Article

To the Editor:

We read with interest the Cutis article by Dobkin et al¹ (Cutis. 2022;109:218-220) regarding guidelines for inpatient and emergency department dermatology consultations. We agree with the authors that dermatology training is lacking in other medical specialties, which makes it challenging for teams to assess the appropriateness of a dermatology consultation in the inpatient setting. Inpatient dermatology consultation can be utilized in a hospital system to aid in rapid and accurate diagnosis, avoid inappropriate therapies, and decrease length of stay² and readmission rates³ while providing education to the primary teams. This is precisely why in many instances the availability of inpatient dermatology consultation is so important because nondermatologists often are unable to determine whether a rash is life-threatening, benign, or something in between. From the perspective of dermatology hospitalists, there is room for improvement in the flowchart Dobkin et al¹ presented to guide inpatient dermatology consultation.

To have a productive relationship with our internal medicine, surgery, pediatrics, psychiatry, and other hospital-based colleagues, we must keep an open mind when a consultation is received. We feel that the flowchart proposed by Dobkin et al¹ presents too narrow a viewpoint on the utility of inpatient dermatology. It rests on assertions that other teams will be able to determine the appropriate dermatologic diagnosis without involving a dermatologist, which often is not the case.

We disagree with several recommendations in the flowchart, the first being the assertion that patients who are “hemodynamically unstable due to [a] nondermatologic problem (eg, intubated on pressors, febrile, and hypotensive)” are not appropriate for inpatient dermatology consultation.¹ Although dermatologists do not commonly encounter patients with critical illness in the outpatient clinic, dermatology consultation can be extremely helpful and even lifesaving in the inpatient setting. It is unrealistic to expect the primary teams to know whether cutaneous manifestations potentially could be related to the patient’s overall clinical picture. On the contrary, we would encourage the primary team in charge of a hemodynamically unstable patient to consult dermatology at the first sign of an unexplained rash. Take for example an acutely ill patient who develops retiform purpura. There are well-established dermatology guidelines for the workup of retiform purpura,⁴ including prompt biopsy and assessment of broad, potentially life-threatening differential diagnoses from calciphylaxis to angioinvasive fungal infection. In this scenario, the dermatology consultant may render the correct diagnosis and recommend immediate treatment that could be lifesaving.

Secondly, we do not agree with the recommendation that a patient in hospice care is not appropriate for inpatient dermatology consultation. Patients receiving hospice or palliative care have high rates of potentially symptomatic cutaneous diseases,⁵ including intertrigo and dermatitis—comprising stasis, seborrheic, and contact dermatitis.⁶ Although aggressive intervention for asymptomatic benign or malignant skin conditions may not be in line with their goals of care, an inpatient dermatology consultation can reduce symptoms and improve quality of life. This population also is one that is unlikely to be able to attend an outpatient dermatology clinic appointment and therefore are good candidates for inpatient consultation.

Lastly, we want to highlight the difference between a stable chronic dermatologic disease and an acute flare that may occur while a patient is hospitalized, regardless of whether it is the reason for admission. For example, a patient with psoriasis affecting limited body surface area who is hospitalized for a myocardial infarction is not appropriate for a dermatology consultation. However, if that same patient develops erythroderma while they are hospitalized for cardiac monitoring, it would certainly be appropriate for dermatology to be consulted. Additionally, there are times when a chronic skin disease is the reason for hospitalization; dermatology, although technically a consulting service, would be the primary decision-maker for the patient’s care in this situation. In these scenarios, it is important for the patient to be able to establish care for long-term outpatient management of their condition; however, it is prudent to involve dermatology while the patient is acutely hospitalized to guide their treatment plan until they are able to see a dermatologist after discharge.

In conclusion, we believe that hospital dermatology is a valuable tool that can be utilized in many different scenarios. Although there are certainly situations more appropriate for outpatient dermatology referral, we would caution against overly simplified algorithms that could discourage valuable inpatient dermatology consultations. It often is worth a conversation with your dermatology consultant (when available at an institution) to determine the best course of action for each patient. Additionally, we recognize the need for more formalized guidelines on when to pursue inpatient dermatology consultation. We are members of the Society of Dermatology Hospitalists and encourage readers to reference their website, which provides additional resources on inpatient dermatology (https://societydermatologyhospitalists.com/inpatient-dermatology-literature/).

We appreciate the letter in response to our commentary on the appropriateness of inpatient dermatology consultations. It is the continued refining and re-evaluation of concepts such as these that allow our field to grow and improve knowledge and patient care.

We sought to provide a nonpatronizing yet simple consultation flowchart that would help guide triage of patients in need or not in need of dermatologic evaluation by the inpatient teams. Understandably, the impressions of our flowchart have been variable based on different readers’ medical backgrounds and experiences. It is certainly possible that our flowchart lacked certain exceptions and oversimplified certain concepts, and we welcome further refining of this flowchart to better guide inpatient dermatology consultations.

We do, however, disagree that the primary team would not know whether a patient is intubated in the intensive care unit for a dermatology reason. If the patient is in such a status, it would be pertinent for the primary team to conduct a timely workup that could include consultations until a diagnosis is made. We were not implying that every dermatology consultation in the intensive care unit is unwarranted, especially if it can lead to a primary dermatologic diagnosis. We do believe that a thorough history could elicit an allergy or other chronic skin condition that could save resources and spending within a hospital. Likewise, psoriasis comes in many different presentations, and although we do not believe a consultation for chronic psoriatic plaques is appropriate in the hospital, it is absolutely appropriate for a patient who is erythrodermic from any cause.

Our flowchart was intended to be the first step to providing education on when consultations are appropriate, and further refinement will be necessary.

Hershel Dobkin, MD; Timothy Blackwell, BS; Robin Ashinoff, MD

Drs. Dobkin and Ashinoff are from Hackensack University Medical Center, New Jersey. Mr. Blackwell is from the Rowan University School of Osteopathic Medicine, Stratford, New Jersey.

The authors report no conflict of interest.

Correspondence: Hershel Dobkin, MD, Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ 07601 ([email protected]).

To the Editor:

We read with interest the Cutis article by Dobkin et al¹ (Cutis. 2022;109:218-220) regarding guidelines for inpatient and emergency department dermatology consultations. We agree with the authors that dermatology training is lacking in other medical specialties, which makes it challenging for teams to assess the appropriateness of a dermatology consultation in the inpatient setting. Inpatient dermatology consultation can be utilized in a hospital system to aid in rapid and accurate diagnosis, avoid inappropriate therapies, and decrease length of stay² and readmission rates³ while providing education to the primary teams. This is precisely why in many instances the availability of inpatient dermatology consultation is so important because nondermatologists often are unable to determine whether a rash is life-threatening, benign, or something in between. From the perspective of dermatology hospitalists, there is room for improvement in the flowchart Dobkin et al¹ presented to guide inpatient dermatology consultation.

To have a productive relationship with our internal medicine, surgery, pediatrics, psychiatry, and other hospital-based colleagues, we must keep an open mind when a consultation is received. We feel that the flowchart proposed by Dobkin et al¹ presents too narrow a viewpoint on the utility of inpatient dermatology. It rests on assertions that other teams will be able to determine the appropriate dermatologic diagnosis without involving a dermatologist, which often is not the case.

We disagree with several recommendations in the flowchart, the first being the assertion that patients who are “hemodynamically unstable due to [a] nondermatologic problem (eg, intubated on pressors, febrile, and hypotensive)” are not appropriate for inpatient dermatology consultation.¹ Although dermatologists do not commonly encounter patients with critical illness in the outpatient clinic, dermatology consultation can be extremely helpful and even lifesaving in the inpatient setting. It is unrealistic to expect the primary teams to know whether cutaneous manifestations potentially could be related to the patient’s overall clinical picture. On the contrary, we would encourage the primary team in charge of a hemodynamically unstable patient to consult dermatology at the first sign of an unexplained rash. Take for example an acutely ill patient who develops retiform purpura. There are well-established dermatology guidelines for the workup of retiform purpura,⁴ including prompt biopsy and assessment of broad, potentially life-threatening differential diagnoses from calciphylaxis to angioinvasive fungal infection. In this scenario, the dermatology consultant may render the correct diagnosis and recommend immediate treatment that could be lifesaving.

Secondly, we do not agree with the recommendation that a patient in hospice care is not appropriate for inpatient dermatology consultation. Patients receiving hospice or palliative care have high rates of potentially symptomatic cutaneous diseases,⁵ including intertrigo and dermatitis—comprising stasis, seborrheic, and contact dermatitis.⁶ Although aggressive intervention for asymptomatic benign or malignant skin conditions may not be in line with their goals of care, an inpatient dermatology consultation can reduce symptoms and improve quality of life. This population also is one that is unlikely to be able to attend an outpatient dermatology clinic appointment and therefore are good candidates for inpatient consultation.

Lastly, we want to highlight the difference between a stable chronic dermatologic disease and an acute flare that may occur while a patient is hospitalized, regardless of whether it is the reason for admission. For example, a patient with psoriasis affecting limited body surface area who is hospitalized for a myocardial infarction is not appropriate for a dermatology consultation. However, if that same patient develops erythroderma while they are hospitalized for cardiac monitoring, it would certainly be appropriate for dermatology to be consulted. Additionally, there are times when a chronic skin disease is the reason for hospitalization; dermatology, although technically a consulting service, would be the primary decision-maker for the patient’s care in this situation. In these scenarios, it is important for the patient to be able to establish care for long-term outpatient management of their condition; however, it is prudent to involve dermatology while the patient is acutely hospitalized to guide their treatment plan until they are able to see a dermatologist after discharge.

In conclusion, we believe that hospital dermatology is a valuable tool that can be utilized in many different scenarios. Although there are certainly situations more appropriate for outpatient dermatology referral, we would caution against overly simplified algorithms that could discourage valuable inpatient dermatology consultations. It often is worth a conversation with your dermatology consultant (when available at an institution) to determine the best course of action for each patient. Additionally, we recognize the need for more formalized guidelines on when to pursue inpatient dermatology consultation. We are members of the Society of Dermatology Hospitalists and encourage readers to reference their website, which provides additional resources on inpatient dermatology (https://societydermatologyhospitalists.com/inpatient-dermatology-literature/).

We appreciate the letter in response to our commentary on the appropriateness of inpatient dermatology consultations. It is the continued refining and re-evaluation of concepts such as these that allow our field to grow and improve knowledge and patient care.

We sought to provide a nonpatronizing yet simple consultation flowchart that would help guide triage of patients in need or not in need of dermatologic evaluation by the inpatient teams. Understandably, the impressions of our flowchart have been variable based on different readers’ medical backgrounds and experiences. It is certainly possible that our flowchart lacked certain exceptions and oversimplified certain concepts, and we welcome further refining of this flowchart to better guide inpatient dermatology consultations.

We do, however, disagree that the primary team would not know whether a patient is intubated in the intensive care unit for a dermatology reason. If the patient is in such a status, it would be pertinent for the primary team to conduct a timely workup that could include consultations until a diagnosis is made. We were not implying that every dermatology consultation in the intensive care unit is unwarranted, especially if it can lead to a primary dermatologic diagnosis. We do believe that a thorough history could elicit an allergy or other chronic skin condition that could save resources and spending within a hospital. Likewise, psoriasis comes in many different presentations, and although we do not believe a consultation for chronic psoriatic plaques is appropriate in the hospital, it is absolutely appropriate for a patient who is erythrodermic from any cause.

Our flowchart was intended to be the first step to providing education on when consultations are appropriate, and further refinement will be necessary.

Hershel Dobkin, MD; Timothy Blackwell, BS; Robin Ashinoff, MD

Drs. Dobkin and Ashinoff are from Hackensack University Medical Center, New Jersey. Mr. Blackwell is from the Rowan University School of Osteopathic Medicine, Stratford, New Jersey.

The authors report no conflict of interest.

Correspondence: Hershel Dobkin, MD, Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ 07601 ([email protected]).

To the Editor:

We read with interest the Cutis article by Dobkin et al¹ (Cutis. 2022;109:218-220) regarding guidelines for inpatient and emergency department dermatology consultations. We agree with the authors that dermatology training is lacking in other medical specialties, which makes it challenging for teams to assess the appropriateness of a dermatology consultation in the inpatient setting. Inpatient dermatology consultation can be utilized in a hospital system to aid in rapid and accurate diagnosis, avoid inappropriate therapies, and decrease length of stay² and readmission rates³ while providing education to the primary teams. This is precisely why in many instances the availability of inpatient dermatology consultation is so important because nondermatologists often are unable to determine whether a rash is life-threatening, benign, or something in between. From the perspective of dermatology hospitalists, there is room for improvement in the flowchart Dobkin et al¹ presented to guide inpatient dermatology consultation.

To have a productive relationship with our internal medicine, surgery, pediatrics, psychiatry, and other hospital-based colleagues, we must keep an open mind when a consultation is received. We feel that the flowchart proposed by Dobkin et al¹ presents too narrow a viewpoint on the utility of inpatient dermatology. It rests on assertions that other teams will be able to determine the appropriate dermatologic diagnosis without involving a dermatologist, which often is not the case.

We disagree with several recommendations in the flowchart, the first being the assertion that patients who are “hemodynamically unstable due to [a] nondermatologic problem (eg, intubated on pressors, febrile, and hypotensive)” are not appropriate for inpatient dermatology consultation.¹ Although dermatologists do not commonly encounter patients with critical illness in the outpatient clinic, dermatology consultation can be extremely helpful and even lifesaving in the inpatient setting. It is unrealistic to expect the primary teams to know whether cutaneous manifestations potentially could be related to the patient’s overall clinical picture. On the contrary, we would encourage the primary team in charge of a hemodynamically unstable patient to consult dermatology at the first sign of an unexplained rash. Take for example an acutely ill patient who develops retiform purpura. There are well-established dermatology guidelines for the workup of retiform purpura,⁴ including prompt biopsy and assessment of broad, potentially life-threatening differential diagnoses from calciphylaxis to angioinvasive fungal infection. In this scenario, the dermatology consultant may render the correct diagnosis and recommend immediate treatment that could be lifesaving.

Secondly, we do not agree with the recommendation that a patient in hospice care is not appropriate for inpatient dermatology consultation. Patients receiving hospice or palliative care have high rates of potentially symptomatic cutaneous diseases,⁵ including intertrigo and dermatitis—comprising stasis, seborrheic, and contact dermatitis.⁶ Although aggressive intervention for asymptomatic benign or malignant skin conditions may not be in line with their goals of care, an inpatient dermatology consultation can reduce symptoms and improve quality of life. This population also is one that is unlikely to be able to attend an outpatient dermatology clinic appointment and therefore are good candidates for inpatient consultation.

Lastly, we want to highlight the difference between a stable chronic dermatologic disease and an acute flare that may occur while a patient is hospitalized, regardless of whether it is the reason for admission. For example, a patient with psoriasis affecting limited body surface area who is hospitalized for a myocardial infarction is not appropriate for a dermatology consultation. However, if that same patient develops erythroderma while they are hospitalized for cardiac monitoring, it would certainly be appropriate for dermatology to be consulted. Additionally, there are times when a chronic skin disease is the reason for hospitalization; dermatology, although technically a consulting service, would be the primary decision-maker for the patient’s care in this situation. In these scenarios, it is important for the patient to be able to establish care for long-term outpatient management of their condition; however, it is prudent to involve dermatology while the patient is acutely hospitalized to guide their treatment plan until they are able to see a dermatologist after discharge.

In conclusion, we believe that hospital dermatology is a valuable tool that can be utilized in many different scenarios. Although there are certainly situations more appropriate for outpatient dermatology referral, we would caution against overly simplified algorithms that could discourage valuable inpatient dermatology consultations. It often is worth a conversation with your dermatology consultant (when available at an institution) to determine the best course of action for each patient. Additionally, we recognize the need for more formalized guidelines on when to pursue inpatient dermatology consultation. We are members of the Society of Dermatology Hospitalists and encourage readers to reference their website, which provides additional resources on inpatient dermatology (https://societydermatologyhospitalists.com/inpatient-dermatology-literature/).

We appreciate the letter in response to our commentary on the appropriateness of inpatient dermatology consultations. It is the continued refining and re-evaluation of concepts such as these that allow our field to grow and improve knowledge and patient care.

We sought to provide a nonpatronizing yet simple consultation flowchart that would help guide triage of patients in need or not in need of dermatologic evaluation by the inpatient teams. Understandably, the impressions of our flowchart have been variable based on different readers’ medical backgrounds and experiences. It is certainly possible that our flowchart lacked certain exceptions and oversimplified certain concepts, and we welcome further refining of this flowchart to better guide inpatient dermatology consultations.

We do, however, disagree that the primary team would not know whether a patient is intubated in the intensive care unit for a dermatology reason. If the patient is in such a status, it would be pertinent for the primary team to conduct a timely workup that could include consultations until a diagnosis is made. We were not implying that every dermatology consultation in the intensive care unit is unwarranted, especially if it can lead to a primary dermatologic diagnosis. We do believe that a thorough history could elicit an allergy or other chronic skin condition that could save resources and spending within a hospital. Likewise, psoriasis comes in many different presentations, and although we do not believe a consultation for chronic psoriatic plaques is appropriate in the hospital, it is absolutely appropriate for a patient who is erythrodermic from any cause.

Our flowchart was intended to be the first step to providing education on when consultations are appropriate, and further refinement will be necessary.

Hershel Dobkin, MD; Timothy Blackwell, BS; Robin Ashinoff, MD

Drs. Dobkin and Ashinoff are from Hackensack University Medical Center, New Jersey. Mr. Blackwell is from the Rowan University School of Osteopathic Medicine, Stratford, New Jersey.

The authors report no conflict of interest.

Correspondence: Hershel Dobkin, MD, Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ 07601 ([email protected]).

THE COMPARISON

A Vitiligo in a young Hispanic female, which spared the area under a ring. The patient has spotty return of pigment on the hand after narrowband UVB treatment.

B Vitiligo on the hand in a young Hispanic male.

Photographs courtesy of Richard P. Usatine, MD.

Vitiligo is a chronic autoimmune disorder characterized by areas of depigmented white patches on the skin due to the loss of melanocytes in the epidermis. Various theories on the pathogenesis of vitiligo exist; however, autoimmune destruction of melanocytes remains the leading hypothesis, followed by intrinsic defects in melanocytes.¹ Vitiligo is associated with various autoimmune diseases but is most frequently reported in conjunction with thyroid disorders.²

Epidemiology

Vitiligo affects approximately 1% of the US population and up to 8% worldwide.² There is no difference in prevalence between races or genders. Females typically acquire the disease earlier than males. Onset may occur at any age, although about half of patients will have vitiligo by 20 years of age.¹

Key clinical features in people with darker skin tones

Bright white patches are characteristic of vitiligo. The patches typically are asymptomatic and often affect the hands (Figures A and B), perioral skin, feet, and scalp, as well as areas more vulnerable to friction and trauma, such as the elbows and knees.² Trichrome lesions—consisting of varying zones of white (depigmented), lighter brown (hypopigmented), and normal skin—are most commonly seen in individuals with darker skin. Trichrome vitiligo is considered an actively progressing variant of vitiligo.²

An important distinction when diagnosing vitiligo is evaluating for segmental vs nonsegmental vitiligo. Although nonsegmental vitiligo—the more common subtype—is characterized by symmetric distribution and a less predictable course, segmental vitiligo manifests in a localized and unilateral distribution, often avoiding extension past the midline. Segmental vitiligo typically manifests at a younger age and follows a more rapidly stabilizing course.³

Worth noting

Given that stark contrasts between pigmented and depigmented lesions are more prominent in darker skin tones, vitiligo can be more socially stigmatizing and psychologically devastating in these patients.^4,5

Treatment of vitiligo includes narrowband UVB (NB-UVB) light phototherapy, excimer laser, topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, and surgical melanocyte transplantation.¹ In July 2022, ruxolitinib cream 1.5% was approved by the US Food and Drug Administration (FDA) for nonsegmental vitiligo in patients 12 years and older.^6,7 It is the only FDA-approved therapy for vitiligo. It is thought to work by inhibiting the Janus kinase– signal transducers and activators of the transcription pathway.⁶ However, topical ruxolitinib is expensive, costing more than $2000 for 60 g.⁸

Health disparity highlight

A 2021 study reviewing the coverage policies of 15 commercial health care insurance companies, 50 BlueCross BlueShield plans, Medicaid, Medicare, and Veterans Affairs plans found inequities in the insurance coverage patterns for therapies used to treat vitiligo. There were 2 commonly cited reasons for denying coverage for therapies: vitiligo was considered cosmetic and therapies were not FDA approved.⁷ In comparison, NB-UVB light phototherapy for psoriasis is not considered cosmetic and has a much higher insurance coverage rate.^9,10 The out-of-pocket cost for a patient to purchase their own NB-UVB light phototherapy is more than $5000.11 Not all patients of color are economically disadvantaged, but in the United States, Black and Hispanic populations experience disproportionately higher rates of poverty (19% and 17%, respectively) compared to their White counterparts (8%).¹²

Final thoughts

US Food and Drug Administration approval of new drugs or new treatment indications comes after years of research discovery and large-scale trials. This pursuit of new discovery, however, is uneven. Vitiligo has historically been understudied and underfunded for research; this is common among several conditions adversely affecting people of color in the United States.¹³

THE COMPARISON

A Vitiligo in a young Hispanic female, which spared the area under a ring. The patient has spotty return of pigment on the hand after narrowband UVB treatment.

B Vitiligo on the hand in a young Hispanic male.

Photographs courtesy of Richard P. Usatine, MD.

Vitiligo is a chronic autoimmune disorder characterized by areas of depigmented white patches on the skin due to the loss of melanocytes in the epidermis. Various theories on the pathogenesis of vitiligo exist; however, autoimmune destruction of melanocytes remains the leading hypothesis, followed by intrinsic defects in melanocytes.¹ Vitiligo is associated with various autoimmune diseases but is most frequently reported in conjunction with thyroid disorders.²

Epidemiology

Vitiligo affects approximately 1% of the US population and up to 8% worldwide.² There is no difference in prevalence between races or genders. Females typically acquire the disease earlier than males. Onset may occur at any age, although about half of patients will have vitiligo by 20 years of age.¹

Key clinical features in people with darker skin tones

Bright white patches are characteristic of vitiligo. The patches typically are asymptomatic and often affect the hands (Figures A and B), perioral skin, feet, and scalp, as well as areas more vulnerable to friction and trauma, such as the elbows and knees.² Trichrome lesions—consisting of varying zones of white (depigmented), lighter brown (hypopigmented), and normal skin—are most commonly seen in individuals with darker skin. Trichrome vitiligo is considered an actively progressing variant of vitiligo.²

An important distinction when diagnosing vitiligo is evaluating for segmental vs nonsegmental vitiligo. Although nonsegmental vitiligo—the more common subtype—is characterized by symmetric distribution and a less predictable course, segmental vitiligo manifests in a localized and unilateral distribution, often avoiding extension past the midline. Segmental vitiligo typically manifests at a younger age and follows a more rapidly stabilizing course.³

Worth noting

Given that stark contrasts between pigmented and depigmented lesions are more prominent in darker skin tones, vitiligo can be more socially stigmatizing and psychologically devastating in these patients.^4,5

Treatment of vitiligo includes narrowband UVB (NB-UVB) light phototherapy, excimer laser, topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, and surgical melanocyte transplantation.¹ In July 2022, ruxolitinib cream 1.5% was approved by the US Food and Drug Administration (FDA) for nonsegmental vitiligo in patients 12 years and older.^6,7 It is the only FDA-approved therapy for vitiligo. It is thought to work by inhibiting the Janus kinase– signal transducers and activators of the transcription pathway.⁶ However, topical ruxolitinib is expensive, costing more than $2000 for 60 g.⁸

Health disparity highlight

A 2021 study reviewing the coverage policies of 15 commercial health care insurance companies, 50 BlueCross BlueShield plans, Medicaid, Medicare, and Veterans Affairs plans found inequities in the insurance coverage patterns for therapies used to treat vitiligo. There were 2 commonly cited reasons for denying coverage for therapies: vitiligo was considered cosmetic and therapies were not FDA approved.⁷ In comparison, NB-UVB light phototherapy for psoriasis is not considered cosmetic and has a much higher insurance coverage rate.^9,10 The out-of-pocket cost for a patient to purchase their own NB-UVB light phototherapy is more than $5000.11 Not all patients of color are economically disadvantaged, but in the United States, Black and Hispanic populations experience disproportionately higher rates of poverty (19% and 17%, respectively) compared to their White counterparts (8%).¹²

Final thoughts

US Food and Drug Administration approval of new drugs or new treatment indications comes after years of research discovery and large-scale trials. This pursuit of new discovery, however, is uneven. Vitiligo has historically been understudied and underfunded for research; this is common among several conditions adversely affecting people of color in the United States.¹³

THE COMPARISON

A Vitiligo in a young Hispanic female, which spared the area under a ring. The patient has spotty return of pigment on the hand after narrowband UVB treatment.

B Vitiligo on the hand in a young Hispanic male.

Photographs courtesy of Richard P. Usatine, MD.

Vitiligo is a chronic autoimmune disorder characterized by areas of depigmented white patches on the skin due to the loss of melanocytes in the epidermis. Various theories on the pathogenesis of vitiligo exist; however, autoimmune destruction of melanocytes remains the leading hypothesis, followed by intrinsic defects in melanocytes.¹ Vitiligo is associated with various autoimmune diseases but is most frequently reported in conjunction with thyroid disorders.²

Epidemiology

Vitiligo affects approximately 1% of the US population and up to 8% worldwide.² There is no difference in prevalence between races or genders. Females typically acquire the disease earlier than males. Onset may occur at any age, although about half of patients will have vitiligo by 20 years of age.¹

Key clinical features in people with darker skin tones

Bright white patches are characteristic of vitiligo. The patches typically are asymptomatic and often affect the hands (Figures A and B), perioral skin, feet, and scalp, as well as areas more vulnerable to friction and trauma, such as the elbows and knees.² Trichrome lesions—consisting of varying zones of white (depigmented), lighter brown (hypopigmented), and normal skin—are most commonly seen in individuals with darker skin. Trichrome vitiligo is considered an actively progressing variant of vitiligo.²

An important distinction when diagnosing vitiligo is evaluating for segmental vs nonsegmental vitiligo. Although nonsegmental vitiligo—the more common subtype—is characterized by symmetric distribution and a less predictable course, segmental vitiligo manifests in a localized and unilateral distribution, often avoiding extension past the midline. Segmental vitiligo typically manifests at a younger age and follows a more rapidly stabilizing course.³

Worth noting

Given that stark contrasts between pigmented and depigmented lesions are more prominent in darker skin tones, vitiligo can be more socially stigmatizing and psychologically devastating in these patients.^4,5

Treatment of vitiligo includes narrowband UVB (NB-UVB) light phototherapy, excimer laser, topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, and surgical melanocyte transplantation.¹ In July 2022, ruxolitinib cream 1.5% was approved by the US Food and Drug Administration (FDA) for nonsegmental vitiligo in patients 12 years and older.^6,7 It is the only FDA-approved therapy for vitiligo. It is thought to work by inhibiting the Janus kinase– signal transducers and activators of the transcription pathway.⁶ However, topical ruxolitinib is expensive, costing more than $2000 for 60 g.⁸

Health disparity highlight

A 2021 study reviewing the coverage policies of 15 commercial health care insurance companies, 50 BlueCross BlueShield plans, Medicaid, Medicare, and Veterans Affairs plans found inequities in the insurance coverage patterns for therapies used to treat vitiligo. There were 2 commonly cited reasons for denying coverage for therapies: vitiligo was considered cosmetic and therapies were not FDA approved.⁷ In comparison, NB-UVB light phototherapy for psoriasis is not considered cosmetic and has a much higher insurance coverage rate.^9,10 The out-of-pocket cost for a patient to purchase their own NB-UVB light phototherapy is more than $5000.11 Not all patients of color are economically disadvantaged, but in the United States, Black and Hispanic populations experience disproportionately higher rates of poverty (19% and 17%, respectively) compared to their White counterparts (8%).¹²

Final thoughts

US Food and Drug Administration approval of new drugs or new treatment indications comes after years of research discovery and large-scale trials. This pursuit of new discovery, however, is uneven. Vitiligo has historically been understudied and underfunded for research; this is common among several conditions adversely affecting people of color in the United States.¹³

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

Practice Gap

Hemostasis after cutaneous surgery typically can be aided by mechanical occlusion with petrolatum and gauze known as a pressure bandage. However, in certain scenarios such as bone bleeding or irregularly shaped areas (eg, conchal bowl), difficulty applying a pressure bandage necessitates alternative hemostatic measures.¹ In those instances, physical hemostatic agents, such as gelatin, oxidized cellulose, microporous polysaccharide spheres, hydrophilic polymers with potassium salts, microfibrillar collagen, and chitin, also can be used.² However, those agents are expensive and often adhere to wound edges, inducing repeat trauma with removal. To avoid such concerns, we propose the use of bone wax as an effective hemostatic technique.

The Technique

When secondary intention healing is chosen or a temporary bandage needs to be placed, we offer the use of bone wax as an alternative to help achieve hemostasis. Bone wax—a combination of beeswax, isopropyl palmitate, and a stabilizing agent such as almond oils or sterilized salicylic acid³—helps achieve hemostasis by purely mechanical means. It is malleable and can be easily adapted to the architecture of the surgical site (Figure 1). The bone wax can be applied immediately following surgery and removed during bandage change.

Practice Implications

Use of bone wax as a physical hemostatic agent provides a practical alternative to other options commonly used in dermatologic surgery for deep wounds or irregular surfaces. It offers several advantages.

Bone wax is not absorbed and does not adhere to wound surfaces, which makes removal easy and painless. Furthermore, bone wax allows for excellent growth of granulation tissue² (Figure 2), most likely due to the healing and emollient properties of the beeswax and the moist occlusive environment created by the bone wax.

Additional advantages are its low cost, especially compared to other hemostatic agents, and long shelf-life (approximately 5 years).² Furthermore, in scenarios when cutaneous tumors extend into the calvarium, bone wax can prevent air emboli from entering noncollapsible emissary veins.⁴

When bone wax is used as a temporary measure in a dermatologic setting, complications inherent to its use in bone healing (eg, granulomatous reaction, infection)—for which it is left in place indefinitely—are avoided.

Practice Gap

Hemostasis after cutaneous surgery typically can be aided by mechanical occlusion with petrolatum and gauze known as a pressure bandage. However, in certain scenarios such as bone bleeding or irregularly shaped areas (eg, conchal bowl), difficulty applying a pressure bandage necessitates alternative hemostatic measures.¹ In those instances, physical hemostatic agents, such as gelatin, oxidized cellulose, microporous polysaccharide spheres, hydrophilic polymers with potassium salts, microfibrillar collagen, and chitin, also can be used.² However, those agents are expensive and often adhere to wound edges, inducing repeat trauma with removal. To avoid such concerns, we propose the use of bone wax as an effective hemostatic technique.

The Technique

When secondary intention healing is chosen or a temporary bandage needs to be placed, we offer the use of bone wax as an alternative to help achieve hemostasis. Bone wax—a combination of beeswax, isopropyl palmitate, and a stabilizing agent such as almond oils or sterilized salicylic acid³—helps achieve hemostasis by purely mechanical means. It is malleable and can be easily adapted to the architecture of the surgical site (Figure 1). The bone wax can be applied immediately following surgery and removed during bandage change.

Practice Implications

Use of bone wax as a physical hemostatic agent provides a practical alternative to other options commonly used in dermatologic surgery for deep wounds or irregular surfaces. It offers several advantages.

Bone wax is not absorbed and does not adhere to wound surfaces, which makes removal easy and painless. Furthermore, bone wax allows for excellent growth of granulation tissue² (Figure 2), most likely due to the healing and emollient properties of the beeswax and the moist occlusive environment created by the bone wax.

Additional advantages are its low cost, especially compared to other hemostatic agents, and long shelf-life (approximately 5 years).² Furthermore, in scenarios when cutaneous tumors extend into the calvarium, bone wax can prevent air emboli from entering noncollapsible emissary veins.⁴

When bone wax is used as a temporary measure in a dermatologic setting, complications inherent to its use in bone healing (eg, granulomatous reaction, infection)—for which it is left in place indefinitely—are avoided.

Practice Gap

Hemostasis after cutaneous surgery typically can be aided by mechanical occlusion with petrolatum and gauze known as a pressure bandage. However, in certain scenarios such as bone bleeding or irregularly shaped areas (eg, conchal bowl), difficulty applying a pressure bandage necessitates alternative hemostatic measures.¹ In those instances, physical hemostatic agents, such as gelatin, oxidized cellulose, microporous polysaccharide spheres, hydrophilic polymers with potassium salts, microfibrillar collagen, and chitin, also can be used.² However, those agents are expensive and often adhere to wound edges, inducing repeat trauma with removal. To avoid such concerns, we propose the use of bone wax as an effective hemostatic technique.

The Technique

When secondary intention healing is chosen or a temporary bandage needs to be placed, we offer the use of bone wax as an alternative to help achieve hemostasis. Bone wax—a combination of beeswax, isopropyl palmitate, and a stabilizing agent such as almond oils or sterilized salicylic acid³—helps achieve hemostasis by purely mechanical means. It is malleable and can be easily adapted to the architecture of the surgical site (Figure 1). The bone wax can be applied immediately following surgery and removed during bandage change.

Practice Implications

Use of bone wax as a physical hemostatic agent provides a practical alternative to other options commonly used in dermatologic surgery for deep wounds or irregular surfaces. It offers several advantages.

Bone wax is not absorbed and does not adhere to wound surfaces, which makes removal easy and painless. Furthermore, bone wax allows for excellent growth of granulation tissue² (Figure 2), most likely due to the healing and emollient properties of the beeswax and the moist occlusive environment created by the bone wax.

Additional advantages are its low cost, especially compared to other hemostatic agents, and long shelf-life (approximately 5 years).² Furthermore, in scenarios when cutaneous tumors extend into the calvarium, bone wax can prevent air emboli from entering noncollapsible emissary veins.⁴

When bone wax is used as a temporary measure in a dermatologic setting, complications inherent to its use in bone healing (eg, granulomatous reaction, infection)—for which it is left in place indefinitely—are avoided.

To the Editor:

Preprint servers allow researchers to post manuscripts before publication in peer-reviewed journals. As of January 2022, 41 public preprint servers accepted medicine/science submissions.¹ We sought to analyze characteristics of dermatology manuscripts in preprint servers and assess preprint publication policies in top dermatology journals.

Thirty-five biology/health sciences preprint servers¹ were searched (March 3 to March 24, 2021) with keywords dermatology, skin, and cutaneous. Preprint server, preprint post date, location, metrics, journal, impact factor (IF), and journal publication date were recorded. Preprint policies of the top 20 dermatology journals—determined by impact factor of the journal (https://www.scimagojr.com/)—were reviewed. Two-tailed t tests and χ² tests were performed (P<.05).

A total of 1420 articles were posted to 11 preprint servers between June 20, 2007, and February 15, 2021 (Table 1); 377 (27%) were published in peer-reviewed journals, with 350 (93%) of those published within 1 year of preprint post. Preprints were published in 203 journals with a mean IF of 6.2. Growth in preprint posts by year (2007-2020) was exponential (R²=0.78)(Figure). On average, preprints were viewed 424 times (Table 2), with published preprints viewed more often than unpublished preprints (596 vs 362 views)(P<.001). Only 23 of 786 (3%) preprints with comments enabled had feedback. Among the top 20 dermatology journals, 18 (90%) allowed preprints, 1 (5%) evaluated case by case, and 1 (5%) prohibited preprints.

Our study showed exponential growth in dermatology preprints, a low proportion published in peer-reviewed journals with high IFs, and a substantial number of page views for both published and unpublished preprints. Very few preprints had feedback. We found that most of the top 20 dermatology journals accept preprints. An analysis of 61 dermatology articles in medRxiv found only 51% (31/61) of articles were subsequently published.² The low rate of publication may be due to the quality of preprints that do not meet criteria to be published following peer review.

Preprint servers are fairly novel, with a majority launched within the last 5 years.¹ The goal of preprints is to claim conception of an idea, solicit feedback prior to submission for peer review, and expedite research distribution.³ Because preprints are uploaded without peer review, manuscripts may lack quality and accuracy. An analysis of 57 of thelargest preprint servers found that few provided guidelines on authorship, image manipulation, or reporting of study limitations; however, most preprint servers do perform some screening.⁴ medRxiv requires full scientific research reports and absence of obscenity, plagiarism, and patient identifiers. In its first year, medRxiv rejected 34% of 176 submissios; reasons were not disclosed.⁵

The low rate of on-site comments suggests that preprint servers may not be effective for obtaining feedback to improve dermatology manuscripts prior to journal submission. Almost all of the top 20 dermatologyjournals accept preprints. Therefore, dermatologists may use these preprint servers to assert project ideas and disseminate research quickly and freely but may not receive constructive criticism.

Our study is subject to several limitations. Although our search was extensive, it is possible manuscripts were missed. Article metrics also were not available on all servers, and we could not account for accepted articles that were not yet indexed.

There has been a surge in posting of dermatology preprints in recent years. Preprints have not been peer reviewed, and data should be corroborated before incorporating new diagnostics or treatments into clinical practice. Utilization of preprint servers by dermatologists is increasing, but because the impact is still unknown, further studies on accuracy and reliability of preprints are warranted.

To the Editor:

Preprint servers allow researchers to post manuscripts before publication in peer-reviewed journals. As of January 2022, 41 public preprint servers accepted medicine/science submissions.¹ We sought to analyze characteristics of dermatology manuscripts in preprint servers and assess preprint publication policies in top dermatology journals.

Thirty-five biology/health sciences preprint servers¹ were searched (March 3 to March 24, 2021) with keywords dermatology, skin, and cutaneous. Preprint server, preprint post date, location, metrics, journal, impact factor (IF), and journal publication date were recorded. Preprint policies of the top 20 dermatology journals—determined by impact factor of the journal (https://www.scimagojr.com/)—were reviewed. Two-tailed t tests and χ² tests were performed (P<.05).

A total of 1420 articles were posted to 11 preprint servers between June 20, 2007, and February 15, 2021 (Table 1); 377 (27%) were published in peer-reviewed journals, with 350 (93%) of those published within 1 year of preprint post. Preprints were published in 203 journals with a mean IF of 6.2. Growth in preprint posts by year (2007-2020) was exponential (R²=0.78)(Figure). On average, preprints were viewed 424 times (Table 2), with published preprints viewed more often than unpublished preprints (596 vs 362 views)(P<.001). Only 23 of 786 (3%) preprints with comments enabled had feedback. Among the top 20 dermatology journals, 18 (90%) allowed preprints, 1 (5%) evaluated case by case, and 1 (5%) prohibited preprints.

Our study showed exponential growth in dermatology preprints, a low proportion published in peer-reviewed journals with high IFs, and a substantial number of page views for both published and unpublished preprints. Very few preprints had feedback. We found that most of the top 20 dermatology journals accept preprints. An analysis of 61 dermatology articles in medRxiv found only 51% (31/61) of articles were subsequently published.² The low rate of publication may be due to the quality of preprints that do not meet criteria to be published following peer review.

Preprint servers are fairly novel, with a majority launched within the last 5 years.¹ The goal of preprints is to claim conception of an idea, solicit feedback prior to submission for peer review, and expedite research distribution.³ Because preprints are uploaded without peer review, manuscripts may lack quality and accuracy. An analysis of 57 of thelargest preprint servers found that few provided guidelines on authorship, image manipulation, or reporting of study limitations; however, most preprint servers do perform some screening.⁴ medRxiv requires full scientific research reports and absence of obscenity, plagiarism, and patient identifiers. In its first year, medRxiv rejected 34% of 176 submissios; reasons were not disclosed.⁵

The low rate of on-site comments suggests that preprint servers may not be effective for obtaining feedback to improve dermatology manuscripts prior to journal submission. Almost all of the top 20 dermatologyjournals accept preprints. Therefore, dermatologists may use these preprint servers to assert project ideas and disseminate research quickly and freely but may not receive constructive criticism.

Our study is subject to several limitations. Although our search was extensive, it is possible manuscripts were missed. Article metrics also were not available on all servers, and we could not account for accepted articles that were not yet indexed.

There has been a surge in posting of dermatology preprints in recent years. Preprints have not been peer reviewed, and data should be corroborated before incorporating new diagnostics or treatments into clinical practice. Utilization of preprint servers by dermatologists is increasing, but because the impact is still unknown, further studies on accuracy and reliability of preprints are warranted.

To the Editor:

Preprint servers allow researchers to post manuscripts before publication in peer-reviewed journals. As of January 2022, 41 public preprint servers accepted medicine/science submissions.¹ We sought to analyze characteristics of dermatology manuscripts in preprint servers and assess preprint publication policies in top dermatology journals.

Thirty-five biology/health sciences preprint servers¹ were searched (March 3 to March 24, 2021) with keywords dermatology, skin, and cutaneous. Preprint server, preprint post date, location, metrics, journal, impact factor (IF), and journal publication date were recorded. Preprint policies of the top 20 dermatology journals—determined by impact factor of the journal (https://www.scimagojr.com/)—were reviewed. Two-tailed t tests and χ² tests were performed (P<.05).

A total of 1420 articles were posted to 11 preprint servers between June 20, 2007, and February 15, 2021 (Table 1); 377 (27%) were published in peer-reviewed journals, with 350 (93%) of those published within 1 year of preprint post. Preprints were published in 203 journals with a mean IF of 6.2. Growth in preprint posts by year (2007-2020) was exponential (R²=0.78)(Figure). On average, preprints were viewed 424 times (Table 2), with published preprints viewed more often than unpublished preprints (596 vs 362 views)(P<.001). Only 23 of 786 (3%) preprints with comments enabled had feedback. Among the top 20 dermatology journals, 18 (90%) allowed preprints, 1 (5%) evaluated case by case, and 1 (5%) prohibited preprints.

Our study showed exponential growth in dermatology preprints, a low proportion published in peer-reviewed journals with high IFs, and a substantial number of page views for both published and unpublished preprints. Very few preprints had feedback. We found that most of the top 20 dermatology journals accept preprints. An analysis of 61 dermatology articles in medRxiv found only 51% (31/61) of articles were subsequently published.² The low rate of publication may be due to the quality of preprints that do not meet criteria to be published following peer review.

Preprint servers are fairly novel, with a majority launched within the last 5 years.¹ The goal of preprints is to claim conception of an idea, solicit feedback prior to submission for peer review, and expedite research distribution.³ Because preprints are uploaded without peer review, manuscripts may lack quality and accuracy. An analysis of 57 of thelargest preprint servers found that few provided guidelines on authorship, image manipulation, or reporting of study limitations; however, most preprint servers do perform some screening.⁴ medRxiv requires full scientific research reports and absence of obscenity, plagiarism, and patient identifiers. In its first year, medRxiv rejected 34% of 176 submissios; reasons were not disclosed.⁵

The low rate of on-site comments suggests that preprint servers may not be effective for obtaining feedback to improve dermatology manuscripts prior to journal submission. Almost all of the top 20 dermatologyjournals accept preprints. Therefore, dermatologists may use these preprint servers to assert project ideas and disseminate research quickly and freely but may not receive constructive criticism.

Our study is subject to several limitations. Although our search was extensive, it is possible manuscripts were missed. Article metrics also were not available on all servers, and we could not account for accepted articles that were not yet indexed.

There has been a surge in posting of dermatology preprints in recent years. Preprints have not been peer reviewed, and data should be corroborated before incorporating new diagnostics or treatments into clinical practice. Utilization of preprint servers by dermatologists is increasing, but because the impact is still unknown, further studies on accuracy and reliability of preprints are warranted.

Several recent studies have assessed the use of glucocorticoids, a frequent companion to disease-modifying antirheumatic drug (DMARD) and biologic therapy. Many patients are treated with glucocorticoids early in their disease course as a bridging therapy to long-term treatment, and others receive glucocorticoid therapy chronically or intermittently for flares. Van Ouwerkerk and colleagues performed a combined analysis of seven clinical trials, identified in a systematic literature review, that included a glucocorticoid taper protocol for the treatment of newly diagnosed rheumatoid arthritis (RA), undifferentiated arthritis, or "high-risk profile for persistent arthritis." These studies encompassed intravenous, intramuscular, and oral glucocorticoid regimens, and the continued use of glucocorticoids after bridging. These regimens, including cumulative doses, were examined and found to result in a low probability of ongoing use, especially in patients with lower initial doses and shorter bridging schedules. However, though reassuring as to the early use of glucocorticoids in clinical practice, this finding can be affected by patient characteristics not examined in detail in the aggregated results, including whether the patients were classified as having RA, undifferentiated arthritis, or a "high-risk profile."

Adami and colleagues also looked at tapering of glucocorticoids in patients with RA (though not necessarily early RA) in order to determine risk for flare associated with different tapering schedules. They examined the characteristics of patients with RA experiencing a flare (defined as an increase in Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein [DAS28-CRP] > 1.2) and their glucocorticoid therapy in the preceding 6 months and found that tapering to a prednisone equivalent ≤ 2.5 mg daily was associated with a higher risk for flare but that doses > 2.5 mg daily were not. Though this finding is perhaps expected, it does not provide further insight into a strategy to minimize the associated adverse effects of glucocorticoid therapy.

Adding further weight to this point is a study performed in Denmark by Dieperink and colleagues examining risk for Staphylococcus aureus bacteremia (SAB) using a nation-wide registry of over 30,000 patients with RA. They found 180 cases of SAB and examined the patient characteristics. Patients who were currently using or previously used a biologic DMARD had an increased risk for SAB as well as those with moderate to high RA disease activity. Study participants who were currently using a prednisone-equivalent of ≤ 7.5 mg daily had an adjusted odds ratio (aOR) of 2.2 and those using > 7.5 mg daily had an aOR of 9.5 for SAB. This concerning finding suggests that even a relatively "low" dose of prednisone use is not benign for patients with RA, and these studies bring to light the need to research optimal strategies for disease control and balancing immunosuppression with the risk for infection and other adverse events.

Heckert and colleagues looked at another aspect of RA disease control, namely, local progression in a single affected joint. Their prior work has suggested that patients with RA may be prone to recurrent inflammation in a single joint despite systemic treatment, a finding that aligns with common clinical observations. This study evaluates radiographic progression in susceptible joints via post hoc analysis using data from the BeSt study including tender and swollen joints, hand and foot radiographs, and disease activity scores. Despite systemic treatment to a target low disease activity or remission state (as per the BeSt protocol), the study found an association between recurrent joint inflammation and radiographic progression (ie, erosions). However, because they only looked at hand and foot joints, the strength of this association in other joints is unknown, as is the use of local treatment, such as steroid injection to minimize inflammation, though both questions may be difficult to evaluate in a small prospective study.

Several recent studies have assessed the use of glucocorticoids, a frequent companion to disease-modifying antirheumatic drug (DMARD) and biologic therapy. Many patients are treated with glucocorticoids early in their disease course as a bridging therapy to long-term treatment, and others receive glucocorticoid therapy chronically or intermittently for flares. Van Ouwerkerk and colleagues performed a combined analysis of seven clinical trials, identified in a systematic literature review, that included a glucocorticoid taper protocol for the treatment of newly diagnosed rheumatoid arthritis (RA), undifferentiated arthritis, or "high-risk profile for persistent arthritis." These studies encompassed intravenous, intramuscular, and oral glucocorticoid regimens, and the continued use of glucocorticoids after bridging. These regimens, including cumulative doses, were examined and found to result in a low probability of ongoing use, especially in patients with lower initial doses and shorter bridging schedules. However, though reassuring as to the early use of glucocorticoids in clinical practice, this finding can be affected by patient characteristics not examined in detail in the aggregated results, including whether the patients were classified as having RA, undifferentiated arthritis, or a "high-risk profile."

Adami and colleagues also looked at tapering of glucocorticoids in patients with RA (though not necessarily early RA) in order to determine risk for flare associated with different tapering schedules. They examined the characteristics of patients with RA experiencing a flare (defined as an increase in Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein [DAS28-CRP] > 1.2) and their glucocorticoid therapy in the preceding 6 months and found that tapering to a prednisone equivalent ≤ 2.5 mg daily was associated with a higher risk for flare but that doses > 2.5 mg daily were not. Though this finding is perhaps expected, it does not provide further insight into a strategy to minimize the associated adverse effects of glucocorticoid therapy.

Adding further weight to this point is a study performed in Denmark by Dieperink and colleagues examining risk for Staphylococcus aureus bacteremia (SAB) using a nation-wide registry of over 30,000 patients with RA. They found 180 cases of SAB and examined the patient characteristics. Patients who were currently using or previously used a biologic DMARD had an increased risk for SAB as well as those with moderate to high RA disease activity. Study participants who were currently using a prednisone-equivalent of ≤ 7.5 mg daily had an adjusted odds ratio (aOR) of 2.2 and those using > 7.5 mg daily had an aOR of 9.5 for SAB. This concerning finding suggests that even a relatively "low" dose of prednisone use is not benign for patients with RA, and these studies bring to light the need to research optimal strategies for disease control and balancing immunosuppression with the risk for infection and other adverse events.

Heckert and colleagues looked at another aspect of RA disease control, namely, local progression in a single affected joint. Their prior work has suggested that patients with RA may be prone to recurrent inflammation in a single joint despite systemic treatment, a finding that aligns with common clinical observations. This study evaluates radiographic progression in susceptible joints via post hoc analysis using data from the BeSt study including tender and swollen joints, hand and foot radiographs, and disease activity scores. Despite systemic treatment to a target low disease activity or remission state (as per the BeSt protocol), the study found an association between recurrent joint inflammation and radiographic progression (ie, erosions). However, because they only looked at hand and foot joints, the strength of this association in other joints is unknown, as is the use of local treatment, such as steroid injection to minimize inflammation, though both questions may be difficult to evaluate in a small prospective study.

Several recent studies have assessed the use of glucocorticoids, a frequent companion to disease-modifying antirheumatic drug (DMARD) and biologic therapy. Many patients are treated with glucocorticoids early in their disease course as a bridging therapy to long-term treatment, and others receive glucocorticoid therapy chronically or intermittently for flares. Van Ouwerkerk and colleagues performed a combined analysis of seven clinical trials, identified in a systematic literature review, that included a glucocorticoid taper protocol for the treatment of newly diagnosed rheumatoid arthritis (RA), undifferentiated arthritis, or "high-risk profile for persistent arthritis." These studies encompassed intravenous, intramuscular, and oral glucocorticoid regimens, and the continued use of glucocorticoids after bridging. These regimens, including cumulative doses, were examined and found to result in a low probability of ongoing use, especially in patients with lower initial doses and shorter bridging schedules. However, though reassuring as to the early use of glucocorticoids in clinical practice, this finding can be affected by patient characteristics not examined in detail in the aggregated results, including whether the patients were classified as having RA, undifferentiated arthritis, or a "high-risk profile."

Adami and colleagues also looked at tapering of glucocorticoids in patients with RA (though not necessarily early RA) in order to determine risk for flare associated with different tapering schedules. They examined the characteristics of patients with RA experiencing a flare (defined as an increase in Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein [DAS28-CRP] > 1.2) and their glucocorticoid therapy in the preceding 6 months and found that tapering to a prednisone equivalent ≤ 2.5 mg daily was associated with a higher risk for flare but that doses > 2.5 mg daily were not. Though this finding is perhaps expected, it does not provide further insight into a strategy to minimize the associated adverse effects of glucocorticoid therapy.

Adding further weight to this point is a study performed in Denmark by Dieperink and colleagues examining risk for Staphylococcus aureus bacteremia (SAB) using a nation-wide registry of over 30,000 patients with RA. They found 180 cases of SAB and examined the patient characteristics. Patients who were currently using or previously used a biologic DMARD had an increased risk for SAB as well as those with moderate to high RA disease activity. Study participants who were currently using a prednisone-equivalent of ≤ 7.5 mg daily had an adjusted odds ratio (aOR) of 2.2 and those using > 7.5 mg daily had an aOR of 9.5 for SAB. This concerning finding suggests that even a relatively "low" dose of prednisone use is not benign for patients with RA, and these studies bring to light the need to research optimal strategies for disease control and balancing immunosuppression with the risk for infection and other adverse events.

Heckert and colleagues looked at another aspect of RA disease control, namely, local progression in a single affected joint. Their prior work has suggested that patients with RA may be prone to recurrent inflammation in a single joint despite systemic treatment, a finding that aligns with common clinical observations. This study evaluates radiographic progression in susceptible joints via post hoc analysis using data from the BeSt study including tender and swollen joints, hand and foot radiographs, and disease activity scores. Despite systemic treatment to a target low disease activity or remission state (as per the BeSt protocol), the study found an association between recurrent joint inflammation and radiographic progression (ie, erosions). However, because they only looked at hand and foot joints, the strength of this association in other joints is unknown, as is the use of local treatment, such as steroid injection to minimize inflammation, though both questions may be difficult to evaluate in a small prospective study.