Cutis

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

Biologics have revolutionized dermatologic treatment, offering substantial relief from chronic and ­debilitating skin conditions such as psoriasis, hidradenitis suppurativa, atopic dermatitis (AD), chronic urticaria, and immunobullous diseases (eg, pemphigus vulgaris, bullous pemphigoid). By drastically decreasing symptom burden, biologics have the potential to transform patients’ lives by improving their overall quality of life (QOL). However, the use of biologics during ­pregnancy raises critical considerations, especially ­regarding safety.

Biologics for Cutaneous Conditions

Biologics—tumor necrosis factor (TNF) α inhibitors; IL-17, IL-23, IL-12, and IL-36 inhibitors; and agents such as omalizumab and dupilumab—have shown remarkable efficacy in controlling severe or recalcitrant dermatologic conditions and typically are more effective than traditional systemic therapies.¹ For instance, randomized clinical trials (RCTs) and real-world data have shown that patients with psoriasis can achieve considerable skin clearance with biologics, greatly enhancing QOL.² Adalimumab and secukinumab, which have been approved for use in moderate to severe cases of hidradenitis suppurativa, reduce the frequency of painful nodules and abscesses, thereby decreasing pain and improving QOL. Dupilumab, an IL-4/13 receptor antagonist, has revolutionized the treatment of AD by drastically reducing itch and skin lesions and improving QOL.³ For chronic urticaria, the anti-IgE antibody omalizumab has effectively reduced the incidence of hives and itching, providing pronounced symptom relief when traditional antihistamines fail.⁴ Use of rituximab, an anti-CD20 monoclonal antibody, has led to remission in severe cases of pemphigus vulgaris and bullous pemphigoid.⁵

Impact of Untreated Cutaneous Conditions in Pregnancy

When treating patients who are pregnant, dermatologists must consider the health of both the expectant mother and the developing fetus. This dual focus complicates decision-making, particularly with the use of biologics. Untreated cutaneous conditions can profoundly impact a pregnant patient’s health and QOL as well as lead to pregnancy complications affecting the fetus, such as preterm birth or low birth weight. In some studies, moderate to severe psoriasis has been associated with increased risk for complications during pregnancy, including preeclampsia and intrauterine growth restriction.⁶ Although specific data on hidradenitis suppurativa are lacking, the highly inflammatory nature of the condition suggests similar adverse effects on pregnancy.⁷ Atopic dermatitis can be exacerbated during pregnancy due to a shift in the immune system to become more allergic dominant.⁸ Generalized pustular psoriasis manifests with widespread pustules, fever, and systemic inflammation, posing serious risks to both the mother and the fetus if left untreated⁹; in such a life-threatening scenario, the use of potent treatments such as spesolimab, an IL-36 receptor antagonist, may be warranted. Therefore, managing these conditions effectively is crucial not only for the mother’s health but also for fetal well-being.

Which Biologics Can Dermatologists Safely Prescribe?

Despite the benefits, many dermatologists are hesitant to prescribe biologics to pregnant patients due to the lack of understanding and definitive safety data.^10,11 Although there are no RCTs that involve pregnant patients, current evidence suggests that several biologics are not teratogenic and do not cause fetal malformations. Extensive postexposure data support the safety of TNF-α inhibitors during pregnancy.¹² Research has shown that children exposed to these agents in utero have normal development, infection rates, and vaccination outcomes comparable to nonexposed children. For example, a systematic review and meta-analysis found no significant increase in the risk for major congenital malformations, spontaneous abortions, or preterm births among patients exposed to anti–TNF-α agents during pregnancy.² The Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project has provided valuable real-world data indicating that the use of TNF-α inhibitors in pregnancy, particularly during the first trimester, does not substantially elevate the risk for adverse outcomes.¹³ These findings have been corroborated by several other registry studies and RCTs, providing a robust safety profile for these agents during pregnancy.¹⁴

Similarly, postexposure data on IL-17 and IL-12/23 inhibitors indicate a favorable safety profile, though the sample sizes are smaller than those for anti–TNF-α agents.^12,14 Studies of drugs such as secukinumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), or ustekinumab (IL-12/23 inhibitor) have shown no association with teratogenic effects or increased risk for miscarriage.¹⁴ However, agents such as spesolimab (IL-36 inhibitor) are relatively new, and ongoing studies are expected to provide more comprehensive safety data.¹⁵ Similarly, omalizumab and dupilumab have not been associated with increased risk for fetal malformations or adverse pregnancy outcomes. Omalizumab, indicated for chronic urticaria, has a good safety profile in pregnancy, with no significant increase in adverse outcomes reported in studies and registries.¹⁶ Dupilumab, used for AD, has demonstrated safety in pregnancy, with ongoing studies continuing to monitor outcomes.¹⁷

Conversely, rituximab (an anti-CD20 antibody for autoimmune bullous diseases) has shown evidence of adverse pregnancy outcomes, including fetal harm.¹⁸ Its use generally is discouraged unless deemed absolutely necessary, and no safer alternatives are available. Rituximab can cross the placenta, especially in the second and third trimesters, and has been associated with B-cell depletion in the fetus, leading to potential immunosuppression and increased risk for infections.⁵

Although the data on the safety of biologics in pregnancy are largely reassuring, it is essential to recognize that potential risks have not been ruled out entirely. There are extensive safety data for anti–TNF-α inhibitors, which provides a level of confidence; although newer agents such as IL-17 and IL-23 inhibitors have shown promising early results, further research is required to solidify their safety profiles during pregnancy.

Dermatologists must balance the risks and benefits of using biologics in pregnant patients. This decision-­making process involves careful consideration of the severity of the mother’s condition, the potential risks to the fetus, and the availability of alternative treatments. For many severe dermatologic conditions, the benefits of biologics in controlling disease activity and improving QOL may outweigh the potential risks, especially when other treatments have failed or are not suitable.

Final Thoughts

The increasing use of biologics in dermatology has undoubtedly improved the management of severe skin conditions, substantially enhancing patients’ QOL. As more data become available and clinical guidelines evolve, health care providers will be better equipped to make informed decisions about the use of biologics, particularly in pregnant patients. Collaborative efforts between dermatologists, obstetricians, and researchers will help refine treatment guidelines and ensure that pregnant patients with severe dermatologic conditions receive the best possible care.

For now, although the current evidence supports the safety of many biologics during pregnancy,^10,11 individualized care and informed decision-making remain paramount. Careful management and adherence to current guidelines make it possible to navigate the complexities of treating severe dermatologic conditions in pregnant patients, ensuring the best outcomes for both mother and child.

Biologics have revolutionized dermatologic treatment, offering substantial relief from chronic and ­debilitating skin conditions such as psoriasis, hidradenitis suppurativa, atopic dermatitis (AD), chronic urticaria, and immunobullous diseases (eg, pemphigus vulgaris, bullous pemphigoid). By drastically decreasing symptom burden, biologics have the potential to transform patients’ lives by improving their overall quality of life (QOL). However, the use of biologics during ­pregnancy raises critical considerations, especially ­regarding safety.

Biologics for Cutaneous Conditions

Biologics—tumor necrosis factor (TNF) α inhibitors; IL-17, IL-23, IL-12, and IL-36 inhibitors; and agents such as omalizumab and dupilumab—have shown remarkable efficacy in controlling severe or recalcitrant dermatologic conditions and typically are more effective than traditional systemic therapies.¹ For instance, randomized clinical trials (RCTs) and real-world data have shown that patients with psoriasis can achieve considerable skin clearance with biologics, greatly enhancing QOL.² Adalimumab and secukinumab, which have been approved for use in moderate to severe cases of hidradenitis suppurativa, reduce the frequency of painful nodules and abscesses, thereby decreasing pain and improving QOL. Dupilumab, an IL-4/13 receptor antagonist, has revolutionized the treatment of AD by drastically reducing itch and skin lesions and improving QOL.³ For chronic urticaria, the anti-IgE antibody omalizumab has effectively reduced the incidence of hives and itching, providing pronounced symptom relief when traditional antihistamines fail.⁴ Use of rituximab, an anti-CD20 monoclonal antibody, has led to remission in severe cases of pemphigus vulgaris and bullous pemphigoid.⁵

Impact of Untreated Cutaneous Conditions in Pregnancy

When treating patients who are pregnant, dermatologists must consider the health of both the expectant mother and the developing fetus. This dual focus complicates decision-making, particularly with the use of biologics. Untreated cutaneous conditions can profoundly impact a pregnant patient’s health and QOL as well as lead to pregnancy complications affecting the fetus, such as preterm birth or low birth weight. In some studies, moderate to severe psoriasis has been associated with increased risk for complications during pregnancy, including preeclampsia and intrauterine growth restriction.⁶ Although specific data on hidradenitis suppurativa are lacking, the highly inflammatory nature of the condition suggests similar adverse effects on pregnancy.⁷ Atopic dermatitis can be exacerbated during pregnancy due to a shift in the immune system to become more allergic dominant.⁸ Generalized pustular psoriasis manifests with widespread pustules, fever, and systemic inflammation, posing serious risks to both the mother and the fetus if left untreated⁹; in such a life-threatening scenario, the use of potent treatments such as spesolimab, an IL-36 receptor antagonist, may be warranted. Therefore, managing these conditions effectively is crucial not only for the mother’s health but also for fetal well-being.

Which Biologics Can Dermatologists Safely Prescribe?

Despite the benefits, many dermatologists are hesitant to prescribe biologics to pregnant patients due to the lack of understanding and definitive safety data.^10,11 Although there are no RCTs that involve pregnant patients, current evidence suggests that several biologics are not teratogenic and do not cause fetal malformations. Extensive postexposure data support the safety of TNF-α inhibitors during pregnancy.¹² Research has shown that children exposed to these agents in utero have normal development, infection rates, and vaccination outcomes comparable to nonexposed children. For example, a systematic review and meta-analysis found no significant increase in the risk for major congenital malformations, spontaneous abortions, or preterm births among patients exposed to anti–TNF-α agents during pregnancy.² The Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project has provided valuable real-world data indicating that the use of TNF-α inhibitors in pregnancy, particularly during the first trimester, does not substantially elevate the risk for adverse outcomes.¹³ These findings have been corroborated by several other registry studies and RCTs, providing a robust safety profile for these agents during pregnancy.¹⁴

Similarly, postexposure data on IL-17 and IL-12/23 inhibitors indicate a favorable safety profile, though the sample sizes are smaller than those for anti–TNF-α agents.^12,14 Studies of drugs such as secukinumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), or ustekinumab (IL-12/23 inhibitor) have shown no association with teratogenic effects or increased risk for miscarriage.¹⁴ However, agents such as spesolimab (IL-36 inhibitor) are relatively new, and ongoing studies are expected to provide more comprehensive safety data.¹⁵ Similarly, omalizumab and dupilumab have not been associated with increased risk for fetal malformations or adverse pregnancy outcomes. Omalizumab, indicated for chronic urticaria, has a good safety profile in pregnancy, with no significant increase in adverse outcomes reported in studies and registries.¹⁶ Dupilumab, used for AD, has demonstrated safety in pregnancy, with ongoing studies continuing to monitor outcomes.¹⁷

Conversely, rituximab (an anti-CD20 antibody for autoimmune bullous diseases) has shown evidence of adverse pregnancy outcomes, including fetal harm.¹⁸ Its use generally is discouraged unless deemed absolutely necessary, and no safer alternatives are available. Rituximab can cross the placenta, especially in the second and third trimesters, and has been associated with B-cell depletion in the fetus, leading to potential immunosuppression and increased risk for infections.⁵

Although the data on the safety of biologics in pregnancy are largely reassuring, it is essential to recognize that potential risks have not been ruled out entirely. There are extensive safety data for anti–TNF-α inhibitors, which provides a level of confidence; although newer agents such as IL-17 and IL-23 inhibitors have shown promising early results, further research is required to solidify their safety profiles during pregnancy.

Dermatologists must balance the risks and benefits of using biologics in pregnant patients. This decision-­making process involves careful consideration of the severity of the mother’s condition, the potential risks to the fetus, and the availability of alternative treatments. For many severe dermatologic conditions, the benefits of biologics in controlling disease activity and improving QOL may outweigh the potential risks, especially when other treatments have failed or are not suitable.

Final Thoughts

The increasing use of biologics in dermatology has undoubtedly improved the management of severe skin conditions, substantially enhancing patients’ QOL. As more data become available and clinical guidelines evolve, health care providers will be better equipped to make informed decisions about the use of biologics, particularly in pregnant patients. Collaborative efforts between dermatologists, obstetricians, and researchers will help refine treatment guidelines and ensure that pregnant patients with severe dermatologic conditions receive the best possible care.

For now, although the current evidence supports the safety of many biologics during pregnancy,^10,11 individualized care and informed decision-making remain paramount. Careful management and adherence to current guidelines make it possible to navigate the complexities of treating severe dermatologic conditions in pregnant patients, ensuring the best outcomes for both mother and child.

Biologics have revolutionized dermatologic treatment, offering substantial relief from chronic and ­debilitating skin conditions such as psoriasis, hidradenitis suppurativa, atopic dermatitis (AD), chronic urticaria, and immunobullous diseases (eg, pemphigus vulgaris, bullous pemphigoid). By drastically decreasing symptom burden, biologics have the potential to transform patients’ lives by improving their overall quality of life (QOL). However, the use of biologics during ­pregnancy raises critical considerations, especially ­regarding safety.

Biologics for Cutaneous Conditions

Biologics—tumor necrosis factor (TNF) α inhibitors; IL-17, IL-23, IL-12, and IL-36 inhibitors; and agents such as omalizumab and dupilumab—have shown remarkable efficacy in controlling severe or recalcitrant dermatologic conditions and typically are more effective than traditional systemic therapies.¹ For instance, randomized clinical trials (RCTs) and real-world data have shown that patients with psoriasis can achieve considerable skin clearance with biologics, greatly enhancing QOL.² Adalimumab and secukinumab, which have been approved for use in moderate to severe cases of hidradenitis suppurativa, reduce the frequency of painful nodules and abscesses, thereby decreasing pain and improving QOL. Dupilumab, an IL-4/13 receptor antagonist, has revolutionized the treatment of AD by drastically reducing itch and skin lesions and improving QOL.³ For chronic urticaria, the anti-IgE antibody omalizumab has effectively reduced the incidence of hives and itching, providing pronounced symptom relief when traditional antihistamines fail.⁴ Use of rituximab, an anti-CD20 monoclonal antibody, has led to remission in severe cases of pemphigus vulgaris and bullous pemphigoid.⁵

Impact of Untreated Cutaneous Conditions in Pregnancy

When treating patients who are pregnant, dermatologists must consider the health of both the expectant mother and the developing fetus. This dual focus complicates decision-making, particularly with the use of biologics. Untreated cutaneous conditions can profoundly impact a pregnant patient’s health and QOL as well as lead to pregnancy complications affecting the fetus, such as preterm birth or low birth weight. In some studies, moderate to severe psoriasis has been associated with increased risk for complications during pregnancy, including preeclampsia and intrauterine growth restriction.⁶ Although specific data on hidradenitis suppurativa are lacking, the highly inflammatory nature of the condition suggests similar adverse effects on pregnancy.⁷ Atopic dermatitis can be exacerbated during pregnancy due to a shift in the immune system to become more allergic dominant.⁸ Generalized pustular psoriasis manifests with widespread pustules, fever, and systemic inflammation, posing serious risks to both the mother and the fetus if left untreated⁹; in such a life-threatening scenario, the use of potent treatments such as spesolimab, an IL-36 receptor antagonist, may be warranted. Therefore, managing these conditions effectively is crucial not only for the mother’s health but also for fetal well-being.

Which Biologics Can Dermatologists Safely Prescribe?

Despite the benefits, many dermatologists are hesitant to prescribe biologics to pregnant patients due to the lack of understanding and definitive safety data.^10,11 Although there are no RCTs that involve pregnant patients, current evidence suggests that several biologics are not teratogenic and do not cause fetal malformations. Extensive postexposure data support the safety of TNF-α inhibitors during pregnancy.¹² Research has shown that children exposed to these agents in utero have normal development, infection rates, and vaccination outcomes comparable to nonexposed children. For example, a systematic review and meta-analysis found no significant increase in the risk for major congenital malformations, spontaneous abortions, or preterm births among patients exposed to anti–TNF-α agents during pregnancy.² The Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project has provided valuable real-world data indicating that the use of TNF-α inhibitors in pregnancy, particularly during the first trimester, does not substantially elevate the risk for adverse outcomes.¹³ These findings have been corroborated by several other registry studies and RCTs, providing a robust safety profile for these agents during pregnancy.¹⁴

Similarly, postexposure data on IL-17 and IL-12/23 inhibitors indicate a favorable safety profile, though the sample sizes are smaller than those for anti–TNF-α agents.^12,14 Studies of drugs such as secukinumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), or ustekinumab (IL-12/23 inhibitor) have shown no association with teratogenic effects or increased risk for miscarriage.¹⁴ However, agents such as spesolimab (IL-36 inhibitor) are relatively new, and ongoing studies are expected to provide more comprehensive safety data.¹⁵ Similarly, omalizumab and dupilumab have not been associated with increased risk for fetal malformations or adverse pregnancy outcomes. Omalizumab, indicated for chronic urticaria, has a good safety profile in pregnancy, with no significant increase in adverse outcomes reported in studies and registries.¹⁶ Dupilumab, used for AD, has demonstrated safety in pregnancy, with ongoing studies continuing to monitor outcomes.¹⁷

Conversely, rituximab (an anti-CD20 antibody for autoimmune bullous diseases) has shown evidence of adverse pregnancy outcomes, including fetal harm.¹⁸ Its use generally is discouraged unless deemed absolutely necessary, and no safer alternatives are available. Rituximab can cross the placenta, especially in the second and third trimesters, and has been associated with B-cell depletion in the fetus, leading to potential immunosuppression and increased risk for infections.⁵

Although the data on the safety of biologics in pregnancy are largely reassuring, it is essential to recognize that potential risks have not been ruled out entirely. There are extensive safety data for anti–TNF-α inhibitors, which provides a level of confidence; although newer agents such as IL-17 and IL-23 inhibitors have shown promising early results, further research is required to solidify their safety profiles during pregnancy.

Dermatologists must balance the risks and benefits of using biologics in pregnant patients. This decision-­making process involves careful consideration of the severity of the mother’s condition, the potential risks to the fetus, and the availability of alternative treatments. For many severe dermatologic conditions, the benefits of biologics in controlling disease activity and improving QOL may outweigh the potential risks, especially when other treatments have failed or are not suitable.

Final Thoughts

The increasing use of biologics in dermatology has undoubtedly improved the management of severe skin conditions, substantially enhancing patients’ QOL. As more data become available and clinical guidelines evolve, health care providers will be better equipped to make informed decisions about the use of biologics, particularly in pregnant patients. Collaborative efforts between dermatologists, obstetricians, and researchers will help refine treatment guidelines and ensure that pregnant patients with severe dermatologic conditions receive the best possible care.

For now, although the current evidence supports the safety of many biologics during pregnancy,^10,11 individualized care and informed decision-making remain paramount. Careful management and adherence to current guidelines make it possible to navigate the complexities of treating severe dermatologic conditions in pregnant patients, ensuring the best outcomes for both mother and child.

Practice Gap

The term nail biopsy (NB) may refer to a punch, excisional, shave, or longitudinal biopsy of the nail matrix and/or nail bed.¹ Nail surgeries, including NBs, are performed relatively infrequently. In a study using data from the Medicare Provider Utilization and Payment Database 2012-2017, only 1.01% of Mohs surgeons and 0.28% of general dermatologists in the United States performed NBs. Thirty-one states had no dermatologist-performed NBs, while 3 states had no nail biopsies performed by any physician, podiatrist, nurse practitioner, or physician assistant, indicating that there is a shortage of dermatology clinicians performing nail surgeries.²

Dermatologists may not be performing NBs due to unfamiliarity with nail unit anatomy and lack of formal NB training during residency.³ In a survey of 240 dermatology residents in the United States, 58% reported performing fewer than 10 nail procedures during residency, with 25% observing only.⁴ Of those surveyed, 1% had no exposure to nail procedures during 3 years of residency. Furthermore, when asked to assess their competency in nail surgery on a scale of not competent, competent, and very competent, approximately 30% responded that they were not competent.⁴ Without sufficient education on procedures involving the nail unit, residents may be reluctant to incorporate nail surgery into their clinical practice.

Due to their complexity, NBs require the use of several specialized surgical instruments that are not used for other dermatologic procedures, and residents and attending physicians who have limited nail training may be unfamiliar with these tools. To address this educational gap, we sought to create a guide that details the surgical instruments used for the nail matrix tangential excision (shave) biopsy technique—the most common technique used in our nail specialty clinic. This guide is intended for educational use by dermatologists who wish to incorporate NB as part of their practice.

Tools and Technique

As a major referral center, our New York City–based nail specialty clinic performs a large volume of NBs, many of them performed for clinically concerning longitudinal melanonychias for which a nail matrix shave biopsy most often is performed. We utilize a standardized tray consisting of 12 surgical instruments that are needed to successfully perform a NB from start to finish (Figure). In addition to standard surgical tray items, such as sutures and tissue scissors, additional specialized instruments are necessary for NB procedures, including a nail elevator, an English nail splitter, and skin hook.

After the initial incisions are made at 45° angles to the proximal nail fold surrounding the longitudinal band, the nail elevator is used to separate the proximal nail plate from the underlying nail bed. The English nail splitter is used to create a transverse split separating the proximal from the distal nail plate, and the proximal nail plate then is retracted using a clamp. The skin hook is used to retract the proximal nail fold to expose the pigment in the nail matrix, which is biopsied using the #15 blade and sent for histopathology. The proximal nail fold and retracted nail plate then are put back in place, and absorbable sutures are used to repair the defect. In certain cases, a 3-mm punch biopsy may be used to sample the nail plate and/or the surrounding soft tissue.

Practice Implications

A guide to surgical tools used during NB procedures, including less commonly encountered tools such as a nail elevator and English nail splitter, helps to close the educational gap of NB procedures among dermatology trainees and attending physicians. In conjunction with practical training with cadavers and models, a guide to surgical tools can be reviewed by trainees before hands-on exposure to nail surgery in a clinical setting. By increasing awareness of the tools needed to complete the procedure from start to finish, dermatologists may feel more prepared and confident in their ability to perform NBs, ultimately allowing for more rapid diagnosis of nail malignancies.

Practice Gap

The term nail biopsy (NB) may refer to a punch, excisional, shave, or longitudinal biopsy of the nail matrix and/or nail bed.¹ Nail surgeries, including NBs, are performed relatively infrequently. In a study using data from the Medicare Provider Utilization and Payment Database 2012-2017, only 1.01% of Mohs surgeons and 0.28% of general dermatologists in the United States performed NBs. Thirty-one states had no dermatologist-performed NBs, while 3 states had no nail biopsies performed by any physician, podiatrist, nurse practitioner, or physician assistant, indicating that there is a shortage of dermatology clinicians performing nail surgeries.²

Dermatologists may not be performing NBs due to unfamiliarity with nail unit anatomy and lack of formal NB training during residency.³ In a survey of 240 dermatology residents in the United States, 58% reported performing fewer than 10 nail procedures during residency, with 25% observing only.⁴ Of those surveyed, 1% had no exposure to nail procedures during 3 years of residency. Furthermore, when asked to assess their competency in nail surgery on a scale of not competent, competent, and very competent, approximately 30% responded that they were not competent.⁴ Without sufficient education on procedures involving the nail unit, residents may be reluctant to incorporate nail surgery into their clinical practice.

Due to their complexity, NBs require the use of several specialized surgical instruments that are not used for other dermatologic procedures, and residents and attending physicians who have limited nail training may be unfamiliar with these tools. To address this educational gap, we sought to create a guide that details the surgical instruments used for the nail matrix tangential excision (shave) biopsy technique—the most common technique used in our nail specialty clinic. This guide is intended for educational use by dermatologists who wish to incorporate NB as part of their practice.

Tools and Technique

As a major referral center, our New York City–based nail specialty clinic performs a large volume of NBs, many of them performed for clinically concerning longitudinal melanonychias for which a nail matrix shave biopsy most often is performed. We utilize a standardized tray consisting of 12 surgical instruments that are needed to successfully perform a NB from start to finish (Figure). In addition to standard surgical tray items, such as sutures and tissue scissors, additional specialized instruments are necessary for NB procedures, including a nail elevator, an English nail splitter, and skin hook.

After the initial incisions are made at 45° angles to the proximal nail fold surrounding the longitudinal band, the nail elevator is used to separate the proximal nail plate from the underlying nail bed. The English nail splitter is used to create a transverse split separating the proximal from the distal nail plate, and the proximal nail plate then is retracted using a clamp. The skin hook is used to retract the proximal nail fold to expose the pigment in the nail matrix, which is biopsied using the #15 blade and sent for histopathology. The proximal nail fold and retracted nail plate then are put back in place, and absorbable sutures are used to repair the defect. In certain cases, a 3-mm punch biopsy may be used to sample the nail plate and/or the surrounding soft tissue.

Practice Implications

A guide to surgical tools used during NB procedures, including less commonly encountered tools such as a nail elevator and English nail splitter, helps to close the educational gap of NB procedures among dermatology trainees and attending physicians. In conjunction with practical training with cadavers and models, a guide to surgical tools can be reviewed by trainees before hands-on exposure to nail surgery in a clinical setting. By increasing awareness of the tools needed to complete the procedure from start to finish, dermatologists may feel more prepared and confident in their ability to perform NBs, ultimately allowing for more rapid diagnosis of nail malignancies.

Practice Gap

The term nail biopsy (NB) may refer to a punch, excisional, shave, or longitudinal biopsy of the nail matrix and/or nail bed.¹ Nail surgeries, including NBs, are performed relatively infrequently. In a study using data from the Medicare Provider Utilization and Payment Database 2012-2017, only 1.01% of Mohs surgeons and 0.28% of general dermatologists in the United States performed NBs. Thirty-one states had no dermatologist-performed NBs, while 3 states had no nail biopsies performed by any physician, podiatrist, nurse practitioner, or physician assistant, indicating that there is a shortage of dermatology clinicians performing nail surgeries.²

Dermatologists may not be performing NBs due to unfamiliarity with nail unit anatomy and lack of formal NB training during residency.³ In a survey of 240 dermatology residents in the United States, 58% reported performing fewer than 10 nail procedures during residency, with 25% observing only.⁴ Of those surveyed, 1% had no exposure to nail procedures during 3 years of residency. Furthermore, when asked to assess their competency in nail surgery on a scale of not competent, competent, and very competent, approximately 30% responded that they were not competent.⁴ Without sufficient education on procedures involving the nail unit, residents may be reluctant to incorporate nail surgery into their clinical practice.

Due to their complexity, NBs require the use of several specialized surgical instruments that are not used for other dermatologic procedures, and residents and attending physicians who have limited nail training may be unfamiliar with these tools. To address this educational gap, we sought to create a guide that details the surgical instruments used for the nail matrix tangential excision (shave) biopsy technique—the most common technique used in our nail specialty clinic. This guide is intended for educational use by dermatologists who wish to incorporate NB as part of their practice.

Tools and Technique

As a major referral center, our New York City–based nail specialty clinic performs a large volume of NBs, many of them performed for clinically concerning longitudinal melanonychias for which a nail matrix shave biopsy most often is performed. We utilize a standardized tray consisting of 12 surgical instruments that are needed to successfully perform a NB from start to finish (Figure). In addition to standard surgical tray items, such as sutures and tissue scissors, additional specialized instruments are necessary for NB procedures, including a nail elevator, an English nail splitter, and skin hook.

After the initial incisions are made at 45° angles to the proximal nail fold surrounding the longitudinal band, the nail elevator is used to separate the proximal nail plate from the underlying nail bed. The English nail splitter is used to create a transverse split separating the proximal from the distal nail plate, and the proximal nail plate then is retracted using a clamp. The skin hook is used to retract the proximal nail fold to expose the pigment in the nail matrix, which is biopsied using the #15 blade and sent for histopathology. The proximal nail fold and retracted nail plate then are put back in place, and absorbable sutures are used to repair the defect. In certain cases, a 3-mm punch biopsy may be used to sample the nail plate and/or the surrounding soft tissue.

Practice Implications

A guide to surgical tools used during NB procedures, including less commonly encountered tools such as a nail elevator and English nail splitter, helps to close the educational gap of NB procedures among dermatology trainees and attending physicians. In conjunction with practical training with cadavers and models, a guide to surgical tools can be reviewed by trainees before hands-on exposure to nail surgery in a clinical setting. By increasing awareness of the tools needed to complete the procedure from start to finish, dermatologists may feel more prepared and confident in their ability to perform NBs, ultimately allowing for more rapid diagnosis of nail malignancies.

Psoriasis is a chronic inflammatory disease affecting approximately 8 million adults in the United States and 2% of the global population.^1,2 Psoriasis causes pain, itching, and disfigurement and is associated with a physical, psychological, and economic burden that substantially affects health-related quality of life.^3-5

Setting treatment goals and treating to target are evidence-based approaches that have been successfully applied to several chronic diseases to improve patient outcomes, including diabetes, hypertension, and rheumatoid arthritis.^6-9 Treat-to-target strategies generally set low disease activity (or remission) as an overall goal and seek to achieve this using available therapeutic options as necessary. Introduced following the availability of biologics and targeted systemic therapies, treat-to-target strategies generally provide guidance on expectations of treatment but not specific treatments, as personalized treatment decisions depend on an assessment of individual patients and consider clinical and demographic features as well as preferences for available therapeutic options. If targets are not achieved in the assigned time span, adjustments can be made to the treatment approach in close consultation with the patient. If the target is reached, follow-up visits can be scheduled to ensure improvement is maintained or to establish if more aggressive goals could be selected.

Treat-to-target strategies for the management of psoriasis developed by the National Psoriasis Foundation (NPF) Medical Board include reducing the extent of psoriasis to 1% or lower total body surface area (BSA) after 3 months of treatment.¹⁰ Treatment targets endorsed by the European Academy of Dermatology and Venereology (EADV) in guidelines on the use of systemic therapies in psoriasis include achieving a 75% or greater reduction in Psoriasis Area and Severity Index (PASI) score within 3 to 4 months of treatment.¹¹

In clinical practice, many patients do not achieve these treatment targets, and topical treatments alone generally are insufficient in achieving treatment goals for psoriasis.^12,13 Moreover, conventional topical treatments (eg, topical corticosteroids) used by most patients with psoriasis regardless of disease severity are associated with adverse events that can limit their use. Most topical corticosteroids have US Food and Drug Administration label restrictions relating to sites of application, duration and extent of use, and frequency of administration.^14,15

Tapinarof cream 1% (VTAMA [Dermavant Sciences, Inc]) is a first-in-class topical nonsteroidal aryl hydrocarbon receptor agonist that was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults¹⁶ and is being studied for the treatment of plaque psoriasis in children 2 years and older as well as for atopic dermatitis in adults and children 2 years and older. In PSOARING 1 (ClinicalTrials .gov identifier NCT03956355) and PSOARING 2 (NCT03983980)—identical 12-week pivotal phase 3 trials—monotherapy with tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy vs vehicle cream and was well tolerated in adults with mild to severe plaque psoriasis (Supplementary Figure S1).¹⁷ Lebwohl et al¹⁷ reported that significantly higher PASI75 responses were observed at week 12 with tapinarof cream vs vehicle in PSOARING 1 and PSOARING 2 (36% and 48% vs 10% and 7%, respectively; both P<.0001). A significantly higher PASI90 response of 19% and 21% at week 12 also was observed with tapinarof cream vs 2% and 3% with vehicle in PSOARING 1 and PSOARING 2, respectively (P=.0005 and P<.0001).¹⁷

In PSOARING 3 (NCT04053387)—the long-term extension trial (Supplementary Figure S1)—efficacy continued to improve or was maintained beyond the two 12-week trials, with improvements in total BSA affected and PASI scores for up to 52 weeks.¹⁸ Tapinarof cream 1% QD demonstrated positive, rapid, and durable outcomes in PSOARING 3, including high rates of complete disease clearance (Physician Global Assessment [PGA] score=0 [clear])(40.9% [312/763]), durability of response on treatment with no evidence of tachyphylaxis, and a remittive effect of approximately 4 months when off therapy (defined as maintenance of a PGA score of 0 [clear] or 1 [almost clear] after first achieving a PGA score of 0).¹⁸

Herein, we report absolute treatment targets for patients with plaque psoriasis who received tapinarof cream 1% QD in the PSOARING trials that are at least as stringent as the corresponding NPF and EADV targets of achieving a total BSA affected of 1% or lower or a PASI75 response within 3 to 4 months, respectively.

METHODS

Study Design

The pooled efficacy analyses included all patients with a baseline PGA score of 2 or higher (mild or worse) before treatment with tapinarof cream 1% QD in the PSOARING trials. This included patients who received tapinarof cream 1% in PSOARING 1 and PSOARING 2 who may or may not have continued into PSOARING 3, as well as those who received the vehicle in PSOARING 1 and PSOARING 2 who enrolled in PSOARING 3 and had a PGA score of 2 or higher before receiving tapinarof cream 1%.

Trial Participants

Full methods, including inclusion and exclusion criteria, for the PSOARING trials have been previously reported.^17,18 Patients were aged 18 to 75 years and had chronic plaque psoriasis that was stable for at least 6 months before randomization; 3% to 20% total BSA affected (excluding the scalp, palms, fingernails, toenails, and soles); and a PGA score of 2 (mild), 3 (moderate), or 4 (severe) at baseline.

The clinical trials were conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval was obtained from local ethics committees or institutional review boards at each center. All patients provided written informed consent.

Trial Treatment

In PSOARING 1 and PSOARING 2, patients were randomized (2:1) to receive tapinarof cream 1% or vehicle QD for 12 weeks. In PSOARING 3 (the long-term extension trial), patients received up to 40 weeks of open-label tapinarof, followed by 4 weeks of follow-up off treatment. Patients received intermittent or continuous treatment with tapinarof cream 1% in PSOARING 3 based on PGA score: those entering the trial with a PGA score of 1 or higher received tapinarof cream 1% until complete disease clearance was achieved (defined as a PGA score of 0 [clear]). Those entering PSOARING 3 with or achieving a PGA score of 0 (clear) discontinued treatment and were observed for the duration of maintenance of a PGA score of 0 (clear) or 1 (almost clear) while off therapy (the protocol-defined “duration of remittive effect”). If disease worsening (defined as a PGA score 2 or higher) occurred, tapinarof cream 1% was restarted and continued until a PGA score of 0 (clear) was achieved. This pattern of treatment, discontinuation on achieving a PGA score of 0 (clear), and retreatment on disease worsening continued until the end of the trial. As a result, patients in PSOARING 3 could receive tapinarof cream 1% continuously or intermittently for 40 weeks.

Outcome Measures and Statistical Analyses

The assessment of total BSA affected by plaque psoriasis is an estimate of the total extent of disease as a percentage of total skin area. In the PSOARING trials, the skin surface of one hand (palm and digits) was assumed to be approximately equivalent to 1% BSA. The total BSA affected by psoriasis was evaluated from 0% to 100%, with greater total BSA affected being an indication of more extensive disease. The BSA efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved a 1% or lower or 0.5% or lower total BSA affected. The smallest BSA affected increment that investigators were trained to measure and could record was 0.1%.

Psoriasis Area and Severity Index scores assess both the severity and extent of psoriasis. A PASI score lower than 5 often is considered indicative of mild psoriasis, a score of 5 to 10 indicates moderate disease, and a score higher than 10 indicates severe disease.¹⁹ The maximum PASI score is 72. The PASI efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved an absolute total PASI score of 3 or lower, 2 or lower, and 1 or lower.

Efficacy analyses were based on pooled data for all patients in the PSOARING trials who had a PGA score of 2 to 4 (mild to severe) before treatment with tapinarof cream 1% in the intention-to-treat population using observed cases. Time-to-target analyses were based on Kaplan-Meier (KM) estimates using observed cases.

Safety analyses included the incidence and frequency of adverse events and were based on all patients who received tapinarof cream 1% in the PSOARING trials.

RESULTS

Baseline Patient Demographics and Disease Characteristics

The pooled efficacy analyses included 915 eligible patients (Table). At baseline, the mean (SD) age was 50.2 (13.25) years, 58.7% were male, the mean (SD) weight was 92.2 (23.67) kg, and the mean (SD) body mass index was 31.6 (7.53) kg/m². The percentage of patients with a PGA score of 2 (mild), 3 (moderate), or 4 (severe) was 13.9%, 78.1%, and 8.0%, respectively. The mean (SD) PASI score was 8.7 (4.23) and mean (SD) total BSA affected was 7.8% (4.98).

Efficacy

Achievement of BSA-Affected Targets—The NPF-recommended target of 1% or lower total BSA affected within 3 months was achieved by 40% of patients (KM estimate [95% CI, 37%-43%])(Figure 1). Across the total trial period of up to 52 weeks, a total BSA affected of 1% or lower was achieved by 61% of patients (561/915), with the median time to target of approximately 4 months (KM estimate: 120 days [95% CI, 113-141])(Supplementary Figure S2a). Approximately 50% of patients (455/915) achieved a total BSA affected of 0.5% or lower, with a median time to target of 199 days (KM estimate [95% CI, 172-228)(Figure 1; Supplementary Figure S2b).

Achievement of Absolute PASI Targets—Across the total trial period (up to 52 weeks), an absolute total PASI score of 3 or lower was achieved by 75% of patients (686/915), with a median time to achieve this of 2 months (KM estimate: 58 days [95% CI, 57-63]); approximately 67% of patients (612/915) achieved a total PASI score of 2 or lower, with a median time to achieve of 3 months (KM estimate: 87 days [95% CI, 85-110])(Figure 2; Supplementary Figures S3a and S3b). A PASI score of 1 or lower was achieved by approximately 50% of patients (460/915), with a median time to achieve of approximately 6 months (KM estimate: 185 days [95% CI, 169-218])(Figure 2, Supplementary Figure S3c).

Illustrative Case—Case photography showing the clinical response in a 63-year-old man with moderate plaque psoriasis in PSOARING 2 is shown in Figure 3. After 12 weeks of treatment with tapinarof cream 1% QD, the patient achieved all primary and secondary efficacy end points. In addition to achieving the regulatory end point of a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points, achievement of 0% total BSA affected and a total PASI score of 0 at week 12 exceeded the NPF and EADV consensus treatment targets.^10,11 Targets were achieved as early as week 4, with a total BSA affected of 0.5% or lower and a total PASI score of 1 or lower, illustrated by marked skin clearing and only faint residual erythema that completely resolved at week 12, with the absence of postinflammatory hyperpigmentation.

Safety

Safety data for the PSOARING trials have been previously reported.^17,18 The most common treatment-emergent adverse events were folliculitis, contact dermatitis, upper respiratory tract infection, and nasopharyngitis. Treatment-emergent adverse events generally were mild or moderate in severity and did not lead to trial discontinuation.^17,18

COMMENT

Treat-to-target management approaches aim to improve patient outcomes by striving to achieve optimal goals. The treat-to-target approach supports shared decision-making between clinicians and patients based on common expectations of what constitutes treatment success.

The findings of this analysis based on pooled data from a large cohort of patients demonstrate that a high proportion of patients can achieve or exceed recommended treatment targets with tapinarof cream 1% QD and maintain improvements long-term. The NPF-recommended treatment target of 1% or lower BSA affected within approximately 3 months (90 days) of treatment was achieved by 40% of tapinarof-treated patients. In addition, 1% or lower BSA affected at any time during the trials was achieved by 61% of patients (median, approximately 4 months). The analyses also indicated that PASI total scores of 3 or lower and 2 or lower were achieved by 75% and 67% of tapinarof-treated patients, respectively, within 2 to 3 months.

These findings support the previously reported efficacy of tapinarof cream, including high rates of complete disease clearance (40.9% [312/763]), durable response following treatment interruption, an off-therapy remittive effect of approximately 4 months, and good disease control on therapy with no evidence of tachyphylaxis.^17,18

CONCLUSION

Taken together with previously reported tapinarof efficacy and safety results, our findings demonstrate that a high proportion of patients treated with tapinarof cream as monotherapy can achieve aggressive treatment targets set by both US and European guidelines developed for systemic and biologic therapies. Tapinarof cream 1% QD is an effective topical treatment option for patients with plaque psoriasis that has been approved without restrictions relating to severity or extent of disease treated, duration of use, or application sites, including application to sensitive and intertriginous skin.

Acknowledgments—Editorial and medical writing support under the guidance of the authors was provided by Melanie Govender, MSc (Med), ApotheCom (United Kingdom), and was funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice (GPP) guidelines.

Psoriasis is a chronic inflammatory disease affecting approximately 8 million adults in the United States and 2% of the global population.^1,2 Psoriasis causes pain, itching, and disfigurement and is associated with a physical, psychological, and economic burden that substantially affects health-related quality of life.^3-5

Setting treatment goals and treating to target are evidence-based approaches that have been successfully applied to several chronic diseases to improve patient outcomes, including diabetes, hypertension, and rheumatoid arthritis.^6-9 Treat-to-target strategies generally set low disease activity (or remission) as an overall goal and seek to achieve this using available therapeutic options as necessary. Introduced following the availability of biologics and targeted systemic therapies, treat-to-target strategies generally provide guidance on expectations of treatment but not specific treatments, as personalized treatment decisions depend on an assessment of individual patients and consider clinical and demographic features as well as preferences for available therapeutic options. If targets are not achieved in the assigned time span, adjustments can be made to the treatment approach in close consultation with the patient. If the target is reached, follow-up visits can be scheduled to ensure improvement is maintained or to establish if more aggressive goals could be selected.

Treat-to-target strategies for the management of psoriasis developed by the National Psoriasis Foundation (NPF) Medical Board include reducing the extent of psoriasis to 1% or lower total body surface area (BSA) after 3 months of treatment.¹⁰ Treatment targets endorsed by the European Academy of Dermatology and Venereology (EADV) in guidelines on the use of systemic therapies in psoriasis include achieving a 75% or greater reduction in Psoriasis Area and Severity Index (PASI) score within 3 to 4 months of treatment.¹¹

In clinical practice, many patients do not achieve these treatment targets, and topical treatments alone generally are insufficient in achieving treatment goals for psoriasis.^12,13 Moreover, conventional topical treatments (eg, topical corticosteroids) used by most patients with psoriasis regardless of disease severity are associated with adverse events that can limit their use. Most topical corticosteroids have US Food and Drug Administration label restrictions relating to sites of application, duration and extent of use, and frequency of administration.^14,15

Tapinarof cream 1% (VTAMA [Dermavant Sciences, Inc]) is a first-in-class topical nonsteroidal aryl hydrocarbon receptor agonist that was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults¹⁶ and is being studied for the treatment of plaque psoriasis in children 2 years and older as well as for atopic dermatitis in adults and children 2 years and older. In PSOARING 1 (ClinicalTrials .gov identifier NCT03956355) and PSOARING 2 (NCT03983980)—identical 12-week pivotal phase 3 trials—monotherapy with tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy vs vehicle cream and was well tolerated in adults with mild to severe plaque psoriasis (Supplementary Figure S1).¹⁷ Lebwohl et al¹⁷ reported that significantly higher PASI75 responses were observed at week 12 with tapinarof cream vs vehicle in PSOARING 1 and PSOARING 2 (36% and 48% vs 10% and 7%, respectively; both P<.0001). A significantly higher PASI90 response of 19% and 21% at week 12 also was observed with tapinarof cream vs 2% and 3% with vehicle in PSOARING 1 and PSOARING 2, respectively (P=.0005 and P<.0001).¹⁷

In PSOARING 3 (NCT04053387)—the long-term extension trial (Supplementary Figure S1)—efficacy continued to improve or was maintained beyond the two 12-week trials, with improvements in total BSA affected and PASI scores for up to 52 weeks.¹⁸ Tapinarof cream 1% QD demonstrated positive, rapid, and durable outcomes in PSOARING 3, including high rates of complete disease clearance (Physician Global Assessment [PGA] score=0 [clear])(40.9% [312/763]), durability of response on treatment with no evidence of tachyphylaxis, and a remittive effect of approximately 4 months when off therapy (defined as maintenance of a PGA score of 0 [clear] or 1 [almost clear] after first achieving a PGA score of 0).¹⁸

Herein, we report absolute treatment targets for patients with plaque psoriasis who received tapinarof cream 1% QD in the PSOARING trials that are at least as stringent as the corresponding NPF and EADV targets of achieving a total BSA affected of 1% or lower or a PASI75 response within 3 to 4 months, respectively.

METHODS

Study Design

The pooled efficacy analyses included all patients with a baseline PGA score of 2 or higher (mild or worse) before treatment with tapinarof cream 1% QD in the PSOARING trials. This included patients who received tapinarof cream 1% in PSOARING 1 and PSOARING 2 who may or may not have continued into PSOARING 3, as well as those who received the vehicle in PSOARING 1 and PSOARING 2 who enrolled in PSOARING 3 and had a PGA score of 2 or higher before receiving tapinarof cream 1%.

Trial Participants

Full methods, including inclusion and exclusion criteria, for the PSOARING trials have been previously reported.^17,18 Patients were aged 18 to 75 years and had chronic plaque psoriasis that was stable for at least 6 months before randomization; 3% to 20% total BSA affected (excluding the scalp, palms, fingernails, toenails, and soles); and a PGA score of 2 (mild), 3 (moderate), or 4 (severe) at baseline.

The clinical trials were conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval was obtained from local ethics committees or institutional review boards at each center. All patients provided written informed consent.

Trial Treatment

In PSOARING 1 and PSOARING 2, patients were randomized (2:1) to receive tapinarof cream 1% or vehicle QD for 12 weeks. In PSOARING 3 (the long-term extension trial), patients received up to 40 weeks of open-label tapinarof, followed by 4 weeks of follow-up off treatment. Patients received intermittent or continuous treatment with tapinarof cream 1% in PSOARING 3 based on PGA score: those entering the trial with a PGA score of 1 or higher received tapinarof cream 1% until complete disease clearance was achieved (defined as a PGA score of 0 [clear]). Those entering PSOARING 3 with or achieving a PGA score of 0 (clear) discontinued treatment and were observed for the duration of maintenance of a PGA score of 0 (clear) or 1 (almost clear) while off therapy (the protocol-defined “duration of remittive effect”). If disease worsening (defined as a PGA score 2 or higher) occurred, tapinarof cream 1% was restarted and continued until a PGA score of 0 (clear) was achieved. This pattern of treatment, discontinuation on achieving a PGA score of 0 (clear), and retreatment on disease worsening continued until the end of the trial. As a result, patients in PSOARING 3 could receive tapinarof cream 1% continuously or intermittently for 40 weeks.

Outcome Measures and Statistical Analyses

The assessment of total BSA affected by plaque psoriasis is an estimate of the total extent of disease as a percentage of total skin area. In the PSOARING trials, the skin surface of one hand (palm and digits) was assumed to be approximately equivalent to 1% BSA. The total BSA affected by psoriasis was evaluated from 0% to 100%, with greater total BSA affected being an indication of more extensive disease. The BSA efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved a 1% or lower or 0.5% or lower total BSA affected. The smallest BSA affected increment that investigators were trained to measure and could record was 0.1%.

Psoriasis Area and Severity Index scores assess both the severity and extent of psoriasis. A PASI score lower than 5 often is considered indicative of mild psoriasis, a score of 5 to 10 indicates moderate disease, and a score higher than 10 indicates severe disease.¹⁹ The maximum PASI score is 72. The PASI efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved an absolute total PASI score of 3 or lower, 2 or lower, and 1 or lower.

Efficacy analyses were based on pooled data for all patients in the PSOARING trials who had a PGA score of 2 to 4 (mild to severe) before treatment with tapinarof cream 1% in the intention-to-treat population using observed cases. Time-to-target analyses were based on Kaplan-Meier (KM) estimates using observed cases.

Safety analyses included the incidence and frequency of adverse events and were based on all patients who received tapinarof cream 1% in the PSOARING trials.

RESULTS

Baseline Patient Demographics and Disease Characteristics

The pooled efficacy analyses included 915 eligible patients (Table). At baseline, the mean (SD) age was 50.2 (13.25) years, 58.7% were male, the mean (SD) weight was 92.2 (23.67) kg, and the mean (SD) body mass index was 31.6 (7.53) kg/m². The percentage of patients with a PGA score of 2 (mild), 3 (moderate), or 4 (severe) was 13.9%, 78.1%, and 8.0%, respectively. The mean (SD) PASI score was 8.7 (4.23) and mean (SD) total BSA affected was 7.8% (4.98).

Efficacy

Achievement of BSA-Affected Targets—The NPF-recommended target of 1% or lower total BSA affected within 3 months was achieved by 40% of patients (KM estimate [95% CI, 37%-43%])(Figure 1). Across the total trial period of up to 52 weeks, a total BSA affected of 1% or lower was achieved by 61% of patients (561/915), with the median time to target of approximately 4 months (KM estimate: 120 days [95% CI, 113-141])(Supplementary Figure S2a). Approximately 50% of patients (455/915) achieved a total BSA affected of 0.5% or lower, with a median time to target of 199 days (KM estimate [95% CI, 172-228)(Figure 1; Supplementary Figure S2b).

Achievement of Absolute PASI Targets—Across the total trial period (up to 52 weeks), an absolute total PASI score of 3 or lower was achieved by 75% of patients (686/915), with a median time to achieve this of 2 months (KM estimate: 58 days [95% CI, 57-63]); approximately 67% of patients (612/915) achieved a total PASI score of 2 or lower, with a median time to achieve of 3 months (KM estimate: 87 days [95% CI, 85-110])(Figure 2; Supplementary Figures S3a and S3b). A PASI score of 1 or lower was achieved by approximately 50% of patients (460/915), with a median time to achieve of approximately 6 months (KM estimate: 185 days [95% CI, 169-218])(Figure 2, Supplementary Figure S3c).

Illustrative Case—Case photography showing the clinical response in a 63-year-old man with moderate plaque psoriasis in PSOARING 2 is shown in Figure 3. After 12 weeks of treatment with tapinarof cream 1% QD, the patient achieved all primary and secondary efficacy end points. In addition to achieving the regulatory end point of a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points, achievement of 0% total BSA affected and a total PASI score of 0 at week 12 exceeded the NPF and EADV consensus treatment targets.^10,11 Targets were achieved as early as week 4, with a total BSA affected of 0.5% or lower and a total PASI score of 1 or lower, illustrated by marked skin clearing and only faint residual erythema that completely resolved at week 12, with the absence of postinflammatory hyperpigmentation.

Safety

Safety data for the PSOARING trials have been previously reported.^17,18 The most common treatment-emergent adverse events were folliculitis, contact dermatitis, upper respiratory tract infection, and nasopharyngitis. Treatment-emergent adverse events generally were mild or moderate in severity and did not lead to trial discontinuation.^17,18

COMMENT

Treat-to-target management approaches aim to improve patient outcomes by striving to achieve optimal goals. The treat-to-target approach supports shared decision-making between clinicians and patients based on common expectations of what constitutes treatment success.

The findings of this analysis based on pooled data from a large cohort of patients demonstrate that a high proportion of patients can achieve or exceed recommended treatment targets with tapinarof cream 1% QD and maintain improvements long-term. The NPF-recommended treatment target of 1% or lower BSA affected within approximately 3 months (90 days) of treatment was achieved by 40% of tapinarof-treated patients. In addition, 1% or lower BSA affected at any time during the trials was achieved by 61% of patients (median, approximately 4 months). The analyses also indicated that PASI total scores of 3 or lower and 2 or lower were achieved by 75% and 67% of tapinarof-treated patients, respectively, within 2 to 3 months.

These findings support the previously reported efficacy of tapinarof cream, including high rates of complete disease clearance (40.9% [312/763]), durable response following treatment interruption, an off-therapy remittive effect of approximately 4 months, and good disease control on therapy with no evidence of tachyphylaxis.^17,18

CONCLUSION

Taken together with previously reported tapinarof efficacy and safety results, our findings demonstrate that a high proportion of patients treated with tapinarof cream as monotherapy can achieve aggressive treatment targets set by both US and European guidelines developed for systemic and biologic therapies. Tapinarof cream 1% QD is an effective topical treatment option for patients with plaque psoriasis that has been approved without restrictions relating to severity or extent of disease treated, duration of use, or application sites, including application to sensitive and intertriginous skin.

Acknowledgments—Editorial and medical writing support under the guidance of the authors was provided by Melanie Govender, MSc (Med), ApotheCom (United Kingdom), and was funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice (GPP) guidelines.

Psoriasis is a chronic inflammatory disease affecting approximately 8 million adults in the United States and 2% of the global population.^1,2 Psoriasis causes pain, itching, and disfigurement and is associated with a physical, psychological, and economic burden that substantially affects health-related quality of life.^3-5

Setting treatment goals and treating to target are evidence-based approaches that have been successfully applied to several chronic diseases to improve patient outcomes, including diabetes, hypertension, and rheumatoid arthritis.^6-9 Treat-to-target strategies generally set low disease activity (or remission) as an overall goal and seek to achieve this using available therapeutic options as necessary. Introduced following the availability of biologics and targeted systemic therapies, treat-to-target strategies generally provide guidance on expectations of treatment but not specific treatments, as personalized treatment decisions depend on an assessment of individual patients and consider clinical and demographic features as well as preferences for available therapeutic options. If targets are not achieved in the assigned time span, adjustments can be made to the treatment approach in close consultation with the patient. If the target is reached, follow-up visits can be scheduled to ensure improvement is maintained or to establish if more aggressive goals could be selected.

Treat-to-target strategies for the management of psoriasis developed by the National Psoriasis Foundation (NPF) Medical Board include reducing the extent of psoriasis to 1% or lower total body surface area (BSA) after 3 months of treatment.¹⁰ Treatment targets endorsed by the European Academy of Dermatology and Venereology (EADV) in guidelines on the use of systemic therapies in psoriasis include achieving a 75% or greater reduction in Psoriasis Area and Severity Index (PASI) score within 3 to 4 months of treatment.¹¹

In clinical practice, many patients do not achieve these treatment targets, and topical treatments alone generally are insufficient in achieving treatment goals for psoriasis.^12,13 Moreover, conventional topical treatments (eg, topical corticosteroids) used by most patients with psoriasis regardless of disease severity are associated with adverse events that can limit their use. Most topical corticosteroids have US Food and Drug Administration label restrictions relating to sites of application, duration and extent of use, and frequency of administration.^14,15

Tapinarof cream 1% (VTAMA [Dermavant Sciences, Inc]) is a first-in-class topical nonsteroidal aryl hydrocarbon receptor agonist that was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults¹⁶ and is being studied for the treatment of plaque psoriasis in children 2 years and older as well as for atopic dermatitis in adults and children 2 years and older. In PSOARING 1 (ClinicalTrials .gov identifier NCT03956355) and PSOARING 2 (NCT03983980)—identical 12-week pivotal phase 3 trials—monotherapy with tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy vs vehicle cream and was well tolerated in adults with mild to severe plaque psoriasis (Supplementary Figure S1).¹⁷ Lebwohl et al¹⁷ reported that significantly higher PASI75 responses were observed at week 12 with tapinarof cream vs vehicle in PSOARING 1 and PSOARING 2 (36% and 48% vs 10% and 7%, respectively; both P<.0001). A significantly higher PASI90 response of 19% and 21% at week 12 also was observed with tapinarof cream vs 2% and 3% with vehicle in PSOARING 1 and PSOARING 2, respectively (P=.0005 and P<.0001).¹⁷

In PSOARING 3 (NCT04053387)—the long-term extension trial (Supplementary Figure S1)—efficacy continued to improve or was maintained beyond the two 12-week trials, with improvements in total BSA affected and PASI scores for up to 52 weeks.¹⁸ Tapinarof cream 1% QD demonstrated positive, rapid, and durable outcomes in PSOARING 3, including high rates of complete disease clearance (Physician Global Assessment [PGA] score=0 [clear])(40.9% [312/763]), durability of response on treatment with no evidence of tachyphylaxis, and a remittive effect of approximately 4 months when off therapy (defined as maintenance of a PGA score of 0 [clear] or 1 [almost clear] after first achieving a PGA score of 0).¹⁸

Herein, we report absolute treatment targets for patients with plaque psoriasis who received tapinarof cream 1% QD in the PSOARING trials that are at least as stringent as the corresponding NPF and EADV targets of achieving a total BSA affected of 1% or lower or a PASI75 response within 3 to 4 months, respectively.

METHODS

Study Design

The pooled efficacy analyses included all patients with a baseline PGA score of 2 or higher (mild or worse) before treatment with tapinarof cream 1% QD in the PSOARING trials. This included patients who received tapinarof cream 1% in PSOARING 1 and PSOARING 2 who may or may not have continued into PSOARING 3, as well as those who received the vehicle in PSOARING 1 and PSOARING 2 who enrolled in PSOARING 3 and had a PGA score of 2 or higher before receiving tapinarof cream 1%.

Trial Participants

Full methods, including inclusion and exclusion criteria, for the PSOARING trials have been previously reported.^17,18 Patients were aged 18 to 75 years and had chronic plaque psoriasis that was stable for at least 6 months before randomization; 3% to 20% total BSA affected (excluding the scalp, palms, fingernails, toenails, and soles); and a PGA score of 2 (mild), 3 (moderate), or 4 (severe) at baseline.

The clinical trials were conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval was obtained from local ethics committees or institutional review boards at each center. All patients provided written informed consent.

Trial Treatment

In PSOARING 1 and PSOARING 2, patients were randomized (2:1) to receive tapinarof cream 1% or vehicle QD for 12 weeks. In PSOARING 3 (the long-term extension trial), patients received up to 40 weeks of open-label tapinarof, followed by 4 weeks of follow-up off treatment. Patients received intermittent or continuous treatment with tapinarof cream 1% in PSOARING 3 based on PGA score: those entering the trial with a PGA score of 1 or higher received tapinarof cream 1% until complete disease clearance was achieved (defined as a PGA score of 0 [clear]). Those entering PSOARING 3 with or achieving a PGA score of 0 (clear) discontinued treatment and were observed for the duration of maintenance of a PGA score of 0 (clear) or 1 (almost clear) while off therapy (the protocol-defined “duration of remittive effect”). If disease worsening (defined as a PGA score 2 or higher) occurred, tapinarof cream 1% was restarted and continued until a PGA score of 0 (clear) was achieved. This pattern of treatment, discontinuation on achieving a PGA score of 0 (clear), and retreatment on disease worsening continued until the end of the trial. As a result, patients in PSOARING 3 could receive tapinarof cream 1% continuously or intermittently for 40 weeks.

Outcome Measures and Statistical Analyses

The assessment of total BSA affected by plaque psoriasis is an estimate of the total extent of disease as a percentage of total skin area. In the PSOARING trials, the skin surface of one hand (palm and digits) was assumed to be approximately equivalent to 1% BSA. The total BSA affected by psoriasis was evaluated from 0% to 100%, with greater total BSA affected being an indication of more extensive disease. The BSA efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved a 1% or lower or 0.5% or lower total BSA affected. The smallest BSA affected increment that investigators were trained to measure and could record was 0.1%.

Psoriasis Area and Severity Index scores assess both the severity and extent of psoriasis. A PASI score lower than 5 often is considered indicative of mild psoriasis, a score of 5 to 10 indicates moderate disease, and a score higher than 10 indicates severe disease.¹⁹ The maximum PASI score is 72. The PASI efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved an absolute total PASI score of 3 or lower, 2 or lower, and 1 or lower.

Efficacy analyses were based on pooled data for all patients in the PSOARING trials who had a PGA score of 2 to 4 (mild to severe) before treatment with tapinarof cream 1% in the intention-to-treat population using observed cases. Time-to-target analyses were based on Kaplan-Meier (KM) estimates using observed cases.

Safety analyses included the incidence and frequency of adverse events and were based on all patients who received tapinarof cream 1% in the PSOARING trials.

RESULTS

Baseline Patient Demographics and Disease Characteristics

The pooled efficacy analyses included 915 eligible patients (Table). At baseline, the mean (SD) age was 50.2 (13.25) years, 58.7% were male, the mean (SD) weight was 92.2 (23.67) kg, and the mean (SD) body mass index was 31.6 (7.53) kg/m². The percentage of patients with a PGA score of 2 (mild), 3 (moderate), or 4 (severe) was 13.9%, 78.1%, and 8.0%, respectively. The mean (SD) PASI score was 8.7 (4.23) and mean (SD) total BSA affected was 7.8% (4.98).

Efficacy

Achievement of BSA-Affected Targets—The NPF-recommended target of 1% or lower total BSA affected within 3 months was achieved by 40% of patients (KM estimate [95% CI, 37%-43%])(Figure 1). Across the total trial period of up to 52 weeks, a total BSA affected of 1% or lower was achieved by 61% of patients (561/915), with the median time to target of approximately 4 months (KM estimate: 120 days [95% CI, 113-141])(Supplementary Figure S2a). Approximately 50% of patients (455/915) achieved a total BSA affected of 0.5% or lower, with a median time to target of 199 days (KM estimate [95% CI, 172-228)(Figure 1; Supplementary Figure S2b).

Achievement of Absolute PASI Targets—Across the total trial period (up to 52 weeks), an absolute total PASI score of 3 or lower was achieved by 75% of patients (686/915), with a median time to achieve this of 2 months (KM estimate: 58 days [95% CI, 57-63]); approximately 67% of patients (612/915) achieved a total PASI score of 2 or lower, with a median time to achieve of 3 months (KM estimate: 87 days [95% CI, 85-110])(Figure 2; Supplementary Figures S3a and S3b). A PASI score of 1 or lower was achieved by approximately 50% of patients (460/915), with a median time to achieve of approximately 6 months (KM estimate: 185 days [95% CI, 169-218])(Figure 2, Supplementary Figure S3c).

Illustrative Case—Case photography showing the clinical response in a 63-year-old man with moderate plaque psoriasis in PSOARING 2 is shown in Figure 3. After 12 weeks of treatment with tapinarof cream 1% QD, the patient achieved all primary and secondary efficacy end points. In addition to achieving the regulatory end point of a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points, achievement of 0% total BSA affected and a total PASI score of 0 at week 12 exceeded the NPF and EADV consensus treatment targets.^10,11 Targets were achieved as early as week 4, with a total BSA affected of 0.5% or lower and a total PASI score of 1 or lower, illustrated by marked skin clearing and only faint residual erythema that completely resolved at week 12, with the absence of postinflammatory hyperpigmentation.

Safety

Safety data for the PSOARING trials have been previously reported.^17,18 The most common treatment-emergent adverse events were folliculitis, contact dermatitis, upper respiratory tract infection, and nasopharyngitis. Treatment-emergent adverse events generally were mild or moderate in severity and did not lead to trial discontinuation.^17,18

COMMENT

Treat-to-target management approaches aim to improve patient outcomes by striving to achieve optimal goals. The treat-to-target approach supports shared decision-making between clinicians and patients based on common expectations of what constitutes treatment success.

The findings of this analysis based on pooled data from a large cohort of patients demonstrate that a high proportion of patients can achieve or exceed recommended treatment targets with tapinarof cream 1% QD and maintain improvements long-term. The NPF-recommended treatment target of 1% or lower BSA affected within approximately 3 months (90 days) of treatment was achieved by 40% of tapinarof-treated patients. In addition, 1% or lower BSA affected at any time during the trials was achieved by 61% of patients (median, approximately 4 months). The analyses also indicated that PASI total scores of 3 or lower and 2 or lower were achieved by 75% and 67% of tapinarof-treated patients, respectively, within 2 to 3 months.

These findings support the previously reported efficacy of tapinarof cream, including high rates of complete disease clearance (40.9% [312/763]), durable response following treatment interruption, an off-therapy remittive effect of approximately 4 months, and good disease control on therapy with no evidence of tachyphylaxis.^17,18

CONCLUSION

Taken together with previously reported tapinarof efficacy and safety results, our findings demonstrate that a high proportion of patients treated with tapinarof cream as monotherapy can achieve aggressive treatment targets set by both US and European guidelines developed for systemic and biologic therapies. Tapinarof cream 1% QD is an effective topical treatment option for patients with plaque psoriasis that has been approved without restrictions relating to severity or extent of disease treated, duration of use, or application sites, including application to sensitive and intertriginous skin.

Acknowledgments—Editorial and medical writing support under the guidance of the authors was provided by Melanie Govender, MSc (Med), ApotheCom (United Kingdom), and was funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice (GPP) guidelines.

The Diagnosis: Nevus Sebaceus of Jadassohn

The diagnosis of nevus sebaceus of Jadassohn was made clinically based on the lesion’s appearance and presence since birth as well as the absence of systemic symptoms. Clinically, nevus sebaceus of Jadassohn typically manifests as a well-demarcated, yellow- brown plaque often located on the scalp, as was seen in our patient. The lack of pruritus and pain further supported the diagnosis in our patient. No biopsy was performed, as the presentation was considered classic for this condition. Our patient opted to forgo surgery and will be routinely monitored for any changes, as nevus sebaceus has a potential risk, albeit low, for malignant transformation later in life. No changes have been observed since the initial presentation, and regular follow-ups are planned to monitor for future developments.

Nevus sebaceus of Jadassohn is a hamartomatous lesion involving the pilosebaceous follicle and adjacent adnexal structures.^1-3 It most commonly forms on the scalp (59.3%) and is accompanied by partial or total alopecia. ^3,4 It is seen less often on the face, periauricular area, or neck^1,4; thorax or limbs⁵; and oral or genital mucosae.⁶ Nevus sebaceus of Jadassohn affects approximately 0.3% of newborns,¹ usually as a solitary lesion that can form an extensive plaque. The male-to-female occurrence ratio has been reported as equal to slightly more predominant in females; all races and ethnicities are affected.^1,5

Nevus sebaceus of Jadassohn follows 3 stages of clinical development: infantile, adolescent, and adulthood. It manifests at birth or shortly afterward as a smooth hairless patch or plaque that is yellowish and can be hyperpigmented in Black patients.⁵ It may have an oval or linear configuration, typically is asymptomatic, and often arises along the Blaschko lines when it occurs as multiple lesions (a rare manifestation).¹ During puberty, hormonal changes cause accelerated growth, sebaceous gland maturation, and epidermal hyperplasia. ⁷ Nevus sebaceus of Jadassohn often is not identified until this stage, when its classic wartlike appearance has fully developed.¹

Patients with nevus sebaceus of Jadassohn have a 10% to 20% risk for tumor development in adulthood.^2,7 Trichoblastoma and syringocystadenoma papilliferum are the most frequently described neoplasms.⁸ Basal cell carcinoma is the most common malignant secondary neoplasm with an occurrence rate of 0.8%.^6,9 However, basal cell carcinoma and trichoblastoma may share histopathologic features, which may lead to misdiagnosis and a higher reported incidence of basal cell carcinoma in adults than is accurate.²

Early prophylactic surgical removal of nevus sebaceus of Jadassohn has been recommended; however, surgical management is controversial because the risk for a benign secondary neoplasm remains relatively high while the risk for malignancy is much lower.^2,7 Surgical excision remains an acceptable option once the patient is mature enough to tolerate the procedure.¹ However, patient education regarding watchful waiting vs a surgical approach— and the risks of each—is critical to ensure shared decision-making and a management plan tailored to the individual.

The differential diagnosis includes hypertrophic lichen planus, Langerhans cell histiocytosis (Letterer-Siwe disease type), epidermal nevus, and seborrheic keratosis. Hypertrophic lichen planus often occurs symmetrically on the dorsal feet and shins with thick, scaly, and extremely pruritic plaques. The lesions often persist for an average of 6 years and may lead to multiple keratoacanthomas or follicular base squamous cell carcinomas. Langerhans cell histiocytosis (Letterer-Siwe disease type) manifests with acute, disseminated, visceral, and cutaneous lesions before 2 years of age. These lesions appear as 1- to 2-mm, pink, seborrheic papules, pustules, or vesicles on the scalp, flexural neck, axilla, perineum, and trunk; they often are associated with petechiae, purpura, scale, crust, erosion, impetiginization, and tender fissures. Epidermal nevus occurs within the first year of life and is a hamartoma of the epidermis and papillary dermis. It manifests as papillomatous pigmented linear lines along the Blaschko lines. Seborrheic keratosis manifests as well-demarcated, waxy/verrucous, brown papules with a “stuck on” appearance on hair-bearing skin sparing the mucosae. They are common benign lesions associated with sun exposure and often manifest in the fourth decade of life.¹⁰

The Diagnosis: Nevus Sebaceus of Jadassohn

The diagnosis of nevus sebaceus of Jadassohn was made clinically based on the lesion’s appearance and presence since birth as well as the absence of systemic symptoms. Clinically, nevus sebaceus of Jadassohn typically manifests as a well-demarcated, yellow- brown plaque often located on the scalp, as was seen in our patient. The lack of pruritus and pain further supported the diagnosis in our patient. No biopsy was performed, as the presentation was considered classic for this condition. Our patient opted to forgo surgery and will be routinely monitored for any changes, as nevus sebaceus has a potential risk, albeit low, for malignant transformation later in life. No changes have been observed since the initial presentation, and regular follow-ups are planned to monitor for future developments.

Nevus sebaceus of Jadassohn is a hamartomatous lesion involving the pilosebaceous follicle and adjacent adnexal structures.^1-3 It most commonly forms on the scalp (59.3%) and is accompanied by partial or total alopecia. ^3,4 It is seen less often on the face, periauricular area, or neck^1,4; thorax or limbs⁵; and oral or genital mucosae.⁶ Nevus sebaceus of Jadassohn affects approximately 0.3% of newborns,¹ usually as a solitary lesion that can form an extensive plaque. The male-to-female occurrence ratio has been reported as equal to slightly more predominant in females; all races and ethnicities are affected.^1,5

Nevus sebaceus of Jadassohn follows 3 stages of clinical development: infantile, adolescent, and adulthood. It manifests at birth or shortly afterward as a smooth hairless patch or plaque that is yellowish and can be hyperpigmented in Black patients.⁵ It may have an oval or linear configuration, typically is asymptomatic, and often arises along the Blaschko lines when it occurs as multiple lesions (a rare manifestation).¹ During puberty, hormonal changes cause accelerated growth, sebaceous gland maturation, and epidermal hyperplasia. ⁷ Nevus sebaceus of Jadassohn often is not identified until this stage, when its classic wartlike appearance has fully developed.¹

Patients with nevus sebaceus of Jadassohn have a 10% to 20% risk for tumor development in adulthood.^2,7 Trichoblastoma and syringocystadenoma papilliferum are the most frequently described neoplasms.⁸ Basal cell carcinoma is the most common malignant secondary neoplasm with an occurrence rate of 0.8%.^6,9 However, basal cell carcinoma and trichoblastoma may share histopathologic features, which may lead to misdiagnosis and a higher reported incidence of basal cell carcinoma in adults than is accurate.²

Early prophylactic surgical removal of nevus sebaceus of Jadassohn has been recommended; however, surgical management is controversial because the risk for a benign secondary neoplasm remains relatively high while the risk for malignancy is much lower.^2,7 Surgical excision remains an acceptable option once the patient is mature enough to tolerate the procedure.¹ However, patient education regarding watchful waiting vs a surgical approach— and the risks of each—is critical to ensure shared decision-making and a management plan tailored to the individual.

The differential diagnosis includes hypertrophic lichen planus, Langerhans cell histiocytosis (Letterer-Siwe disease type), epidermal nevus, and seborrheic keratosis. Hypertrophic lichen planus often occurs symmetrically on the dorsal feet and shins with thick, scaly, and extremely pruritic plaques. The lesions often persist for an average of 6 years and may lead to multiple keratoacanthomas or follicular base squamous cell carcinomas. Langerhans cell histiocytosis (Letterer-Siwe disease type) manifests with acute, disseminated, visceral, and cutaneous lesions before 2 years of age. These lesions appear as 1- to 2-mm, pink, seborrheic papules, pustules, or vesicles on the scalp, flexural neck, axilla, perineum, and trunk; they often are associated with petechiae, purpura, scale, crust, erosion, impetiginization, and tender fissures. Epidermal nevus occurs within the first year of life and is a hamartoma of the epidermis and papillary dermis. It manifests as papillomatous pigmented linear lines along the Blaschko lines. Seborrheic keratosis manifests as well-demarcated, waxy/verrucous, brown papules with a “stuck on” appearance on hair-bearing skin sparing the mucosae. They are common benign lesions associated with sun exposure and often manifest in the fourth decade of life.¹⁰

The Diagnosis: Nevus Sebaceus of Jadassohn

The diagnosis of nevus sebaceus of Jadassohn was made clinically based on the lesion’s appearance and presence since birth as well as the absence of systemic symptoms. Clinically, nevus sebaceus of Jadassohn typically manifests as a well-demarcated, yellow- brown plaque often located on the scalp, as was seen in our patient. The lack of pruritus and pain further supported the diagnosis in our patient. No biopsy was performed, as the presentation was considered classic for this condition. Our patient opted to forgo surgery and will be routinely monitored for any changes, as nevus sebaceus has a potential risk, albeit low, for malignant transformation later in life. No changes have been observed since the initial presentation, and regular follow-ups are planned to monitor for future developments.

Nevus sebaceus of Jadassohn is a hamartomatous lesion involving the pilosebaceous follicle and adjacent adnexal structures.^1-3 It most commonly forms on the scalp (59.3%) and is accompanied by partial or total alopecia. ^3,4 It is seen less often on the face, periauricular area, or neck^1,4; thorax or limbs⁵; and oral or genital mucosae.⁶ Nevus sebaceus of Jadassohn affects approximately 0.3% of newborns,¹ usually as a solitary lesion that can form an extensive plaque. The male-to-female occurrence ratio has been reported as equal to slightly more predominant in females; all races and ethnicities are affected.^1,5

Nevus sebaceus of Jadassohn follows 3 stages of clinical development: infantile, adolescent, and adulthood. It manifests at birth or shortly afterward as a smooth hairless patch or plaque that is yellowish and can be hyperpigmented in Black patients.⁵ It may have an oval or linear configuration, typically is asymptomatic, and often arises along the Blaschko lines when it occurs as multiple lesions (a rare manifestation).¹ During puberty, hormonal changes cause accelerated growth, sebaceous gland maturation, and epidermal hyperplasia. ⁷ Nevus sebaceus of Jadassohn often is not identified until this stage, when its classic wartlike appearance has fully developed.¹

Patients with nevus sebaceus of Jadassohn have a 10% to 20% risk for tumor development in adulthood.^2,7 Trichoblastoma and syringocystadenoma papilliferum are the most frequently described neoplasms.⁸ Basal cell carcinoma is the most common malignant secondary neoplasm with an occurrence rate of 0.8%.^6,9 However, basal cell carcinoma and trichoblastoma may share histopathologic features, which may lead to misdiagnosis and a higher reported incidence of basal cell carcinoma in adults than is accurate.²

Early prophylactic surgical removal of nevus sebaceus of Jadassohn has been recommended; however, surgical management is controversial because the risk for a benign secondary neoplasm remains relatively high while the risk for malignancy is much lower.^2,7 Surgical excision remains an acceptable option once the patient is mature enough to tolerate the procedure.¹ However, patient education regarding watchful waiting vs a surgical approach— and the risks of each—is critical to ensure shared decision-making and a management plan tailored to the individual.

The differential diagnosis includes hypertrophic lichen planus, Langerhans cell histiocytosis (Letterer-Siwe disease type), epidermal nevus, and seborrheic keratosis. Hypertrophic lichen planus often occurs symmetrically on the dorsal feet and shins with thick, scaly, and extremely pruritic plaques. The lesions often persist for an average of 6 years and may lead to multiple keratoacanthomas or follicular base squamous cell carcinomas. Langerhans cell histiocytosis (Letterer-Siwe disease type) manifests with acute, disseminated, visceral, and cutaneous lesions before 2 years of age. These lesions appear as 1- to 2-mm, pink, seborrheic papules, pustules, or vesicles on the scalp, flexural neck, axilla, perineum, and trunk; they often are associated with petechiae, purpura, scale, crust, erosion, impetiginization, and tender fissures. Epidermal nevus occurs within the first year of life and is a hamartoma of the epidermis and papillary dermis. It manifests as papillomatous pigmented linear lines along the Blaschko lines. Seborrheic keratosis manifests as well-demarcated, waxy/verrucous, brown papules with a “stuck on” appearance on hair-bearing skin sparing the mucosae. They are common benign lesions associated with sun exposure and often manifest in the fourth decade of life.¹⁰

There are 375 species of poisonous snakes, with approximately 20,000 deaths worldwide each year due to snakebites, mostly in Asia and Africa.¹ The death rate in the United States is 14 to 20 cases per year. In the United States, a variety of rattlesnakes are poisonous. There are 2 genera of rattlesnakes: Sistrurus (3 species) and Crotalus (23 species). The pygmy rattlesnake belongs to the Sistrurus miliarius species that is divided into 3 subspecies: the Carolina pigmy rattlesnake (S miliarius miliarius), the western pygmy rattlesnake (S miliarius streckeri), and the dusky pygmy rattlesnake (S miliarius barbouri).²

The western pygmy rattlesnake belongs to the Crotalidae family. The rattlesnakes in this family also are known as pit vipers. All pit vipers have common characteristics for identification: triangular head, fangs, elliptical pupils, and a heat-sensing pit between the eyes. The western pygmy rattlesnake is found in Missouri, Arkansas, Oklahoma, Kentucky, and Tennessee.¹ It is small bodied (15–20 inches)³ and grayish-brown, with a brown dorsal stripe with black blotches on its back. It is found in glades, second-growth forests near rock ledges, and areas where powerlines cut through dense forest.³ Its venom is hemorrhagic, causing tissue damage, but does not contain neurotoxins.⁴ Bites from the western pygmy rattlesnake often do not lead to death, but the venom, which contains numerous proteins and enzymes, does cause necrotic hemorrhagic ulceration at the site of envenomation and possible loss of digit.^5,6

We present a case of a man who was bitten on the right third digit by a western pygmy rattlesnake. We describe the clinical course and treatment.

Case Report

A 56-year-old right-handed man presented to the emergency department with a rapidly swelling, painful hand following a snakebite to the dorsal aspect of the right third digit (Figure 1). He was able to capture a photograph of the snake at the time of injury, which helped identify it as a western pygmy rattlesnake (Figure 2). He also photographed the hand immediately after the bite occurred (Figure 3). Vitals on presentation included an elevated blood pressure of 161/100 mm Hg; no fever (temperature, 36.4 °C); and normal pulse oximetry of 98%, pulse of 86 beats per minute, and respiratory rate of 16 breaths per minute.

After the snakebite, the patient’s family called the Missouri Poison Center immediately. The family identified the snake species and shared this information with the poison center. Poison control recommended calling the nearest hospitals to determine if antivenom was available and make notification of arrival. 

The patient’s tetanus toxoid immunization was updated immediately upon arrival. The hand was marked to monitor swelling. Initial laboratory test results revealed the following values: sodium, 133 mmol/L (reference range, 136–145 mmol/L); potassium, 3.4 mmol/L (3.6–5.2 mmol/L); lactic acid, 2.4 mmol/L (0.5–2.2 mmol/L); creatine kinase, 425 U/L (55–170 U/L); platelet count, 68/µL (150,000–450,000/µL); fibrinogen, 169 mg/dL (185–410 mg/dL); and glucose, 121 mg/dL (74–106 mg/dL). The remainder of the complete blood cell count and metabolic panel was unremarkable. Radiographs of the hand did not show any fractures, dislocations, or foreign bodies. Missouri Poison Center was consulted. Given the patient’s severe pain, edema beyond 40 cm, and developing ecchymosis on the inner arm, the bite was graded as a 3 on the traditional snakebite severity scale. Poison control recommended 4 to 6 vials of antivenom over 60 minutes. Six vials of Crotalidae polyvalent immune fab antivenom were given.

The patient’s complete blood cell count remained unremarkable throughout his admission. His metabolic panel returned to normal at 6 hours postadmission: sodium, 139 mmol/L; potassium, 4.0 mmol/L. His lactate and creatinine kinase were not rechecked. His fibrinogen was trending upward. Serial laboratory test results revealed fibrinogen levels of 153, 158, 161, 159, 173, and 216 mg/dL at 6, 12, 18, 24, 30, and 36 hours, respectively. Other laboratory test results including prothrombin time (11.0 s) and international normalized ratio (0.98) remained within reference range (11–13 s and 0.80–1.39, respectively) during serial monitoring.

The patient was hospitalized for 40 hours while waiting for his fibrinogen level to normalize. The local skin necrosis worsened acutely in this 40-hour window (Figure 4). Intravenous antibiotics were not administered during the hospital stay. Before discharge, the patient was evaluated by the surgery service, who did not recommend debridement.

Surgical Management of Snakebites

The surgeon’s role in managing snakebites is controversial. Snakebites were once perceived as a surgical emergency due to symptoms mimicking compartment syndrome; however, snakebites rarely cause a true compartment syndrome.⁷ Prophylactic bite excision and fasciotomies are not recommended. Incision and suction of the fang marks may be beneficial if performed within 15 to 30 minutes from the time of the bite.⁸ With access to a surgeon in this short time period being nearly impossible, incision and suctioning of fang marks generally is not recommended.⁹ Retained snake fangs are a possibility, and the infection could spread to a nearby joint, causing septic arthritis,¹⁰ which would be an indication for surgical intervention. Bites to the finger often cause major swelling, and the benefits of dermotomy are documented.¹¹ Generally, early administration of antivenom will decrease local tissue reaction and prevent additional tissue loss.¹² In our patient, the decision to perform dermotomy was made when the area of necrosis had declared itself and the skin reached its elastic limit. Bozkurt et al¹³ described the neurovascular bundles within the digit as functioning as small compartments. When the skin of the digit reaches its elastic limit, pressure within the compartment may exceed the capillary closing pressure, and the integrity of small vessels and nerves may be compromised. Our case highlights the benefit of dermotomy as well as the functional and cosmetic results that can be achieved.

Wound Care for Snakebites

There is little published on the treatment of snakebites after patients are stabilized medically for hospital discharge. Venomous snakes inject toxins that predominantly consist of enzymes (eg, phospholipase A2, phosphodiesterase, hyaluronidase, peptidase, metalloproteinase) that cause tissue destruction through diverse mechanisms.¹⁴ The venom of western pygmy rattlesnakes is hemotoxic and can cause necrotic hemorrhagic ulceration,⁴ as was the case in our patient.

Silver sulfadiazine commonly is used to prevent infection in burn patients. Given the large surface area of exposed dermis after debridement and concern for infection, silver sulfadiazine was chosen in our patient for local wound care treatment. Silver sulfadiazine is a widely available and low-cost drug.¹⁵ Its antibacterial effects are due to the silver ions, which only act superficially and therefore limit systemic absorption.¹⁶ Application should be performed in a clean manner with minimal trauma to the tissue. This technique is best achieved by using sterile gloves and applying the medication manually. A 0.0625-inch layer should be applied to entirely cover the cleaned debrided area.¹⁷ When performing application with tongue blades or cotton swabs, it is important to never “double dip.” Patient education on proper administration is imperative to a successful outcome.

Final Thoughts

Our case demonstrates the safe use of Crotalidae polyvalent immune fab antivenom for the treatment of western pygmy rattlesnake (S miliarius streckeri) envenomation. Early administration of antivenom following pit viper rattlesnake envenomations is important to mitigate systemic effects and the extent of soft tissue damage. There are few studies on local wound care treatment after rattlesnake envenomation. This case highlights the role of dermotomy and wound care with silver sulfadiazine cream 1%.

There are 375 species of poisonous snakes, with approximately 20,000 deaths worldwide each year due to snakebites, mostly in Asia and Africa.¹ The death rate in the United States is 14 to 20 cases per year. In the United States, a variety of rattlesnakes are poisonous. There are 2 genera of rattlesnakes: Sistrurus (3 species) and Crotalus (23 species). The pygmy rattlesnake belongs to the Sistrurus miliarius species that is divided into 3 subspecies: the Carolina pigmy rattlesnake (S miliarius miliarius), the western pygmy rattlesnake (S miliarius streckeri), and the dusky pygmy rattlesnake (S miliarius barbouri).²

The western pygmy rattlesnake belongs to the Crotalidae family. The rattlesnakes in this family also are known as pit vipers. All pit vipers have common characteristics for identification: triangular head, fangs, elliptical pupils, and a heat-sensing pit between the eyes. The western pygmy rattlesnake is found in Missouri, Arkansas, Oklahoma, Kentucky, and Tennessee.¹ It is small bodied (15–20 inches)³ and grayish-brown, with a brown dorsal stripe with black blotches on its back. It is found in glades, second-growth forests near rock ledges, and areas where powerlines cut through dense forest.³ Its venom is hemorrhagic, causing tissue damage, but does not contain neurotoxins.⁴ Bites from the western pygmy rattlesnake often do not lead to death, but the venom, which contains numerous proteins and enzymes, does cause necrotic hemorrhagic ulceration at the site of envenomation and possible loss of digit.^5,6

We present a case of a man who was bitten on the right third digit by a western pygmy rattlesnake. We describe the clinical course and treatment.

Case Report

A 56-year-old right-handed man presented to the emergency department with a rapidly swelling, painful hand following a snakebite to the dorsal aspect of the right third digit (Figure 1). He was able to capture a photograph of the snake at the time of injury, which helped identify it as a western pygmy rattlesnake (Figure 2). He also photographed the hand immediately after the bite occurred (Figure 3). Vitals on presentation included an elevated blood pressure of 161/100 mm Hg; no fever (temperature, 36.4 °C); and normal pulse oximetry of 98%, pulse of 86 beats per minute, and respiratory rate of 16 breaths per minute.

After the snakebite, the patient’s family called the Missouri Poison Center immediately. The family identified the snake species and shared this information with the poison center. Poison control recommended calling the nearest hospitals to determine if antivenom was available and make notification of arrival. 

The patient’s tetanus toxoid immunization was updated immediately upon arrival. The hand was marked to monitor swelling. Initial laboratory test results revealed the following values: sodium, 133 mmol/L (reference range, 136–145 mmol/L); potassium, 3.4 mmol/L (3.6–5.2 mmol/L); lactic acid, 2.4 mmol/L (0.5–2.2 mmol/L); creatine kinase, 425 U/L (55–170 U/L); platelet count, 68/µL (150,000–450,000/µL); fibrinogen, 169 mg/dL (185–410 mg/dL); and glucose, 121 mg/dL (74–106 mg/dL). The remainder of the complete blood cell count and metabolic panel was unremarkable. Radiographs of the hand did not show any fractures, dislocations, or foreign bodies. Missouri Poison Center was consulted. Given the patient’s severe pain, edema beyond 40 cm, and developing ecchymosis on the inner arm, the bite was graded as a 3 on the traditional snakebite severity scale. Poison control recommended 4 to 6 vials of antivenom over 60 minutes. Six vials of Crotalidae polyvalent immune fab antivenom were given.

The patient’s complete blood cell count remained unremarkable throughout his admission. His metabolic panel returned to normal at 6 hours postadmission: sodium, 139 mmol/L; potassium, 4.0 mmol/L. His lactate and creatinine kinase were not rechecked. His fibrinogen was trending upward. Serial laboratory test results revealed fibrinogen levels of 153, 158, 161, 159, 173, and 216 mg/dL at 6, 12, 18, 24, 30, and 36 hours, respectively. Other laboratory test results including prothrombin time (11.0 s) and international normalized ratio (0.98) remained within reference range (11–13 s and 0.80–1.39, respectively) during serial monitoring.

The patient was hospitalized for 40 hours while waiting for his fibrinogen level to normalize. The local skin necrosis worsened acutely in this 40-hour window (Figure 4). Intravenous antibiotics were not administered during the hospital stay. Before discharge, the patient was evaluated by the surgery service, who did not recommend debridement.

Surgical Management of Snakebites

The surgeon’s role in managing snakebites is controversial. Snakebites were once perceived as a surgical emergency due to symptoms mimicking compartment syndrome; however, snakebites rarely cause a true compartment syndrome.⁷ Prophylactic bite excision and fasciotomies are not recommended. Incision and suction of the fang marks may be beneficial if performed within 15 to 30 minutes from the time of the bite.⁸ With access to a surgeon in this short time period being nearly impossible, incision and suctioning of fang marks generally is not recommended.⁹ Retained snake fangs are a possibility, and the infection could spread to a nearby joint, causing septic arthritis,¹⁰ which would be an indication for surgical intervention. Bites to the finger often cause major swelling, and the benefits of dermotomy are documented.¹¹ Generally, early administration of antivenom will decrease local tissue reaction and prevent additional tissue loss.¹² In our patient, the decision to perform dermotomy was made when the area of necrosis had declared itself and the skin reached its elastic limit. Bozkurt et al¹³ described the neurovascular bundles within the digit as functioning as small compartments. When the skin of the digit reaches its elastic limit, pressure within the compartment may exceed the capillary closing pressure, and the integrity of small vessels and nerves may be compromised. Our case highlights the benefit of dermotomy as well as the functional and cosmetic results that can be achieved.

Wound Care for Snakebites

There is little published on the treatment of snakebites after patients are stabilized medically for hospital discharge. Venomous snakes inject toxins that predominantly consist of enzymes (eg, phospholipase A2, phosphodiesterase, hyaluronidase, peptidase, metalloproteinase) that cause tissue destruction through diverse mechanisms.¹⁴ The venom of western pygmy rattlesnakes is hemotoxic and can cause necrotic hemorrhagic ulceration,⁴ as was the case in our patient.

Silver sulfadiazine commonly is used to prevent infection in burn patients. Given the large surface area of exposed dermis after debridement and concern for infection, silver sulfadiazine was chosen in our patient for local wound care treatment. Silver sulfadiazine is a widely available and low-cost drug.¹⁵ Its antibacterial effects are due to the silver ions, which only act superficially and therefore limit systemic absorption.¹⁶ Application should be performed in a clean manner with minimal trauma to the tissue. This technique is best achieved by using sterile gloves and applying the medication manually. A 0.0625-inch layer should be applied to entirely cover the cleaned debrided area.¹⁷ When performing application with tongue blades or cotton swabs, it is important to never “double dip.” Patient education on proper administration is imperative to a successful outcome.

Final Thoughts

Our case demonstrates the safe use of Crotalidae polyvalent immune fab antivenom for the treatment of western pygmy rattlesnake (S miliarius streckeri) envenomation. Early administration of antivenom following pit viper rattlesnake envenomations is important to mitigate systemic effects and the extent of soft tissue damage. There are few studies on local wound care treatment after rattlesnake envenomation. This case highlights the role of dermotomy and wound care with silver sulfadiazine cream 1%.

There are 375 species of poisonous snakes, with approximately 20,000 deaths worldwide each year due to snakebites, mostly in Asia and Africa.¹ The death rate in the United States is 14 to 20 cases per year. In the United States, a variety of rattlesnakes are poisonous. There are 2 genera of rattlesnakes: Sistrurus (3 species) and Crotalus (23 species). The pygmy rattlesnake belongs to the Sistrurus miliarius species that is divided into 3 subspecies: the Carolina pigmy rattlesnake (S miliarius miliarius), the western pygmy rattlesnake (S miliarius streckeri), and the dusky pygmy rattlesnake (S miliarius barbouri).²

The western pygmy rattlesnake belongs to the Crotalidae family. The rattlesnakes in this family also are known as pit vipers. All pit vipers have common characteristics for identification: triangular head, fangs, elliptical pupils, and a heat-sensing pit between the eyes. The western pygmy rattlesnake is found in Missouri, Arkansas, Oklahoma, Kentucky, and Tennessee.¹ It is small bodied (15–20 inches)³ and grayish-brown, with a brown dorsal stripe with black blotches on its back. It is found in glades, second-growth forests near rock ledges, and areas where powerlines cut through dense forest.³ Its venom is hemorrhagic, causing tissue damage, but does not contain neurotoxins.⁴ Bites from the western pygmy rattlesnake often do not lead to death, but the venom, which contains numerous proteins and enzymes, does cause necrotic hemorrhagic ulceration at the site of envenomation and possible loss of digit.^5,6

We present a case of a man who was bitten on the right third digit by a western pygmy rattlesnake. We describe the clinical course and treatment.

Case Report

A 56-year-old right-handed man presented to the emergency department with a rapidly swelling, painful hand following a snakebite to the dorsal aspect of the right third digit (Figure 1). He was able to capture a photograph of the snake at the time of injury, which helped identify it as a western pygmy rattlesnake (Figure 2). He also photographed the hand immediately after the bite occurred (Figure 3). Vitals on presentation included an elevated blood pressure of 161/100 mm Hg; no fever (temperature, 36.4 °C); and normal pulse oximetry of 98%, pulse of 86 beats per minute, and respiratory rate of 16 breaths per minute.

After the snakebite, the patient’s family called the Missouri Poison Center immediately. The family identified the snake species and shared this information with the poison center. Poison control recommended calling the nearest hospitals to determine if antivenom was available and make notification of arrival. 

The patient’s tetanus toxoid immunization was updated immediately upon arrival. The hand was marked to monitor swelling. Initial laboratory test results revealed the following values: sodium, 133 mmol/L (reference range, 136–145 mmol/L); potassium, 3.4 mmol/L (3.6–5.2 mmol/L); lactic acid, 2.4 mmol/L (0.5–2.2 mmol/L); creatine kinase, 425 U/L (55–170 U/L); platelet count, 68/µL (150,000–450,000/µL); fibrinogen, 169 mg/dL (185–410 mg/dL); and glucose, 121 mg/dL (74–106 mg/dL). The remainder of the complete blood cell count and metabolic panel was unremarkable. Radiographs of the hand did not show any fractures, dislocations, or foreign bodies. Missouri Poison Center was consulted. Given the patient’s severe pain, edema beyond 40 cm, and developing ecchymosis on the inner arm, the bite was graded as a 3 on the traditional snakebite severity scale. Poison control recommended 4 to 6 vials of antivenom over 60 minutes. Six vials of Crotalidae polyvalent immune fab antivenom were given.

The patient’s complete blood cell count remained unremarkable throughout his admission. His metabolic panel returned to normal at 6 hours postadmission: sodium, 139 mmol/L; potassium, 4.0 mmol/L. His lactate and creatinine kinase were not rechecked. His fibrinogen was trending upward. Serial laboratory test results revealed fibrinogen levels of 153, 158, 161, 159, 173, and 216 mg/dL at 6, 12, 18, 24, 30, and 36 hours, respectively. Other laboratory test results including prothrombin time (11.0 s) and international normalized ratio (0.98) remained within reference range (11–13 s and 0.80–1.39, respectively) during serial monitoring.

The patient was hospitalized for 40 hours while waiting for his fibrinogen level to normalize. The local skin necrosis worsened acutely in this 40-hour window (Figure 4). Intravenous antibiotics were not administered during the hospital stay. Before discharge, the patient was evaluated by the surgery service, who did not recommend debridement.

Surgical Management of Snakebites

The surgeon’s role in managing snakebites is controversial. Snakebites were once perceived as a surgical emergency due to symptoms mimicking compartment syndrome; however, snakebites rarely cause a true compartment syndrome.⁷ Prophylactic bite excision and fasciotomies are not recommended. Incision and suction of the fang marks may be beneficial if performed within 15 to 30 minutes from the time of the bite.⁸ With access to a surgeon in this short time period being nearly impossible, incision and suctioning of fang marks generally is not recommended.⁹ Retained snake fangs are a possibility, and the infection could spread to a nearby joint, causing septic arthritis,¹⁰ which would be an indication for surgical intervention. Bites to the finger often cause major swelling, and the benefits of dermotomy are documented.¹¹ Generally, early administration of antivenom will decrease local tissue reaction and prevent additional tissue loss.¹² In our patient, the decision to perform dermotomy was made when the area of necrosis had declared itself and the skin reached its elastic limit. Bozkurt et al¹³ described the neurovascular bundles within the digit as functioning as small compartments. When the skin of the digit reaches its elastic limit, pressure within the compartment may exceed the capillary closing pressure, and the integrity of small vessels and nerves may be compromised. Our case highlights the benefit of dermotomy as well as the functional and cosmetic results that can be achieved.

Wound Care for Snakebites

There is little published on the treatment of snakebites after patients are stabilized medically for hospital discharge. Venomous snakes inject toxins that predominantly consist of enzymes (eg, phospholipase A2, phosphodiesterase, hyaluronidase, peptidase, metalloproteinase) that cause tissue destruction through diverse mechanisms.¹⁴ The venom of western pygmy rattlesnakes is hemotoxic and can cause necrotic hemorrhagic ulceration,⁴ as was the case in our patient.

Silver sulfadiazine commonly is used to prevent infection in burn patients. Given the large surface area of exposed dermis after debridement and concern for infection, silver sulfadiazine was chosen in our patient for local wound care treatment. Silver sulfadiazine is a widely available and low-cost drug.¹⁵ Its antibacterial effects are due to the silver ions, which only act superficially and therefore limit systemic absorption.¹⁶ Application should be performed in a clean manner with minimal trauma to the tissue. This technique is best achieved by using sterile gloves and applying the medication manually. A 0.0625-inch layer should be applied to entirely cover the cleaned debrided area.¹⁷ When performing application with tongue blades or cotton swabs, it is important to never “double dip.” Patient education on proper administration is imperative to a successful outcome.

Final Thoughts

Our case demonstrates the safe use of Crotalidae polyvalent immune fab antivenom for the treatment of western pygmy rattlesnake (S miliarius streckeri) envenomation. Early administration of antivenom following pit viper rattlesnake envenomations is important to mitigate systemic effects and the extent of soft tissue damage. There are few studies on local wound care treatment after rattlesnake envenomation. This case highlights the role of dermotomy and wound care with silver sulfadiazine cream 1%.

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

To the Editor:

Skin cancers are extremely common worldwide. Malignant melanomas comprise approximately 1 in 5 of these cancers. Exposure to UV radiation is postulated to be responsible for a global rise in melanoma cases over the past 50 years.¹ Pediatric melanoma is a particularly rare condition that affects approximately 6 in every 1 million children.² Melanoma incidence in children ranges by age, increasing by approximately 10-fold from age 1 to 4 years to age 15 to 19 years. Tumor ulceration is a feature more commonly seen among children younger than 10 years and is associated with worse outcomes. Tumor thickness and ulceration strongly predict sentinel lymph node metastases among children, which also is associated with a poor prognosis.³

A recent study evaluating stage IV melanoma survival rates in adolescents and young adults (AYAs) vs older adults found that survival is much worse among AYAs. Thicker tumors and public health insurance also were associated with worse survival rates for AYAs, while early detection was associated with better survival rates.⁴

Health disparities and their role in the prognosis of pediatric melanoma is another important factor. One study analyzed this relationship at the state level using Texas Cancer Registry data (1995-2009).⁵ Patients’ socioeconomic status (SES) and driving distance to the nearest pediatric cancer care center were included in the analysis. Hispanic children were found to be 3 times more likely to present with advanced disease than non-Hispanic White children. Although SES and distance to the nearest treatment center were not found to affect the melanoma stage at presentation, Hispanic ethnicity or being in the lowest SES quartile were correlated with a higher mortality risk.⁵

When considering specific subtypes of melanoma, acral lentiginous melanoma (ALM) is known to develop in patients with skin of color. A 2023 study by Holman et al⁶ reported that the percentage of melanomas that were ALMs ranged from 0.8% in non-Hispanic White individuals to 19.1% in Hispanic Black, American Indian/Alaska Native, and Asian/Pacific Islander individuals. However, ALM is rare in children. In a pooled cohort study with patient information retrieved from the nationwide Dutch Pathology Registry, only 1 child and 1 adolescent were found to have ALM across a total of 514 patients.⁷ We sought to analyze pediatric melanoma outcomes based on race and other barriers to appropriate care.

We conducted a search of the Surveillance, Epidemiology, and End Results (SEER) database from January 1995 to December 2016 for patients aged 21 years and younger with a primary melanoma diagnosis. The primary outcome was the 5-year survival rate. County-level SES variables were used to calculate a prosperity index. Kaplan-Meier analysis and Cox proportional hazards model were used to compare 5-year survival rates among the different racial/ethnic groups.

A sample of 2742 patients was identified during the study period and followed for 5 years. Eighty-two percent were White, 6% Hispanic, 2% Asian, 1% Black, and 5% classified as other/unknown race (data were missing for 4%). The cohort was predominantly female (61%). White patients were more likely to present with localized disease than any other race/ethnicity (83% vs 65% in Hispanic, 60% in Asian/Pacific Islander, and 45% in Black patients [P<.05]).

Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis. On multivariate analysis, this finding remained significant for Hispanic patients when compared with White patients (hazard ratio, 2.37 [P<.05]). Increasing age, male sex, advanced stage at diagnosis, and failure to receive surgery were associated with increased odds of mortality.

Patients with regionalized and disseminated disease had increased odds of mortality (6.16 and 64.45, respectively; P<.05) compared with patients with localized disease. Socioeconomic status and urbanization were not found to influence 5-year survival rates.

Pediatric melanoma often presents a clinical challenge with special considerations. Pediatric-specific predisposing risk factors for melanoma and an atypical clinical presentation are some of the major concerns that necessitate a tailored approach to this malignancy, especially among different age groups, skin types, and racial and socioeconomic groups.⁵

Standard ABCDE criteria often are inadequate for accurate detection of pediatric melanomas. Initial lesions often manifest as raised, red, amelanotic lesions mimicking pyogenic granulomas. Lesions tend to be very small (<6 mm in diameter) and can be uniform in color, thereby making the melanoma more difficult to detect compared to the characteristic findings in adults.⁵ Bleeding or ulceration often can be a warning sign during physical examination.

With regard to incidence, pediatric melanoma is relatively rare. Since the 1970s, the incidence of pediatric melanoma has been increasing; however, a recent analysis of the SEER database showed a decreasing trend from 2000 to 2010.⁴

Our analysis of the SEER data showed an increased risk for pediatric melanoma in older adolescents. In addition, the incidence of pediatric melanoma was higher in females of all racial groups except Asian/Pacific Islander individuals. However, SES was not found to significantly influence the 5-year survival rate in pediatric melanoma.

White pediatric patients were more likely to present with localized disease compared with other races. Pediatric melanoma patients with regional disease had a 6-fold increase in mortality rate vs those with localized disease; those with disseminated disease had a 65-fold higher risk. Consistent with this, Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis.

These findings suggest a relationship between race, melanoma spread, and disease severity. Patient education programs need to be directed specifically to minority groups to improve their knowledge on evolving skin lesions and sun protection practices. Physicians also need to have heightened suspicion and better knowledge of the unique traits of pediatric melanoma.⁵

Given the considerable influence these disparities can have on melanoma outcomes, further research is needed to characterize outcomes based on race and determine obstacles to appropriate care. Improved public outreach initiatives that accommodate specific cultural barriers (eg, language, traditional patterns of behavior) also are required to improve current circumstances.

To the Editor:

Skin cancers are extremely common worldwide. Malignant melanomas comprise approximately 1 in 5 of these cancers. Exposure to UV radiation is postulated to be responsible for a global rise in melanoma cases over the past 50 years.¹ Pediatric melanoma is a particularly rare condition that affects approximately 6 in every 1 million children.² Melanoma incidence in children ranges by age, increasing by approximately 10-fold from age 1 to 4 years to age 15 to 19 years. Tumor ulceration is a feature more commonly seen among children younger than 10 years and is associated with worse outcomes. Tumor thickness and ulceration strongly predict sentinel lymph node metastases among children, which also is associated with a poor prognosis.³

A recent study evaluating stage IV melanoma survival rates in adolescents and young adults (AYAs) vs older adults found that survival is much worse among AYAs. Thicker tumors and public health insurance also were associated with worse survival rates for AYAs, while early detection was associated with better survival rates.⁴

Health disparities and their role in the prognosis of pediatric melanoma is another important factor. One study analyzed this relationship at the state level using Texas Cancer Registry data (1995-2009).⁵ Patients’ socioeconomic status (SES) and driving distance to the nearest pediatric cancer care center were included in the analysis. Hispanic children were found to be 3 times more likely to present with advanced disease than non-Hispanic White children. Although SES and distance to the nearest treatment center were not found to affect the melanoma stage at presentation, Hispanic ethnicity or being in the lowest SES quartile were correlated with a higher mortality risk.⁵

When considering specific subtypes of melanoma, acral lentiginous melanoma (ALM) is known to develop in patients with skin of color. A 2023 study by Holman et al⁶ reported that the percentage of melanomas that were ALMs ranged from 0.8% in non-Hispanic White individuals to 19.1% in Hispanic Black, American Indian/Alaska Native, and Asian/Pacific Islander individuals. However, ALM is rare in children. In a pooled cohort study with patient information retrieved from the nationwide Dutch Pathology Registry, only 1 child and 1 adolescent were found to have ALM across a total of 514 patients.⁷ We sought to analyze pediatric melanoma outcomes based on race and other barriers to appropriate care.

We conducted a search of the Surveillance, Epidemiology, and End Results (SEER) database from January 1995 to December 2016 for patients aged 21 years and younger with a primary melanoma diagnosis. The primary outcome was the 5-year survival rate. County-level SES variables were used to calculate a prosperity index. Kaplan-Meier analysis and Cox proportional hazards model were used to compare 5-year survival rates among the different racial/ethnic groups.

A sample of 2742 patients was identified during the study period and followed for 5 years. Eighty-two percent were White, 6% Hispanic, 2% Asian, 1% Black, and 5% classified as other/unknown race (data were missing for 4%). The cohort was predominantly female (61%). White patients were more likely to present with localized disease than any other race/ethnicity (83% vs 65% in Hispanic, 60% in Asian/Pacific Islander, and 45% in Black patients [P<.05]).

Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis. On multivariate analysis, this finding remained significant for Hispanic patients when compared with White patients (hazard ratio, 2.37 [P<.05]). Increasing age, male sex, advanced stage at diagnosis, and failure to receive surgery were associated with increased odds of mortality.

Patients with regionalized and disseminated disease had increased odds of mortality (6.16 and 64.45, respectively; P<.05) compared with patients with localized disease. Socioeconomic status and urbanization were not found to influence 5-year survival rates.

Pediatric melanoma often presents a clinical challenge with special considerations. Pediatric-specific predisposing risk factors for melanoma and an atypical clinical presentation are some of the major concerns that necessitate a tailored approach to this malignancy, especially among different age groups, skin types, and racial and socioeconomic groups.⁵

Standard ABCDE criteria often are inadequate for accurate detection of pediatric melanomas. Initial lesions often manifest as raised, red, amelanotic lesions mimicking pyogenic granulomas. Lesions tend to be very small (<6 mm in diameter) and can be uniform in color, thereby making the melanoma more difficult to detect compared to the characteristic findings in adults.⁵ Bleeding or ulceration often can be a warning sign during physical examination.

With regard to incidence, pediatric melanoma is relatively rare. Since the 1970s, the incidence of pediatric melanoma has been increasing; however, a recent analysis of the SEER database showed a decreasing trend from 2000 to 2010.⁴

Our analysis of the SEER data showed an increased risk for pediatric melanoma in older adolescents. In addition, the incidence of pediatric melanoma was higher in females of all racial groups except Asian/Pacific Islander individuals. However, SES was not found to significantly influence the 5-year survival rate in pediatric melanoma.

White pediatric patients were more likely to present with localized disease compared with other races. Pediatric melanoma patients with regional disease had a 6-fold increase in mortality rate vs those with localized disease; those with disseminated disease had a 65-fold higher risk. Consistent with this, Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis.

These findings suggest a relationship between race, melanoma spread, and disease severity. Patient education programs need to be directed specifically to minority groups to improve their knowledge on evolving skin lesions and sun protection practices. Physicians also need to have heightened suspicion and better knowledge of the unique traits of pediatric melanoma.⁵

Given the considerable influence these disparities can have on melanoma outcomes, further research is needed to characterize outcomes based on race and determine obstacles to appropriate care. Improved public outreach initiatives that accommodate specific cultural barriers (eg, language, traditional patterns of behavior) also are required to improve current circumstances.

To the Editor:

Skin cancers are extremely common worldwide. Malignant melanomas comprise approximately 1 in 5 of these cancers. Exposure to UV radiation is postulated to be responsible for a global rise in melanoma cases over the past 50 years.¹ Pediatric melanoma is a particularly rare condition that affects approximately 6 in every 1 million children.² Melanoma incidence in children ranges by age, increasing by approximately 10-fold from age 1 to 4 years to age 15 to 19 years. Tumor ulceration is a feature more commonly seen among children younger than 10 years and is associated with worse outcomes. Tumor thickness and ulceration strongly predict sentinel lymph node metastases among children, which also is associated with a poor prognosis.³

A recent study evaluating stage IV melanoma survival rates in adolescents and young adults (AYAs) vs older adults found that survival is much worse among AYAs. Thicker tumors and public health insurance also were associated with worse survival rates for AYAs, while early detection was associated with better survival rates.⁴

Health disparities and their role in the prognosis of pediatric melanoma is another important factor. One study analyzed this relationship at the state level using Texas Cancer Registry data (1995-2009).⁵ Patients’ socioeconomic status (SES) and driving distance to the nearest pediatric cancer care center were included in the analysis. Hispanic children were found to be 3 times more likely to present with advanced disease than non-Hispanic White children. Although SES and distance to the nearest treatment center were not found to affect the melanoma stage at presentation, Hispanic ethnicity or being in the lowest SES quartile were correlated with a higher mortality risk.⁵

When considering specific subtypes of melanoma, acral lentiginous melanoma (ALM) is known to develop in patients with skin of color. A 2023 study by Holman et al⁶ reported that the percentage of melanomas that were ALMs ranged from 0.8% in non-Hispanic White individuals to 19.1% in Hispanic Black, American Indian/Alaska Native, and Asian/Pacific Islander individuals. However, ALM is rare in children. In a pooled cohort study with patient information retrieved from the nationwide Dutch Pathology Registry, only 1 child and 1 adolescent were found to have ALM across a total of 514 patients.⁷ We sought to analyze pediatric melanoma outcomes based on race and other barriers to appropriate care.

We conducted a search of the Surveillance, Epidemiology, and End Results (SEER) database from January 1995 to December 2016 for patients aged 21 years and younger with a primary melanoma diagnosis. The primary outcome was the 5-year survival rate. County-level SES variables were used to calculate a prosperity index. Kaplan-Meier analysis and Cox proportional hazards model were used to compare 5-year survival rates among the different racial/ethnic groups.

A sample of 2742 patients was identified during the study period and followed for 5 years. Eighty-two percent were White, 6% Hispanic, 2% Asian, 1% Black, and 5% classified as other/unknown race (data were missing for 4%). The cohort was predominantly female (61%). White patients were more likely to present with localized disease than any other race/ethnicity (83% vs 65% in Hispanic, 60% in Asian/Pacific Islander, and 45% in Black patients [P<.05]).

Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis. On multivariate analysis, this finding remained significant for Hispanic patients when compared with White patients (hazard ratio, 2.37 [P<.05]). Increasing age, male sex, advanced stage at diagnosis, and failure to receive surgery were associated with increased odds of mortality.

Patients with regionalized and disseminated disease had increased odds of mortality (6.16 and 64.45, respectively; P<.05) compared with patients with localized disease. Socioeconomic status and urbanization were not found to influence 5-year survival rates.

Pediatric melanoma often presents a clinical challenge with special considerations. Pediatric-specific predisposing risk factors for melanoma and an atypical clinical presentation are some of the major concerns that necessitate a tailored approach to this malignancy, especially among different age groups, skin types, and racial and socioeconomic groups.⁵

Standard ABCDE criteria often are inadequate for accurate detection of pediatric melanomas. Initial lesions often manifest as raised, red, amelanotic lesions mimicking pyogenic granulomas. Lesions tend to be very small (<6 mm in diameter) and can be uniform in color, thereby making the melanoma more difficult to detect compared to the characteristic findings in adults.⁵ Bleeding or ulceration often can be a warning sign during physical examination.

With regard to incidence, pediatric melanoma is relatively rare. Since the 1970s, the incidence of pediatric melanoma has been increasing; however, a recent analysis of the SEER database showed a decreasing trend from 2000 to 2010.⁴

Our analysis of the SEER data showed an increased risk for pediatric melanoma in older adolescents. In addition, the incidence of pediatric melanoma was higher in females of all racial groups except Asian/Pacific Islander individuals. However, SES was not found to significantly influence the 5-year survival rate in pediatric melanoma.

White pediatric patients were more likely to present with localized disease compared with other races. Pediatric melanoma patients with regional disease had a 6-fold increase in mortality rate vs those with localized disease; those with disseminated disease had a 65-fold higher risk. Consistent with this, Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis.

These findings suggest a relationship between race, melanoma spread, and disease severity. Patient education programs need to be directed specifically to minority groups to improve their knowledge on evolving skin lesions and sun protection practices. Physicians also need to have heightened suspicion and better knowledge of the unique traits of pediatric melanoma.⁵

Given the considerable influence these disparities can have on melanoma outcomes, further research is needed to characterize outcomes based on race and determine obstacles to appropriate care. Improved public outreach initiatives that accommodate specific cultural barriers (eg, language, traditional patterns of behavior) also are required to improve current circumstances.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.