Mixed Topics

Federal grants have supported cutting-edge research in scientific and biomedical fields since the mid-20th century, fueling public health breakthroughs and health innovations. This crucial support has been greatly diminished in recent months with deep cuts to federal research dollars.

As these acute policy changes continue to disrupt academic institutions and their investigators, introducing financial strain and operational uncertainty, the importance of research support from professional societies and foundations has become increasingly evident. Their targeted funding plays a critical role in sustaining biomedical research, which directly impacts clinical innovation and patient care. As one example, the AGA Research Foundation provides over $2 million annually to spur discoveries in gastroenterology and hepatology. This vital research support, awarded to 74 unique recipients (including 7 early-career Research Scholar Award recipients) in 2025, represents one of the most important investments that AGA makes in the future of gastroenterology and the patients we treat.

While foundation awards such as these cannot completely close the federal funding gap, they serve as an important lifeline both in supporting the core work of early career and established investigators in an uncertain funding environment and in funding high-risk, high-reward research that more conservative funders are often hesitant to invest in. Please consider joining me in contributing to the AGA Research Foundation to support its important work – now more than ever, the funding it provides has tremendous impact.

In this issue of GI & Hepatology News, we update you on the FDA’s recent approval of semaglutide as a treatment for MASH with fibrosis and highlight a recent target trial emulation study that casts doubt on our traditional understanding regarding the link between common medications such as PPIs and NSAIDs and microscopic colitis in older adults. We also summarize newly-released, global guidelines for pregnancy and IBD, which deserve a careful read. In this month’s Member Spotlight, we feature Pascale White, MD, MBA, MS (Mount Sinai), a recent recipient of the AGA-Pfizer Beacon of Hope Award for Gender and Health Equity, who shares her inspirational work to improve colorectal cancer screening among underserved, high-risk patients in East Harlem. We hope you enjoy this and all the exciting content in our October issue.

Megan A. Adams, MD, JD, MSc 

Editor in Chief

Federal grants have supported cutting-edge research in scientific and biomedical fields since the mid-20th century, fueling public health breakthroughs and health innovations. This crucial support has been greatly diminished in recent months with deep cuts to federal research dollars.

As these acute policy changes continue to disrupt academic institutions and their investigators, introducing financial strain and operational uncertainty, the importance of research support from professional societies and foundations has become increasingly evident. Their targeted funding plays a critical role in sustaining biomedical research, which directly impacts clinical innovation and patient care. As one example, the AGA Research Foundation provides over $2 million annually to spur discoveries in gastroenterology and hepatology. This vital research support, awarded to 74 unique recipients (including 7 early-career Research Scholar Award recipients) in 2025, represents one of the most important investments that AGA makes in the future of gastroenterology and the patients we treat.

While foundation awards such as these cannot completely close the federal funding gap, they serve as an important lifeline both in supporting the core work of early career and established investigators in an uncertain funding environment and in funding high-risk, high-reward research that more conservative funders are often hesitant to invest in. Please consider joining me in contributing to the AGA Research Foundation to support its important work – now more than ever, the funding it provides has tremendous impact.

In this issue of GI & Hepatology News, we update you on the FDA’s recent approval of semaglutide as a treatment for MASH with fibrosis and highlight a recent target trial emulation study that casts doubt on our traditional understanding regarding the link between common medications such as PPIs and NSAIDs and microscopic colitis in older adults. We also summarize newly-released, global guidelines for pregnancy and IBD, which deserve a careful read. In this month’s Member Spotlight, we feature Pascale White, MD, MBA, MS (Mount Sinai), a recent recipient of the AGA-Pfizer Beacon of Hope Award for Gender and Health Equity, who shares her inspirational work to improve colorectal cancer screening among underserved, high-risk patients in East Harlem. We hope you enjoy this and all the exciting content in our October issue.

Megan A. Adams, MD, JD, MSc 

Editor in Chief

Federal grants have supported cutting-edge research in scientific and biomedical fields since the mid-20th century, fueling public health breakthroughs and health innovations. This crucial support has been greatly diminished in recent months with deep cuts to federal research dollars.

As these acute policy changes continue to disrupt academic institutions and their investigators, introducing financial strain and operational uncertainty, the importance of research support from professional societies and foundations has become increasingly evident. Their targeted funding plays a critical role in sustaining biomedical research, which directly impacts clinical innovation and patient care. As one example, the AGA Research Foundation provides over $2 million annually to spur discoveries in gastroenterology and hepatology. This vital research support, awarded to 74 unique recipients (including 7 early-career Research Scholar Award recipients) in 2025, represents one of the most important investments that AGA makes in the future of gastroenterology and the patients we treat.

While foundation awards such as these cannot completely close the federal funding gap, they serve as an important lifeline both in supporting the core work of early career and established investigators in an uncertain funding environment and in funding high-risk, high-reward research that more conservative funders are often hesitant to invest in. Please consider joining me in contributing to the AGA Research Foundation to support its important work – now more than ever, the funding it provides has tremendous impact.

In this issue of GI & Hepatology News, we update you on the FDA’s recent approval of semaglutide as a treatment for MASH with fibrosis and highlight a recent target trial emulation study that casts doubt on our traditional understanding regarding the link between common medications such as PPIs and NSAIDs and microscopic colitis in older adults. We also summarize newly-released, global guidelines for pregnancy and IBD, which deserve a careful read. In this month’s Member Spotlight, we feature Pascale White, MD, MBA, MS (Mount Sinai), a recent recipient of the AGA-Pfizer Beacon of Hope Award for Gender and Health Equity, who shares her inspirational work to improve colorectal cancer screening among underserved, high-risk patients in East Harlem. We hope you enjoy this and all the exciting content in our October issue.

Megan A. Adams, MD, JD, MSc 

Editor in Chief

Cydnidae is a family of small to medium-sized shield bugs with spiny legs that commonly are known as burrowing bugs (or burrower bugs). The family Cydnidae includes more than 100 genera and approximately 600 species worldwide.¹ These insects are arthropods of the order Hemiptera (suborder: Heteroptera; superfamily: Pentatomoidae) and largely are concentrated in tropical and temperate regions. Approximately 145 species have been recorded in the Neotropical Region and have been included in the subfamilies Amnestinae, Cephalocteinae, and Sehirinae, in addition to Cydnidae.² Burrowing bugs are ovoid in shape and 2 to 20 mm in length and morphologically are well adapted for burrowing. Their life span is 100 to 300 days. Being phytophagous, they burrow to feed on plants and roots. Adult burrowing bugs have wings and can fly. They have specialized glands located in either the abdomen (nymph) or thorax (adult) that secrete odorous chemicals for self-protection.³ The secretions contain hydrocarbonates that function as repellents and danger signals, can cause paralysis in prey, and act as a chemoattractant for mates.^4-6 They also cause hyperpigmentation upon contact with the skin.

In this article, we present a series of cases from the same community to demonstrate the characteristic features of hyperpigmented macules caused by exposure to burrowing bugs. Dermatologists should be aware of this entity to prevent misdiagnosis and unnecessary investigations and treatment.

Case Series

A 36-year-old woman and 6 children (age range, 6-12 years) presented with a widespread, acute, brown-pigmented, macular eruption with lesions that increased in number over a 1-week period. All 7 patients resided in the same locality and were otherwise systemically healthy. Initially, the index case, a 7-year-old girl, was referred to our tertiary care center by a dermatologist with a provisional diagnosis of idiopathic macular eruptive pigmentation. The patient’s mother recalled noticing a tiny black insect on the child's scalp that left pigment on the skin when she crushed it between her fingers. The rest of the patients presented over the next few days: 3 of the children belonged to the same household as the index case, and there was history of all 6 children playing in the neighborhood park during late evening hours. The adult patient was the parent of one of the affected children. The lesions were associated with mild itching and tingling in 3 children but were asymptomatic in the other patients.

Clinical examination of the patients revealed multiple dark- to light-brown, discrete, irregularly shaped macules over the trunk, arms, and soles (eFigure 1). Dermoscopic examination of a pigmented macule showed an irregularly shaped, brownish, structureless area with accentuation of the pigment at skin creases and perieccrine pigmentation (eFigure 2). The pigmentation was unaffected by rubbing with alcohol or water. Clinicoepidemiologic parameters of the patients are summarized in the eTable.

One of the children’s parents conducted a geological examination of the ground in the neighborhood park during evening hours and found tiny burrowing bugs (eFigure 3). When crushed between the fingers, these insects left a similar brownish hyperpigmentation on the skin. The parents were counseled on the nature of the eruption, and the patients were kept under observation for 2 weeks. On follow-up after 5 days, the lesions showed markedly decreased intensity of hyperpigmentation, and no new lesions were observed in any of the 7 patients.

Comment

Pentatomoidae insects generally are benign and harmless to humans. There have been isolated reports of erythematous plaques caused by Antiteuchus mixtus and Edessa maculate.⁷ Malhotra et al⁸ reported the first known series of cases with Cydnidae insect–induced hyperpigmented macules. The reported patients presented with asymptomatic, brown, hyperpigmented macules over exposed sites such as the feet, neck, and chest. All the cases occurred during the monsoon season in tropical and temperate regions of the world, and the patients were characteristically clustered in similar geographic areas. The causative insect was identified as Chilocoris assmuthi Breddin, 1904, belonging to the family Cydnidae. When it was crushed between the fingers, the skin became hyperpigmented, confirming the role of the secretions from the insect in the etiology.⁸

A second case was described by Sonthalia,⁹ who also described the dermoscopic features of hyperpigmented macules caused by burrowing bugs. The lesions showed a stuck-on, clustered appearance of ovoid and bizarre pigmented clods, globules, and granules.⁹ Although the lesions occur mainly over exposed sites, pigmented macules occurring over unusual sites such as the abdomen and back also have been reported in association with burrowing bugs.¹⁰ Characteristically, the lesions initially are faint and darken with time and usually fade within a week. They can be rubbed off with acetone but persist when washed with soap and water. The fleeting nature of the pigmentation also has led to the term transient pseudo-lentigines sign to describe hyperpigmentation caused by burrowing bugs.¹¹

Soil and plants are burrowing bugs’ natural habitats, and the insects typically are seen in vegetation-rich, moist areas adjoining human dwellings (eg, parks, gardens), where clusters of cases can occur. These insects proliferate during the monsoon season in tropical and temperate areas, leading to more cases occurring during these months. 

Compared to prior reports,^8,9 a few of our patients had predominant trunk and neck involvement with an occasional tingling sensation or pruritus while the rest were asymptomatic. Dermoscopic features from our patients shared similar reported features of Cydnidae pigmentation.^4,5 The accentuation of pigment over skin creases seen on dermoscopy was due to accumulation of Cydnidae secretion at these sites. 

The differential diagnosis commonly includes idiopathic macular eruptive pigmentation, which is characterized by an asymptomatic progressive eruption of hyperpigmented macules over the trunk that persists from a few months up to 3 years. Other conditions in the differential include benign conditions such as acral benign melanocytic nevi, lentigines, pigmented purpuric dermatosis, and postinflammatory hyperpigmentation, as well as malignant conditions such as acral melanoma. Dermoscopy is a helpful, easy-to-use tool in differentiating these pigmentation disorders, obviating the need for an invasive investigation such as histopathologic analysis. Simultaneous involvement in a group of people living together or visiting the same place, abrupt onset, predominant involvement of the exposed sites, characteristic clinical and dermoscopic features, self-limiting course, and timing with the monsoon season should suggest a possibility of Cydnidae dermatitis/pigmentation, which can be confirmed by finding the causative bug in the affected locality.

Management

No specific treatment is required for the pigmentation caused by Cydnidae, as it is self-resolving. The macules can, however, be removed with acetone. Patients must be counseled regarding the benign and fleeting nature of this condition, as the abrupt onset may alarm them of a systemic disease. Affected patients should be advised against walking barefoot in areas where the insects can be found. Spraying insecticides in the affected locality also helps to reduce the presence of burrowing bugs.

Cydnidae is a family of small to medium-sized shield bugs with spiny legs that commonly are known as burrowing bugs (or burrower bugs). The family Cydnidae includes more than 100 genera and approximately 600 species worldwide.¹ These insects are arthropods of the order Hemiptera (suborder: Heteroptera; superfamily: Pentatomoidae) and largely are concentrated in tropical and temperate regions. Approximately 145 species have been recorded in the Neotropical Region and have been included in the subfamilies Amnestinae, Cephalocteinae, and Sehirinae, in addition to Cydnidae.² Burrowing bugs are ovoid in shape and 2 to 20 mm in length and morphologically are well adapted for burrowing. Their life span is 100 to 300 days. Being phytophagous, they burrow to feed on plants and roots. Adult burrowing bugs have wings and can fly. They have specialized glands located in either the abdomen (nymph) or thorax (adult) that secrete odorous chemicals for self-protection.³ The secretions contain hydrocarbonates that function as repellents and danger signals, can cause paralysis in prey, and act as a chemoattractant for mates.^4-6 They also cause hyperpigmentation upon contact with the skin.

In this article, we present a series of cases from the same community to demonstrate the characteristic features of hyperpigmented macules caused by exposure to burrowing bugs. Dermatologists should be aware of this entity to prevent misdiagnosis and unnecessary investigations and treatment.

Case Series

A 36-year-old woman and 6 children (age range, 6-12 years) presented with a widespread, acute, brown-pigmented, macular eruption with lesions that increased in number over a 1-week period. All 7 patients resided in the same locality and were otherwise systemically healthy. Initially, the index case, a 7-year-old girl, was referred to our tertiary care center by a dermatologist with a provisional diagnosis of idiopathic macular eruptive pigmentation. The patient’s mother recalled noticing a tiny black insect on the child's scalp that left pigment on the skin when she crushed it between her fingers. The rest of the patients presented over the next few days: 3 of the children belonged to the same household as the index case, and there was history of all 6 children playing in the neighborhood park during late evening hours. The adult patient was the parent of one of the affected children. The lesions were associated with mild itching and tingling in 3 children but were asymptomatic in the other patients.

Clinical examination of the patients revealed multiple dark- to light-brown, discrete, irregularly shaped macules over the trunk, arms, and soles (eFigure 1). Dermoscopic examination of a pigmented macule showed an irregularly shaped, brownish, structureless area with accentuation of the pigment at skin creases and perieccrine pigmentation (eFigure 2). The pigmentation was unaffected by rubbing with alcohol or water. Clinicoepidemiologic parameters of the patients are summarized in the eTable.

One of the children’s parents conducted a geological examination of the ground in the neighborhood park during evening hours and found tiny burrowing bugs (eFigure 3). When crushed between the fingers, these insects left a similar brownish hyperpigmentation on the skin. The parents were counseled on the nature of the eruption, and the patients were kept under observation for 2 weeks. On follow-up after 5 days, the lesions showed markedly decreased intensity of hyperpigmentation, and no new lesions were observed in any of the 7 patients.

Comment

Pentatomoidae insects generally are benign and harmless to humans. There have been isolated reports of erythematous plaques caused by Antiteuchus mixtus and Edessa maculate.⁷ Malhotra et al⁸ reported the first known series of cases with Cydnidae insect–induced hyperpigmented macules. The reported patients presented with asymptomatic, brown, hyperpigmented macules over exposed sites such as the feet, neck, and chest. All the cases occurred during the monsoon season in tropical and temperate regions of the world, and the patients were characteristically clustered in similar geographic areas. The causative insect was identified as Chilocoris assmuthi Breddin, 1904, belonging to the family Cydnidae. When it was crushed between the fingers, the skin became hyperpigmented, confirming the role of the secretions from the insect in the etiology.⁸

A second case was described by Sonthalia,⁹ who also described the dermoscopic features of hyperpigmented macules caused by burrowing bugs. The lesions showed a stuck-on, clustered appearance of ovoid and bizarre pigmented clods, globules, and granules.⁹ Although the lesions occur mainly over exposed sites, pigmented macules occurring over unusual sites such as the abdomen and back also have been reported in association with burrowing bugs.¹⁰ Characteristically, the lesions initially are faint and darken with time and usually fade within a week. They can be rubbed off with acetone but persist when washed with soap and water. The fleeting nature of the pigmentation also has led to the term transient pseudo-lentigines sign to describe hyperpigmentation caused by burrowing bugs.¹¹

Soil and plants are burrowing bugs’ natural habitats, and the insects typically are seen in vegetation-rich, moist areas adjoining human dwellings (eg, parks, gardens), where clusters of cases can occur. These insects proliferate during the monsoon season in tropical and temperate areas, leading to more cases occurring during these months. 

Compared to prior reports,^8,9 a few of our patients had predominant trunk and neck involvement with an occasional tingling sensation or pruritus while the rest were asymptomatic. Dermoscopic features from our patients shared similar reported features of Cydnidae pigmentation.^4,5 The accentuation of pigment over skin creases seen on dermoscopy was due to accumulation of Cydnidae secretion at these sites. 

The differential diagnosis commonly includes idiopathic macular eruptive pigmentation, which is characterized by an asymptomatic progressive eruption of hyperpigmented macules over the trunk that persists from a few months up to 3 years. Other conditions in the differential include benign conditions such as acral benign melanocytic nevi, lentigines, pigmented purpuric dermatosis, and postinflammatory hyperpigmentation, as well as malignant conditions such as acral melanoma. Dermoscopy is a helpful, easy-to-use tool in differentiating these pigmentation disorders, obviating the need for an invasive investigation such as histopathologic analysis. Simultaneous involvement in a group of people living together or visiting the same place, abrupt onset, predominant involvement of the exposed sites, characteristic clinical and dermoscopic features, self-limiting course, and timing with the monsoon season should suggest a possibility of Cydnidae dermatitis/pigmentation, which can be confirmed by finding the causative bug in the affected locality.

Management

No specific treatment is required for the pigmentation caused by Cydnidae, as it is self-resolving. The macules can, however, be removed with acetone. Patients must be counseled regarding the benign and fleeting nature of this condition, as the abrupt onset may alarm them of a systemic disease. Affected patients should be advised against walking barefoot in areas where the insects can be found. Spraying insecticides in the affected locality also helps to reduce the presence of burrowing bugs.

Cydnidae is a family of small to medium-sized shield bugs with spiny legs that commonly are known as burrowing bugs (or burrower bugs). The family Cydnidae includes more than 100 genera and approximately 600 species worldwide.¹ These insects are arthropods of the order Hemiptera (suborder: Heteroptera; superfamily: Pentatomoidae) and largely are concentrated in tropical and temperate regions. Approximately 145 species have been recorded in the Neotropical Region and have been included in the subfamilies Amnestinae, Cephalocteinae, and Sehirinae, in addition to Cydnidae.² Burrowing bugs are ovoid in shape and 2 to 20 mm in length and morphologically are well adapted for burrowing. Their life span is 100 to 300 days. Being phytophagous, they burrow to feed on plants and roots. Adult burrowing bugs have wings and can fly. They have specialized glands located in either the abdomen (nymph) or thorax (adult) that secrete odorous chemicals for self-protection.³ The secretions contain hydrocarbonates that function as repellents and danger signals, can cause paralysis in prey, and act as a chemoattractant for mates.^4-6 They also cause hyperpigmentation upon contact with the skin.

In this article, we present a series of cases from the same community to demonstrate the characteristic features of hyperpigmented macules caused by exposure to burrowing bugs. Dermatologists should be aware of this entity to prevent misdiagnosis and unnecessary investigations and treatment.

Case Series

A 36-year-old woman and 6 children (age range, 6-12 years) presented with a widespread, acute, brown-pigmented, macular eruption with lesions that increased in number over a 1-week period. All 7 patients resided in the same locality and were otherwise systemically healthy. Initially, the index case, a 7-year-old girl, was referred to our tertiary care center by a dermatologist with a provisional diagnosis of idiopathic macular eruptive pigmentation. The patient’s mother recalled noticing a tiny black insect on the child's scalp that left pigment on the skin when she crushed it between her fingers. The rest of the patients presented over the next few days: 3 of the children belonged to the same household as the index case, and there was history of all 6 children playing in the neighborhood park during late evening hours. The adult patient was the parent of one of the affected children. The lesions were associated with mild itching and tingling in 3 children but were asymptomatic in the other patients.

Clinical examination of the patients revealed multiple dark- to light-brown, discrete, irregularly shaped macules over the trunk, arms, and soles (eFigure 1). Dermoscopic examination of a pigmented macule showed an irregularly shaped, brownish, structureless area with accentuation of the pigment at skin creases and perieccrine pigmentation (eFigure 2). The pigmentation was unaffected by rubbing with alcohol or water. Clinicoepidemiologic parameters of the patients are summarized in the eTable.

One of the children’s parents conducted a geological examination of the ground in the neighborhood park during evening hours and found tiny burrowing bugs (eFigure 3). When crushed between the fingers, these insects left a similar brownish hyperpigmentation on the skin. The parents were counseled on the nature of the eruption, and the patients were kept under observation for 2 weeks. On follow-up after 5 days, the lesions showed markedly decreased intensity of hyperpigmentation, and no new lesions were observed in any of the 7 patients.

Comment

Pentatomoidae insects generally are benign and harmless to humans. There have been isolated reports of erythematous plaques caused by Antiteuchus mixtus and Edessa maculate.⁷ Malhotra et al⁸ reported the first known series of cases with Cydnidae insect–induced hyperpigmented macules. The reported patients presented with asymptomatic, brown, hyperpigmented macules over exposed sites such as the feet, neck, and chest. All the cases occurred during the monsoon season in tropical and temperate regions of the world, and the patients were characteristically clustered in similar geographic areas. The causative insect was identified as Chilocoris assmuthi Breddin, 1904, belonging to the family Cydnidae. When it was crushed between the fingers, the skin became hyperpigmented, confirming the role of the secretions from the insect in the etiology.⁸

A second case was described by Sonthalia,⁹ who also described the dermoscopic features of hyperpigmented macules caused by burrowing bugs. The lesions showed a stuck-on, clustered appearance of ovoid and bizarre pigmented clods, globules, and granules.⁹ Although the lesions occur mainly over exposed sites, pigmented macules occurring over unusual sites such as the abdomen and back also have been reported in association with burrowing bugs.¹⁰ Characteristically, the lesions initially are faint and darken with time and usually fade within a week. They can be rubbed off with acetone but persist when washed with soap and water. The fleeting nature of the pigmentation also has led to the term transient pseudo-lentigines sign to describe hyperpigmentation caused by burrowing bugs.¹¹

Soil and plants are burrowing bugs’ natural habitats, and the insects typically are seen in vegetation-rich, moist areas adjoining human dwellings (eg, parks, gardens), where clusters of cases can occur. These insects proliferate during the monsoon season in tropical and temperate areas, leading to more cases occurring during these months. 

Compared to prior reports,^8,9 a few of our patients had predominant trunk and neck involvement with an occasional tingling sensation or pruritus while the rest were asymptomatic. Dermoscopic features from our patients shared similar reported features of Cydnidae pigmentation.^4,5 The accentuation of pigment over skin creases seen on dermoscopy was due to accumulation of Cydnidae secretion at these sites. 

The differential diagnosis commonly includes idiopathic macular eruptive pigmentation, which is characterized by an asymptomatic progressive eruption of hyperpigmented macules over the trunk that persists from a few months up to 3 years. Other conditions in the differential include benign conditions such as acral benign melanocytic nevi, lentigines, pigmented purpuric dermatosis, and postinflammatory hyperpigmentation, as well as malignant conditions such as acral melanoma. Dermoscopy is a helpful, easy-to-use tool in differentiating these pigmentation disorders, obviating the need for an invasive investigation such as histopathologic analysis. Simultaneous involvement in a group of people living together or visiting the same place, abrupt onset, predominant involvement of the exposed sites, characteristic clinical and dermoscopic features, self-limiting course, and timing with the monsoon season should suggest a possibility of Cydnidae dermatitis/pigmentation, which can be confirmed by finding the causative bug in the affected locality.

Management

No specific treatment is required for the pigmentation caused by Cydnidae, as it is self-resolving. The macules can, however, be removed with acetone. Patients must be counseled regarding the benign and fleeting nature of this condition, as the abrupt onset may alarm them of a systemic disease. Affected patients should be advised against walking barefoot in areas where the insects can be found. Spraying insecticides in the affected locality also helps to reduce the presence of burrowing bugs.

Practice Gap

Pain during minimally invasive dermatologic procedures such as lidocaine injections, cryotherapy, nail unit injections, and cosmetic procedures including neurotoxin injections can cause patient discomfort leading to procedural anxiety, poor compliance with treatment regimens, and avoidance of necessary care. Current solutions to manage pain during dermatologic procedures present several limitations; for example, topical anesthetics seldom alleviate procedural pain,¹ particularly in sensitive areas (eg, nail unit, face) or for patients with a needle phobia. Additionally, topical anesthetics often require up to 2 hours to take effect, making them impractical for quick outpatient procedures. Other pain reduction strategies including vibration devices or cold sprays^2,3 can be effective but are an added expense to the physician or clinic, which may preclude their use in resource-limited settings. Psychological distraction techniques such as deep breathing require active patient participation and might reinforce pain expectations and increase patient anxiety.⁴ Given these challenges, there is a need for effective, affordable, nonpharmacologic pain reduction strategies that can be integrated seamlessly into clinical practice to enhance the patient experience.

The Technique

Tapping is a simple noninvasive distraction technique that may alleviate procedural pain by exploiting the gate control theory of pain.⁵ According to this theory, tactile stimuli activate mechanoreceptors that send inhibitory signals to the spinal cord, effectively closing the gate to pain transmission. Unlike the Helfer skin tap technique,⁶ which involves 15 preinjection taps and 3 postinjection taps directly on the injection site, our approach targets distant bony prominences. This modification allows for immediate needle insertion without interfering with the sterile field or increasing the risk for needlestick injuries from tapping near the injection site. Bony sites such as the shoulder or knee are ideal for this technique due to their high density and rigidity that efficiently transmit tactile stimuli––similar to how sound travels faster through solids than through liquids or gases.⁷

To implement this technique in practice, we first stabilize the injection site to reduce movement from tapping. This can be done by stabilizing the injection site (eg, resting the hand on an instrument stand during a nail unit injection). A second person—such as a medical assistant, medical student, resident, or even the patient’s family member—taps at a distant site at least an arm’s length away from the injection site (Figure). The tapping pressure should be firm enough for the patient to feel the vibration but not forceful enough that it becomes unpleasant or disrupts the injection area. Tapping starts just before needle insertion and continues through the injection. No warning is given to the patient, as the surprise element may help distract them from pain. Varying the rhythm, intensity, or location of the tapping can enhance its distracting effect. 

This tapping technique can be effectively combined with other pain reduction strategies in a multimodal approach; for example, when used concurrently with topical anesthetics, both the central (tapping) and peripheral (anesthetic) pain pathways are addressed, potentially yielding additive effects. For patients with a needle ­phobia, pairing tapping with cognitive distraction (eg, talkesthesia) may further reduce anxiety. In our nail specialty clinic at Weill Cornell Medicine (New York, New York), we often combine tapping with cold sprays and talkesthesia, which improves patient comfort without prolonging the visit. Importantly, the technique enables seamless integration with most pharmacologic and nonpharmacologic methods, eliminating the need for additional patient education or procedure time.

Practice Implications

The tapping technique described here is free, easy to implement, and requires no additional resources aside from another person to tap the patient during the procedure. It can be used for a wide range of dermatologic procedures, including biopsies, intralesional injections, and cosmetic treatments, including neurotoxin injections. The minimal learning curve and ease of integration into procedural workflows make this technique a valuable tool for dermatologists aiming to improve patient comfort without disrupting workflow. In our practice, we have observed that tapping reduces self-reported pain and helps ease anxiety, particularly in patients with a needle phobia. Its simplicity and accessibility make it a valuable addition to a wide range of dermatologic procedures. Prospective studies investigating patient-reported outcomes could help establish this technique’s role in clinical practice.

Practice Gap

Pain during minimally invasive dermatologic procedures such as lidocaine injections, cryotherapy, nail unit injections, and cosmetic procedures including neurotoxin injections can cause patient discomfort leading to procedural anxiety, poor compliance with treatment regimens, and avoidance of necessary care. Current solutions to manage pain during dermatologic procedures present several limitations; for example, topical anesthetics seldom alleviate procedural pain,¹ particularly in sensitive areas (eg, nail unit, face) or for patients with a needle phobia. Additionally, topical anesthetics often require up to 2 hours to take effect, making them impractical for quick outpatient procedures. Other pain reduction strategies including vibration devices or cold sprays^2,3 can be effective but are an added expense to the physician or clinic, which may preclude their use in resource-limited settings. Psychological distraction techniques such as deep breathing require active patient participation and might reinforce pain expectations and increase patient anxiety.⁴ Given these challenges, there is a need for effective, affordable, nonpharmacologic pain reduction strategies that can be integrated seamlessly into clinical practice to enhance the patient experience.

The Technique

Tapping is a simple noninvasive distraction technique that may alleviate procedural pain by exploiting the gate control theory of pain.⁵ According to this theory, tactile stimuli activate mechanoreceptors that send inhibitory signals to the spinal cord, effectively closing the gate to pain transmission. Unlike the Helfer skin tap technique,⁶ which involves 15 preinjection taps and 3 postinjection taps directly on the injection site, our approach targets distant bony prominences. This modification allows for immediate needle insertion without interfering with the sterile field or increasing the risk for needlestick injuries from tapping near the injection site. Bony sites such as the shoulder or knee are ideal for this technique due to their high density and rigidity that efficiently transmit tactile stimuli––similar to how sound travels faster through solids than through liquids or gases.⁷

To implement this technique in practice, we first stabilize the injection site to reduce movement from tapping. This can be done by stabilizing the injection site (eg, resting the hand on an instrument stand during a nail unit injection). A second person—such as a medical assistant, medical student, resident, or even the patient’s family member—taps at a distant site at least an arm’s length away from the injection site (Figure). The tapping pressure should be firm enough for the patient to feel the vibration but not forceful enough that it becomes unpleasant or disrupts the injection area. Tapping starts just before needle insertion and continues through the injection. No warning is given to the patient, as the surprise element may help distract them from pain. Varying the rhythm, intensity, or location of the tapping can enhance its distracting effect. 

This tapping technique can be effectively combined with other pain reduction strategies in a multimodal approach; for example, when used concurrently with topical anesthetics, both the central (tapping) and peripheral (anesthetic) pain pathways are addressed, potentially yielding additive effects. For patients with a needle ­phobia, pairing tapping with cognitive distraction (eg, talkesthesia) may further reduce anxiety. In our nail specialty clinic at Weill Cornell Medicine (New York, New York), we often combine tapping with cold sprays and talkesthesia, which improves patient comfort without prolonging the visit. Importantly, the technique enables seamless integration with most pharmacologic and nonpharmacologic methods, eliminating the need for additional patient education or procedure time.

Practice Implications

The tapping technique described here is free, easy to implement, and requires no additional resources aside from another person to tap the patient during the procedure. It can be used for a wide range of dermatologic procedures, including biopsies, intralesional injections, and cosmetic treatments, including neurotoxin injections. The minimal learning curve and ease of integration into procedural workflows make this technique a valuable tool for dermatologists aiming to improve patient comfort without disrupting workflow. In our practice, we have observed that tapping reduces self-reported pain and helps ease anxiety, particularly in patients with a needle phobia. Its simplicity and accessibility make it a valuable addition to a wide range of dermatologic procedures. Prospective studies investigating patient-reported outcomes could help establish this technique’s role in clinical practice.

Practice Gap

Pain during minimally invasive dermatologic procedures such as lidocaine injections, cryotherapy, nail unit injections, and cosmetic procedures including neurotoxin injections can cause patient discomfort leading to procedural anxiety, poor compliance with treatment regimens, and avoidance of necessary care. Current solutions to manage pain during dermatologic procedures present several limitations; for example, topical anesthetics seldom alleviate procedural pain,¹ particularly in sensitive areas (eg, nail unit, face) or for patients with a needle phobia. Additionally, topical anesthetics often require up to 2 hours to take effect, making them impractical for quick outpatient procedures. Other pain reduction strategies including vibration devices or cold sprays^2,3 can be effective but are an added expense to the physician or clinic, which may preclude their use in resource-limited settings. Psychological distraction techniques such as deep breathing require active patient participation and might reinforce pain expectations and increase patient anxiety.⁴ Given these challenges, there is a need for effective, affordable, nonpharmacologic pain reduction strategies that can be integrated seamlessly into clinical practice to enhance the patient experience.

The Technique

Tapping is a simple noninvasive distraction technique that may alleviate procedural pain by exploiting the gate control theory of pain.⁵ According to this theory, tactile stimuli activate mechanoreceptors that send inhibitory signals to the spinal cord, effectively closing the gate to pain transmission. Unlike the Helfer skin tap technique,⁶ which involves 15 preinjection taps and 3 postinjection taps directly on the injection site, our approach targets distant bony prominences. This modification allows for immediate needle insertion without interfering with the sterile field or increasing the risk for needlestick injuries from tapping near the injection site. Bony sites such as the shoulder or knee are ideal for this technique due to their high density and rigidity that efficiently transmit tactile stimuli––similar to how sound travels faster through solids than through liquids or gases.⁷

To implement this technique in practice, we first stabilize the injection site to reduce movement from tapping. This can be done by stabilizing the injection site (eg, resting the hand on an instrument stand during a nail unit injection). A second person—such as a medical assistant, medical student, resident, or even the patient’s family member—taps at a distant site at least an arm’s length away from the injection site (Figure). The tapping pressure should be firm enough for the patient to feel the vibration but not forceful enough that it becomes unpleasant or disrupts the injection area. Tapping starts just before needle insertion and continues through the injection. No warning is given to the patient, as the surprise element may help distract them from pain. Varying the rhythm, intensity, or location of the tapping can enhance its distracting effect. 

This tapping technique can be effectively combined with other pain reduction strategies in a multimodal approach; for example, when used concurrently with topical anesthetics, both the central (tapping) and peripheral (anesthetic) pain pathways are addressed, potentially yielding additive effects. For patients with a needle ­phobia, pairing tapping with cognitive distraction (eg, talkesthesia) may further reduce anxiety. In our nail specialty clinic at Weill Cornell Medicine (New York, New York), we often combine tapping with cold sprays and talkesthesia, which improves patient comfort without prolonging the visit. Importantly, the technique enables seamless integration with most pharmacologic and nonpharmacologic methods, eliminating the need for additional patient education or procedure time.

Practice Implications

The tapping technique described here is free, easy to implement, and requires no additional resources aside from another person to tap the patient during the procedure. It can be used for a wide range of dermatologic procedures, including biopsies, intralesional injections, and cosmetic treatments, including neurotoxin injections. The minimal learning curve and ease of integration into procedural workflows make this technique a valuable tool for dermatologists aiming to improve patient comfort without disrupting workflow. In our practice, we have observed that tapping reduces self-reported pain and helps ease anxiety, particularly in patients with a needle phobia. Its simplicity and accessibility make it a valuable addition to a wide range of dermatologic procedures. Prospective studies investigating patient-reported outcomes could help establish this technique’s role in clinical practice.

To the Editor:

The popularity of the social media platform TikTok, which is known for its short-form videos, has surged in recent years. Viral videos demonstrating skin care routines reach millions of viewers,¹ showcasing specific products, detailing beauty regimens, and setting fads that many users eagerly follow. These trends often influence consumer behavior—in 2023, viral videos using the tag #TikTokMadeMeBuy lead to a 14% growth in the sale of skin care products.² However, they also encourage purchasing decisions that may escalate environmental waste through plastic packaging and single-use products. In this study, we analyzed videos on TikTok to assess the environmental impact of trending skin care routines. By examining the types of products promoted, their packaging, and the frequency with which they appear in viral content, we aimed to investigate how these trends, which may be imitated by users, impact the environment.

A search of TikTok videos using #skincareroutine was conducted on June 21, 2024. Sponsored content, non–English language videos, videos without demonstrated skin care routines, and videos showing makeup routines were excluded from our analysis. Data collected from each video included username, date posted, number of likes, total number of skin care products used, number of single-use skin care products used, average amount of product used, number of skin care applicators used, and number of single-use applicators used. Single-use items, defined as those intended for one-time use and subsequent disposal, were identified visually by packaging, manufacturer intent, and common consumer usage patterns. The amount of product used per application was graded on a scale of 1 to 3 (1=pea-sized amount or less; 2=single full pump/spray; 3=multiple pumps/sprays). Videos were categorized as personal (ie, skin care routine walk-throughs by the creator) or autonomous sensory meridian response (ASMR)(focused on product sounds and aesthetics).³ A Mann-Whitney U test was utilized to statistically compare the 2 groups. Statistical analysis was performed using Microsoft Excel (α=0.05). 

A total of 50 videos met the inclusion criteria and were included in the analysis. The average number of likes per video was 499,696.15, with skin care routines featuring an average of 6.4 unique products (Table). There was a weak positive correlation (r=0.1809) between the number of skin care products used and the number of likes. A total of 320 products were used across the videos, 23 of which were single-use (7.2%).On average, single-use skin care items were used 0.46 times per routine, comprising a mean 7.99% of total products per video. The average score for the amount of product used per application was 2.18. There was no difference in personal vs ASMR videos with regard to the total number of skin care products used or the average amount of product used per application (P>.05). Thirty-three (70.2%) of the 47 applicators used across all videos were single-use. An average of 0.94 applicators per routine were utilized, with a mean 68.83% being single-use applicators. Common single-use products were toner wipes and eye patches, and single-use applicators included cotton pads and plastic spatulas. 

Our findings indicated a prevalence of multiple products and large amount of product used in trending skin care routines, suggesting a shift toward multistep skin care. This implies a high rate of product consumption that may accelerate the carbon footprint associated with skin care products,³ which could contribute to climate change and environmental degradation. Consumers also may feel compelled to purchase and discard numerous partially used products in order to keep up with the latest trends, exacerbating the environmental impact. Furthermore, the utilization of single-use products and applicators contributes to increased plastic waste, pollution, and resource depletion. Single-use items often are difficult to recycle due to their mixed materials and small size,^4,5 and therefore they can accumulate in landfills and oceans. This impact can be mitigated by switching to reusable applicators, refillable packaging, and biodegradable materials. 

The substantial average number of likes per video indicates high engagement with skin care content among TikTok users. The continued popularity of complex multi­step skin care routines, despite a weak correlation between the number of skin care products used and the number of likes per video, likely stems from factors such as aesthetic appeal, ASMR effects, and creators’ established followings, which may drive user engagement to contribute to unsustainable consumption patterns. Factors such as presentation style, aesthetics, or creators’ pre-existing online following may have a major impact on how well a video performs on TikTok. The similarity between personal and ASMR videos, particularly in the number of products used and the amount applied, suggests that both formats employ common approaches to meet audience expectations and align with promotional trends, relying more on sensory and aesthetic strategies than substantive differences in skin care routines.

Our use of only one tag in our search as well as the subjective quantity scale limits the generalizability of these findings to broader TikTok skin care content.

Overall, our study underscores the role of brands and social media influencers in skin care education and promotion of sustainable practices. The extensive number of products used and generous application of each product in skin care routines demonstrated in TikTok videos may mislead viewers into believing that using more product improves outcomes, when often, less is more. We recommend that dermatologists counsel patients about informed skin care regimens that prioritize individual needs over social media fads.

To the Editor:

The popularity of the social media platform TikTok, which is known for its short-form videos, has surged in recent years. Viral videos demonstrating skin care routines reach millions of viewers,¹ showcasing specific products, detailing beauty regimens, and setting fads that many users eagerly follow. These trends often influence consumer behavior—in 2023, viral videos using the tag #TikTokMadeMeBuy lead to a 14% growth in the sale of skin care products.² However, they also encourage purchasing decisions that may escalate environmental waste through plastic packaging and single-use products. In this study, we analyzed videos on TikTok to assess the environmental impact of trending skin care routines. By examining the types of products promoted, their packaging, and the frequency with which they appear in viral content, we aimed to investigate how these trends, which may be imitated by users, impact the environment.

A search of TikTok videos using #skincareroutine was conducted on June 21, 2024. Sponsored content, non–English language videos, videos without demonstrated skin care routines, and videos showing makeup routines were excluded from our analysis. Data collected from each video included username, date posted, number of likes, total number of skin care products used, number of single-use skin care products used, average amount of product used, number of skin care applicators used, and number of single-use applicators used. Single-use items, defined as those intended for one-time use and subsequent disposal, were identified visually by packaging, manufacturer intent, and common consumer usage patterns. The amount of product used per application was graded on a scale of 1 to 3 (1=pea-sized amount or less; 2=single full pump/spray; 3=multiple pumps/sprays). Videos were categorized as personal (ie, skin care routine walk-throughs by the creator) or autonomous sensory meridian response (ASMR)(focused on product sounds and aesthetics).³ A Mann-Whitney U test was utilized to statistically compare the 2 groups. Statistical analysis was performed using Microsoft Excel (α=0.05). 

A total of 50 videos met the inclusion criteria and were included in the analysis. The average number of likes per video was 499,696.15, with skin care routines featuring an average of 6.4 unique products (Table). There was a weak positive correlation (r=0.1809) between the number of skin care products used and the number of likes. A total of 320 products were used across the videos, 23 of which were single-use (7.2%).On average, single-use skin care items were used 0.46 times per routine, comprising a mean 7.99% of total products per video. The average score for the amount of product used per application was 2.18. There was no difference in personal vs ASMR videos with regard to the total number of skin care products used or the average amount of product used per application (P>.05). Thirty-three (70.2%) of the 47 applicators used across all videos were single-use. An average of 0.94 applicators per routine were utilized, with a mean 68.83% being single-use applicators. Common single-use products were toner wipes and eye patches, and single-use applicators included cotton pads and plastic spatulas. 

Our findings indicated a prevalence of multiple products and large amount of product used in trending skin care routines, suggesting a shift toward multistep skin care. This implies a high rate of product consumption that may accelerate the carbon footprint associated with skin care products,³ which could contribute to climate change and environmental degradation. Consumers also may feel compelled to purchase and discard numerous partially used products in order to keep up with the latest trends, exacerbating the environmental impact. Furthermore, the utilization of single-use products and applicators contributes to increased plastic waste, pollution, and resource depletion. Single-use items often are difficult to recycle due to their mixed materials and small size,^4,5 and therefore they can accumulate in landfills and oceans. This impact can be mitigated by switching to reusable applicators, refillable packaging, and biodegradable materials. 

The substantial average number of likes per video indicates high engagement with skin care content among TikTok users. The continued popularity of complex multi­step skin care routines, despite a weak correlation between the number of skin care products used and the number of likes per video, likely stems from factors such as aesthetic appeal, ASMR effects, and creators’ established followings, which may drive user engagement to contribute to unsustainable consumption patterns. Factors such as presentation style, aesthetics, or creators’ pre-existing online following may have a major impact on how well a video performs on TikTok. The similarity between personal and ASMR videos, particularly in the number of products used and the amount applied, suggests that both formats employ common approaches to meet audience expectations and align with promotional trends, relying more on sensory and aesthetic strategies than substantive differences in skin care routines.

Our use of only one tag in our search as well as the subjective quantity scale limits the generalizability of these findings to broader TikTok skin care content.

Overall, our study underscores the role of brands and social media influencers in skin care education and promotion of sustainable practices. The extensive number of products used and generous application of each product in skin care routines demonstrated in TikTok videos may mislead viewers into believing that using more product improves outcomes, when often, less is more. We recommend that dermatologists counsel patients about informed skin care regimens that prioritize individual needs over social media fads.

To the Editor:

The popularity of the social media platform TikTok, which is known for its short-form videos, has surged in recent years. Viral videos demonstrating skin care routines reach millions of viewers,¹ showcasing specific products, detailing beauty regimens, and setting fads that many users eagerly follow. These trends often influence consumer behavior—in 2023, viral videos using the tag #TikTokMadeMeBuy lead to a 14% growth in the sale of skin care products.² However, they also encourage purchasing decisions that may escalate environmental waste through plastic packaging and single-use products. In this study, we analyzed videos on TikTok to assess the environmental impact of trending skin care routines. By examining the types of products promoted, their packaging, and the frequency with which they appear in viral content, we aimed to investigate how these trends, which may be imitated by users, impact the environment.

A search of TikTok videos using #skincareroutine was conducted on June 21, 2024. Sponsored content, non–English language videos, videos without demonstrated skin care routines, and videos showing makeup routines were excluded from our analysis. Data collected from each video included username, date posted, number of likes, total number of skin care products used, number of single-use skin care products used, average amount of product used, number of skin care applicators used, and number of single-use applicators used. Single-use items, defined as those intended for one-time use and subsequent disposal, were identified visually by packaging, manufacturer intent, and common consumer usage patterns. The amount of product used per application was graded on a scale of 1 to 3 (1=pea-sized amount or less; 2=single full pump/spray; 3=multiple pumps/sprays). Videos were categorized as personal (ie, skin care routine walk-throughs by the creator) or autonomous sensory meridian response (ASMR)(focused on product sounds and aesthetics).³ A Mann-Whitney U test was utilized to statistically compare the 2 groups. Statistical analysis was performed using Microsoft Excel (α=0.05). 

A total of 50 videos met the inclusion criteria and were included in the analysis. The average number of likes per video was 499,696.15, with skin care routines featuring an average of 6.4 unique products (Table). There was a weak positive correlation (r=0.1809) between the number of skin care products used and the number of likes. A total of 320 products were used across the videos, 23 of which were single-use (7.2%).On average, single-use skin care items were used 0.46 times per routine, comprising a mean 7.99% of total products per video. The average score for the amount of product used per application was 2.18. There was no difference in personal vs ASMR videos with regard to the total number of skin care products used or the average amount of product used per application (P>.05). Thirty-three (70.2%) of the 47 applicators used across all videos were single-use. An average of 0.94 applicators per routine were utilized, with a mean 68.83% being single-use applicators. Common single-use products were toner wipes and eye patches, and single-use applicators included cotton pads and plastic spatulas. 

Our findings indicated a prevalence of multiple products and large amount of product used in trending skin care routines, suggesting a shift toward multistep skin care. This implies a high rate of product consumption that may accelerate the carbon footprint associated with skin care products,³ which could contribute to climate change and environmental degradation. Consumers also may feel compelled to purchase and discard numerous partially used products in order to keep up with the latest trends, exacerbating the environmental impact. Furthermore, the utilization of single-use products and applicators contributes to increased plastic waste, pollution, and resource depletion. Single-use items often are difficult to recycle due to their mixed materials and small size,^4,5 and therefore they can accumulate in landfills and oceans. This impact can be mitigated by switching to reusable applicators, refillable packaging, and biodegradable materials. 

The substantial average number of likes per video indicates high engagement with skin care content among TikTok users. The continued popularity of complex multi­step skin care routines, despite a weak correlation between the number of skin care products used and the number of likes per video, likely stems from factors such as aesthetic appeal, ASMR effects, and creators’ established followings, which may drive user engagement to contribute to unsustainable consumption patterns. Factors such as presentation style, aesthetics, or creators’ pre-existing online following may have a major impact on how well a video performs on TikTok. The similarity between personal and ASMR videos, particularly in the number of products used and the amount applied, suggests that both formats employ common approaches to meet audience expectations and align with promotional trends, relying more on sensory and aesthetic strategies than substantive differences in skin care routines.

Our use of only one tag in our search as well as the subjective quantity scale limits the generalizability of these findings to broader TikTok skin care content.

Overall, our study underscores the role of brands and social media influencers in skin care education and promotion of sustainable practices. The extensive number of products used and generous application of each product in skin care routines demonstrated in TikTok videos may mislead viewers into believing that using more product improves outcomes, when often, less is more. We recommend that dermatologists counsel patients about informed skin care regimens that prioritize individual needs over social media fads.

Prurigo nodularis (PN) is a chronic, severely pruritic neuroimmunologic skin disorder characterized by multiple firm hyperkeratotic nodules and intense pruritus, often leading to considerable impairment in quality of life and increased rates of depression and anxiety.¹ It is considered difficult to treat due to its complex pathogenesis, the severity and chronicity of pruritus, and the limited efficacy of conventional therapies.^2,3 The disease is driven by a self-perpetuating itch-scratch cycle, underpinned by dysregulation of both immune and neural pathways including type 2 (interleukin [IL] 4, IL-13, IL-31), Th17, and Th22 cytokines as well as neuropeptides and altered cutaneous nerve architecture.^1,3 This results in persistent severe pruritus and nodular lesions that are highly refractory to standard treatments.¹ Conventional therapies (eg, locally acting agents, phototherapy, and systemic immunomodulators and neuromodulators) have varied efficacy and notable adverse effect profiles.³ While the approval of targeted biologics has transformed the therapeutic landscape, several other treatment options also are being explored in clinical trials. Herein, we review all recently approved therapies as well as emerging treatments currently under investigation.

Dupilumab

Dupilumab, the first therapy for PN approved by the US Food and Drug Administration (FDA) in 2022—is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation implicated in PN pathogenesis.^4,5 In 2 pivotal phase 3 randomized controlled trials (LIBERTY-PN PRIME and PRIME2),⁵ dupilumab demonstrated notable efficacy in adults with moderate to severe PN. A reduction of 4 points or more on the Worst Itch Numeric Rating Scale (WI-NRS) was achieved by 60.0% (45/75) of patients treated with dupilumab at week 24 compared with 18.4% (14/76) receiving placebo in the PRIME trial. In PRIME2, the same outcome was achieved by 37.2% (29/78) of patients receiving dupilumab at week 12 compared with 22.0% (18/82) of patients receiving placebo.⁵ Dupilumab also led to a greater proportion of patients achieving a substantial reduction in nodule count (≤5 nodules) and improved quality of life compared with placebo.^5,6 The safety profile of dupilumab for treatment of PN was favorable and consistent with prior experience in atopic dermatitis; conjunctivitis was the most common adverse event.^5,6

Nemolizumab

Nemolizumab, an IL-31 receptor A antagonist, is the most recent agent approved by the FDA for PN in 2024.⁷ In the OLYMPIA 1 and OLYMPIA 2 phase 3 trials,⁸ nemolizumab produced a clinically meaningful reduction in itch (defined as a ≥4-point improvement in the Peak Pruritus Numerical Rating Scale score) in 56.3% (103/183) of patients at week 16 compared with 20.9% (19/91) receiving placebo. Additionally, 37.7% (69/183) of patients receiving nemolizumab achieved clear or almost clear skin (Investigator’s Global Assessment score of 0 or 1 with a ≥2-point reduction) vs 11.0% with placebo (both P<.001). Benefits were observed as early as week 4, including rapid improvements in itch, sleep disturbance, and nodule count.⁸ Nemolizumab also improved quality of life and reduced symptoms of anxiety and depression. The safety profile was favorable, with headache and atopic dermatitis the most common adverse events; serious adverse events were infrequent and similar between groups.⁸

Abrocitinib

Abrocitinib, an oral selective Janus kinase 1 inhibitor, is an investigational therapy for PN and currently has not been approved by the FDA for this indication. In a phase 2 open-label trial, abrocitinib 200 mg daily for 12 weeks led to a 78.3% reduction in weekly Peak Pruritus Numerical Rating Scale scores in PN, with 80.0% (8/10) of patients achieving a clinically meaningful improvement of 4 points or higher. Nodule counts and quality of life also improved, with an onset of itch relief as early as week 2. The safety profile was favorable, with acneform eruptions the most common adverse event and no serious adverse events reported⁹; however, these results are based on small, nonrandomized studies and require confirmation in larger randomized controlled trials before abrocitinib can be considered a standard therapy for PN.

Cryosim-1

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing ion channel found in unmyelinated sensory neurons within the dorsal root and trigeminal ­ganglia.¹⁰ It is activated by cool temperatures (15-28 °C) and compounds such as menthol, leading to calcium influx and a cooling sensation. In a randomized, double-blind, vehicle-controlled trial, researchers investigated the efficacy of cryosim-1 (a synthetic TRPM8 agonist) in treating PN.¹⁰ Thirty patients were enrolled, with 18 (60.0%) receiving cryosim-1 and 12 (40.0%) receiving placebo over 8 weeks. By week 8, cryosim-1 significantly reduced itch severity (mean numerical rating scale score postapplication, 2.8 vs 4.3; P=.031) and improved sleep disturbances (2.2 vs 4.2; P=.031) compared to placebo. Patients reported higher satisfaction with itch relief, and no adverse effects were observed. The study concluded that cryosim-1 is a safe, effective topical therapy for PN, likely working by interrupting the itch-scratch cycle and potentially modulating inflammatory pathways involved in chronic itch.¹⁰

Nalbuphine

Nalbuphine is a κ opioid receptor agonist and μ opioid receptor antagonist that has been investigated for the treatment of PN.¹¹ In a phase 2 randomized controlled trial, oral nalbuphine extended release (NAL-ER) 162 mg twice daily provided measurable antipruritic efficacy, with 44.4% (8/18) of patients achieving at least a 30% reduction in 7-day WI-NRS at week 10 compared with 36.4% (8/22) in the placebo group. Among those who completed the study, 66.7% (8/12) of patients receiving NAL-ER 162 mg achieved significant itch reduction vs 40% (8/20) receiving placebo (P=.03). At least a 50% reduction in WI-NRS was achieved by 33.3% (6/18) of patients receiving NAL-ER 162 mg twice daily. Extended open-label treatment was associated with further improvements in itch and lesion activity. Adverse events were mostly mild to moderate (eg, nausea, dizziness, headache, and fatigue) and occurred during dose titration. Physiologic opioid withdrawal symptoms were limited and resolved within a few days of discontinuing the medication.¹¹

Final Thoughts

In conclusion, PN remains one of the most challenging chronic dermatologic conditions to manage and is driven by a complex interplay of neuroimmune mechanisms and resistance to many conventional therapies. The approval of dupilumab and nemolizumab has marked a pivotal shift in the therapeutic landscape, offering hope to patients who previously had limited options^5,8; however, the burden of PN remains substantial, and many patients continue to experience relentless itch, poor sleep, and reduced quality of life.¹ Emerging therapies such as TRPM8 agonists, Janus kinase inhibitors, and opioid modulators represent promising additions to the treatment options, targeting novel pathways beyond traditional immunosuppression.^9-11

Prurigo nodularis (PN) is a chronic, severely pruritic neuroimmunologic skin disorder characterized by multiple firm hyperkeratotic nodules and intense pruritus, often leading to considerable impairment in quality of life and increased rates of depression and anxiety.¹ It is considered difficult to treat due to its complex pathogenesis, the severity and chronicity of pruritus, and the limited efficacy of conventional therapies.^2,3 The disease is driven by a self-perpetuating itch-scratch cycle, underpinned by dysregulation of both immune and neural pathways including type 2 (interleukin [IL] 4, IL-13, IL-31), Th17, and Th22 cytokines as well as neuropeptides and altered cutaneous nerve architecture.^1,3 This results in persistent severe pruritus and nodular lesions that are highly refractory to standard treatments.¹ Conventional therapies (eg, locally acting agents, phototherapy, and systemic immunomodulators and neuromodulators) have varied efficacy and notable adverse effect profiles.³ While the approval of targeted biologics has transformed the therapeutic landscape, several other treatment options also are being explored in clinical trials. Herein, we review all recently approved therapies as well as emerging treatments currently under investigation.

Dupilumab

Dupilumab, the first therapy for PN approved by the US Food and Drug Administration (FDA) in 2022—is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation implicated in PN pathogenesis.^4,5 In 2 pivotal phase 3 randomized controlled trials (LIBERTY-PN PRIME and PRIME2),⁵ dupilumab demonstrated notable efficacy in adults with moderate to severe PN. A reduction of 4 points or more on the Worst Itch Numeric Rating Scale (WI-NRS) was achieved by 60.0% (45/75) of patients treated with dupilumab at week 24 compared with 18.4% (14/76) receiving placebo in the PRIME trial. In PRIME2, the same outcome was achieved by 37.2% (29/78) of patients receiving dupilumab at week 12 compared with 22.0% (18/82) of patients receiving placebo.⁵ Dupilumab also led to a greater proportion of patients achieving a substantial reduction in nodule count (≤5 nodules) and improved quality of life compared with placebo.^5,6 The safety profile of dupilumab for treatment of PN was favorable and consistent with prior experience in atopic dermatitis; conjunctivitis was the most common adverse event.^5,6

Nemolizumab

Nemolizumab, an IL-31 receptor A antagonist, is the most recent agent approved by the FDA for PN in 2024.⁷ In the OLYMPIA 1 and OLYMPIA 2 phase 3 trials,⁸ nemolizumab produced a clinically meaningful reduction in itch (defined as a ≥4-point improvement in the Peak Pruritus Numerical Rating Scale score) in 56.3% (103/183) of patients at week 16 compared with 20.9% (19/91) receiving placebo. Additionally, 37.7% (69/183) of patients receiving nemolizumab achieved clear or almost clear skin (Investigator’s Global Assessment score of 0 or 1 with a ≥2-point reduction) vs 11.0% with placebo (both P<.001). Benefits were observed as early as week 4, including rapid improvements in itch, sleep disturbance, and nodule count.⁸ Nemolizumab also improved quality of life and reduced symptoms of anxiety and depression. The safety profile was favorable, with headache and atopic dermatitis the most common adverse events; serious adverse events were infrequent and similar between groups.⁸

Abrocitinib

Abrocitinib, an oral selective Janus kinase 1 inhibitor, is an investigational therapy for PN and currently has not been approved by the FDA for this indication. In a phase 2 open-label trial, abrocitinib 200 mg daily for 12 weeks led to a 78.3% reduction in weekly Peak Pruritus Numerical Rating Scale scores in PN, with 80.0% (8/10) of patients achieving a clinically meaningful improvement of 4 points or higher. Nodule counts and quality of life also improved, with an onset of itch relief as early as week 2. The safety profile was favorable, with acneform eruptions the most common adverse event and no serious adverse events reported⁹; however, these results are based on small, nonrandomized studies and require confirmation in larger randomized controlled trials before abrocitinib can be considered a standard therapy for PN.

Cryosim-1

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing ion channel found in unmyelinated sensory neurons within the dorsal root and trigeminal ­ganglia.¹⁰ It is activated by cool temperatures (15-28 °C) and compounds such as menthol, leading to calcium influx and a cooling sensation. In a randomized, double-blind, vehicle-controlled trial, researchers investigated the efficacy of cryosim-1 (a synthetic TRPM8 agonist) in treating PN.¹⁰ Thirty patients were enrolled, with 18 (60.0%) receiving cryosim-1 and 12 (40.0%) receiving placebo over 8 weeks. By week 8, cryosim-1 significantly reduced itch severity (mean numerical rating scale score postapplication, 2.8 vs 4.3; P=.031) and improved sleep disturbances (2.2 vs 4.2; P=.031) compared to placebo. Patients reported higher satisfaction with itch relief, and no adverse effects were observed. The study concluded that cryosim-1 is a safe, effective topical therapy for PN, likely working by interrupting the itch-scratch cycle and potentially modulating inflammatory pathways involved in chronic itch.¹⁰

Nalbuphine

Nalbuphine is a κ opioid receptor agonist and μ opioid receptor antagonist that has been investigated for the treatment of PN.¹¹ In a phase 2 randomized controlled trial, oral nalbuphine extended release (NAL-ER) 162 mg twice daily provided measurable antipruritic efficacy, with 44.4% (8/18) of patients achieving at least a 30% reduction in 7-day WI-NRS at week 10 compared with 36.4% (8/22) in the placebo group. Among those who completed the study, 66.7% (8/12) of patients receiving NAL-ER 162 mg achieved significant itch reduction vs 40% (8/20) receiving placebo (P=.03). At least a 50% reduction in WI-NRS was achieved by 33.3% (6/18) of patients receiving NAL-ER 162 mg twice daily. Extended open-label treatment was associated with further improvements in itch and lesion activity. Adverse events were mostly mild to moderate (eg, nausea, dizziness, headache, and fatigue) and occurred during dose titration. Physiologic opioid withdrawal symptoms were limited and resolved within a few days of discontinuing the medication.¹¹

Final Thoughts

In conclusion, PN remains one of the most challenging chronic dermatologic conditions to manage and is driven by a complex interplay of neuroimmune mechanisms and resistance to many conventional therapies. The approval of dupilumab and nemolizumab has marked a pivotal shift in the therapeutic landscape, offering hope to patients who previously had limited options^5,8; however, the burden of PN remains substantial, and many patients continue to experience relentless itch, poor sleep, and reduced quality of life.¹ Emerging therapies such as TRPM8 agonists, Janus kinase inhibitors, and opioid modulators represent promising additions to the treatment options, targeting novel pathways beyond traditional immunosuppression.^9-11

Prurigo nodularis (PN) is a chronic, severely pruritic neuroimmunologic skin disorder characterized by multiple firm hyperkeratotic nodules and intense pruritus, often leading to considerable impairment in quality of life and increased rates of depression and anxiety.¹ It is considered difficult to treat due to its complex pathogenesis, the severity and chronicity of pruritus, and the limited efficacy of conventional therapies.^2,3 The disease is driven by a self-perpetuating itch-scratch cycle, underpinned by dysregulation of both immune and neural pathways including type 2 (interleukin [IL] 4, IL-13, IL-31), Th17, and Th22 cytokines as well as neuropeptides and altered cutaneous nerve architecture.^1,3 This results in persistent severe pruritus and nodular lesions that are highly refractory to standard treatments.¹ Conventional therapies (eg, locally acting agents, phototherapy, and systemic immunomodulators and neuromodulators) have varied efficacy and notable adverse effect profiles.³ While the approval of targeted biologics has transformed the therapeutic landscape, several other treatment options also are being explored in clinical trials. Herein, we review all recently approved therapies as well as emerging treatments currently under investigation.

Dupilumab

Dupilumab, the first therapy for PN approved by the US Food and Drug Administration (FDA) in 2022—is a monoclonal antibody that inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation implicated in PN pathogenesis.^4,5 In 2 pivotal phase 3 randomized controlled trials (LIBERTY-PN PRIME and PRIME2),⁵ dupilumab demonstrated notable efficacy in adults with moderate to severe PN. A reduction of 4 points or more on the Worst Itch Numeric Rating Scale (WI-NRS) was achieved by 60.0% (45/75) of patients treated with dupilumab at week 24 compared with 18.4% (14/76) receiving placebo in the PRIME trial. In PRIME2, the same outcome was achieved by 37.2% (29/78) of patients receiving dupilumab at week 12 compared with 22.0% (18/82) of patients receiving placebo.⁵ Dupilumab also led to a greater proportion of patients achieving a substantial reduction in nodule count (≤5 nodules) and improved quality of life compared with placebo.^5,6 The safety profile of dupilumab for treatment of PN was favorable and consistent with prior experience in atopic dermatitis; conjunctivitis was the most common adverse event.^5,6

Nemolizumab

Nemolizumab, an IL-31 receptor A antagonist, is the most recent agent approved by the FDA for PN in 2024.⁷ In the OLYMPIA 1 and OLYMPIA 2 phase 3 trials,⁸ nemolizumab produced a clinically meaningful reduction in itch (defined as a ≥4-point improvement in the Peak Pruritus Numerical Rating Scale score) in 56.3% (103/183) of patients at week 16 compared with 20.9% (19/91) receiving placebo. Additionally, 37.7% (69/183) of patients receiving nemolizumab achieved clear or almost clear skin (Investigator’s Global Assessment score of 0 or 1 with a ≥2-point reduction) vs 11.0% with placebo (both P<.001). Benefits were observed as early as week 4, including rapid improvements in itch, sleep disturbance, and nodule count.⁸ Nemolizumab also improved quality of life and reduced symptoms of anxiety and depression. The safety profile was favorable, with headache and atopic dermatitis the most common adverse events; serious adverse events were infrequent and similar between groups.⁸

Abrocitinib

Abrocitinib, an oral selective Janus kinase 1 inhibitor, is an investigational therapy for PN and currently has not been approved by the FDA for this indication. In a phase 2 open-label trial, abrocitinib 200 mg daily for 12 weeks led to a 78.3% reduction in weekly Peak Pruritus Numerical Rating Scale scores in PN, with 80.0% (8/10) of patients achieving a clinically meaningful improvement of 4 points or higher. Nodule counts and quality of life also improved, with an onset of itch relief as early as week 2. The safety profile was favorable, with acneform eruptions the most common adverse event and no serious adverse events reported⁹; however, these results are based on small, nonrandomized studies and require confirmation in larger randomized controlled trials before abrocitinib can be considered a standard therapy for PN.

Cryosim-1

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing ion channel found in unmyelinated sensory neurons within the dorsal root and trigeminal ­ganglia.¹⁰ It is activated by cool temperatures (15-28 °C) and compounds such as menthol, leading to calcium influx and a cooling sensation. In a randomized, double-blind, vehicle-controlled trial, researchers investigated the efficacy of cryosim-1 (a synthetic TRPM8 agonist) in treating PN.¹⁰ Thirty patients were enrolled, with 18 (60.0%) receiving cryosim-1 and 12 (40.0%) receiving placebo over 8 weeks. By week 8, cryosim-1 significantly reduced itch severity (mean numerical rating scale score postapplication, 2.8 vs 4.3; P=.031) and improved sleep disturbances (2.2 vs 4.2; P=.031) compared to placebo. Patients reported higher satisfaction with itch relief, and no adverse effects were observed. The study concluded that cryosim-1 is a safe, effective topical therapy for PN, likely working by interrupting the itch-scratch cycle and potentially modulating inflammatory pathways involved in chronic itch.¹⁰

Nalbuphine

Nalbuphine is a κ opioid receptor agonist and μ opioid receptor antagonist that has been investigated for the treatment of PN.¹¹ In a phase 2 randomized controlled trial, oral nalbuphine extended release (NAL-ER) 162 mg twice daily provided measurable antipruritic efficacy, with 44.4% (8/18) of patients achieving at least a 30% reduction in 7-day WI-NRS at week 10 compared with 36.4% (8/22) in the placebo group. Among those who completed the study, 66.7% (8/12) of patients receiving NAL-ER 162 mg achieved significant itch reduction vs 40% (8/20) receiving placebo (P=.03). At least a 50% reduction in WI-NRS was achieved by 33.3% (6/18) of patients receiving NAL-ER 162 mg twice daily. Extended open-label treatment was associated with further improvements in itch and lesion activity. Adverse events were mostly mild to moderate (eg, nausea, dizziness, headache, and fatigue) and occurred during dose titration. Physiologic opioid withdrawal symptoms were limited and resolved within a few days of discontinuing the medication.¹¹

Final Thoughts

In conclusion, PN remains one of the most challenging chronic dermatologic conditions to manage and is driven by a complex interplay of neuroimmune mechanisms and resistance to many conventional therapies. The approval of dupilumab and nemolizumab has marked a pivotal shift in the therapeutic landscape, offering hope to patients who previously had limited options^5,8; however, the burden of PN remains substantial, and many patients continue to experience relentless itch, poor sleep, and reduced quality of life.¹ Emerging therapies such as TRPM8 agonists, Janus kinase inhibitors, and opioid modulators represent promising additions to the treatment options, targeting novel pathways beyond traditional immunosuppression.^9-11

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

THE DIAGNOSIS: Impetigo Herpetiformis

Histopathology revealed epidermal acanthosis and spongiosis with overlying parakeratosis associated with subcorneal and intracorneal neutrophils, papillary dermal edema, and dermal mixed inflammation with neutrophils and eosinophils. Both direct immunofluorescence and periodic acid–Schiff studies were negative. Blood and pustule cultures were sterile and the skin flora were normal. Based on these findings, a diagnosis of impetigo herpetiformis (IH) was made. The condition improved with systemic and topical steroids, supportive care, and an intravenous infusion of infliximab 5 mg/kg. At 3 weeks’ follow-up, the patient demonstrated near-complete resolution and later delivered successfully at 40 weeks’ gestation without complications.

Impetigo herpetiformis, also known as pustular psoriasis of pregnancy, is an exceedingly rare gestational dermatosis that typically manifests in the third trimester and can be life-threatening for both the mother and fetus. The term was first used in 1872 to describe 5 pregnant women with extensive acute pustular eruptions, all in unstable condition; 4 (80%)of the cases resulted in maternal death, and all resulted in fetal death.¹ Impetigo herpetiformis is characterized by pruritic and painful erythematous patches studded at the periphery with subcorneal pustules. Eruptions usually occur in the flexural areas and spread centrifugally, with extension of the lesions peripherally as the center erodes and crusts. Sparing of the face, palms, and soles is expected, and mucosal involvement is rare. Generalized involvement and exfoliation may occur in extreme cases.² While IH typically manifests during the third trimester, it may occur any time throughout pregnancy or immediately postpartum.³ A few cases have been reported in the puerperium.² Common symptoms include fever, chills, malaise, anorexia, nausea, vomiting, diarrhea, and arthralgias. Less common complications include hypoalbuminemia and severe hypocalcemia leading to tetany, seizures, and delirium.^2,3 While maternal mortality is uncommon, fetal mortality often is a more pressing risk and is attributed to placental insufficiency.^3,4 For this reason, early delivery commonly is considered in severe cases.

Whether IH is a separate entity or a variant of pustular psoriasis remains heavily debated. Although the histopathology of IH is identical to pustular psoriasis, the lack of a personal and family history of psoriasis, symptom resolution with delivery, and possible recurrence during successive pregnancies help differentiate IH from generalized pustular psoriasis.^2,5 Earlier onset, diffuse involvement, faster progression, and recurrence in subsequent pregnancies all have been linked to a worse prognosis.⁴

The differential diagnosis for IH includes acute generalized exanthematous pustulosis, pemphigoid gestationis, dermatitis herpetiformis, and subcorneal pustular dermatosis. Acute generalized exanthematous pustulosis is an uncommon severe cutaneous drug reaction characterized by the sudden onset of numerous sterile pustules on erythematous skin within 48 hours of exposure. The most common offending medications include pristinamycin and beta-lactam antibiotics. A high fever, neutrophilic leukocytosis, and hypocalcemia often accompany acute generalized exanthematous pustulosis.⁶ Prompt diagnosis and withdrawal of the offending drug as well as supportive care and symptomatic treatment are crucial for disease management, as systemic symptoms and even organ involvement may occur.⁶

Pemphigoid gestationis, also known as gestational pemphigoid or herpes gestationis, is a rare autoimmune blistering disorder that primarily affects pregnant women. It typically manifests in the second or third trimester or shortly after delivery. Clinically, it manifests as an intensely pruritic polymorphic eruption of urticarial papules and plaques accompanied by vesicles and bullae and often is distributed on the abdomen and extends to other body regions. Although the exact etiology is unknown, pemphigoid gestationis is caused by autoantibodies targeting the BP180 and BP230 hemidesmosomal proteins.⁷ Treatment usually involves systemic corticosteroids and may require additional immunosuppressive therapy. In most cases, patients see resolution within 6 months of delivery.⁷

Dermatitis herpetiformis is a chronic autoimmune blistering skin disorder characterized by intensely pruritic, grouped vesicles and papules, often distributed symmetrically on extensor surfaces such as the elbows, knees, buttocks, and back. It is closely associated with celiac disease and is triggered by gluten ingestion in genetically predisposed individuals with human leukocyte antigen DQ2 and DQ8 haplotypes. Dermatitis herpetiformis is caused by deposition of IgA antibodies that target tissue transglutaminase 3 at the dermal papillae, leading to inflammation and blister formation. ⁸ Treatment typically involves a gluten-free diet and medications such as dapsone to alleviate symptoms and prevent recurrence.

Subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a rare chronic relapsing pustular dermatosis characterized by sterile superficial pustules arranged in annular or circinate patterns on erythematous plaques. It predominantly affects middleaged women and often is associated with underlying conditions such as IgA gammopathy or monoclonal gammopathy of undetermined significance. The pathogenesis remains unclear, but immune dysregulation is thought to play a role. Some authors still question whether subcorneal pustular dermatosis is a distinct entity from pustular psoriasis.^4,5,12 Dapsone is the preferred first-line treatment, with adjunct therapies including topical or systemic corticosteroids, other immunosuppressive agents, tumor necrosis factor inhibitors, and UV light therapy.⁹

Definitive management of IH is achieved through early delivery; however, systemic corticosteroids often are used in varying doses to control the disease and to extend the pregnancy period closer to term or until delivery is considered viable. Additional therapies that can be considered include infliximab, cyclosporine, and topical corticosteroids, in conjunction with fluid and electrolyte maintenance.^2,4,10 If symptoms persist despite supportive care and pharmacologic intervention, induction of labor or termination of pregnancy may be indicated. In nonbreastfeeding postpartum mothers with persistent disease, therapies commonly used in generalized pustular psoriasis may be given.¹¹

THE DIAGNOSIS: Impetigo Herpetiformis

Histopathology revealed epidermal acanthosis and spongiosis with overlying parakeratosis associated with subcorneal and intracorneal neutrophils, papillary dermal edema, and dermal mixed inflammation with neutrophils and eosinophils. Both direct immunofluorescence and periodic acid–Schiff studies were negative. Blood and pustule cultures were sterile and the skin flora were normal. Based on these findings, a diagnosis of impetigo herpetiformis (IH) was made. The condition improved with systemic and topical steroids, supportive care, and an intravenous infusion of infliximab 5 mg/kg. At 3 weeks’ follow-up, the patient demonstrated near-complete resolution and later delivered successfully at 40 weeks’ gestation without complications.

Impetigo herpetiformis, also known as pustular psoriasis of pregnancy, is an exceedingly rare gestational dermatosis that typically manifests in the third trimester and can be life-threatening for both the mother and fetus. The term was first used in 1872 to describe 5 pregnant women with extensive acute pustular eruptions, all in unstable condition; 4 (80%)of the cases resulted in maternal death, and all resulted in fetal death.¹ Impetigo herpetiformis is characterized by pruritic and painful erythematous patches studded at the periphery with subcorneal pustules. Eruptions usually occur in the flexural areas and spread centrifugally, with extension of the lesions peripherally as the center erodes and crusts. Sparing of the face, palms, and soles is expected, and mucosal involvement is rare. Generalized involvement and exfoliation may occur in extreme cases.² While IH typically manifests during the third trimester, it may occur any time throughout pregnancy or immediately postpartum.³ A few cases have been reported in the puerperium.² Common symptoms include fever, chills, malaise, anorexia, nausea, vomiting, diarrhea, and arthralgias. Less common complications include hypoalbuminemia and severe hypocalcemia leading to tetany, seizures, and delirium.^2,3 While maternal mortality is uncommon, fetal mortality often is a more pressing risk and is attributed to placental insufficiency.^3,4 For this reason, early delivery commonly is considered in severe cases.

Whether IH is a separate entity or a variant of pustular psoriasis remains heavily debated. Although the histopathology of IH is identical to pustular psoriasis, the lack of a personal and family history of psoriasis, symptom resolution with delivery, and possible recurrence during successive pregnancies help differentiate IH from generalized pustular psoriasis.^2,5 Earlier onset, diffuse involvement, faster progression, and recurrence in subsequent pregnancies all have been linked to a worse prognosis.⁴

The differential diagnosis for IH includes acute generalized exanthematous pustulosis, pemphigoid gestationis, dermatitis herpetiformis, and subcorneal pustular dermatosis. Acute generalized exanthematous pustulosis is an uncommon severe cutaneous drug reaction characterized by the sudden onset of numerous sterile pustules on erythematous skin within 48 hours of exposure. The most common offending medications include pristinamycin and beta-lactam antibiotics. A high fever, neutrophilic leukocytosis, and hypocalcemia often accompany acute generalized exanthematous pustulosis.⁶ Prompt diagnosis and withdrawal of the offending drug as well as supportive care and symptomatic treatment are crucial for disease management, as systemic symptoms and even organ involvement may occur.⁶

Pemphigoid gestationis, also known as gestational pemphigoid or herpes gestationis, is a rare autoimmune blistering disorder that primarily affects pregnant women. It typically manifests in the second or third trimester or shortly after delivery. Clinically, it manifests as an intensely pruritic polymorphic eruption of urticarial papules and plaques accompanied by vesicles and bullae and often is distributed on the abdomen and extends to other body regions. Although the exact etiology is unknown, pemphigoid gestationis is caused by autoantibodies targeting the BP180 and BP230 hemidesmosomal proteins.⁷ Treatment usually involves systemic corticosteroids and may require additional immunosuppressive therapy. In most cases, patients see resolution within 6 months of delivery.⁷

Dermatitis herpetiformis is a chronic autoimmune blistering skin disorder characterized by intensely pruritic, grouped vesicles and papules, often distributed symmetrically on extensor surfaces such as the elbows, knees, buttocks, and back. It is closely associated with celiac disease and is triggered by gluten ingestion in genetically predisposed individuals with human leukocyte antigen DQ2 and DQ8 haplotypes. Dermatitis herpetiformis is caused by deposition of IgA antibodies that target tissue transglutaminase 3 at the dermal papillae, leading to inflammation and blister formation. ⁸ Treatment typically involves a gluten-free diet and medications such as dapsone to alleviate symptoms and prevent recurrence.

Subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a rare chronic relapsing pustular dermatosis characterized by sterile superficial pustules arranged in annular or circinate patterns on erythematous plaques. It predominantly affects middleaged women and often is associated with underlying conditions such as IgA gammopathy or monoclonal gammopathy of undetermined significance. The pathogenesis remains unclear, but immune dysregulation is thought to play a role. Some authors still question whether subcorneal pustular dermatosis is a distinct entity from pustular psoriasis.^4,5,12 Dapsone is the preferred first-line treatment, with adjunct therapies including topical or systemic corticosteroids, other immunosuppressive agents, tumor necrosis factor inhibitors, and UV light therapy.⁹

Definitive management of IH is achieved through early delivery; however, systemic corticosteroids often are used in varying doses to control the disease and to extend the pregnancy period closer to term or until delivery is considered viable. Additional therapies that can be considered include infliximab, cyclosporine, and topical corticosteroids, in conjunction with fluid and electrolyte maintenance.^2,4,10 If symptoms persist despite supportive care and pharmacologic intervention, induction of labor or termination of pregnancy may be indicated. In nonbreastfeeding postpartum mothers with persistent disease, therapies commonly used in generalized pustular psoriasis may be given.¹¹

THE DIAGNOSIS: Impetigo Herpetiformis

Histopathology revealed epidermal acanthosis and spongiosis with overlying parakeratosis associated with subcorneal and intracorneal neutrophils, papillary dermal edema, and dermal mixed inflammation with neutrophils and eosinophils. Both direct immunofluorescence and periodic acid–Schiff studies were negative. Blood and pustule cultures were sterile and the skin flora were normal. Based on these findings, a diagnosis of impetigo herpetiformis (IH) was made. The condition improved with systemic and topical steroids, supportive care, and an intravenous infusion of infliximab 5 mg/kg. At 3 weeks’ follow-up, the patient demonstrated near-complete resolution and later delivered successfully at 40 weeks’ gestation without complications.

Impetigo herpetiformis, also known as pustular psoriasis of pregnancy, is an exceedingly rare gestational dermatosis that typically manifests in the third trimester and can be life-threatening for both the mother and fetus. The term was first used in 1872 to describe 5 pregnant women with extensive acute pustular eruptions, all in unstable condition; 4 (80%)of the cases resulted in maternal death, and all resulted in fetal death.¹ Impetigo herpetiformis is characterized by pruritic and painful erythematous patches studded at the periphery with subcorneal pustules. Eruptions usually occur in the flexural areas and spread centrifugally, with extension of the lesions peripherally as the center erodes and crusts. Sparing of the face, palms, and soles is expected, and mucosal involvement is rare. Generalized involvement and exfoliation may occur in extreme cases.² While IH typically manifests during the third trimester, it may occur any time throughout pregnancy or immediately postpartum.³ A few cases have been reported in the puerperium.² Common symptoms include fever, chills, malaise, anorexia, nausea, vomiting, diarrhea, and arthralgias. Less common complications include hypoalbuminemia and severe hypocalcemia leading to tetany, seizures, and delirium.^2,3 While maternal mortality is uncommon, fetal mortality often is a more pressing risk and is attributed to placental insufficiency.^3,4 For this reason, early delivery commonly is considered in severe cases.

Whether IH is a separate entity or a variant of pustular psoriasis remains heavily debated. Although the histopathology of IH is identical to pustular psoriasis, the lack of a personal and family history of psoriasis, symptom resolution with delivery, and possible recurrence during successive pregnancies help differentiate IH from generalized pustular psoriasis.^2,5 Earlier onset, diffuse involvement, faster progression, and recurrence in subsequent pregnancies all have been linked to a worse prognosis.⁴

The differential diagnosis for IH includes acute generalized exanthematous pustulosis, pemphigoid gestationis, dermatitis herpetiformis, and subcorneal pustular dermatosis. Acute generalized exanthematous pustulosis is an uncommon severe cutaneous drug reaction characterized by the sudden onset of numerous sterile pustules on erythematous skin within 48 hours of exposure. The most common offending medications include pristinamycin and beta-lactam antibiotics. A high fever, neutrophilic leukocytosis, and hypocalcemia often accompany acute generalized exanthematous pustulosis.⁶ Prompt diagnosis and withdrawal of the offending drug as well as supportive care and symptomatic treatment are crucial for disease management, as systemic symptoms and even organ involvement may occur.⁶

Pemphigoid gestationis, also known as gestational pemphigoid or herpes gestationis, is a rare autoimmune blistering disorder that primarily affects pregnant women. It typically manifests in the second or third trimester or shortly after delivery. Clinically, it manifests as an intensely pruritic polymorphic eruption of urticarial papules and plaques accompanied by vesicles and bullae and often is distributed on the abdomen and extends to other body regions. Although the exact etiology is unknown, pemphigoid gestationis is caused by autoantibodies targeting the BP180 and BP230 hemidesmosomal proteins.⁷ Treatment usually involves systemic corticosteroids and may require additional immunosuppressive therapy. In most cases, patients see resolution within 6 months of delivery.⁷

Dermatitis herpetiformis is a chronic autoimmune blistering skin disorder characterized by intensely pruritic, grouped vesicles and papules, often distributed symmetrically on extensor surfaces such as the elbows, knees, buttocks, and back. It is closely associated with celiac disease and is triggered by gluten ingestion in genetically predisposed individuals with human leukocyte antigen DQ2 and DQ8 haplotypes. Dermatitis herpetiformis is caused by deposition of IgA antibodies that target tissue transglutaminase 3 at the dermal papillae, leading to inflammation and blister formation. ⁸ Treatment typically involves a gluten-free diet and medications such as dapsone to alleviate symptoms and prevent recurrence.

Subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a rare chronic relapsing pustular dermatosis characterized by sterile superficial pustules arranged in annular or circinate patterns on erythematous plaques. It predominantly affects middleaged women and often is associated with underlying conditions such as IgA gammopathy or monoclonal gammopathy of undetermined significance. The pathogenesis remains unclear, but immune dysregulation is thought to play a role. Some authors still question whether subcorneal pustular dermatosis is a distinct entity from pustular psoriasis.^4,5,12 Dapsone is the preferred first-line treatment, with adjunct therapies including topical or systemic corticosteroids, other immunosuppressive agents, tumor necrosis factor inhibitors, and UV light therapy.⁹

Definitive management of IH is achieved through early delivery; however, systemic corticosteroids often are used in varying doses to control the disease and to extend the pregnancy period closer to term or until delivery is considered viable. Additional therapies that can be considered include infliximab, cyclosporine, and topical corticosteroids, in conjunction with fluid and electrolyte maintenance.^2,4,10 If symptoms persist despite supportive care and pharmacologic intervention, induction of labor or termination of pregnancy may be indicated. In nonbreastfeeding postpartum mothers with persistent disease, therapies commonly used in generalized pustular psoriasis may be given.¹¹