Cutis

Dermatology patients experience a high burden of mental health disturbance. Psychiatric disease is seen in an estimated 30% to 60% of our patients.¹ It can be secondary to or comorbid with dermatologic disorders, or it can be the primary condition that is driving cutaneous disease. Patients with secondary or comorbid psychiatric disorders often are amenable to referral to a mental health provider or are already participating in some form of mental health treatment; however, patients with primary psychiatric disease who present to dermatology generally do not accept these referrals.² Therefore, if these patients are to receive care anywhere in the health care system, it often must be in the department of dermatology.

What primary psychiatric conditions do we see in dermatology?

Common primary psychiatric conditions seen in dermatology include delusional infestation, obsessive-compulsive disorder and related disorders, and dermatitis artefacta.

Delusional Infestation
Also known as delusions of parasitosis or delusional parasitosis, delusional infestation presents as a fixed false belief that there is an organism or other foreign entity that is present in the skin and is the cause of cutaneous disruption. It often is an isolated delusion but can have a notable psychosocial impact. The term delusional infestation is sometimes preferred, as it is inclusive of delusions focused on any type of organism, not just parasites. It also encompasses delusions of infestation with nonliving matter such as fibers, also known as Morgellons disease.³

Obsessive-Compulsive Disorder and Related Disorders
This broad category includes several conditions encountered in dermatology. Body dysmorphic disorder (BDD), olfactory reference syndrome (ORS), excoriation disorder, and trichotillomania are some of the most common variants. In patients with BDD, skin and hair are the 2 most common preoccupations. It has been estimated that 12% of dermatology patients experience BDD. Unsurprisingly, it is more common in patients presenting to cosmetic dermatology, but general dermatology patients also are affected at a rate of 7%.² Patients with ORS falsely believe they have body odor and/or halitosis. Excoriation disorder manifests as repetitive skin picking, either of normal skin or of lesions such as pimples and scabs. Trichotillomania presents as repeated hair pulling, and trichophagia (eating the pulled hair) also may be present.

Dermatitis Artefacta
Almost 1 in 4 patients who seek dermatologic evaluation for primarily psychiatric disorders have dermatitis artefacta, the presence of deliberately self-inflicted skin lesions.² Patients with dermatitis artefacta have unconscious motives for their behavior and should be distinguished from malingering patients who have a conscious goal of secondary gain.

What treatments are available?

Antidepressants
Selective serotonin reuptake inhibitors are one of the first-line treatments for BDD and may be useful in ORS. In excoriation disorder and trichotillomania, selective serotonin reuptake inhibitors are the most commonly prescribed pharmacotherapy, but they have limited efficacy.²

Antipsychotics
The recommended treatment of delusional infestation is antipsychotic pharmacotherapy. Treatment with risperidone and olanzapine has been reported to achieve full or partial remission in more than two-thirds of cases.⁴ Aripiprazole, a newer antipsychotic, has fewer side effects and has been successful in several case reports.^5-7

Cognitive Behavioral Therapy
Psychotherapy, most often in the form of cognitive behavioral therapy, has been reported as effective treatment of several psychocutaneous diseases. Cognitive behavioral therapy is considered first-line treatment of body-focused repetitive behavior disorders such as excoriation disorder and trichotillomania.² It addresses maladaptive thought patterns to modify behavior.

Who treats patients with neurodermatoses?

If a patient presents to dermatology with a rash found to be related to an underlying thyroid disorder, the treatment plan likely would include referral to an endocrinologist. Similarly, patients with primary psychiatric conditions presenting to dermatology should ideally be referred to psychiatrists or psychotherapists, the providers most thoroughly trained and best equipped to treat them. The challenge in psychodermatology is that patients often are resistant to the assessment that the primary pathology is psychiatric. Patients may deny that they are “crazy” and see numerous providers in search of a dermatologist who “believes” them.⁸

Referral to mental health professionals almost always is refused by patients with primarily psychiatric neurodermatoses, which presents dermatologists with a dilemma. As the authors of the “Psychotropic Agents” chapter of Comprehensive Dermatologic Drug Therapy put it: “A dermatologist has two choices. The first is to try to ‘look the other way’ and pacify the patient by providing relatively benign, but minimally effective treatments. The other option is to try to directly address the psychological/psychiatric problems.” The chapter then provides a thorough guide for the use of psychotropic medications in the dermatology population, advocating for option 2: treatment by dermatologists.⁹

Should a dermatologist prescribe psychotropic drugs?

In Dermatology, the principle reference textbook in many dermatology training programs, it is stated that “[a]lthough less comprehensive than treatment delivered in collaboration with a psychiatrist, in the authors’ opinion, management of these issues by a dermatologist is better than no treatment at all.”¹⁰ Recent reviews in the dermatologic literature of psychiatric diseases and drugs in dermatology agree that dermatologists should feel comfortable with prescribing pharmacologic treatment.^2,8,11 Performance of psychotherapy by dermatologists, on the other hand, is not recommended based on time constraints and lack of training.

Despite the apparent agreement in the texts and literature that pharmacotherapy of psychiatric neurodermatoses is within our scope of practice in dermatology, most dermatologists do not prescribe psychotropic agents. Dermatology residencies generally do not provide thorough training in psychopharmacotherapy.⁹ Unsurprisingly, a survey of 40 dermatologists at one academic institution found that only 11% felt comfortable prescribing an antidepressant and a mere 3% were comfortable prescribing an antipsychotic.¹²

Final Thoughts

The challenges involved in managing patients with primary psychiatric disease in dermatology are great and many patients are undertreated despite the availability of effective, evidence-based treatment options. We need to continue to work toward providing better access to these treatments in a way that maximizes the chance that our patients will accept our care.

Dermatology patients experience a high burden of mental health disturbance. Psychiatric disease is seen in an estimated 30% to 60% of our patients.¹ It can be secondary to or comorbid with dermatologic disorders, or it can be the primary condition that is driving cutaneous disease. Patients with secondary or comorbid psychiatric disorders often are amenable to referral to a mental health provider or are already participating in some form of mental health treatment; however, patients with primary psychiatric disease who present to dermatology generally do not accept these referrals.² Therefore, if these patients are to receive care anywhere in the health care system, it often must be in the department of dermatology.

What primary psychiatric conditions do we see in dermatology?

Common primary psychiatric conditions seen in dermatology include delusional infestation, obsessive-compulsive disorder and related disorders, and dermatitis artefacta.

Delusional Infestation
Also known as delusions of parasitosis or delusional parasitosis, delusional infestation presents as a fixed false belief that there is an organism or other foreign entity that is present in the skin and is the cause of cutaneous disruption. It often is an isolated delusion but can have a notable psychosocial impact. The term delusional infestation is sometimes preferred, as it is inclusive of delusions focused on any type of organism, not just parasites. It also encompasses delusions of infestation with nonliving matter such as fibers, also known as Morgellons disease.³

Obsessive-Compulsive Disorder and Related Disorders
This broad category includes several conditions encountered in dermatology. Body dysmorphic disorder (BDD), olfactory reference syndrome (ORS), excoriation disorder, and trichotillomania are some of the most common variants. In patients with BDD, skin and hair are the 2 most common preoccupations. It has been estimated that 12% of dermatology patients experience BDD. Unsurprisingly, it is more common in patients presenting to cosmetic dermatology, but general dermatology patients also are affected at a rate of 7%.² Patients with ORS falsely believe they have body odor and/or halitosis. Excoriation disorder manifests as repetitive skin picking, either of normal skin or of lesions such as pimples and scabs. Trichotillomania presents as repeated hair pulling, and trichophagia (eating the pulled hair) also may be present.

Dermatitis Artefacta
Almost 1 in 4 patients who seek dermatologic evaluation for primarily psychiatric disorders have dermatitis artefacta, the presence of deliberately self-inflicted skin lesions.² Patients with dermatitis artefacta have unconscious motives for their behavior and should be distinguished from malingering patients who have a conscious goal of secondary gain.

What treatments are available?

Antidepressants
Selective serotonin reuptake inhibitors are one of the first-line treatments for BDD and may be useful in ORS. In excoriation disorder and trichotillomania, selective serotonin reuptake inhibitors are the most commonly prescribed pharmacotherapy, but they have limited efficacy.²

Antipsychotics
The recommended treatment of delusional infestation is antipsychotic pharmacotherapy. Treatment with risperidone and olanzapine has been reported to achieve full or partial remission in more than two-thirds of cases.⁴ Aripiprazole, a newer antipsychotic, has fewer side effects and has been successful in several case reports.^5-7

Cognitive Behavioral Therapy
Psychotherapy, most often in the form of cognitive behavioral therapy, has been reported as effective treatment of several psychocutaneous diseases. Cognitive behavioral therapy is considered first-line treatment of body-focused repetitive behavior disorders such as excoriation disorder and trichotillomania.² It addresses maladaptive thought patterns to modify behavior.

Who treats patients with neurodermatoses?

If a patient presents to dermatology with a rash found to be related to an underlying thyroid disorder, the treatment plan likely would include referral to an endocrinologist. Similarly, patients with primary psychiatric conditions presenting to dermatology should ideally be referred to psychiatrists or psychotherapists, the providers most thoroughly trained and best equipped to treat them. The challenge in psychodermatology is that patients often are resistant to the assessment that the primary pathology is psychiatric. Patients may deny that they are “crazy” and see numerous providers in search of a dermatologist who “believes” them.⁸

Referral to mental health professionals almost always is refused by patients with primarily psychiatric neurodermatoses, which presents dermatologists with a dilemma. As the authors of the “Psychotropic Agents” chapter of Comprehensive Dermatologic Drug Therapy put it: “A dermatologist has two choices. The first is to try to ‘look the other way’ and pacify the patient by providing relatively benign, but minimally effective treatments. The other option is to try to directly address the psychological/psychiatric problems.” The chapter then provides a thorough guide for the use of psychotropic medications in the dermatology population, advocating for option 2: treatment by dermatologists.⁹

Should a dermatologist prescribe psychotropic drugs?

In Dermatology, the principle reference textbook in many dermatology training programs, it is stated that “[a]lthough less comprehensive than treatment delivered in collaboration with a psychiatrist, in the authors’ opinion, management of these issues by a dermatologist is better than no treatment at all.”¹⁰ Recent reviews in the dermatologic literature of psychiatric diseases and drugs in dermatology agree that dermatologists should feel comfortable with prescribing pharmacologic treatment.^2,8,11 Performance of psychotherapy by dermatologists, on the other hand, is not recommended based on time constraints and lack of training.

Despite the apparent agreement in the texts and literature that pharmacotherapy of psychiatric neurodermatoses is within our scope of practice in dermatology, most dermatologists do not prescribe psychotropic agents. Dermatology residencies generally do not provide thorough training in psychopharmacotherapy.⁹ Unsurprisingly, a survey of 40 dermatologists at one academic institution found that only 11% felt comfortable prescribing an antidepressant and a mere 3% were comfortable prescribing an antipsychotic.¹²

Final Thoughts

The challenges involved in managing patients with primary psychiatric disease in dermatology are great and many patients are undertreated despite the availability of effective, evidence-based treatment options. We need to continue to work toward providing better access to these treatments in a way that maximizes the chance that our patients will accept our care.

Dermatology patients experience a high burden of mental health disturbance. Psychiatric disease is seen in an estimated 30% to 60% of our patients.¹ It can be secondary to or comorbid with dermatologic disorders, or it can be the primary condition that is driving cutaneous disease. Patients with secondary or comorbid psychiatric disorders often are amenable to referral to a mental health provider or are already participating in some form of mental health treatment; however, patients with primary psychiatric disease who present to dermatology generally do not accept these referrals.² Therefore, if these patients are to receive care anywhere in the health care system, it often must be in the department of dermatology.

What primary psychiatric conditions do we see in dermatology?

Common primary psychiatric conditions seen in dermatology include delusional infestation, obsessive-compulsive disorder and related disorders, and dermatitis artefacta.

Delusional Infestation
Also known as delusions of parasitosis or delusional parasitosis, delusional infestation presents as a fixed false belief that there is an organism or other foreign entity that is present in the skin and is the cause of cutaneous disruption. It often is an isolated delusion but can have a notable psychosocial impact. The term delusional infestation is sometimes preferred, as it is inclusive of delusions focused on any type of organism, not just parasites. It also encompasses delusions of infestation with nonliving matter such as fibers, also known as Morgellons disease.³

Obsessive-Compulsive Disorder and Related Disorders
This broad category includes several conditions encountered in dermatology. Body dysmorphic disorder (BDD), olfactory reference syndrome (ORS), excoriation disorder, and trichotillomania are some of the most common variants. In patients with BDD, skin and hair are the 2 most common preoccupations. It has been estimated that 12% of dermatology patients experience BDD. Unsurprisingly, it is more common in patients presenting to cosmetic dermatology, but general dermatology patients also are affected at a rate of 7%.² Patients with ORS falsely believe they have body odor and/or halitosis. Excoriation disorder manifests as repetitive skin picking, either of normal skin or of lesions such as pimples and scabs. Trichotillomania presents as repeated hair pulling, and trichophagia (eating the pulled hair) also may be present.

Dermatitis Artefacta
Almost 1 in 4 patients who seek dermatologic evaluation for primarily psychiatric disorders have dermatitis artefacta, the presence of deliberately self-inflicted skin lesions.² Patients with dermatitis artefacta have unconscious motives for their behavior and should be distinguished from malingering patients who have a conscious goal of secondary gain.

What treatments are available?

Antidepressants
Selective serotonin reuptake inhibitors are one of the first-line treatments for BDD and may be useful in ORS. In excoriation disorder and trichotillomania, selective serotonin reuptake inhibitors are the most commonly prescribed pharmacotherapy, but they have limited efficacy.²

Antipsychotics
The recommended treatment of delusional infestation is antipsychotic pharmacotherapy. Treatment with risperidone and olanzapine has been reported to achieve full or partial remission in more than two-thirds of cases.⁴ Aripiprazole, a newer antipsychotic, has fewer side effects and has been successful in several case reports.^5-7

Cognitive Behavioral Therapy
Psychotherapy, most often in the form of cognitive behavioral therapy, has been reported as effective treatment of several psychocutaneous diseases. Cognitive behavioral therapy is considered first-line treatment of body-focused repetitive behavior disorders such as excoriation disorder and trichotillomania.² It addresses maladaptive thought patterns to modify behavior.

Who treats patients with neurodermatoses?

If a patient presents to dermatology with a rash found to be related to an underlying thyroid disorder, the treatment plan likely would include referral to an endocrinologist. Similarly, patients with primary psychiatric conditions presenting to dermatology should ideally be referred to psychiatrists or psychotherapists, the providers most thoroughly trained and best equipped to treat them. The challenge in psychodermatology is that patients often are resistant to the assessment that the primary pathology is psychiatric. Patients may deny that they are “crazy” and see numerous providers in search of a dermatologist who “believes” them.⁸

Referral to mental health professionals almost always is refused by patients with primarily psychiatric neurodermatoses, which presents dermatologists with a dilemma. As the authors of the “Psychotropic Agents” chapter of Comprehensive Dermatologic Drug Therapy put it: “A dermatologist has two choices. The first is to try to ‘look the other way’ and pacify the patient by providing relatively benign, but minimally effective treatments. The other option is to try to directly address the psychological/psychiatric problems.” The chapter then provides a thorough guide for the use of psychotropic medications in the dermatology population, advocating for option 2: treatment by dermatologists.⁹

Should a dermatologist prescribe psychotropic drugs?

In Dermatology, the principle reference textbook in many dermatology training programs, it is stated that “[a]lthough less comprehensive than treatment delivered in collaboration with a psychiatrist, in the authors’ opinion, management of these issues by a dermatologist is better than no treatment at all.”¹⁰ Recent reviews in the dermatologic literature of psychiatric diseases and drugs in dermatology agree that dermatologists should feel comfortable with prescribing pharmacologic treatment.^2,8,11 Performance of psychotherapy by dermatologists, on the other hand, is not recommended based on time constraints and lack of training.

Despite the apparent agreement in the texts and literature that pharmacotherapy of psychiatric neurodermatoses is within our scope of practice in dermatology, most dermatologists do not prescribe psychotropic agents. Dermatology residencies generally do not provide thorough training in psychopharmacotherapy.⁹ Unsurprisingly, a survey of 40 dermatologists at one academic institution found that only 11% felt comfortable prescribing an antidepressant and a mere 3% were comfortable prescribing an antipsychotic.¹²

Final Thoughts

The challenges involved in managing patients with primary psychiatric disease in dermatology are great and many patients are undertreated despite the availability of effective, evidence-based treatment options. We need to continue to work toward providing better access to these treatments in a way that maximizes the chance that our patients will accept our care.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

The Diagnosis: Granulosis Rubra Nasi 

A history of prominent nasal sweating was later elicited and the patient was subsequently diagnosed with granulosis rubra nasi. She was instructed to continue daily use of topical pimecrolimus with the addition of topical atropine, resulting in complete resolution of the eruption at 6-week follow-up (Figure, A). She was then maintained on topical atropine monotherapy, only noting recurrence with cessation of the atropine (Figure, B).  

Other successful treatment regimens of granulosis rubra nasi include injection of botulinum toxin into the nose,¹ monotherapy with topical tacrolimus,² topical indomethacin, steroids, and cryotherapy, among other modalities.¹ Topical atropine and pimecrolimus were selected as first-line agents for treating our pediatric patient due to tolerability and their anti-inflammatory and anticholinergic properties.  

Granulosis rubra nasi is a form of focal hyperhidrosis that presents as erythematous papules, pustules, and vesicles of the midface, especially the nose.3 It is a fairly rare condition that can mimic many other common clinical entities, including comedonal acne, nevus comedonicus, periorificial dermatitis, and tinea faciei, but is resistant to treatments aimed at these disorders. It was first described as a "peculiar disease of the skin of the nose in children" in a case report by Jadassohn⁴ in 1901. It is most common in children aged 7 to 12 years and typically resolves at puberty; adults rarely are affected. Although the etiology has not yet been elucidated, autosomal-dominant transmission has been described, and the cutaneous changes are hypothesized to be secondary to hyperhidrosis.⁵ This postulation is further corroborated by a case report of a pheochromocytoma-associated granulosis rubra nasi that resolved with surgical excision of the pheochromocytoma.⁶ It is not uncommon for patients to have concomitant palmoplantar hyperhidrosis and acrocyanosis.⁵ Histopathologic examination is not necessary for diagnosis, but when performed, it discloses a mononuclear cellular infiltrate surrounding eccrine sweat ducts, blood vessels, and lymphatics without other abnormalities of the epidermis or pilosebaceous unit.^1-3,7 
 

The Diagnosis: Granulosis Rubra Nasi 

A history of prominent nasal sweating was later elicited and the patient was subsequently diagnosed with granulosis rubra nasi. She was instructed to continue daily use of topical pimecrolimus with the addition of topical atropine, resulting in complete resolution of the eruption at 6-week follow-up (Figure, A). She was then maintained on topical atropine monotherapy, only noting recurrence with cessation of the atropine (Figure, B).  

Other successful treatment regimens of granulosis rubra nasi include injection of botulinum toxin into the nose,¹ monotherapy with topical tacrolimus,² topical indomethacin, steroids, and cryotherapy, among other modalities.¹ Topical atropine and pimecrolimus were selected as first-line agents for treating our pediatric patient due to tolerability and their anti-inflammatory and anticholinergic properties.  

Granulosis rubra nasi is a form of focal hyperhidrosis that presents as erythematous papules, pustules, and vesicles of the midface, especially the nose.3 It is a fairly rare condition that can mimic many other common clinical entities, including comedonal acne, nevus comedonicus, periorificial dermatitis, and tinea faciei, but is resistant to treatments aimed at these disorders. It was first described as a "peculiar disease of the skin of the nose in children" in a case report by Jadassohn⁴ in 1901. It is most common in children aged 7 to 12 years and typically resolves at puberty; adults rarely are affected. Although the etiology has not yet been elucidated, autosomal-dominant transmission has been described, and the cutaneous changes are hypothesized to be secondary to hyperhidrosis.⁵ This postulation is further corroborated by a case report of a pheochromocytoma-associated granulosis rubra nasi that resolved with surgical excision of the pheochromocytoma.⁶ It is not uncommon for patients to have concomitant palmoplantar hyperhidrosis and acrocyanosis.⁵ Histopathologic examination is not necessary for diagnosis, but when performed, it discloses a mononuclear cellular infiltrate surrounding eccrine sweat ducts, blood vessels, and lymphatics without other abnormalities of the epidermis or pilosebaceous unit.^1-3,7 
 

The Diagnosis: Granulosis Rubra Nasi 

A history of prominent nasal sweating was later elicited and the patient was subsequently diagnosed with granulosis rubra nasi. She was instructed to continue daily use of topical pimecrolimus with the addition of topical atropine, resulting in complete resolution of the eruption at 6-week follow-up (Figure, A). She was then maintained on topical atropine monotherapy, only noting recurrence with cessation of the atropine (Figure, B).  

Other successful treatment regimens of granulosis rubra nasi include injection of botulinum toxin into the nose,¹ monotherapy with topical tacrolimus,² topical indomethacin, steroids, and cryotherapy, among other modalities.¹ Topical atropine and pimecrolimus were selected as first-line agents for treating our pediatric patient due to tolerability and their anti-inflammatory and anticholinergic properties.  

Granulosis rubra nasi is a form of focal hyperhidrosis that presents as erythematous papules, pustules, and vesicles of the midface, especially the nose.3 It is a fairly rare condition that can mimic many other common clinical entities, including comedonal acne, nevus comedonicus, periorificial dermatitis, and tinea faciei, but is resistant to treatments aimed at these disorders. It was first described as a "peculiar disease of the skin of the nose in children" in a case report by Jadassohn⁴ in 1901. It is most common in children aged 7 to 12 years and typically resolves at puberty; adults rarely are affected. Although the etiology has not yet been elucidated, autosomal-dominant transmission has been described, and the cutaneous changes are hypothesized to be secondary to hyperhidrosis.⁵ This postulation is further corroborated by a case report of a pheochromocytoma-associated granulosis rubra nasi that resolved with surgical excision of the pheochromocytoma.⁶ It is not uncommon for patients to have concomitant palmoplantar hyperhidrosis and acrocyanosis.⁵ Histopathologic examination is not necessary for diagnosis, but when performed, it discloses a mononuclear cellular infiltrate surrounding eccrine sweat ducts, blood vessels, and lymphatics without other abnormalities of the epidermis or pilosebaceous unit.^1-3,7 
 

To improve patient care and outcomes, leading dermatologists from the Cutis and Dermatology News Editorial Boards answered 5 questions on monitoring acne patients on oral therapy. Here’s what we found.

Do you check potassium levels for patients taking spironolactone for acne?

Half of dermatologists surveyed never check potassium levels for patients taking spironolactone for acne. For those who do check levels, 8% do it at baseline only, 8% at baseline and every 6 months, 23% at baseline and yearly, and 13% at baseline and for dosing changes.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Although some dermatologists are still checking for potassium levels in patients taking spironolactone for acne, there is a clear trend toward foregoing laboratory monitoring. This change was likely spurred by a retrospective study of healthy young women taking spironolactone for acne that found a hyperkalemia rate of 0.72%, which is practically equivalent to the 0.76% baseline rate of hyperkalemia in this age group. Furthermore, since repeat testing in 6 of 13 patients showed normal values, the original potassium measurements may have been erroneous. Based on this study, routine potassium monitoring is likely unnecessary for healthy young women taking spironolactone for acne (Plovanich et al). In another retrospective study of women aged 18 to 65 years taking spironolactone for acne, women aged 46 to 65 years had a significantly higher rate of hyperkalemia with spironolactone compared with women aged 18 to 45 years (2/12 women [16.7%] vs 1/112 women [<1%]; P=.0245). Based on this study, potassium monitoring may be indicated for women older than 45 years taking spironolactone for acne (Thiede et al). 

Next page: Cholesterol levels

Do you monitor cholesterol levels in patients taking isotretinoin?

Almost two-thirds of dermatologists indicated that they monitor all cholesterol levels in patients taking isotretinoin, including low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, and triglycerides, but almost one-third monitor triglycerides only. Five percent do not monitor cholesterol levels.

Do you routinely monitor cholesterol levels in patients taking isotretinoin?

More than 80% of dermatologists surveyed routinely monitor cholesterol levels in patients taking isotretinoin, with almost half (45%) at baseline and every 2 to 3 months. Eight percent check levels at baseline only, 28% at baseline and monthly, and 3% at baseline and end of therapy. Eighteen percent indicated they do not routinely monitor cholesterol levels. 

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

In this survey, dermatologists most often check cholesterol levels at baseline and then every 2 to 3 months, with most monitoring all cholesterol types. Elevations in cholesterol are by far the most common laboratory abnormality seen with isotretinoin therapy. In a retrospective study of 515 patients undergoing isotretinoin treatment of acne, mild to moderate triglyceride elevations were seen in 23.5% of patients (Hansen et al). At least in part, these elevations are likely due to the fact the levels were not drawn during fasting. Keep in mind that triglyceride-induced pancreatitis due to isotretinoin is remarkably rare, so monthly screening for triglycerides is likely not warranted. It is reasonable to monitor triglyceride levels during isotretinoin dose adjustments and for patients whose values are trending upward. 

Next page: Monitoring CBC

Do you routinely monitor complete blood cell count (CBC) in patients taking isotretinoin?

More than half (55%) of dermatologists surveyed routinely monitor complete blood cell (CBC) counts in patients taking isotretinoin, while 45% do not. Of those who do monitor CBC, 13% do so at baseline only, 26% at baseline and monthly, 13% at baseline only and every 2 to 3 months, and only 3% at baseline and end of therapy.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Slightly more than half of dermatologists in this survey are obtaining CBC for their patients taking isotretinoin for acne and many of those are performing the test at baseline and monthly. Multiple studies as well as American Academy of Dermatology guidelines have substantiated that routine CBC monitoring is unwarranted in healthy patients, as abnormal values usually resolve or remain stable with therapy (American Academy of Dermatology, Isotretinoin: Recommendations). Therefore, it is worthwhile to consider foregoing CBC testing or obtaining just a baseline CBC in healthy patients being treated with isotretinoin.

Next page: Pregnancy testing

Which pregnancy test do you perform on female patients taking isotretinoin?

More than 40% of dermatologists surveyed use the urine β-human chorionic gonadotropin (hCG) pregnancy test for female patients taking isotretinoin, while 30% use the serum B-hCG test; 28% indicated that they use both tests.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

The iPLEDGE program was implemented in 2006 to avoid fetal exposure to isotretinoin and requires pregnancy testing (urine or serum) for females of childbearing potential taking isotretinoin. In a study of pregnancy-related adverse events associated with isotretinoin reported to the US Food and Drug Administration, 6740 total pregnancies were reported from 1997 to 2017. The rate peaked with 768 pregnancies in 2006 and then decreased. Because several hundred pregnancies in women taking isotretinoin have been reported yearly in the last 10 years, there is a clear need to have better systems in place and patient education to prevent fetal exposure to isotretinoin. 

Next page: More tips from derms

More Tips From Dermatologists

The dermatologists we polled had the following advice for their peers:

I see lab monitoring as an opportunity to engage patients and families in co-directing their care (ie, practice patient- and family-centered care). Some families and patients like frequent monitoring and some want as few blood draws as possible. I do my best to make sure the decision includes components of the patients’ preferences, medical evidence and my best clinical judgement.—Craig Burkhart, MD, MS, MPH (Chapel Hill, North Caroline)

Being familiar with and following the standard of care guidelines for the individual oral therapies used in the treatment of acne is very important. However, it is equally as important to assure the individual patient (medical history, physical examination, social history, etc) is taken into consideration to determine if additional monitoring is required.—Fran E. Cook-Bolden, MD (New York, New York)

The trend seems to be towards less routine monitoring other than pregnancy. Baseline tests may pick out the occasional patient with comorbidities that would preclude or delay treatment, but the majority of patients may not need the repetitive and costly testing that we have done in the past.—Richard Glogau, MD (San Francisco, California)
I have loosened my lab monitoring with isotretinoin over the past few years. If a patient has normal lipid values, comprehensive panel and complete blood cell count for the first 3 months of tests, I skip labs until the end of therapy.—Lawrence J. Green, MD (Washington, DC)

Interestingly, we focus quite a bit of attention on the risk of pregnancy with isotretinoin, and often don't focus enough on the risk with spironolactone. In our practice, we are careful to warn the patients on spironolactone about pregnancy prevention.—Stephen Stone, MD (Springfield, Illinois)

About This Survey

The survey was fielded electronically to Cutis and Dermatology News Editorial Board Members within the United States from May 5, 2019, to June 23, 2019. A total of 40 usable responses were received.

To improve patient care and outcomes, leading dermatologists from the Cutis and Dermatology News Editorial Boards answered 5 questions on monitoring acne patients on oral therapy. Here’s what we found.

Do you check potassium levels for patients taking spironolactone for acne?

Half of dermatologists surveyed never check potassium levels for patients taking spironolactone for acne. For those who do check levels, 8% do it at baseline only, 8% at baseline and every 6 months, 23% at baseline and yearly, and 13% at baseline and for dosing changes.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Although some dermatologists are still checking for potassium levels in patients taking spironolactone for acne, there is a clear trend toward foregoing laboratory monitoring. This change was likely spurred by a retrospective study of healthy young women taking spironolactone for acne that found a hyperkalemia rate of 0.72%, which is practically equivalent to the 0.76% baseline rate of hyperkalemia in this age group. Furthermore, since repeat testing in 6 of 13 patients showed normal values, the original potassium measurements may have been erroneous. Based on this study, routine potassium monitoring is likely unnecessary for healthy young women taking spironolactone for acne (Plovanich et al). In another retrospective study of women aged 18 to 65 years taking spironolactone for acne, women aged 46 to 65 years had a significantly higher rate of hyperkalemia with spironolactone compared with women aged 18 to 45 years (2/12 women [16.7%] vs 1/112 women [<1%]; P=.0245). Based on this study, potassium monitoring may be indicated for women older than 45 years taking spironolactone for acne (Thiede et al). 

Next page: Cholesterol levels

Do you monitor cholesterol levels in patients taking isotretinoin?

Almost two-thirds of dermatologists indicated that they monitor all cholesterol levels in patients taking isotretinoin, including low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, and triglycerides, but almost one-third monitor triglycerides only. Five percent do not monitor cholesterol levels.

Do you routinely monitor cholesterol levels in patients taking isotretinoin?

More than 80% of dermatologists surveyed routinely monitor cholesterol levels in patients taking isotretinoin, with almost half (45%) at baseline and every 2 to 3 months. Eight percent check levels at baseline only, 28% at baseline and monthly, and 3% at baseline and end of therapy. Eighteen percent indicated they do not routinely monitor cholesterol levels. 

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

In this survey, dermatologists most often check cholesterol levels at baseline and then every 2 to 3 months, with most monitoring all cholesterol types. Elevations in cholesterol are by far the most common laboratory abnormality seen with isotretinoin therapy. In a retrospective study of 515 patients undergoing isotretinoin treatment of acne, mild to moderate triglyceride elevations were seen in 23.5% of patients (Hansen et al). At least in part, these elevations are likely due to the fact the levels were not drawn during fasting. Keep in mind that triglyceride-induced pancreatitis due to isotretinoin is remarkably rare, so monthly screening for triglycerides is likely not warranted. It is reasonable to monitor triglyceride levels during isotretinoin dose adjustments and for patients whose values are trending upward. 

Next page: Monitoring CBC

Do you routinely monitor complete blood cell count (CBC) in patients taking isotretinoin?

More than half (55%) of dermatologists surveyed routinely monitor complete blood cell (CBC) counts in patients taking isotretinoin, while 45% do not. Of those who do monitor CBC, 13% do so at baseline only, 26% at baseline and monthly, 13% at baseline only and every 2 to 3 months, and only 3% at baseline and end of therapy.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Slightly more than half of dermatologists in this survey are obtaining CBC for their patients taking isotretinoin for acne and many of those are performing the test at baseline and monthly. Multiple studies as well as American Academy of Dermatology guidelines have substantiated that routine CBC monitoring is unwarranted in healthy patients, as abnormal values usually resolve or remain stable with therapy (American Academy of Dermatology, Isotretinoin: Recommendations). Therefore, it is worthwhile to consider foregoing CBC testing or obtaining just a baseline CBC in healthy patients being treated with isotretinoin.

Next page: Pregnancy testing

Which pregnancy test do you perform on female patients taking isotretinoin?

More than 40% of dermatologists surveyed use the urine β-human chorionic gonadotropin (hCG) pregnancy test for female patients taking isotretinoin, while 30% use the serum B-hCG test; 28% indicated that they use both tests.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

The iPLEDGE program was implemented in 2006 to avoid fetal exposure to isotretinoin and requires pregnancy testing (urine or serum) for females of childbearing potential taking isotretinoin. In a study of pregnancy-related adverse events associated with isotretinoin reported to the US Food and Drug Administration, 6740 total pregnancies were reported from 1997 to 2017. The rate peaked with 768 pregnancies in 2006 and then decreased. Because several hundred pregnancies in women taking isotretinoin have been reported yearly in the last 10 years, there is a clear need to have better systems in place and patient education to prevent fetal exposure to isotretinoin. 

Next page: More tips from derms

More Tips From Dermatologists

The dermatologists we polled had the following advice for their peers:

I see lab monitoring as an opportunity to engage patients and families in co-directing their care (ie, practice patient- and family-centered care). Some families and patients like frequent monitoring and some want as few blood draws as possible. I do my best to make sure the decision includes components of the patients’ preferences, medical evidence and my best clinical judgement.—Craig Burkhart, MD, MS, MPH (Chapel Hill, North Caroline)

Being familiar with and following the standard of care guidelines for the individual oral therapies used in the treatment of acne is very important. However, it is equally as important to assure the individual patient (medical history, physical examination, social history, etc) is taken into consideration to determine if additional monitoring is required.—Fran E. Cook-Bolden, MD (New York, New York)

The trend seems to be towards less routine monitoring other than pregnancy. Baseline tests may pick out the occasional patient with comorbidities that would preclude or delay treatment, but the majority of patients may not need the repetitive and costly testing that we have done in the past.—Richard Glogau, MD (San Francisco, California)
I have loosened my lab monitoring with isotretinoin over the past few years. If a patient has normal lipid values, comprehensive panel and complete blood cell count for the first 3 months of tests, I skip labs until the end of therapy.—Lawrence J. Green, MD (Washington, DC)

Interestingly, we focus quite a bit of attention on the risk of pregnancy with isotretinoin, and often don't focus enough on the risk with spironolactone. In our practice, we are careful to warn the patients on spironolactone about pregnancy prevention.—Stephen Stone, MD (Springfield, Illinois)

About This Survey

The survey was fielded electronically to Cutis and Dermatology News Editorial Board Members within the United States from May 5, 2019, to June 23, 2019. A total of 40 usable responses were received.

To improve patient care and outcomes, leading dermatologists from the Cutis and Dermatology News Editorial Boards answered 5 questions on monitoring acne patients on oral therapy. Here’s what we found.

Do you check potassium levels for patients taking spironolactone for acne?

Half of dermatologists surveyed never check potassium levels for patients taking spironolactone for acne. For those who do check levels, 8% do it at baseline only, 8% at baseline and every 6 months, 23% at baseline and yearly, and 13% at baseline and for dosing changes.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Although some dermatologists are still checking for potassium levels in patients taking spironolactone for acne, there is a clear trend toward foregoing laboratory monitoring. This change was likely spurred by a retrospective study of healthy young women taking spironolactone for acne that found a hyperkalemia rate of 0.72%, which is practically equivalent to the 0.76% baseline rate of hyperkalemia in this age group. Furthermore, since repeat testing in 6 of 13 patients showed normal values, the original potassium measurements may have been erroneous. Based on this study, routine potassium monitoring is likely unnecessary for healthy young women taking spironolactone for acne (Plovanich et al). In another retrospective study of women aged 18 to 65 years taking spironolactone for acne, women aged 46 to 65 years had a significantly higher rate of hyperkalemia with spironolactone compared with women aged 18 to 45 years (2/12 women [16.7%] vs 1/112 women [<1%]; P=.0245). Based on this study, potassium monitoring may be indicated for women older than 45 years taking spironolactone for acne (Thiede et al). 

Next page: Cholesterol levels

Do you monitor cholesterol levels in patients taking isotretinoin?

Almost two-thirds of dermatologists indicated that they monitor all cholesterol levels in patients taking isotretinoin, including low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, and triglycerides, but almost one-third monitor triglycerides only. Five percent do not monitor cholesterol levels.

Do you routinely monitor cholesterol levels in patients taking isotretinoin?

More than 80% of dermatologists surveyed routinely monitor cholesterol levels in patients taking isotretinoin, with almost half (45%) at baseline and every 2 to 3 months. Eight percent check levels at baseline only, 28% at baseline and monthly, and 3% at baseline and end of therapy. Eighteen percent indicated they do not routinely monitor cholesterol levels. 

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

In this survey, dermatologists most often check cholesterol levels at baseline and then every 2 to 3 months, with most monitoring all cholesterol types. Elevations in cholesterol are by far the most common laboratory abnormality seen with isotretinoin therapy. In a retrospective study of 515 patients undergoing isotretinoin treatment of acne, mild to moderate triglyceride elevations were seen in 23.5% of patients (Hansen et al). At least in part, these elevations are likely due to the fact the levels were not drawn during fasting. Keep in mind that triglyceride-induced pancreatitis due to isotretinoin is remarkably rare, so monthly screening for triglycerides is likely not warranted. It is reasonable to monitor triglyceride levels during isotretinoin dose adjustments and for patients whose values are trending upward. 

Next page: Monitoring CBC

Do you routinely monitor complete blood cell count (CBC) in patients taking isotretinoin?

More than half (55%) of dermatologists surveyed routinely monitor complete blood cell (CBC) counts in patients taking isotretinoin, while 45% do not. Of those who do monitor CBC, 13% do so at baseline only, 26% at baseline and monthly, 13% at baseline only and every 2 to 3 months, and only 3% at baseline and end of therapy.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Slightly more than half of dermatologists in this survey are obtaining CBC for their patients taking isotretinoin for acne and many of those are performing the test at baseline and monthly. Multiple studies as well as American Academy of Dermatology guidelines have substantiated that routine CBC monitoring is unwarranted in healthy patients, as abnormal values usually resolve or remain stable with therapy (American Academy of Dermatology, Isotretinoin: Recommendations). Therefore, it is worthwhile to consider foregoing CBC testing or obtaining just a baseline CBC in healthy patients being treated with isotretinoin.

Next page: Pregnancy testing

Which pregnancy test do you perform on female patients taking isotretinoin?

More than 40% of dermatologists surveyed use the urine β-human chorionic gonadotropin (hCG) pregnancy test for female patients taking isotretinoin, while 30% use the serum B-hCG test; 28% indicated that they use both tests.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

The iPLEDGE program was implemented in 2006 to avoid fetal exposure to isotretinoin and requires pregnancy testing (urine or serum) for females of childbearing potential taking isotretinoin. In a study of pregnancy-related adverse events associated with isotretinoin reported to the US Food and Drug Administration, 6740 total pregnancies were reported from 1997 to 2017. The rate peaked with 768 pregnancies in 2006 and then decreased. Because several hundred pregnancies in women taking isotretinoin have been reported yearly in the last 10 years, there is a clear need to have better systems in place and patient education to prevent fetal exposure to isotretinoin. 

Next page: More tips from derms

More Tips From Dermatologists

The dermatologists we polled had the following advice for their peers:

I see lab monitoring as an opportunity to engage patients and families in co-directing their care (ie, practice patient- and family-centered care). Some families and patients like frequent monitoring and some want as few blood draws as possible. I do my best to make sure the decision includes components of the patients’ preferences, medical evidence and my best clinical judgement.—Craig Burkhart, MD, MS, MPH (Chapel Hill, North Caroline)

Being familiar with and following the standard of care guidelines for the individual oral therapies used in the treatment of acne is very important. However, it is equally as important to assure the individual patient (medical history, physical examination, social history, etc) is taken into consideration to determine if additional monitoring is required.—Fran E. Cook-Bolden, MD (New York, New York)

The trend seems to be towards less routine monitoring other than pregnancy. Baseline tests may pick out the occasional patient with comorbidities that would preclude or delay treatment, but the majority of patients may not need the repetitive and costly testing that we have done in the past.—Richard Glogau, MD (San Francisco, California)
I have loosened my lab monitoring with isotretinoin over the past few years. If a patient has normal lipid values, comprehensive panel and complete blood cell count for the first 3 months of tests, I skip labs until the end of therapy.—Lawrence J. Green, MD (Washington, DC)

Interestingly, we focus quite a bit of attention on the risk of pregnancy with isotretinoin, and often don't focus enough on the risk with spironolactone. In our practice, we are careful to warn the patients on spironolactone about pregnancy prevention.—Stephen Stone, MD (Springfield, Illinois)

About This Survey

The survey was fielded electronically to Cutis and Dermatology News Editorial Board Members within the United States from May 5, 2019, to June 23, 2019. A total of 40 usable responses were received.

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

To the Editor:

An 8-year-old girl presented with new lesions on the scalp that were mildly painful to palpation and had been increasing in size and number over the last 2 months. Her medical history was remarkable for seizures, keratosis pilaris, and seborrheic dermatitis. The seizures had been well controlled on oxcarbazepine; however, she was switched to lamotrigine 6 months prior to presentation under the care of her neurologist. The patient was not taking other oral medications, and she denied any trauma/insect bites to the affected area or systemic symptoms such as fever, fatigue, weight loss, nausea, swollen lymph nodes, or night sweats. Physical examination revealed 3 well-circumscribed, pink, slightly scaly, indurated nodules on the frontal and vertex scalp (Figure 1). She reported pain on palpation of the lesions. Treatment with ketoconazole shampoo and high-potency topical corticosteroids was ineffective.

Over a period of 2 months after the initial presentation, the patient developed a total of 9 scalp lesions. Testing was performed 4 months after presentation of lesions. Bacterial and fungal cultures of the lesional skin of the scalp were negative. Two biopsies of lesions on the scalp were performed, the first of which showed a nonspecific lymphohistiocytic infiltrate. The second biopsy revealed a dense, nodular, atypical dermal lymphoid infiltrate composed primarily of round regular lymphocytes intermixed with some larger, more irregular lymphocytes and few scattered mitoses (Figure 2).

After conferring with the patient’s neurologist, lamotrigine was discontinued. Within a few weeks of cessation, the scalp lesions resolved without recurrence at 9-month follow-up. In addition to the lack of clinical, histological, or immunohistochemical evidence of underlying malignancy, the temporal association of the development of lesions after starting lamotrigine and rapid resolution upon its discontinuation suggested a diagnosis of lamotrigine-induced cutaneous pseudolymphoma.

Cutaneous pseudolymphoma is a term used to describe a heterogenous group of benign reactive T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.¹ Historically, these types of proliferations have been classified under many alternative names that originally served to describe only B-cell–type proliferations. With advances in immunohistochemistry allowing for more specific cell marker identification, cutaneous pseudolymphomas often are found to contain a mixture of T-cell and B-cell populations, which also led to identifying and describing T-cell–type pseudolymphomas.²

The clinical appearance of cutaneous pseudolymphoma is variable, ranging from discrete nodules or papules to even confluent erythroderma in certain cases.² The high clinical variability further complicates diagnosis. Although our patient presented with 9 individual nodular lesions, this finding alone is not sufficient to have high suspicion for cutaneous pseudolymphoma without including a much broader differential diagnosis. In our case, the differential diagnosis also included cutaneous lymphoma, arthropod bite reaction, lymphomatoid papulosis, tumid lupus, follicular mucinosis, lymphocytic infiltrate of Jessner, and leukemia cutis.

The primary concern regarding diagnosis of cutaneous pseudolymphoma is the clinician’s ability to effectively differentiate this entity from a true malignant lymphoma. Immunostaining has some value by identification of heterogeneous cell–type populations with a mixed T-cell and B-cell infiltrate that is more characteristic of a benign reactive process. Subsequent polymerase chain reaction analysis can detect the presence or absence of monoclonal T-cell receptor gene rearrangement or immunoglobulin heavy chain rearrangement.³ If these monoclonal rearrangements are absent, a benign diagnosis is favored; however, these rearrangements also have been shown to exist in a case of cutaneous pseudolymphoma that earned the final diagnosis when removal of the offending agent led to spontaneous lesion regression, similar to our case.⁴

Many different entities have been described as causative factors for the development of cutaneous pseudolymphoma. Of those that have been considered causative, simple categories have emerged, including endogenous, exogenous, and iatrogenic causes. One potential endogenous etiology of cutaneous pseudolymphoma is IgG4-related disease.⁵ A multitude of exogenous causes have been reported, including several cases of cutaneous pseudolymphoma developing in a prior tattoo site.⁶ Viruses, specifically molluscum contagiosum, also have been implicated as exogenous causes, and a report of cutaneous pseudolymphoma development at a prior site of herpes zoster lesions has been described.⁷ Development of cutaneous pseudolymphoma in vaccination sites also has been reported,⁸ as well as more obscure inciting events such as Leishmania donovani infection and medicinal leech therapy.⁹

A considerable number of reported cases of cutaneous pseudolymphoma have been attributed to drugs, including monoclonal antibodies,¹⁰ herbal supplements,¹¹ and a multitude of other medications.¹ As a class, anticonvulsants are considered more likely to cause lymph node pseudolymphomas than strictly cutaneous pseudolymphomas¹²; however, many drugs in this class of medications have been described in the development of cutaneous pseudolymphoma.³ A review of the literature by Ploysangam et al¹ revealed reports of the development of cutaneous pseudolymphomas after administration of phenytoin, carbamazepine, mephenytoin, trimethadione, phenobarbital, primidone, butabarbital, methsuximide, phensuximide, and valproic acid.

Our patient represents a rare case of strictly cutaneous pseudolymphoma caused by administration of lamotrigine. Our case demonstrated a clear temporal relation between the cessation of lamotrigine and rapid and spontaneous disappearance of cutaneous lesions. We found another case of pseudolymphoma in which lamotrigine was deemed causative, but only lymph node involvement was observed.¹²

Proper diagnosis of cutaneous pseudolymphoma is important not only with regard to the initial differentiation from true malignant lymphoma but in allowing for appropriate follow-up and vigilant surveillance. Cases of progression from cutaneous pseudolymphoma to true lymphoma have been reported.^1,2 It is recommended that watchful follow-up for these patients be carried out until at least 5 years after the diagnosis of cutaneous pseudolymphoma is made to rule out the possibility of malignant transformation, particularly in idiopathic cases.¹³

To the Editor:

An 8-year-old girl presented with new lesions on the scalp that were mildly painful to palpation and had been increasing in size and number over the last 2 months. Her medical history was remarkable for seizures, keratosis pilaris, and seborrheic dermatitis. The seizures had been well controlled on oxcarbazepine; however, she was switched to lamotrigine 6 months prior to presentation under the care of her neurologist. The patient was not taking other oral medications, and she denied any trauma/insect bites to the affected area or systemic symptoms such as fever, fatigue, weight loss, nausea, swollen lymph nodes, or night sweats. Physical examination revealed 3 well-circumscribed, pink, slightly scaly, indurated nodules on the frontal and vertex scalp (Figure 1). She reported pain on palpation of the lesions. Treatment with ketoconazole shampoo and high-potency topical corticosteroids was ineffective.

Over a period of 2 months after the initial presentation, the patient developed a total of 9 scalp lesions. Testing was performed 4 months after presentation of lesions. Bacterial and fungal cultures of the lesional skin of the scalp were negative. Two biopsies of lesions on the scalp were performed, the first of which showed a nonspecific lymphohistiocytic infiltrate. The second biopsy revealed a dense, nodular, atypical dermal lymphoid infiltrate composed primarily of round regular lymphocytes intermixed with some larger, more irregular lymphocytes and few scattered mitoses (Figure 2).

After conferring with the patient’s neurologist, lamotrigine was discontinued. Within a few weeks of cessation, the scalp lesions resolved without recurrence at 9-month follow-up. In addition to the lack of clinical, histological, or immunohistochemical evidence of underlying malignancy, the temporal association of the development of lesions after starting lamotrigine and rapid resolution upon its discontinuation suggested a diagnosis of lamotrigine-induced cutaneous pseudolymphoma.

Cutaneous pseudolymphoma is a term used to describe a heterogenous group of benign reactive T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.¹ Historically, these types of proliferations have been classified under many alternative names that originally served to describe only B-cell–type proliferations. With advances in immunohistochemistry allowing for more specific cell marker identification, cutaneous pseudolymphomas often are found to contain a mixture of T-cell and B-cell populations, which also led to identifying and describing T-cell–type pseudolymphomas.²

The clinical appearance of cutaneous pseudolymphoma is variable, ranging from discrete nodules or papules to even confluent erythroderma in certain cases.² The high clinical variability further complicates diagnosis. Although our patient presented with 9 individual nodular lesions, this finding alone is not sufficient to have high suspicion for cutaneous pseudolymphoma without including a much broader differential diagnosis. In our case, the differential diagnosis also included cutaneous lymphoma, arthropod bite reaction, lymphomatoid papulosis, tumid lupus, follicular mucinosis, lymphocytic infiltrate of Jessner, and leukemia cutis.

The primary concern regarding diagnosis of cutaneous pseudolymphoma is the clinician’s ability to effectively differentiate this entity from a true malignant lymphoma. Immunostaining has some value by identification of heterogeneous cell–type populations with a mixed T-cell and B-cell infiltrate that is more characteristic of a benign reactive process. Subsequent polymerase chain reaction analysis can detect the presence or absence of monoclonal T-cell receptor gene rearrangement or immunoglobulin heavy chain rearrangement.³ If these monoclonal rearrangements are absent, a benign diagnosis is favored; however, these rearrangements also have been shown to exist in a case of cutaneous pseudolymphoma that earned the final diagnosis when removal of the offending agent led to spontaneous lesion regression, similar to our case.⁴

Many different entities have been described as causative factors for the development of cutaneous pseudolymphoma. Of those that have been considered causative, simple categories have emerged, including endogenous, exogenous, and iatrogenic causes. One potential endogenous etiology of cutaneous pseudolymphoma is IgG4-related disease.⁵ A multitude of exogenous causes have been reported, including several cases of cutaneous pseudolymphoma developing in a prior tattoo site.⁶ Viruses, specifically molluscum contagiosum, also have been implicated as exogenous causes, and a report of cutaneous pseudolymphoma development at a prior site of herpes zoster lesions has been described.⁷ Development of cutaneous pseudolymphoma in vaccination sites also has been reported,⁸ as well as more obscure inciting events such as Leishmania donovani infection and medicinal leech therapy.⁹

A considerable number of reported cases of cutaneous pseudolymphoma have been attributed to drugs, including monoclonal antibodies,¹⁰ herbal supplements,¹¹ and a multitude of other medications.¹ As a class, anticonvulsants are considered more likely to cause lymph node pseudolymphomas than strictly cutaneous pseudolymphomas¹²; however, many drugs in this class of medications have been described in the development of cutaneous pseudolymphoma.³ A review of the literature by Ploysangam et al¹ revealed reports of the development of cutaneous pseudolymphomas after administration of phenytoin, carbamazepine, mephenytoin, trimethadione, phenobarbital, primidone, butabarbital, methsuximide, phensuximide, and valproic acid.

Our patient represents a rare case of strictly cutaneous pseudolymphoma caused by administration of lamotrigine. Our case demonstrated a clear temporal relation between the cessation of lamotrigine and rapid and spontaneous disappearance of cutaneous lesions. We found another case of pseudolymphoma in which lamotrigine was deemed causative, but only lymph node involvement was observed.¹²

Proper diagnosis of cutaneous pseudolymphoma is important not only with regard to the initial differentiation from true malignant lymphoma but in allowing for appropriate follow-up and vigilant surveillance. Cases of progression from cutaneous pseudolymphoma to true lymphoma have been reported.^1,2 It is recommended that watchful follow-up for these patients be carried out until at least 5 years after the diagnosis of cutaneous pseudolymphoma is made to rule out the possibility of malignant transformation, particularly in idiopathic cases.¹³

To the Editor:

An 8-year-old girl presented with new lesions on the scalp that were mildly painful to palpation and had been increasing in size and number over the last 2 months. Her medical history was remarkable for seizures, keratosis pilaris, and seborrheic dermatitis. The seizures had been well controlled on oxcarbazepine; however, she was switched to lamotrigine 6 months prior to presentation under the care of her neurologist. The patient was not taking other oral medications, and she denied any trauma/insect bites to the affected area or systemic symptoms such as fever, fatigue, weight loss, nausea, swollen lymph nodes, or night sweats. Physical examination revealed 3 well-circumscribed, pink, slightly scaly, indurated nodules on the frontal and vertex scalp (Figure 1). She reported pain on palpation of the lesions. Treatment with ketoconazole shampoo and high-potency topical corticosteroids was ineffective.

Over a period of 2 months after the initial presentation, the patient developed a total of 9 scalp lesions. Testing was performed 4 months after presentation of lesions. Bacterial and fungal cultures of the lesional skin of the scalp were negative. Two biopsies of lesions on the scalp were performed, the first of which showed a nonspecific lymphohistiocytic infiltrate. The second biopsy revealed a dense, nodular, atypical dermal lymphoid infiltrate composed primarily of round regular lymphocytes intermixed with some larger, more irregular lymphocytes and few scattered mitoses (Figure 2).

After conferring with the patient’s neurologist, lamotrigine was discontinued. Within a few weeks of cessation, the scalp lesions resolved without recurrence at 9-month follow-up. In addition to the lack of clinical, histological, or immunohistochemical evidence of underlying malignancy, the temporal association of the development of lesions after starting lamotrigine and rapid resolution upon its discontinuation suggested a diagnosis of lamotrigine-induced cutaneous pseudolymphoma.

Cutaneous pseudolymphoma is a term used to describe a heterogenous group of benign reactive T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.¹ Historically, these types of proliferations have been classified under many alternative names that originally served to describe only B-cell–type proliferations. With advances in immunohistochemistry allowing for more specific cell marker identification, cutaneous pseudolymphomas often are found to contain a mixture of T-cell and B-cell populations, which also led to identifying and describing T-cell–type pseudolymphomas.²

The clinical appearance of cutaneous pseudolymphoma is variable, ranging from discrete nodules or papules to even confluent erythroderma in certain cases.² The high clinical variability further complicates diagnosis. Although our patient presented with 9 individual nodular lesions, this finding alone is not sufficient to have high suspicion for cutaneous pseudolymphoma without including a much broader differential diagnosis. In our case, the differential diagnosis also included cutaneous lymphoma, arthropod bite reaction, lymphomatoid papulosis, tumid lupus, follicular mucinosis, lymphocytic infiltrate of Jessner, and leukemia cutis.

The primary concern regarding diagnosis of cutaneous pseudolymphoma is the clinician’s ability to effectively differentiate this entity from a true malignant lymphoma. Immunostaining has some value by identification of heterogeneous cell–type populations with a mixed T-cell and B-cell infiltrate that is more characteristic of a benign reactive process. Subsequent polymerase chain reaction analysis can detect the presence or absence of monoclonal T-cell receptor gene rearrangement or immunoglobulin heavy chain rearrangement.³ If these monoclonal rearrangements are absent, a benign diagnosis is favored; however, these rearrangements also have been shown to exist in a case of cutaneous pseudolymphoma that earned the final diagnosis when removal of the offending agent led to spontaneous lesion regression, similar to our case.⁴

Many different entities have been described as causative factors for the development of cutaneous pseudolymphoma. Of those that have been considered causative, simple categories have emerged, including endogenous, exogenous, and iatrogenic causes. One potential endogenous etiology of cutaneous pseudolymphoma is IgG4-related disease.⁵ A multitude of exogenous causes have been reported, including several cases of cutaneous pseudolymphoma developing in a prior tattoo site.⁶ Viruses, specifically molluscum contagiosum, also have been implicated as exogenous causes, and a report of cutaneous pseudolymphoma development at a prior site of herpes zoster lesions has been described.⁷ Development of cutaneous pseudolymphoma in vaccination sites also has been reported,⁸ as well as more obscure inciting events such as Leishmania donovani infection and medicinal leech therapy.⁹

A considerable number of reported cases of cutaneous pseudolymphoma have been attributed to drugs, including monoclonal antibodies,¹⁰ herbal supplements,¹¹ and a multitude of other medications.¹ As a class, anticonvulsants are considered more likely to cause lymph node pseudolymphomas than strictly cutaneous pseudolymphomas¹²; however, many drugs in this class of medications have been described in the development of cutaneous pseudolymphoma.³ A review of the literature by Ploysangam et al¹ revealed reports of the development of cutaneous pseudolymphomas after administration of phenytoin, carbamazepine, mephenytoin, trimethadione, phenobarbital, primidone, butabarbital, methsuximide, phensuximide, and valproic acid.

Our patient represents a rare case of strictly cutaneous pseudolymphoma caused by administration of lamotrigine. Our case demonstrated a clear temporal relation between the cessation of lamotrigine and rapid and spontaneous disappearance of cutaneous lesions. We found another case of pseudolymphoma in which lamotrigine was deemed causative, but only lymph node involvement was observed.¹²

Proper diagnosis of cutaneous pseudolymphoma is important not only with regard to the initial differentiation from true malignant lymphoma but in allowing for appropriate follow-up and vigilant surveillance. Cases of progression from cutaneous pseudolymphoma to true lymphoma have been reported.^1,2 It is recommended that watchful follow-up for these patients be carried out until at least 5 years after the diagnosis of cutaneous pseudolymphoma is made to rule out the possibility of malignant transformation, particularly in idiopathic cases.¹³

The Diagnosis: Pigmented Dermatofibrosarcoma Protuberans  

Pigmented dermatofibrosarcoma protuberans (PDFSP), also known as Bednar tumor, is an uncommon variant of dermatofibrosarcoma protuberans (DFSP). Pigmented dermatofibrosarcoma protuberans constitutes 1% to 5% of all DFSP cases and most commonly is seen in nonwhite adults in the fourth decade of life, with occasional cases seen in pediatric patients, including some congenital cases. Typical sites of involvement include the shoulders, trunk, arms, legs, head, and neck.^1,2 It also has been reported at sites of prior immunization, trauma, and insect bites.³  

Histopathologic examination of our patient's shoulder nodule revealed an infiltrative neoplasm in the dermis and subcutaneous tissue composed of spindled cells with a storiform pattern and foci of scattered elongated dendritic pigmented cells. A narrow grenz zone separated the tumor from the epidermis, and characteristic honeycomb infiltration by tumor cells was noted in the subcutaneous fat. The nuclei were bland and monomorphous with areas of neuroid differentiation containing whorls and nerve cord-like structures (quiz image). The tumor cells were diffusely CD34 and vimentin positive, while S-100, SOX-10, neurofilament, smooth muscle actin, desmin, epithelial membrane antigen, and cytokeratins were negative. The immunophenotype excluded the possibility of neurogenic, pericytic, myofibroblastic, and myoid differentiation.  

Wang and Yang⁴ previously reported a case of PDFSP with prominent meningothelial-like whorls focally resembling extracranial meningioma; however, the tumor cells were CD34 positive and epithelial membrane antigen negative, weighing against a diagnosis of meningioma. Most cases of PDFSP demonstrate the COL1A1-PDGFB (collagen type I α; 1/platelet-derived growth factor B-chain) fusion protein caused by the translocation t(17;22)(q22;q13), as in classic DFSP.⁵  

Cellular blue nevus (CBN) is a benign melanocytic neoplasm that can present at any age and often occurs on the buttocks and in the sacrococcygeal region. Clinically, CBN presents as a firm, bluish black to bluish gray, dome-shaped nodule. The size varies from a few millimeters to several centimeters.^6,7 Histologically, CBN is located completely in the dermis, extending along the adnexae into the subcutaneous tissue with a dumbbell-shaped outline (Figure 1).^6-8 The tumor demonstrates oval epithelioid melanocytes with vesicular nuclei and prominent nucleoli. Immunohistochemically, tumor cells stain positively for melanocytic markers such as S-100, SOX-10, MART-1, and human melanoma black 45. CD34 expression rarely is reported in a subset of CBN.⁹  

Pigmented neurofibroma is a rare variant of neurofibroma that produces melanin pigment and has a strong association with neurofibromatosis.¹⁰ It occurs most frequently in dark-skinned populations (Fitzpatrick skin types IV-VI). The most common location is the head and neck region.^11,12 Histologically, pigmented neurofibroma resembles a diffuse neurofibroma admixed with melanin-producing cells (Figure 2).¹² Immunostaining shows positivity for S-100 in both pigmented and Schwann cells; however, the pigmented cells stain positively for human melanoma black 45, Melan-A, and tyrosinase.¹⁰ CD34 can be fingerprint positive in neurofibroma, but a distinction from DFSP can be made by S-100 and SOX-10 immunostaining.¹³ 

Desmoplastic melanoma (DM) is an uncommon variant of malignant melanoma and has a higher tendency for persistent local growth and less frequent metastases than other variants of melanoma. It has a predilection for chronically sun-exposed areas such as the head and neck and occurs later in life. Clinically, DM appears as nonspecific, often amelanotic nodules or plaques or as scarlike lesions.¹⁴ Histologically, DM can be classified as mixed or pure based on the degree of desmoplasia and cellularity. A paucicellular proliferation of malignant spindled melanocytes within a densely fibrotic stroma with lymphoid nodules in the dermis is characteristic (Figure 3); perineural involvement is common.^14,15 The most reliable confirmative stains are S-100 and SOX-10.¹⁶ 

Cutaneous meningioma is a rare tumor and could be subtyped into 3 groups. Type I is primary cutaneous meningioma and usually is present at birth on the scalp and paravertebral regions with a relatively good prognosis. Type II is ectopic soft-tissue meningioma that extends into the skin from around the sensory organs on the face. Type III is local invasion or true metastasis from a central nervous system meningioma. Types II and III develop later in life and the prognosis is poor.^17,18 Clinically, lesions present as firm subcutaneous nodules or swellings. Cutaneous meningioma has several histopathologic variants. The classic presentation reveals concentric wrapping of tumor cells with round-oval nuclei containing delicate chromatin. Psammoma bodies are a common finding (Figure 4). Immunohistochemically, tumor cells are diffusely positive for epithelial membrane antigen and vimentin.^18,19 

The Diagnosis: Pigmented Dermatofibrosarcoma Protuberans  

Pigmented dermatofibrosarcoma protuberans (PDFSP), also known as Bednar tumor, is an uncommon variant of dermatofibrosarcoma protuberans (DFSP). Pigmented dermatofibrosarcoma protuberans constitutes 1% to 5% of all DFSP cases and most commonly is seen in nonwhite adults in the fourth decade of life, with occasional cases seen in pediatric patients, including some congenital cases. Typical sites of involvement include the shoulders, trunk, arms, legs, head, and neck.^1,2 It also has been reported at sites of prior immunization, trauma, and insect bites.³  

Histopathologic examination of our patient's shoulder nodule revealed an infiltrative neoplasm in the dermis and subcutaneous tissue composed of spindled cells with a storiform pattern and foci of scattered elongated dendritic pigmented cells. A narrow grenz zone separated the tumor from the epidermis, and characteristic honeycomb infiltration by tumor cells was noted in the subcutaneous fat. The nuclei were bland and monomorphous with areas of neuroid differentiation containing whorls and nerve cord-like structures (quiz image). The tumor cells were diffusely CD34 and vimentin positive, while S-100, SOX-10, neurofilament, smooth muscle actin, desmin, epithelial membrane antigen, and cytokeratins were negative. The immunophenotype excluded the possibility of neurogenic, pericytic, myofibroblastic, and myoid differentiation.  

Wang and Yang⁴ previously reported a case of PDFSP with prominent meningothelial-like whorls focally resembling extracranial meningioma; however, the tumor cells were CD34 positive and epithelial membrane antigen negative, weighing against a diagnosis of meningioma. Most cases of PDFSP demonstrate the COL1A1-PDGFB (collagen type I α; 1/platelet-derived growth factor B-chain) fusion protein caused by the translocation t(17;22)(q22;q13), as in classic DFSP.⁵  

Cellular blue nevus (CBN) is a benign melanocytic neoplasm that can present at any age and often occurs on the buttocks and in the sacrococcygeal region. Clinically, CBN presents as a firm, bluish black to bluish gray, dome-shaped nodule. The size varies from a few millimeters to several centimeters.^6,7 Histologically, CBN is located completely in the dermis, extending along the adnexae into the subcutaneous tissue with a dumbbell-shaped outline (Figure 1).^6-8 The tumor demonstrates oval epithelioid melanocytes with vesicular nuclei and prominent nucleoli. Immunohistochemically, tumor cells stain positively for melanocytic markers such as S-100, SOX-10, MART-1, and human melanoma black 45. CD34 expression rarely is reported in a subset of CBN.⁹  

Pigmented neurofibroma is a rare variant of neurofibroma that produces melanin pigment and has a strong association with neurofibromatosis.¹⁰ It occurs most frequently in dark-skinned populations (Fitzpatrick skin types IV-VI). The most common location is the head and neck region.^11,12 Histologically, pigmented neurofibroma resembles a diffuse neurofibroma admixed with melanin-producing cells (Figure 2).¹² Immunostaining shows positivity for S-100 in both pigmented and Schwann cells; however, the pigmented cells stain positively for human melanoma black 45, Melan-A, and tyrosinase.¹⁰ CD34 can be fingerprint positive in neurofibroma, but a distinction from DFSP can be made by S-100 and SOX-10 immunostaining.¹³ 

Desmoplastic melanoma (DM) is an uncommon variant of malignant melanoma and has a higher tendency for persistent local growth and less frequent metastases than other variants of melanoma. It has a predilection for chronically sun-exposed areas such as the head and neck and occurs later in life. Clinically, DM appears as nonspecific, often amelanotic nodules or plaques or as scarlike lesions.¹⁴ Histologically, DM can be classified as mixed or pure based on the degree of desmoplasia and cellularity. A paucicellular proliferation of malignant spindled melanocytes within a densely fibrotic stroma with lymphoid nodules in the dermis is characteristic (Figure 3); perineural involvement is common.^14,15 The most reliable confirmative stains are S-100 and SOX-10.¹⁶ 

Cutaneous meningioma is a rare tumor and could be subtyped into 3 groups. Type I is primary cutaneous meningioma and usually is present at birth on the scalp and paravertebral regions with a relatively good prognosis. Type II is ectopic soft-tissue meningioma that extends into the skin from around the sensory organs on the face. Type III is local invasion or true metastasis from a central nervous system meningioma. Types II and III develop later in life and the prognosis is poor.^17,18 Clinically, lesions present as firm subcutaneous nodules or swellings. Cutaneous meningioma has several histopathologic variants. The classic presentation reveals concentric wrapping of tumor cells with round-oval nuclei containing delicate chromatin. Psammoma bodies are a common finding (Figure 4). Immunohistochemically, tumor cells are diffusely positive for epithelial membrane antigen and vimentin.^18,19 

The Diagnosis: Pigmented Dermatofibrosarcoma Protuberans  

Pigmented dermatofibrosarcoma protuberans (PDFSP), also known as Bednar tumor, is an uncommon variant of dermatofibrosarcoma protuberans (DFSP). Pigmented dermatofibrosarcoma protuberans constitutes 1% to 5% of all DFSP cases and most commonly is seen in nonwhite adults in the fourth decade of life, with occasional cases seen in pediatric patients, including some congenital cases. Typical sites of involvement include the shoulders, trunk, arms, legs, head, and neck.^1,2 It also has been reported at sites of prior immunization, trauma, and insect bites.³  

Histopathologic examination of our patient's shoulder nodule revealed an infiltrative neoplasm in the dermis and subcutaneous tissue composed of spindled cells with a storiform pattern and foci of scattered elongated dendritic pigmented cells. A narrow grenz zone separated the tumor from the epidermis, and characteristic honeycomb infiltration by tumor cells was noted in the subcutaneous fat. The nuclei were bland and monomorphous with areas of neuroid differentiation containing whorls and nerve cord-like structures (quiz image). The tumor cells were diffusely CD34 and vimentin positive, while S-100, SOX-10, neurofilament, smooth muscle actin, desmin, epithelial membrane antigen, and cytokeratins were negative. The immunophenotype excluded the possibility of neurogenic, pericytic, myofibroblastic, and myoid differentiation.  

Wang and Yang⁴ previously reported a case of PDFSP with prominent meningothelial-like whorls focally resembling extracranial meningioma; however, the tumor cells were CD34 positive and epithelial membrane antigen negative, weighing against a diagnosis of meningioma. Most cases of PDFSP demonstrate the COL1A1-PDGFB (collagen type I α; 1/platelet-derived growth factor B-chain) fusion protein caused by the translocation t(17;22)(q22;q13), as in classic DFSP.⁵  

Cellular blue nevus (CBN) is a benign melanocytic neoplasm that can present at any age and often occurs on the buttocks and in the sacrococcygeal region. Clinically, CBN presents as a firm, bluish black to bluish gray, dome-shaped nodule. The size varies from a few millimeters to several centimeters.^6,7 Histologically, CBN is located completely in the dermis, extending along the adnexae into the subcutaneous tissue with a dumbbell-shaped outline (Figure 1).^6-8 The tumor demonstrates oval epithelioid melanocytes with vesicular nuclei and prominent nucleoli. Immunohistochemically, tumor cells stain positively for melanocytic markers such as S-100, SOX-10, MART-1, and human melanoma black 45. CD34 expression rarely is reported in a subset of CBN.⁹  

Pigmented neurofibroma is a rare variant of neurofibroma that produces melanin pigment and has a strong association with neurofibromatosis.¹⁰ It occurs most frequently in dark-skinned populations (Fitzpatrick skin types IV-VI). The most common location is the head and neck region.^11,12 Histologically, pigmented neurofibroma resembles a diffuse neurofibroma admixed with melanin-producing cells (Figure 2).¹² Immunostaining shows positivity for S-100 in both pigmented and Schwann cells; however, the pigmented cells stain positively for human melanoma black 45, Melan-A, and tyrosinase.¹⁰ CD34 can be fingerprint positive in neurofibroma, but a distinction from DFSP can be made by S-100 and SOX-10 immunostaining.¹³ 

Desmoplastic melanoma (DM) is an uncommon variant of malignant melanoma and has a higher tendency for persistent local growth and less frequent metastases than other variants of melanoma. It has a predilection for chronically sun-exposed areas such as the head and neck and occurs later in life. Clinically, DM appears as nonspecific, often amelanotic nodules or plaques or as scarlike lesions.¹⁴ Histologically, DM can be classified as mixed or pure based on the degree of desmoplasia and cellularity. A paucicellular proliferation of malignant spindled melanocytes within a densely fibrotic stroma with lymphoid nodules in the dermis is characteristic (Figure 3); perineural involvement is common.^14,15 The most reliable confirmative stains are S-100 and SOX-10.¹⁶ 

Cutaneous meningioma is a rare tumor and could be subtyped into 3 groups. Type I is primary cutaneous meningioma and usually is present at birth on the scalp and paravertebral regions with a relatively good prognosis. Type II is ectopic soft-tissue meningioma that extends into the skin from around the sensory organs on the face. Type III is local invasion or true metastasis from a central nervous system meningioma. Types II and III develop later in life and the prognosis is poor.^17,18 Clinically, lesions present as firm subcutaneous nodules or swellings. Cutaneous meningioma has several histopathologic variants. The classic presentation reveals concentric wrapping of tumor cells with round-oval nuclei containing delicate chromatin. Psammoma bodies are a common finding (Figure 4). Immunohistochemically, tumor cells are diffusely positive for epithelial membrane antigen and vimentin.^18,19 

During the last year, the field of psoriasis has continued to expand, with new therapies, new guidelines, and further understanding of the impact of treatment on associated comorbidities. 

One of the most exciting prospects of the treatment of psoriasis with biologics is the potential for the reduction in major adverse cardiovascular events (MACEs). It has been well established that psoriasis is associated with increased cardiovascular risk.^1,2 Ahlehoff et al¹ conducted a cohort study of the entire Danish population 18 years and older followed from 1997 to 2006 by individual-level linkage of nationwide registers. They concluded that psoriasis is associated with increased risk for adverse cardiovascular events and all-cause mortality. Young age, severe skin affection, and/or psoriatic arthritis (PsA) carry the most risk. They suggested that patients with psoriasis may be candidates for early cardiovascular risk factor modification.¹  

Ogdie et al² endeavored to quantify the risk for MACE among patients with PsA, rheumatoid arthritis (RA), and psoriasis without known PsA compared to the general population after adjusting for traditional cardiovascular risk factors. Patients with PsA (N=8706), RA (N=41,752), psoriasis (N=138,424), and unexposed controls (N=81,573) were identified. After adjustment for traditional risk factors, the risk for MACE was higher in patients with PsA not prescribed a disease-modifying antirheumatic drug (DMARD)(hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.49), patients with RA (no DMARD: HR, 1.39; 95% CI, 1.28-1.50; DMARD: HR, 1.58; 95% CI, 1.46-1.70), patients with psoriasis not prescribed a DMARD (HR, 1.08; 95% CI, 1.02-1.15), and patients with severe psoriasis (DMARD: HR, 1.42; 95% CI, 1.17-1.73).² These data are one aspect of our increasing insight into the management of psoriasis. 

To expand on the new guidelines and new therapies presented in 2019, this issue includes review articles looking at these facets. Wu and Weinberg3 review the impact of diet on psoriasis. Pithadia et al⁴ explain the American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management of psoriasis with biologics for the prescribing dermatologist, with an emphasis on the most clinically significant considerations during each step of treatment with biologic therapies (ie, choosing a biologic, initiating therapy, assessing treatment response, switching biologics). Havnaer et al⁵ provide an update on the newly approved and pipeline systemic agents for psoriasis.  

We hope that you find this issue enjoyable and informative. 

During the last year, the field of psoriasis has continued to expand, with new therapies, new guidelines, and further understanding of the impact of treatment on associated comorbidities. 

One of the most exciting prospects of the treatment of psoriasis with biologics is the potential for the reduction in major adverse cardiovascular events (MACEs). It has been well established that psoriasis is associated with increased cardiovascular risk.^1,2 Ahlehoff et al¹ conducted a cohort study of the entire Danish population 18 years and older followed from 1997 to 2006 by individual-level linkage of nationwide registers. They concluded that psoriasis is associated with increased risk for adverse cardiovascular events and all-cause mortality. Young age, severe skin affection, and/or psoriatic arthritis (PsA) carry the most risk. They suggested that patients with psoriasis may be candidates for early cardiovascular risk factor modification.¹  

Ogdie et al² endeavored to quantify the risk for MACE among patients with PsA, rheumatoid arthritis (RA), and psoriasis without known PsA compared to the general population after adjusting for traditional cardiovascular risk factors. Patients with PsA (N=8706), RA (N=41,752), psoriasis (N=138,424), and unexposed controls (N=81,573) were identified. After adjustment for traditional risk factors, the risk for MACE was higher in patients with PsA not prescribed a disease-modifying antirheumatic drug (DMARD)(hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.49), patients with RA (no DMARD: HR, 1.39; 95% CI, 1.28-1.50; DMARD: HR, 1.58; 95% CI, 1.46-1.70), patients with psoriasis not prescribed a DMARD (HR, 1.08; 95% CI, 1.02-1.15), and patients with severe psoriasis (DMARD: HR, 1.42; 95% CI, 1.17-1.73).² These data are one aspect of our increasing insight into the management of psoriasis. 

To expand on the new guidelines and new therapies presented in 2019, this issue includes review articles looking at these facets. Wu and Weinberg3 review the impact of diet on psoriasis. Pithadia et al⁴ explain the American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management of psoriasis with biologics for the prescribing dermatologist, with an emphasis on the most clinically significant considerations during each step of treatment with biologic therapies (ie, choosing a biologic, initiating therapy, assessing treatment response, switching biologics). Havnaer et al⁵ provide an update on the newly approved and pipeline systemic agents for psoriasis.  

We hope that you find this issue enjoyable and informative. 

During the last year, the field of psoriasis has continued to expand, with new therapies, new guidelines, and further understanding of the impact of treatment on associated comorbidities. 

One of the most exciting prospects of the treatment of psoriasis with biologics is the potential for the reduction in major adverse cardiovascular events (MACEs). It has been well established that psoriasis is associated with increased cardiovascular risk.^1,2 Ahlehoff et al¹ conducted a cohort study of the entire Danish population 18 years and older followed from 1997 to 2006 by individual-level linkage of nationwide registers. They concluded that psoriasis is associated with increased risk for adverse cardiovascular events and all-cause mortality. Young age, severe skin affection, and/or psoriatic arthritis (PsA) carry the most risk. They suggested that patients with psoriasis may be candidates for early cardiovascular risk factor modification.¹  

Ogdie et al² endeavored to quantify the risk for MACE among patients with PsA, rheumatoid arthritis (RA), and psoriasis without known PsA compared to the general population after adjusting for traditional cardiovascular risk factors. Patients with PsA (N=8706), RA (N=41,752), psoriasis (N=138,424), and unexposed controls (N=81,573) were identified. After adjustment for traditional risk factors, the risk for MACE was higher in patients with PsA not prescribed a disease-modifying antirheumatic drug (DMARD)(hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.49), patients with RA (no DMARD: HR, 1.39; 95% CI, 1.28-1.50; DMARD: HR, 1.58; 95% CI, 1.46-1.70), patients with psoriasis not prescribed a DMARD (HR, 1.08; 95% CI, 1.02-1.15), and patients with severe psoriasis (DMARD: HR, 1.42; 95% CI, 1.17-1.73).² These data are one aspect of our increasing insight into the management of psoriasis. 

To expand on the new guidelines and new therapies presented in 2019, this issue includes review articles looking at these facets. Wu and Weinberg3 review the impact of diet on psoriasis. Pithadia et al⁴ explain the American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management of psoriasis with biologics for the prescribing dermatologist, with an emphasis on the most clinically significant considerations during each step of treatment with biologic therapies (ie, choosing a biologic, initiating therapy, assessing treatment response, switching biologics). Havnaer et al⁵ provide an update on the newly approved and pipeline systemic agents for psoriasis.  

We hope that you find this issue enjoyable and informative.