken diseases are important not to miss and can “also be quite challenging when we think about their management,” he said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Dr. Friedman, also director of the GW dermatology residency program, reviewed several of these diseases – along with tips for management – during a session at the meeting.

Granuloma annulare (GA). This condition, Dr. Friedman said, can have “a lot of faces” – with a localized, general, perforating, subcutaneous, micropapular, or patchy appearance. It does not always have the classic ring pattern for which it is best known, he said. And in patients with darker skin tones, it is characterized by more of a brown or black color, rather than the pink-red color.

Dr. Friedman said that despite a kind of “Pavlovian response” linking GA with diabetes, this link might not be as strong as the field has come to believe, since the studies on which this belief was based included a patient population with narrow demographics. “Maybe GA and type 1 diabetes aren’t necessarily connected,” he said.

Dyslipidemia, on the other hand, has a strong connection with GA, he said. The disease is also linked to thyroid disease and is linked with malignancy, especially in older patients with generalized or atypical presentations of GA, he said.

Spontaneous resolution of the disease is seen within 2 years for 50% to 75% of patients, so “no treatment may be the best treatment,” but antimalarials can be effective, Dr. Friedman said. “I use antimalarials frequently in my practice,” he said. “The key is, they take time to work (4-5 months),” which should be explained to patients.

Antibiotics, he said, can be “somewhat effective,” but in the case of doxycycline at least, the disease can resolve within weeks but then may return when treatment is stopped.

There is some evidence to support using biologics and more recently, Janus kinase (JAK) inhibitors, off-label, to treat GA. Efficacy has been seen with the tumor necrosis factor (TNF) blocker infliximab and with the JAK inhibitor tofacitinib, he said.

 Lichen planus (LP). This is another common disease that can go off-script with its presentation. The disease is often described with the “six P’s” indicating the following characteristics: pruritic, polygonal, planar or flat-topped, purple papules, and plaques. But LP “didn’t read the textbook,” Dr. Friedman said.

“The clinical presentation of lichen planus can be quite broad,” he said. “The P’s aren’t always followed as there are a variety of colors and configurations which can be witnessed.”

With LP, there is a clear association with dyslipidemia and diabetes, so “asking the right questions is going to be important” when talking to the patient. There is also a higher risk of autoimmune diseases, especially of the thyroid type, associated with LP, he said.

No treatment has been Food and Drug Administration approved for LP, but some are expected in the future, he said.

For now, he emphasized creativity in the management of patients with LP. “I love oral retinoids for this,” he said. Antimalarials and methotrexate are also options.

In one case Dr. Friedman saw, nothing seemed to work: light therapy for a year; metronidazole; isotretinoin; halobetasol/tazarotene lotion; and the TNF-blocker adalimumab either weren’t effective or resulted in complications in the patient.

Knowing the recent implication of the interleukin (IL)-17 pathway in the pathophysiology of LP, he then tried the anti-IL17 antibody secukinumab. “This patient had a pretty robust response to treatment,” Dr. Friedman said. “He was very excited. The problem, as always, is access, especially for off-label therapies.”

Tumid lupus erythematosus. This disease is characterized by erythematous, edematous, nonscarring plaques on sun-exposed sites. For treatment, Dr. Friedman said antimalarials can be up to 90% effective, sometimes with rapid resolution of the lesions.

“You want to dose below that 5 mg per kg of true body weight to limit the small potential for ocular toxicity over time,” he said. And, he emphasized, “always combine treatment with good sun-protective measures.”

Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis, and other companies.

ORLANDO – Three weeks after a course of trimethoprim/sulfamethoxazole (Bactrim), a young female patient developed facial edema that involved “dusky erythematous papules” that were itchy. The eruption spread away from the head and her transaminase levels were “dramatic,” in the 700s, said Kalyani S. Marathe, MD, MPH, associate professor of dermatology and pediatrics at the University of Cincinnati.

Dr. Marathe, director of the division of dermatology at Cincinnati Children’s Hospital, reviewed this case in a presentation on pediatric dermatologic emergencies at the ODAC Dermatology, Aesthetic & Surgery Conference, pointing out potential pitfalls and important aspects that might require swift action.

The patient was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS).

Facial involvement is common in pediatric cases of DRESS, but edema of the face is less common in children than adults, Dr. Marathe said.

Antiepileptic medications are the most common cause of DRESS, followed by antibiotics – most often, vancomycin and trimethoprim/sulfamethoxazole, she said. But sometimes the trigger is not clear, she noted, recalling a vexing case she once saw in which IV contrast was eventually identified as the cause.

When DRESS is suspected, she said, lab work should be done during the acute eruption and after resolution. This should include CBC, liver function tests, creatinine, and urinalysis, and human herpesvirus 6 (HHV-6) and thyroid testing.

Treatment typically includes supportive care, unless symptoms are systemic, or if there is impending liver failure, when steroids, cyclosporine, or IVIG can be used.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): Mortality rates when these diseases overlap is 4%, Dr. Marathe said. Clues to diagnosing this other medication-induced condition include involvement of the palms and the soles of the feet; presence of the Nikolsky sign in which the top layers of the skin slip away from the lower layers when rubbed; mucosal involvement, which often precedes cutaneous involvement; and these symptoms occurring within the first 8 weeks of taking a medication, which are most commonly antibiotics and anti-epileptics.

Dr. Marathe underscored how important it is to get ophthalmology involved right away, because of the risk of vision loss. Amniotic membrane transfer to the eye at the time of diagnosis has been found to produce dramatically better outcomes, she said. The membrane has anti-inflammatory and antiscarring properties and can promote wound healing on the surface of the eye.

“I would recommend getting your ophthalmology team on board early because they have to advocate for these patients,” she said.

Corticosteroids and IVIG can improve ocular outcomes, but cyclosporine is associated with better mortality outcomes, she said. Emerging data on etanercept has also led to more use of that drug, she said.

Erythema multiforme (EM): unlike urticaria, multiforme EM can have mucosal involvement, Dr. Marathe said. Clinicians should look for three zones of color: A central duskiness, a rim of pallor, and a ring of erythema.

EM is triggered by a virus, which is usually herpes simplex virus (HSV). But she added that HSV is not always found. “So, there are certainly other triggers out there that we just haven’t identified,” she said.

If HSV is suspected, oral acyclovir is effective, she noted.

Other cases might not be as straightforward. Dr. Marathe said that during her fellowship, she saw a patient with EM that was controlled only by IVIG, so it was administered every 3 months. In that case, the trigger was never found.

Multisystem inflammatory syndrome in children (MIS-C): This syndrome can follow COVID-19 infection, and usually presents with 3-5 days of fever after COVID has resolved. It can include gastrointestinal, cardiorespiratory, and neurocognitive symptoms.

The skin presentation is mainly a morbilliform pattern, but clinicians might also see conjunctival involvement, mucosal involvement, and “COVID toes,” painful red or purple lesions on the toes.

Treatment is usually IVIG and systemic corticosteroids, with the treatment course depending on the severity.

MIS-C was initially thought to be Kawasaki’s disease, another autoinflammatory disorder, which is related but distinct, Dr. Marathe said.

Patients with MIS-C “are usually going to have COVID-positive antibodies,” she said. But since almost everybody may have COVID antibodies, “it’s not usually a helpful test for you now. But early on, that’s what we used as helpful indicator.”

Dr. Marathe reported no relevant financial relationships.

ORLANDO – Three weeks after a course of trimethoprim/sulfamethoxazole (Bactrim), a young female patient developed facial edema that involved “dusky erythematous papules” that were itchy. The eruption spread away from the head and her transaminase levels were “dramatic,” in the 700s, said Kalyani S. Marathe, MD, MPH, associate professor of dermatology and pediatrics at the University of Cincinnati.

Dr. Marathe, director of the division of dermatology at Cincinnati Children’s Hospital, reviewed this case in a presentation on pediatric dermatologic emergencies at the ODAC Dermatology, Aesthetic & Surgery Conference, pointing out potential pitfalls and important aspects that might require swift action.

The patient was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS).

Facial involvement is common in pediatric cases of DRESS, but edema of the face is less common in children than adults, Dr. Marathe said.

Antiepileptic medications are the most common cause of DRESS, followed by antibiotics – most often, vancomycin and trimethoprim/sulfamethoxazole, she said. But sometimes the trigger is not clear, she noted, recalling a vexing case she once saw in which IV contrast was eventually identified as the cause.

When DRESS is suspected, she said, lab work should be done during the acute eruption and after resolution. This should include CBC, liver function tests, creatinine, and urinalysis, and human herpesvirus 6 (HHV-6) and thyroid testing.

Treatment typically includes supportive care, unless symptoms are systemic, or if there is impending liver failure, when steroids, cyclosporine, or IVIG can be used.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): Mortality rates when these diseases overlap is 4%, Dr. Marathe said. Clues to diagnosing this other medication-induced condition include involvement of the palms and the soles of the feet; presence of the Nikolsky sign in which the top layers of the skin slip away from the lower layers when rubbed; mucosal involvement, which often precedes cutaneous involvement; and these symptoms occurring within the first 8 weeks of taking a medication, which are most commonly antibiotics and anti-epileptics.

Dr. Marathe underscored how important it is to get ophthalmology involved right away, because of the risk of vision loss. Amniotic membrane transfer to the eye at the time of diagnosis has been found to produce dramatically better outcomes, she said. The membrane has anti-inflammatory and antiscarring properties and can promote wound healing on the surface of the eye.

“I would recommend getting your ophthalmology team on board early because they have to advocate for these patients,” she said.

Corticosteroids and IVIG can improve ocular outcomes, but cyclosporine is associated with better mortality outcomes, she said. Emerging data on etanercept has also led to more use of that drug, she said.

Erythema multiforme (EM): unlike urticaria, multiforme EM can have mucosal involvement, Dr. Marathe said. Clinicians should look for three zones of color: A central duskiness, a rim of pallor, and a ring of erythema.

EM is triggered by a virus, which is usually herpes simplex virus (HSV). But she added that HSV is not always found. “So, there are certainly other triggers out there that we just haven’t identified,” she said.

If HSV is suspected, oral acyclovir is effective, she noted.

Other cases might not be as straightforward. Dr. Marathe said that during her fellowship, she saw a patient with EM that was controlled only by IVIG, so it was administered every 3 months. In that case, the trigger was never found.

Multisystem inflammatory syndrome in children (MIS-C): This syndrome can follow COVID-19 infection, and usually presents with 3-5 days of fever after COVID has resolved. It can include gastrointestinal, cardiorespiratory, and neurocognitive symptoms.

The skin presentation is mainly a morbilliform pattern, but clinicians might also see conjunctival involvement, mucosal involvement, and “COVID toes,” painful red or purple lesions on the toes.

Treatment is usually IVIG and systemic corticosteroids, with the treatment course depending on the severity.

MIS-C was initially thought to be Kawasaki’s disease, another autoinflammatory disorder, which is related but distinct, Dr. Marathe said.

Patients with MIS-C “are usually going to have COVID-positive antibodies,” she said. But since almost everybody may have COVID antibodies, “it’s not usually a helpful test for you now. But early on, that’s what we used as helpful indicator.”

Dr. Marathe reported no relevant financial relationships.

ORLANDO – Three weeks after a course of trimethoprim/sulfamethoxazole (Bactrim), a young female patient developed facial edema that involved “dusky erythematous papules” that were itchy. The eruption spread away from the head and her transaminase levels were “dramatic,” in the 700s, said Kalyani S. Marathe, MD, MPH, associate professor of dermatology and pediatrics at the University of Cincinnati.

Dr. Marathe, director of the division of dermatology at Cincinnati Children’s Hospital, reviewed this case in a presentation on pediatric dermatologic emergencies at the ODAC Dermatology, Aesthetic & Surgery Conference, pointing out potential pitfalls and important aspects that might require swift action.

The patient was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS).

Facial involvement is common in pediatric cases of DRESS, but edema of the face is less common in children than adults, Dr. Marathe said.

Antiepileptic medications are the most common cause of DRESS, followed by antibiotics – most often, vancomycin and trimethoprim/sulfamethoxazole, she said. But sometimes the trigger is not clear, she noted, recalling a vexing case she once saw in which IV contrast was eventually identified as the cause.

When DRESS is suspected, she said, lab work should be done during the acute eruption and after resolution. This should include CBC, liver function tests, creatinine, and urinalysis, and human herpesvirus 6 (HHV-6) and thyroid testing.

Treatment typically includes supportive care, unless symptoms are systemic, or if there is impending liver failure, when steroids, cyclosporine, or IVIG can be used.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): Mortality rates when these diseases overlap is 4%, Dr. Marathe said. Clues to diagnosing this other medication-induced condition include involvement of the palms and the soles of the feet; presence of the Nikolsky sign in which the top layers of the skin slip away from the lower layers when rubbed; mucosal involvement, which often precedes cutaneous involvement; and these symptoms occurring within the first 8 weeks of taking a medication, which are most commonly antibiotics and anti-epileptics.

Dr. Marathe underscored how important it is to get ophthalmology involved right away, because of the risk of vision loss. Amniotic membrane transfer to the eye at the time of diagnosis has been found to produce dramatically better outcomes, she said. The membrane has anti-inflammatory and antiscarring properties and can promote wound healing on the surface of the eye.

“I would recommend getting your ophthalmology team on board early because they have to advocate for these patients,” she said.

Corticosteroids and IVIG can improve ocular outcomes, but cyclosporine is associated with better mortality outcomes, she said. Emerging data on etanercept has also led to more use of that drug, she said.

Erythema multiforme (EM): unlike urticaria, multiforme EM can have mucosal involvement, Dr. Marathe said. Clinicians should look for three zones of color: A central duskiness, a rim of pallor, and a ring of erythema.

EM is triggered by a virus, which is usually herpes simplex virus (HSV). But she added that HSV is not always found. “So, there are certainly other triggers out there that we just haven’t identified,” she said.

If HSV is suspected, oral acyclovir is effective, she noted.

Other cases might not be as straightforward. Dr. Marathe said that during her fellowship, she saw a patient with EM that was controlled only by IVIG, so it was administered every 3 months. In that case, the trigger was never found.

Multisystem inflammatory syndrome in children (MIS-C): This syndrome can follow COVID-19 infection, and usually presents with 3-5 days of fever after COVID has resolved. It can include gastrointestinal, cardiorespiratory, and neurocognitive symptoms.

The skin presentation is mainly a morbilliform pattern, but clinicians might also see conjunctival involvement, mucosal involvement, and “COVID toes,” painful red or purple lesions on the toes.

Treatment is usually IVIG and systemic corticosteroids, with the treatment course depending on the severity.

MIS-C was initially thought to be Kawasaki’s disease, another autoinflammatory disorder, which is related but distinct, Dr. Marathe said.

Patients with MIS-C “are usually going to have COVID-positive antibodies,” she said. But since almost everybody may have COVID antibodies, “it’s not usually a helpful test for you now. But early on, that’s what we used as helpful indicator.”

Dr. Marathe reported no relevant financial relationships.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The gyrate or cerebriform pattern of inflammatory, often pus-filled, subcutaneous tracts of the scalp pointed to a diagnosis of dissecting cellulitis. This patient did not have the fluctuant tracts frequently seen in more active disease but did have the scarring and alopecia common with this disorder.

Dissecting cellulitis is similar to acne and hidradenitis suppurativa in that it starts with follicular plugging. This plugging leads to inflammation, dilation and rupture of the follicle, and purulent sinus tract formation. The sinus tracts of the scalp can be extensive. Dissecting cellulitis is most common in 18- to 40-year-olds and more common in Black individuals.¹ When it occurs in conjunction with cystic acne and hidradenitis suppurativa, it is known as the follicular occlusion triad syndrome.

While oral antibiotics are an option for the treatment of dissecting cellulitis, oral isotretinoin is the first-line approach. Tumor necrosis factor alfa inhibitors have also been used with success, according to case reports.¹

Given that this patient had a small area of current inflammation, he was started on oral doxycycline 100 mg twice daily for 2 months. He was scheduled for a follow-up appointment in 3 months to reassess his progress and to explore treatment with isotretinoin if the condition worsened or did not improve.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The gyrate or cerebriform pattern of inflammatory, often pus-filled, subcutaneous tracts of the scalp pointed to a diagnosis of dissecting cellulitis. This patient did not have the fluctuant tracts frequently seen in more active disease but did have the scarring and alopecia common with this disorder.

Dissecting cellulitis is similar to acne and hidradenitis suppurativa in that it starts with follicular plugging. This plugging leads to inflammation, dilation and rupture of the follicle, and purulent sinus tract formation. The sinus tracts of the scalp can be extensive. Dissecting cellulitis is most common in 18- to 40-year-olds and more common in Black individuals.¹ When it occurs in conjunction with cystic acne and hidradenitis suppurativa, it is known as the follicular occlusion triad syndrome.

While oral antibiotics are an option for the treatment of dissecting cellulitis, oral isotretinoin is the first-line approach. Tumor necrosis factor alfa inhibitors have also been used with success, according to case reports.¹

Given that this patient had a small area of current inflammation, he was started on oral doxycycline 100 mg twice daily for 2 months. He was scheduled for a follow-up appointment in 3 months to reassess his progress and to explore treatment with isotretinoin if the condition worsened or did not improve.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The gyrate or cerebriform pattern of inflammatory, often pus-filled, subcutaneous tracts of the scalp pointed to a diagnosis of dissecting cellulitis. This patient did not have the fluctuant tracts frequently seen in more active disease but did have the scarring and alopecia common with this disorder.

Dissecting cellulitis is similar to acne and hidradenitis suppurativa in that it starts with follicular plugging. This plugging leads to inflammation, dilation and rupture of the follicle, and purulent sinus tract formation. The sinus tracts of the scalp can be extensive. Dissecting cellulitis is most common in 18- to 40-year-olds and more common in Black individuals.¹ When it occurs in conjunction with cystic acne and hidradenitis suppurativa, it is known as the follicular occlusion triad syndrome.

While oral antibiotics are an option for the treatment of dissecting cellulitis, oral isotretinoin is the first-line approach. Tumor necrosis factor alfa inhibitors have also been used with success, according to case reports.¹

Given that this patient had a small area of current inflammation, he was started on oral doxycycline 100 mg twice daily for 2 months. He was scheduled for a follow-up appointment in 3 months to reassess his progress and to explore treatment with isotretinoin if the condition worsened or did not improve.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

This patient’s targetoid and tingling skin lesions, in association with herpes simplex virus (HSV) infection, are a classic presentation of erythema multiforme (EM).

EM is an acute, self-limited, immune-mediated process that most commonly arises in a symmetrical pattern on acral surfaces. These lesions may be accompanied by eruptions on oral, anogenital, or ocular mucosa. EM is classified into 2 subtypes: major and minor. EM major refers to EM with significant mucosal involvement on at least 2 mucosal sites; it may also manifest with a prodrome of fevers, arthralgias, and malaise. EM minor is used to classify EM with minimal mucosal involvement.¹

The term “multiforme” denotes the varied dermatologic changes, including macules, papules, and targetoid lesions with 3 identifiable zones, which are pathognomonic for EM. The classic 3 zones consist of an inner dusky, vesicular, or necrotic center; a middle elevated edematous surrounding ring; and an outer ring of macular erythema. Patients may also present with an atypical macular target lesion, characterized by fewer than 3 zones with an ill-defined border between the zones. The lesions may be asymptomatic, or patients may describe an itchy or burning sensation.

The differential diagnosis of EM includes urticaria, fixed drug eruption, subacute lupus erythematosus, Kawasaki disease, erythema annulare centrifugum, vasculitis, and Stevens-Johnson syndrome.

Infections with HSV types 1 or 2 are the leading cause of EM and are thought to involve a cell-mediated immune process directed against viral antigens in skin.² Other infectious causes include cytomegalovirus, Epstein-Barr virus, influenza virus, and—rarely—newer strains of coronavirus.³ Pharmacologic reactions are the cause in a small percentage of patients, and may involve nonsteroidal anti-inflammatory drugs, antibiotics, sulfonamides, antiepileptics, and tumor necrosis factor-alpha inhibitors. Studies also link the development of EM to primary malignancy, autoimmune disease, and immunizations.¹

The treatment of EM is dependent on the clinical course and severity of the disease. If a causative agent is identified, it should be discontinued (if a drug) or treated (if an infection). Topical antiseptic mouthwashes, antihistamines, and topical corticosteroids can be used to relieve cutaneous discomfort. Biologics and immunosuppressants can be used with patients who have severe symptoms or functional impairment. Patients who have recurrences associated with HSV should be given antiviral prophylaxis for 6 months consisting of oral acyclovir 10 mg/kg/d, valacyclovir 500 to 1000 mg/d, or famciclovir 250 mg twice daily.¹

Given the recurrent nature of this patient’s disease, and its association with HSV outbreaks, he was prescribed prophylactic valacyclovir 1000 mg/d orally for 6 months to reduce HSV outbreaks and hopefully prevent future EM episodes.

‌

Photo courtesy of Cyrelle F. Finan, MD. Text courtesy of Lynn Midani, BS, University of New Mexico School of Medicine, and Cyrelle F. Finan, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

This patient’s targetoid and tingling skin lesions, in association with herpes simplex virus (HSV) infection, are a classic presentation of erythema multiforme (EM).

EM is an acute, self-limited, immune-mediated process that most commonly arises in a symmetrical pattern on acral surfaces. These lesions may be accompanied by eruptions on oral, anogenital, or ocular mucosa. EM is classified into 2 subtypes: major and minor. EM major refers to EM with significant mucosal involvement on at least 2 mucosal sites; it may also manifest with a prodrome of fevers, arthralgias, and malaise. EM minor is used to classify EM with minimal mucosal involvement.¹

The term “multiforme” denotes the varied dermatologic changes, including macules, papules, and targetoid lesions with 3 identifiable zones, which are pathognomonic for EM. The classic 3 zones consist of an inner dusky, vesicular, or necrotic center; a middle elevated edematous surrounding ring; and an outer ring of macular erythema. Patients may also present with an atypical macular target lesion, characterized by fewer than 3 zones with an ill-defined border between the zones. The lesions may be asymptomatic, or patients may describe an itchy or burning sensation.

The differential diagnosis of EM includes urticaria, fixed drug eruption, subacute lupus erythematosus, Kawasaki disease, erythema annulare centrifugum, vasculitis, and Stevens-Johnson syndrome.

Infections with HSV types 1 or 2 are the leading cause of EM and are thought to involve a cell-mediated immune process directed against viral antigens in skin.² Other infectious causes include cytomegalovirus, Epstein-Barr virus, influenza virus, and—rarely—newer strains of coronavirus.³ Pharmacologic reactions are the cause in a small percentage of patients, and may involve nonsteroidal anti-inflammatory drugs, antibiotics, sulfonamides, antiepileptics, and tumor necrosis factor-alpha inhibitors. Studies also link the development of EM to primary malignancy, autoimmune disease, and immunizations.¹

The treatment of EM is dependent on the clinical course and severity of the disease. If a causative agent is identified, it should be discontinued (if a drug) or treated (if an infection). Topical antiseptic mouthwashes, antihistamines, and topical corticosteroids can be used to relieve cutaneous discomfort. Biologics and immunosuppressants can be used with patients who have severe symptoms or functional impairment. Patients who have recurrences associated with HSV should be given antiviral prophylaxis for 6 months consisting of oral acyclovir 10 mg/kg/d, valacyclovir 500 to 1000 mg/d, or famciclovir 250 mg twice daily.¹

Given the recurrent nature of this patient’s disease, and its association with HSV outbreaks, he was prescribed prophylactic valacyclovir 1000 mg/d orally for 6 months to reduce HSV outbreaks and hopefully prevent future EM episodes.

‌

Photo courtesy of Cyrelle F. Finan, MD. Text courtesy of Lynn Midani, BS, University of New Mexico School of Medicine, and Cyrelle F. Finan, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

This patient’s targetoid and tingling skin lesions, in association with herpes simplex virus (HSV) infection, are a classic presentation of erythema multiforme (EM).

EM is an acute, self-limited, immune-mediated process that most commonly arises in a symmetrical pattern on acral surfaces. These lesions may be accompanied by eruptions on oral, anogenital, or ocular mucosa. EM is classified into 2 subtypes: major and minor. EM major refers to EM with significant mucosal involvement on at least 2 mucosal sites; it may also manifest with a prodrome of fevers, arthralgias, and malaise. EM minor is used to classify EM with minimal mucosal involvement.¹

The term “multiforme” denotes the varied dermatologic changes, including macules, papules, and targetoid lesions with 3 identifiable zones, which are pathognomonic for EM. The classic 3 zones consist of an inner dusky, vesicular, or necrotic center; a middle elevated edematous surrounding ring; and an outer ring of macular erythema. Patients may also present with an atypical macular target lesion, characterized by fewer than 3 zones with an ill-defined border between the zones. The lesions may be asymptomatic, or patients may describe an itchy or burning sensation.

The differential diagnosis of EM includes urticaria, fixed drug eruption, subacute lupus erythematosus, Kawasaki disease, erythema annulare centrifugum, vasculitis, and Stevens-Johnson syndrome.

Infections with HSV types 1 or 2 are the leading cause of EM and are thought to involve a cell-mediated immune process directed against viral antigens in skin.² Other infectious causes include cytomegalovirus, Epstein-Barr virus, influenza virus, and—rarely—newer strains of coronavirus.³ Pharmacologic reactions are the cause in a small percentage of patients, and may involve nonsteroidal anti-inflammatory drugs, antibiotics, sulfonamides, antiepileptics, and tumor necrosis factor-alpha inhibitors. Studies also link the development of EM to primary malignancy, autoimmune disease, and immunizations.¹

The treatment of EM is dependent on the clinical course and severity of the disease. If a causative agent is identified, it should be discontinued (if a drug) or treated (if an infection). Topical antiseptic mouthwashes, antihistamines, and topical corticosteroids can be used to relieve cutaneous discomfort. Biologics and immunosuppressants can be used with patients who have severe symptoms or functional impairment. Patients who have recurrences associated with HSV should be given antiviral prophylaxis for 6 months consisting of oral acyclovir 10 mg/kg/d, valacyclovir 500 to 1000 mg/d, or famciclovir 250 mg twice daily.¹

Given the recurrent nature of this patient’s disease, and its association with HSV outbreaks, he was prescribed prophylactic valacyclovir 1000 mg/d orally for 6 months to reduce HSV outbreaks and hopefully prevent future EM episodes.

‌

Photo courtesy of Cyrelle F. Finan, MD. Text courtesy of Lynn Midani, BS, University of New Mexico School of Medicine, and Cyrelle F. Finan, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

petekarici/Getty Images

This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.

Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.

An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.

“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.

While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.

While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.

“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”

While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.

This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“

From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.

Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

petekarici/Getty Images

This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.

Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.

An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.

“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.

While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.

While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.

“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”

While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.

This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“

From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.

Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

petekarici/Getty Images

This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.

Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.

An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.

“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.

While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.

While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.

“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”

While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.

This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“

From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.

Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.