MDedge Dermatology

Prior research has demonstrated that museum-based programming decreases resident burnout and depersonalization.¹ A partnership between the Museum of Fine Arts Boston and the Harvard Combined Dermatology Residency Program was well received by residents and resulted in improvement of their observational skills.² The impact of museum-based programming on the clinical practice skills and well-being of Duke dermatology residents and faculty has not been previously assessed.

In this study, our objective was to evaluate the impact of a 3-part museum-based arts retreat on arts appreciation, clinical practice skills, and well-being among dermatology resident and faculty participants. Surveys administered before and after the retreat were used to assess the value that participants attributed to the arts in various areas of clinical practice.

Methods

A 3-part museum-based retreat held on February 7, 2024, was developed with a Nasher Museum of Art (Durham, North Carolina) curator (E.R.). Part 1 was a personal response tour in which 15 residents and 3 faculty members were given individualized prompts and asked to identify an art piece in the museum that encapsulated their response; they then were asked to explain to the group why they chose that particular piece. Participants were given 10 minutes to explore the museum galleries to choose their piece, followed by 15 minutes to share their selected work in groups of 3 to 4.

Part 2 encompassed visual-thinking strategies, a research-based method that uses art to teach visual literacy, thinking, and communication skills.² Using this method, facilitators follow a specific protocol to guide participants in the exploration of an art piece through sharing observations and interpretations.⁴ Participants were divided into 2 groups led by trained museum educators (including E.R.) to analyze and ascribe meaning to a chosen art piece. Three questions were asked: What’s going on in this picture? What do you see that makes you say that? What else can we find? 

Part 3 involved back-to-back drawing, in which participants were paired up and tasked with recreating an art piece in the museum based solely on their partner’s verbal description. In each pair, both participants took turns as the describer and the drawer.

After each part of the retreat, 5 to 10 minutes were dedicated to debriefing in small groups about how each activity may connect to the role of a clinician. A total of 15 participants completed pre- and post-retreat surveys to assess the value they attributed to the arts and identify in which aspects of clinical practice they believe the arts play a role.

Results

Seventy-three percent of participants (11/15) found the museum-based retreat “extremely useful” or “very useful.” There was a 20% increase in those who attributed at least moderate value to the arts as a clinician after compared to before the retreat (13/15 [87%] vs 8/15 [53%]), and 100% of the participants desired to participate in future arts-based programming. Following the retreat, a greater percentage of participants believed the arts have a role in the following aspects of clinical practice: education, observation, listening, communication, empathy, compassion, forming connections, cultural sensitivity, tolerance for ambiguity, reflection, mindfulness, stress reduction, preventing burnout, bias prevention, mental wellness, spiritual wellness, and physical wellness (eTable). Qualitative feedback compiled from the participants’ responses to survey questions following the retreat about their thoughts on each activity and overall feedback was used to create a word cloud (eFigure).

Comment

The importance of arts and humanities integration into medical education previously has been described.⁵ Our survey results suggest that museum-based programming increases dermatology resident and faculty appreciation for the arts and encourages participation in future arts-based programming. Our results also demonstrate that arts-based programming positively impacts important resident competencies in the practice of medicine including tolerance for ambiguity, bias prevention, and cultural competency, and that the incorporation of arts-based programming can enhance residents’ well-being (physical, mental, and spiritual) as well as their ability to be better clinicians by addressing skills in communication, listening, and observation. The structure of our 3-part museum-based retreat offers practical implementation strategies for integrating the humanities into dermatology residency curricula and easily can be modified to meet the needs of different dermatology residency programs. 

Prior research has demonstrated that museum-based programming decreases resident burnout and depersonalization.¹ A partnership between the Museum of Fine Arts Boston and the Harvard Combined Dermatology Residency Program was well received by residents and resulted in improvement of their observational skills.² The impact of museum-based programming on the clinical practice skills and well-being of Duke dermatology residents and faculty has not been previously assessed.

In this study, our objective was to evaluate the impact of a 3-part museum-based arts retreat on arts appreciation, clinical practice skills, and well-being among dermatology resident and faculty participants. Surveys administered before and after the retreat were used to assess the value that participants attributed to the arts in various areas of clinical practice.

Methods

A 3-part museum-based retreat held on February 7, 2024, was developed with a Nasher Museum of Art (Durham, North Carolina) curator (E.R.). Part 1 was a personal response tour in which 15 residents and 3 faculty members were given individualized prompts and asked to identify an art piece in the museum that encapsulated their response; they then were asked to explain to the group why they chose that particular piece. Participants were given 10 minutes to explore the museum galleries to choose their piece, followed by 15 minutes to share their selected work in groups of 3 to 4.

Part 2 encompassed visual-thinking strategies, a research-based method that uses art to teach visual literacy, thinking, and communication skills.² Using this method, facilitators follow a specific protocol to guide participants in the exploration of an art piece through sharing observations and interpretations.⁴ Participants were divided into 2 groups led by trained museum educators (including E.R.) to analyze and ascribe meaning to a chosen art piece. Three questions were asked: What’s going on in this picture? What do you see that makes you say that? What else can we find? 

Part 3 involved back-to-back drawing, in which participants were paired up and tasked with recreating an art piece in the museum based solely on their partner’s verbal description. In each pair, both participants took turns as the describer and the drawer.

After each part of the retreat, 5 to 10 minutes were dedicated to debriefing in small groups about how each activity may connect to the role of a clinician. A total of 15 participants completed pre- and post-retreat surveys to assess the value they attributed to the arts and identify in which aspects of clinical practice they believe the arts play a role.

Results

Seventy-three percent of participants (11/15) found the museum-based retreat “extremely useful” or “very useful.” There was a 20% increase in those who attributed at least moderate value to the arts as a clinician after compared to before the retreat (13/15 [87%] vs 8/15 [53%]), and 100% of the participants desired to participate in future arts-based programming. Following the retreat, a greater percentage of participants believed the arts have a role in the following aspects of clinical practice: education, observation, listening, communication, empathy, compassion, forming connections, cultural sensitivity, tolerance for ambiguity, reflection, mindfulness, stress reduction, preventing burnout, bias prevention, mental wellness, spiritual wellness, and physical wellness (eTable). Qualitative feedback compiled from the participants’ responses to survey questions following the retreat about their thoughts on each activity and overall feedback was used to create a word cloud (eFigure).

Comment

The importance of arts and humanities integration into medical education previously has been described.⁵ Our survey results suggest that museum-based programming increases dermatology resident and faculty appreciation for the arts and encourages participation in future arts-based programming. Our results also demonstrate that arts-based programming positively impacts important resident competencies in the practice of medicine including tolerance for ambiguity, bias prevention, and cultural competency, and that the incorporation of arts-based programming can enhance residents’ well-being (physical, mental, and spiritual) as well as their ability to be better clinicians by addressing skills in communication, listening, and observation. The structure of our 3-part museum-based retreat offers practical implementation strategies for integrating the humanities into dermatology residency curricula and easily can be modified to meet the needs of different dermatology residency programs. 

Prior research has demonstrated that museum-based programming decreases resident burnout and depersonalization.¹ A partnership between the Museum of Fine Arts Boston and the Harvard Combined Dermatology Residency Program was well received by residents and resulted in improvement of their observational skills.² The impact of museum-based programming on the clinical practice skills and well-being of Duke dermatology residents and faculty has not been previously assessed.

In this study, our objective was to evaluate the impact of a 3-part museum-based arts retreat on arts appreciation, clinical practice skills, and well-being among dermatology resident and faculty participants. Surveys administered before and after the retreat were used to assess the value that participants attributed to the arts in various areas of clinical practice.

Methods

A 3-part museum-based retreat held on February 7, 2024, was developed with a Nasher Museum of Art (Durham, North Carolina) curator (E.R.). Part 1 was a personal response tour in which 15 residents and 3 faculty members were given individualized prompts and asked to identify an art piece in the museum that encapsulated their response; they then were asked to explain to the group why they chose that particular piece. Participants were given 10 minutes to explore the museum galleries to choose their piece, followed by 15 minutes to share their selected work in groups of 3 to 4.

Part 2 encompassed visual-thinking strategies, a research-based method that uses art to teach visual literacy, thinking, and communication skills.² Using this method, facilitators follow a specific protocol to guide participants in the exploration of an art piece through sharing observations and interpretations.⁴ Participants were divided into 2 groups led by trained museum educators (including E.R.) to analyze and ascribe meaning to a chosen art piece. Three questions were asked: What’s going on in this picture? What do you see that makes you say that? What else can we find? 

Part 3 involved back-to-back drawing, in which participants were paired up and tasked with recreating an art piece in the museum based solely on their partner’s verbal description. In each pair, both participants took turns as the describer and the drawer.

After each part of the retreat, 5 to 10 minutes were dedicated to debriefing in small groups about how each activity may connect to the role of a clinician. A total of 15 participants completed pre- and post-retreat surveys to assess the value they attributed to the arts and identify in which aspects of clinical practice they believe the arts play a role.

Results

Seventy-three percent of participants (11/15) found the museum-based retreat “extremely useful” or “very useful.” There was a 20% increase in those who attributed at least moderate value to the arts as a clinician after compared to before the retreat (13/15 [87%] vs 8/15 [53%]), and 100% of the participants desired to participate in future arts-based programming. Following the retreat, a greater percentage of participants believed the arts have a role in the following aspects of clinical practice: education, observation, listening, communication, empathy, compassion, forming connections, cultural sensitivity, tolerance for ambiguity, reflection, mindfulness, stress reduction, preventing burnout, bias prevention, mental wellness, spiritual wellness, and physical wellness (eTable). Qualitative feedback compiled from the participants’ responses to survey questions following the retreat about their thoughts on each activity and overall feedback was used to create a word cloud (eFigure).

Comment

The importance of arts and humanities integration into medical education previously has been described.⁵ Our survey results suggest that museum-based programming increases dermatology resident and faculty appreciation for the arts and encourages participation in future arts-based programming. Our results also demonstrate that arts-based programming positively impacts important resident competencies in the practice of medicine including tolerance for ambiguity, bias prevention, and cultural competency, and that the incorporation of arts-based programming can enhance residents’ well-being (physical, mental, and spiritual) as well as their ability to be better clinicians by addressing skills in communication, listening, and observation. The structure of our 3-part museum-based retreat offers practical implementation strategies for integrating the humanities into dermatology residency curricula and easily can be modified to meet the needs of different dermatology residency programs. 

Practice Gap

Tissue processing and complete margin assessment in Mohs micrographic surgery (MMS) are challenging concepts for residents, yet they are essential components of the dermatology residency curriculum. We propose a hands-on active teaching method using craft foam blocks to help residents master these techniques. Prior educational tools have included instructional videos¹ as well as the peanut butter–cup and cantaloupe analogies.^2,3 Specifically, our method utilizes inexpensive, readily available supplies that allow for repeated practice in a low-stakes environment without limitation of resources. This method provides an immersive, hands-on experience that allows residents to perform multiple practice excisions and simulate positive peripheral or deep margins, unlike tools that offer only fixed-depth or purely visual representations. Additionally, our learning model uniquely enables residents to flatten the simulated tissue, providing a clearer understanding of how a 3-dimensional specimen is transformed on a slide during histologic preparation. This step is particularly important, as tissue architecture can shift during processing, making it one of the most difficult concepts to grasp without hands-on experience. Having a multitude of teaching methods is crucial to accommodate various learning styles, and active learning has been shown to enhance retention for dermatology residents.⁴

The Technique

Residents use simple art supplies (including craft foam blocks and ink) and inexpensive, readily available surgical tools to simulate MMS (Table)(Figure 1). If desired, the resident can follow along with the comprehensive, stepwise textbook description of MMS, outlined by Benedetto et al⁵ to contextualize this hands-on exercise within a standardized didactic framework.

The foam block, which represents patient tissue, serves as the specimen. The resident begins by freehand drawing a simulated cutaneous tumor directly onto the foam using a surgical marking pen. At this point, the instructor discusses the advantages and limitations of tumor debulking with a sharp blade or curette. Residents then mark appropriate margins (1-3 mm) of normal-appearing “epidermis” on the foam block and add hash marks for orientation. This is another opportunity for the instructor to discuss common methods for marking tissue in vivo and to review situations when larger or smaller margins might be appropriate. 

Next, the resident removes the first layer of simulated tissue using a disposable #15 blade scalpel at a 45° angle circumferentially and deep around the representative tumor. The resident also may use scissors and tissue forceps to remove the representative tumor. Next, the excised foam layer (the simulated “specimen”) is transferred to gauze. To demonstrate a positive margin, the resident or instructor marks the deep or peripheral foam block with a surgical marking pen, indicating residual tumor (Figure 2). This allows for multiple sequential layers of foam to be removed, demonstrating successive stages of MMS. 

An inkwell holds different colors of washable paint to simulate tissue inking. After excision, the resident uses cotton-tipped applicators to apply different paint colors to the edges of the excised foam specimen at designated orientation points (eg, 3 o'clock and 12 o'clock). The resident then records the location of the excised sample by hand-drawing it on a printable Mohs map, labeling the corresponding paint colors to indicate orientation (Figure 3). 

The resident then places the specimen between 2 ­plastic page protectors mimicking a glass slide and cover slip. Clear tape can be used to help flatten the specimen (Figure 4). The tissue is compressed between the page protector so that the simulated epidermis, dermis, and subcutaneous fat are all in the same plane. At this stage, the instructor may discuss the use of relaxing incisions, especially for deeper tissue specimens or when excision at a 45° bevel is not achieved.⁵ The view from the underside of the page protector reveals 100% of the specimen’s margin and mimics the first cut off the tissue block. The resident can visualize the complete circumferential, peripheral, and deep margins and can easily identify any positive margins. At this point, the exercise can conclude, or the resident can explore further stages for positive margins, bisected specimens, or other tissue preparation variations.

Practice Implications

By individually designing and removing a representative tumor with margins, creating hash marks, and preparing a tissue specimen for histologic analysis, our interactive teaching method provides dermatology residents with a relatively simple, effective, and active learning experience for MMS outside the surgical setting. Using a piece of craft foam allows the representative tissue to be manipulated and flattened, similar to cutaneous tissue. This method was implemented and refined across 3 separate teaching sessions held by teaching faculty (E.I.P and E.B.W.) at the San Antonio Uniformed Services Health Education Consortium Dermatology Residency Program (San Antonio, Texas). This method has consistently generated strong resident engagement and prompted insightful questions and discussions. Program directors at other residency programs can readily incorporate this method in their surgical curriculum by allocating a brief didactic period to the exercise and facilitating the discussion with a dermatologic surgeon. Its simplicity, low cost, and effectiveness make the foam block model an easily adoptable teaching tool for dermatology residency programs seeking to provide a comprehensive, hands-on understanding of MMS.

Practice Gap

Tissue processing and complete margin assessment in Mohs micrographic surgery (MMS) are challenging concepts for residents, yet they are essential components of the dermatology residency curriculum. We propose a hands-on active teaching method using craft foam blocks to help residents master these techniques. Prior educational tools have included instructional videos¹ as well as the peanut butter–cup and cantaloupe analogies.^2,3 Specifically, our method utilizes inexpensive, readily available supplies that allow for repeated practice in a low-stakes environment without limitation of resources. This method provides an immersive, hands-on experience that allows residents to perform multiple practice excisions and simulate positive peripheral or deep margins, unlike tools that offer only fixed-depth or purely visual representations. Additionally, our learning model uniquely enables residents to flatten the simulated tissue, providing a clearer understanding of how a 3-dimensional specimen is transformed on a slide during histologic preparation. This step is particularly important, as tissue architecture can shift during processing, making it one of the most difficult concepts to grasp without hands-on experience. Having a multitude of teaching methods is crucial to accommodate various learning styles, and active learning has been shown to enhance retention for dermatology residents.⁴

The Technique

Residents use simple art supplies (including craft foam blocks and ink) and inexpensive, readily available surgical tools to simulate MMS (Table)(Figure 1). If desired, the resident can follow along with the comprehensive, stepwise textbook description of MMS, outlined by Benedetto et al⁵ to contextualize this hands-on exercise within a standardized didactic framework.

The foam block, which represents patient tissue, serves as the specimen. The resident begins by freehand drawing a simulated cutaneous tumor directly onto the foam using a surgical marking pen. At this point, the instructor discusses the advantages and limitations of tumor debulking with a sharp blade or curette. Residents then mark appropriate margins (1-3 mm) of normal-appearing “epidermis” on the foam block and add hash marks for orientation. This is another opportunity for the instructor to discuss common methods for marking tissue in vivo and to review situations when larger or smaller margins might be appropriate. 

Next, the resident removes the first layer of simulated tissue using a disposable #15 blade scalpel at a 45° angle circumferentially and deep around the representative tumor. The resident also may use scissors and tissue forceps to remove the representative tumor. Next, the excised foam layer (the simulated “specimen”) is transferred to gauze. To demonstrate a positive margin, the resident or instructor marks the deep or peripheral foam block with a surgical marking pen, indicating residual tumor (Figure 2). This allows for multiple sequential layers of foam to be removed, demonstrating successive stages of MMS. 

An inkwell holds different colors of washable paint to simulate tissue inking. After excision, the resident uses cotton-tipped applicators to apply different paint colors to the edges of the excised foam specimen at designated orientation points (eg, 3 o'clock and 12 o'clock). The resident then records the location of the excised sample by hand-drawing it on a printable Mohs map, labeling the corresponding paint colors to indicate orientation (Figure 3). 

The resident then places the specimen between 2 ­plastic page protectors mimicking a glass slide and cover slip. Clear tape can be used to help flatten the specimen (Figure 4). The tissue is compressed between the page protector so that the simulated epidermis, dermis, and subcutaneous fat are all in the same plane. At this stage, the instructor may discuss the use of relaxing incisions, especially for deeper tissue specimens or when excision at a 45° bevel is not achieved.⁵ The view from the underside of the page protector reveals 100% of the specimen’s margin and mimics the first cut off the tissue block. The resident can visualize the complete circumferential, peripheral, and deep margins and can easily identify any positive margins. At this point, the exercise can conclude, or the resident can explore further stages for positive margins, bisected specimens, or other tissue preparation variations.

Practice Implications

By individually designing and removing a representative tumor with margins, creating hash marks, and preparing a tissue specimen for histologic analysis, our interactive teaching method provides dermatology residents with a relatively simple, effective, and active learning experience for MMS outside the surgical setting. Using a piece of craft foam allows the representative tissue to be manipulated and flattened, similar to cutaneous tissue. This method was implemented and refined across 3 separate teaching sessions held by teaching faculty (E.I.P and E.B.W.) at the San Antonio Uniformed Services Health Education Consortium Dermatology Residency Program (San Antonio, Texas). This method has consistently generated strong resident engagement and prompted insightful questions and discussions. Program directors at other residency programs can readily incorporate this method in their surgical curriculum by allocating a brief didactic period to the exercise and facilitating the discussion with a dermatologic surgeon. Its simplicity, low cost, and effectiveness make the foam block model an easily adoptable teaching tool for dermatology residency programs seeking to provide a comprehensive, hands-on understanding of MMS.

Practice Gap

Tissue processing and complete margin assessment in Mohs micrographic surgery (MMS) are challenging concepts for residents, yet they are essential components of the dermatology residency curriculum. We propose a hands-on active teaching method using craft foam blocks to help residents master these techniques. Prior educational tools have included instructional videos¹ as well as the peanut butter–cup and cantaloupe analogies.^2,3 Specifically, our method utilizes inexpensive, readily available supplies that allow for repeated practice in a low-stakes environment without limitation of resources. This method provides an immersive, hands-on experience that allows residents to perform multiple practice excisions and simulate positive peripheral or deep margins, unlike tools that offer only fixed-depth or purely visual representations. Additionally, our learning model uniquely enables residents to flatten the simulated tissue, providing a clearer understanding of how a 3-dimensional specimen is transformed on a slide during histologic preparation. This step is particularly important, as tissue architecture can shift during processing, making it one of the most difficult concepts to grasp without hands-on experience. Having a multitude of teaching methods is crucial to accommodate various learning styles, and active learning has been shown to enhance retention for dermatology residents.⁴

The Technique

Residents use simple art supplies (including craft foam blocks and ink) and inexpensive, readily available surgical tools to simulate MMS (Table)(Figure 1). If desired, the resident can follow along with the comprehensive, stepwise textbook description of MMS, outlined by Benedetto et al⁵ to contextualize this hands-on exercise within a standardized didactic framework.

The foam block, which represents patient tissue, serves as the specimen. The resident begins by freehand drawing a simulated cutaneous tumor directly onto the foam using a surgical marking pen. At this point, the instructor discusses the advantages and limitations of tumor debulking with a sharp blade or curette. Residents then mark appropriate margins (1-3 mm) of normal-appearing “epidermis” on the foam block and add hash marks for orientation. This is another opportunity for the instructor to discuss common methods for marking tissue in vivo and to review situations when larger or smaller margins might be appropriate. 

Next, the resident removes the first layer of simulated tissue using a disposable #15 blade scalpel at a 45° angle circumferentially and deep around the representative tumor. The resident also may use scissors and tissue forceps to remove the representative tumor. Next, the excised foam layer (the simulated “specimen”) is transferred to gauze. To demonstrate a positive margin, the resident or instructor marks the deep or peripheral foam block with a surgical marking pen, indicating residual tumor (Figure 2). This allows for multiple sequential layers of foam to be removed, demonstrating successive stages of MMS. 

An inkwell holds different colors of washable paint to simulate tissue inking. After excision, the resident uses cotton-tipped applicators to apply different paint colors to the edges of the excised foam specimen at designated orientation points (eg, 3 o'clock and 12 o'clock). The resident then records the location of the excised sample by hand-drawing it on a printable Mohs map, labeling the corresponding paint colors to indicate orientation (Figure 3). 

The resident then places the specimen between 2 ­plastic page protectors mimicking a glass slide and cover slip. Clear tape can be used to help flatten the specimen (Figure 4). The tissue is compressed between the page protector so that the simulated epidermis, dermis, and subcutaneous fat are all in the same plane. At this stage, the instructor may discuss the use of relaxing incisions, especially for deeper tissue specimens or when excision at a 45° bevel is not achieved.⁵ The view from the underside of the page protector reveals 100% of the specimen’s margin and mimics the first cut off the tissue block. The resident can visualize the complete circumferential, peripheral, and deep margins and can easily identify any positive margins. At this point, the exercise can conclude, or the resident can explore further stages for positive margins, bisected specimens, or other tissue preparation variations.

Practice Implications

By individually designing and removing a representative tumor with margins, creating hash marks, and preparing a tissue specimen for histologic analysis, our interactive teaching method provides dermatology residents with a relatively simple, effective, and active learning experience for MMS outside the surgical setting. Using a piece of craft foam allows the representative tissue to be manipulated and flattened, similar to cutaneous tissue. This method was implemented and refined across 3 separate teaching sessions held by teaching faculty (E.I.P and E.B.W.) at the San Antonio Uniformed Services Health Education Consortium Dermatology Residency Program (San Antonio, Texas). This method has consistently generated strong resident engagement and prompted insightful questions and discussions. Program directors at other residency programs can readily incorporate this method in their surgical curriculum by allocating a brief didactic period to the exercise and facilitating the discussion with a dermatologic surgeon. Its simplicity, low cost, and effectiveness make the foam block model an easily adoptable teaching tool for dermatology residency programs seeking to provide a comprehensive, hands-on understanding of MMS.

The Diagnosis: Spiradenocylindroma

T he biopsy results confirmed the diagnosis of spiradenocylindroma with negative margins. At 6-week follow-up, the patient had no signs of recurrence. Spiradenocylindroma is a benign hybrid neoplasm consisting of histologically intermixed areas representing the spectrum of morphology between spiradenoma and cylindromas.^1,2 Both spiradenoma and cylindroma comprise 2 distinct populations of dark and pale basaloid cells.^2,3 The spiradenomatous areas of the spiradenocylindroma are arranged in large, well-circumscribed collections of small, darkly staining cells with interspersed lymphocytes and a thin basement membrane surrounding spiradenocylindroma component.^2,3 The spiradenocylindroma regions also may contain tubular structures dilated by hemorrhage.² In contrast, the cylindromatous regions have a jigsaw-puzzle configuration of polygonal tumor nests containing peripherally palisading dark cells and central pale cells, surrounded by a thick basement membrane (top quiz image).^2,3 

Clinically, sporadic spiradenocylindromas may resemble other lesions, manifesting as a papule or nodule with coloration ranging from gray-blue to salmon pink along with arborizing telangiectasias.^4,5 Although spiradenocylindromas typically are found on the head, neck, and trunk, they also have been reported in the kidney, vulva, anus, and rectum.^2,6,7 Not only are spiradenocylindromas clinically indistinct from other adnexal growths, but they also share some features with basal cell carcinomas (BCCs) and amelanotic melanomas.⁸ Features of arborizing telangiectasias on a papule may resemble BCC, requiring histopathology for a definitive diagnosis. 

Spiradenocylindromas classically are associated with Brooke-Spiegler syndrome, a rare, autosomal-dominant genodermatosis caused by a germline mutation in the cylindromatosis lysine 63 deubiquitinase tumor-suppressor gene.⁵ Patients develop adnexal neoplasms of the folliculosebaceous-apocrine unit, including spiradenomas, cylindromas, and trichoepitheliomas.⁵ Rarely, malignant transformation to spiradenocylindrocarcinoma has been reported.⁹ Features of malignant transformation include loss of the 2-cell population, cytologic atypia, increased mitotic activity, and loss of intratumoral lymphocytes.¹⁰ 

Trichoepitheliomas are benign, firm, flesh-colored papules to nodules that commonly are found on the mid face but may appear on the scalp, neck, and upper trunk.^5-11 Trichoepitheliomas are closely related to spiradenomas and cylindromas; the familial form, multiple familial trichoepitheliomas, exists on a spectrum with Brooke-Spiegler syndrome.^3,11 Multiple familial trichoepithelioma is characterized by multiple trichoepitheliomas without accompanying spiradenomas, cylindromas, or spiradenocylindromas.3 On histopathology, trichoepitheliomas are distinguished by cribriform clusters or nests of basaloid follicular germinative cells with bulbar differentiation, known as papillary mesenchymal bodies, surrounded by an adherent stroma (eFigure 1).^3,5,11 In addition to follicular bulbar differentiation, trichoepitheliomas are surrounded by an adherent cellular stroma without the retraction artifact around tumor islands seen in BCC, although artifactual clefts may occur within the stroma.¹¹ In contrast, spiradenocylindromas do not demonstrate keratin cysts or artifactual clefts within the stroma.

Trichilemmal cysts, or pilar cysts, are benign adnexal neoplasms derived from the outer root sheath at the isthmus.^12-14 Approximately 90% of pilar cysts are found on the scalp and 2% of trichilemmal cysts may progress to a proliferating trichilemmal cyst, which is locally aggressive and contains an expanding buckled epithelium within the cyst space.^12,14 Clinically, trichilemmal cysts are slow-growing, smooth, round, mobile nodules without a central punctum.^12,13 On histopathology, the cyst wall contains peripherally palisading basal cells and maturing cells showing no intercellular bridging (eFigure 2). As the cells mature, they swell with pale cytoplasm and abruptly keratinize without a granular layer, a process known as trichilemmal keratinization.^12-14 Additionally, cholesterol clefts are common in the keratinous lumen, and about 25% of cysts contain calcifications.^13,14 The broadly basophilic spiradenocylindromas sharply contrast the abundant eosinophilic keratin of trichilemmal cysts. 

Basal cell carcinoma is a slow-growing, locally destructive neoplasm that develops due to chronic sun exposure; thus, BCCs commonly arise on exposed areas of the face, head, neck, arms, and legs.¹⁵ Nodular BCC is the most common subtype and typically manifests as a shiny pearly papule or nodule with a smooth surface, rolled borders, and arborizing telangiectasias.¹⁶ On histopathology, nodular BCCs demonstrate nests or nodules of basaloid keratinocytes with peripheral palisading and retraction artifact between the tumor and stroma (eFigure 3).^15,16 A lack of retraction artifact, cystic dilation of tubular structures, jigsaw molding of nests, and a distinct 2-cell population distinguish spiradenocylindroma from BCC. Of note, in rare instances BCCs also may display a thick fibrous stroma, similar to the stroma of cylindromas.¹⁵ 

Amelanotic melanoma is a variant of melanoma characterized by little to no pigment. Any of the 4 classic subtypes of melanoma (nodular, superficial spreading, lentigo maligna, acral lentiginous) can be amelanotic.¹⁷ Clinically, amelanotic melanomas can vary greatly, manifesting as erythematous macules, dermal plaques, or papulonodular lesions, often with scaling.¹⁸ On histopathology, findings common to all melanomas include cellular atypia, mitoses, pagetoid spread, and pleomorphism (eFigure 4).^18,19 Immunohistochemistry is an important method to distinguish melanoma from other melanocytic proliferations and to aid in the assessment of Breslow depth. Markers include SOX10 (sex-determining region Y-box transcription factor 10), S100, and MART-1 (melanoma antigen recognized by T cells 1/melan-A).^19,20 Expression of PRAME (preferentially expressed antigen in melanoma) often is positive but is not necessary for diagnosis.²¹ Histologically, the atypical pleomorphic cells of melanoma are markedly distinct from both spiradenomas and cylindromas.

The Diagnosis: Spiradenocylindroma

T he biopsy results confirmed the diagnosis of spiradenocylindroma with negative margins. At 6-week follow-up, the patient had no signs of recurrence. Spiradenocylindroma is a benign hybrid neoplasm consisting of histologically intermixed areas representing the spectrum of morphology between spiradenoma and cylindromas.^1,2 Both spiradenoma and cylindroma comprise 2 distinct populations of dark and pale basaloid cells.^2,3 The spiradenomatous areas of the spiradenocylindroma are arranged in large, well-circumscribed collections of small, darkly staining cells with interspersed lymphocytes and a thin basement membrane surrounding spiradenocylindroma component.^2,3 The spiradenocylindroma regions also may contain tubular structures dilated by hemorrhage.² In contrast, the cylindromatous regions have a jigsaw-puzzle configuration of polygonal tumor nests containing peripherally palisading dark cells and central pale cells, surrounded by a thick basement membrane (top quiz image).^2,3 

Clinically, sporadic spiradenocylindromas may resemble other lesions, manifesting as a papule or nodule with coloration ranging from gray-blue to salmon pink along with arborizing telangiectasias.^4,5 Although spiradenocylindromas typically are found on the head, neck, and trunk, they also have been reported in the kidney, vulva, anus, and rectum.^2,6,7 Not only are spiradenocylindromas clinically indistinct from other adnexal growths, but they also share some features with basal cell carcinomas (BCCs) and amelanotic melanomas.⁸ Features of arborizing telangiectasias on a papule may resemble BCC, requiring histopathology for a definitive diagnosis. 

Spiradenocylindromas classically are associated with Brooke-Spiegler syndrome, a rare, autosomal-dominant genodermatosis caused by a germline mutation in the cylindromatosis lysine 63 deubiquitinase tumor-suppressor gene.⁵ Patients develop adnexal neoplasms of the folliculosebaceous-apocrine unit, including spiradenomas, cylindromas, and trichoepitheliomas.⁵ Rarely, malignant transformation to spiradenocylindrocarcinoma has been reported.⁹ Features of malignant transformation include loss of the 2-cell population, cytologic atypia, increased mitotic activity, and loss of intratumoral lymphocytes.¹⁰ 

Trichoepitheliomas are benign, firm, flesh-colored papules to nodules that commonly are found on the mid face but may appear on the scalp, neck, and upper trunk.^5-11 Trichoepitheliomas are closely related to spiradenomas and cylindromas; the familial form, multiple familial trichoepitheliomas, exists on a spectrum with Brooke-Spiegler syndrome.^3,11 Multiple familial trichoepithelioma is characterized by multiple trichoepitheliomas without accompanying spiradenomas, cylindromas, or spiradenocylindromas.3 On histopathology, trichoepitheliomas are distinguished by cribriform clusters or nests of basaloid follicular germinative cells with bulbar differentiation, known as papillary mesenchymal bodies, surrounded by an adherent stroma (eFigure 1).^3,5,11 In addition to follicular bulbar differentiation, trichoepitheliomas are surrounded by an adherent cellular stroma without the retraction artifact around tumor islands seen in BCC, although artifactual clefts may occur within the stroma.¹¹ In contrast, spiradenocylindromas do not demonstrate keratin cysts or artifactual clefts within the stroma.

Trichilemmal cysts, or pilar cysts, are benign adnexal neoplasms derived from the outer root sheath at the isthmus.^12-14 Approximately 90% of pilar cysts are found on the scalp and 2% of trichilemmal cysts may progress to a proliferating trichilemmal cyst, which is locally aggressive and contains an expanding buckled epithelium within the cyst space.^12,14 Clinically, trichilemmal cysts are slow-growing, smooth, round, mobile nodules without a central punctum.^12,13 On histopathology, the cyst wall contains peripherally palisading basal cells and maturing cells showing no intercellular bridging (eFigure 2). As the cells mature, they swell with pale cytoplasm and abruptly keratinize without a granular layer, a process known as trichilemmal keratinization.^12-14 Additionally, cholesterol clefts are common in the keratinous lumen, and about 25% of cysts contain calcifications.^13,14 The broadly basophilic spiradenocylindromas sharply contrast the abundant eosinophilic keratin of trichilemmal cysts. 

Basal cell carcinoma is a slow-growing, locally destructive neoplasm that develops due to chronic sun exposure; thus, BCCs commonly arise on exposed areas of the face, head, neck, arms, and legs.¹⁵ Nodular BCC is the most common subtype and typically manifests as a shiny pearly papule or nodule with a smooth surface, rolled borders, and arborizing telangiectasias.¹⁶ On histopathology, nodular BCCs demonstrate nests or nodules of basaloid keratinocytes with peripheral palisading and retraction artifact between the tumor and stroma (eFigure 3).^15,16 A lack of retraction artifact, cystic dilation of tubular structures, jigsaw molding of nests, and a distinct 2-cell population distinguish spiradenocylindroma from BCC. Of note, in rare instances BCCs also may display a thick fibrous stroma, similar to the stroma of cylindromas.¹⁵ 

Amelanotic melanoma is a variant of melanoma characterized by little to no pigment. Any of the 4 classic subtypes of melanoma (nodular, superficial spreading, lentigo maligna, acral lentiginous) can be amelanotic.¹⁷ Clinically, amelanotic melanomas can vary greatly, manifesting as erythematous macules, dermal plaques, or papulonodular lesions, often with scaling.¹⁸ On histopathology, findings common to all melanomas include cellular atypia, mitoses, pagetoid spread, and pleomorphism (eFigure 4).^18,19 Immunohistochemistry is an important method to distinguish melanoma from other melanocytic proliferations and to aid in the assessment of Breslow depth. Markers include SOX10 (sex-determining region Y-box transcription factor 10), S100, and MART-1 (melanoma antigen recognized by T cells 1/melan-A).^19,20 Expression of PRAME (preferentially expressed antigen in melanoma) often is positive but is not necessary for diagnosis.²¹ Histologically, the atypical pleomorphic cells of melanoma are markedly distinct from both spiradenomas and cylindromas.

The Diagnosis: Spiradenocylindroma

T he biopsy results confirmed the diagnosis of spiradenocylindroma with negative margins. At 6-week follow-up, the patient had no signs of recurrence. Spiradenocylindroma is a benign hybrid neoplasm consisting of histologically intermixed areas representing the spectrum of morphology between spiradenoma and cylindromas.^1,2 Both spiradenoma and cylindroma comprise 2 distinct populations of dark and pale basaloid cells.^2,3 The spiradenomatous areas of the spiradenocylindroma are arranged in large, well-circumscribed collections of small, darkly staining cells with interspersed lymphocytes and a thin basement membrane surrounding spiradenocylindroma component.^2,3 The spiradenocylindroma regions also may contain tubular structures dilated by hemorrhage.² In contrast, the cylindromatous regions have a jigsaw-puzzle configuration of polygonal tumor nests containing peripherally palisading dark cells and central pale cells, surrounded by a thick basement membrane (top quiz image).^2,3 

Clinically, sporadic spiradenocylindromas may resemble other lesions, manifesting as a papule or nodule with coloration ranging from gray-blue to salmon pink along with arborizing telangiectasias.^4,5 Although spiradenocylindromas typically are found on the head, neck, and trunk, they also have been reported in the kidney, vulva, anus, and rectum.^2,6,7 Not only are spiradenocylindromas clinically indistinct from other adnexal growths, but they also share some features with basal cell carcinomas (BCCs) and amelanotic melanomas.⁸ Features of arborizing telangiectasias on a papule may resemble BCC, requiring histopathology for a definitive diagnosis. 

Spiradenocylindromas classically are associated with Brooke-Spiegler syndrome, a rare, autosomal-dominant genodermatosis caused by a germline mutation in the cylindromatosis lysine 63 deubiquitinase tumor-suppressor gene.⁵ Patients develop adnexal neoplasms of the folliculosebaceous-apocrine unit, including spiradenomas, cylindromas, and trichoepitheliomas.⁵ Rarely, malignant transformation to spiradenocylindrocarcinoma has been reported.⁹ Features of malignant transformation include loss of the 2-cell population, cytologic atypia, increased mitotic activity, and loss of intratumoral lymphocytes.¹⁰ 

Trichoepitheliomas are benign, firm, flesh-colored papules to nodules that commonly are found on the mid face but may appear on the scalp, neck, and upper trunk.^5-11 Trichoepitheliomas are closely related to spiradenomas and cylindromas; the familial form, multiple familial trichoepitheliomas, exists on a spectrum with Brooke-Spiegler syndrome.^3,11 Multiple familial trichoepithelioma is characterized by multiple trichoepitheliomas without accompanying spiradenomas, cylindromas, or spiradenocylindromas.3 On histopathology, trichoepitheliomas are distinguished by cribriform clusters or nests of basaloid follicular germinative cells with bulbar differentiation, known as papillary mesenchymal bodies, surrounded by an adherent stroma (eFigure 1).^3,5,11 In addition to follicular bulbar differentiation, trichoepitheliomas are surrounded by an adherent cellular stroma without the retraction artifact around tumor islands seen in BCC, although artifactual clefts may occur within the stroma.¹¹ In contrast, spiradenocylindromas do not demonstrate keratin cysts or artifactual clefts within the stroma.

Trichilemmal cysts, or pilar cysts, are benign adnexal neoplasms derived from the outer root sheath at the isthmus.^12-14 Approximately 90% of pilar cysts are found on the scalp and 2% of trichilemmal cysts may progress to a proliferating trichilemmal cyst, which is locally aggressive and contains an expanding buckled epithelium within the cyst space.^12,14 Clinically, trichilemmal cysts are slow-growing, smooth, round, mobile nodules without a central punctum.^12,13 On histopathology, the cyst wall contains peripherally palisading basal cells and maturing cells showing no intercellular bridging (eFigure 2). As the cells mature, they swell with pale cytoplasm and abruptly keratinize without a granular layer, a process known as trichilemmal keratinization.^12-14 Additionally, cholesterol clefts are common in the keratinous lumen, and about 25% of cysts contain calcifications.^13,14 The broadly basophilic spiradenocylindromas sharply contrast the abundant eosinophilic keratin of trichilemmal cysts. 

Basal cell carcinoma is a slow-growing, locally destructive neoplasm that develops due to chronic sun exposure; thus, BCCs commonly arise on exposed areas of the face, head, neck, arms, and legs.¹⁵ Nodular BCC is the most common subtype and typically manifests as a shiny pearly papule or nodule with a smooth surface, rolled borders, and arborizing telangiectasias.¹⁶ On histopathology, nodular BCCs demonstrate nests or nodules of basaloid keratinocytes with peripheral palisading and retraction artifact between the tumor and stroma (eFigure 3).^15,16 A lack of retraction artifact, cystic dilation of tubular structures, jigsaw molding of nests, and a distinct 2-cell population distinguish spiradenocylindroma from BCC. Of note, in rare instances BCCs also may display a thick fibrous stroma, similar to the stroma of cylindromas.¹⁵ 

Amelanotic melanoma is a variant of melanoma characterized by little to no pigment. Any of the 4 classic subtypes of melanoma (nodular, superficial spreading, lentigo maligna, acral lentiginous) can be amelanotic.¹⁷ Clinically, amelanotic melanomas can vary greatly, manifesting as erythematous macules, dermal plaques, or papulonodular lesions, often with scaling.¹⁸ On histopathology, findings common to all melanomas include cellular atypia, mitoses, pagetoid spread, and pleomorphism (eFigure 4).^18,19 Immunohistochemistry is an important method to distinguish melanoma from other melanocytic proliferations and to aid in the assessment of Breslow depth. Markers include SOX10 (sex-determining region Y-box transcription factor 10), S100, and MART-1 (melanoma antigen recognized by T cells 1/melan-A).^19,20 Expression of PRAME (preferentially expressed antigen in melanoma) often is positive but is not necessary for diagnosis.²¹ Histologically, the atypical pleomorphic cells of melanoma are markedly distinct from both spiradenomas and cylindromas.

To the Editor:

In dermatology, rupioid describes ­dirty-appearing scale. The term is derived from the Greek word rhupos, which translates to “dirty” or “filthy.” This type of scale also is called ostraceous, owing to its resemblance to an oyster shell. Histopathologically, rupioid or ostraceous scale corresponds to epidermal hyperplasia and hyperkeratosis. Therefore, the presence of rupioid scale is believed to reflect an exuberant inflammatory response. Several dermatologic conditions have been associated with rupioid scale, including psoriasis, secondary syphilis, reactive arthritis, histoplasmosis, and Norwegian scabies.^1-4 Peripheral eosinophilia has been reported in eczematous dermatoses such as atopic dermatitis and contact dermatitis,^5,6 but our review of the literature did not find it described in the context of id reactions. We report the case of a patient who developed a rupioid id reaction with peripheral eosinophilia.

An otherwise healthy 40-year-old woman presented with a generalized pruritic eruption of 1 month’s duration. Prior to onset, she was bitten by a bug on the left arm and covered the site with a bandage. She subsequently noticed an erythematous papulopustular rash corresponding to the shape of the bandage adhesive. Shortly thereafter, a generalized eruption developed, prompting the patient to present for evaluation 1 month later. A review of systems was negative for fevers, chills, headaches, vision changes, and joint symptoms. She denied having a history of atopy.

Physical examination revealed numerous pink papules and plaques with rupioid scale scattered over the trunk and extremities (Figure). The palms, soles, and mucous membranes were spared. Laboratory studies revealed peripheral eosinophilia (9% eosinophils [reference range, 1%-6%] and an absolute eosinophil count of 600/µL [reference range, 0-400/µL]). A 3-mm punch biopsy of a representative lesion revealed a superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils along with epidermal hyperplasia, spongiosis, and mounds of parakeratosis. Clinicopathologic correlation led to the diagnosis of a rupioid id reaction secondary to an arthropod assault and/or a reaction to the bandage adhesive.

Treatment with topical corticosteroids was avoided at the patient’s request. Instead, a ceramide-based emollient and oral antihistamines (fexofenadine 180 mg in the morning and cetirizine 10 mg in the evening) were recommended and resulted in resolution of the eruption with postinflammatory hyperpigmentation at 2-week follow-up. The patient was advised to avoid further exposure to bandage adhesives.

An id reaction, or autoeczematization, is a cutaneous immunologic response to antigen(s) released from an initial, often distant site of inflammation.^7,8 Clinically, it typically manifests as a pruritic, symmetrically distributed papulovesicular eruption. Although the pathogenesis of id reactions is uncertain, overactivation of T lymphocytes responding to the initial inflammatory insult has been implicated.⁷ A variety of noninfectious (eg, stasis dermatitis, contact dermatitis) and infectious dermatoses (eg, fungal, bacterial, viral, parasitic) may trigger id reactions.^7,9-13 In this case, we believe an arthropod assault and/or reaction to the bandage adhesive was the primary insult, and the id reaction that ensued was so exuberant that it resulted not only in rupioid scale but also in peripheral eosinophilia—similar to how more severe forms of atopic dermatitis have been associated with peripheral eosinophilia.⁵ As such presentations of id reactions not have been widely described in the literature, this report expands our understanding of this condition to include rupioid scale and peripheral eosinophilia.

To the Editor:

In dermatology, rupioid describes ­dirty-appearing scale. The term is derived from the Greek word rhupos, which translates to “dirty” or “filthy.” This type of scale also is called ostraceous, owing to its resemblance to an oyster shell. Histopathologically, rupioid or ostraceous scale corresponds to epidermal hyperplasia and hyperkeratosis. Therefore, the presence of rupioid scale is believed to reflect an exuberant inflammatory response. Several dermatologic conditions have been associated with rupioid scale, including psoriasis, secondary syphilis, reactive arthritis, histoplasmosis, and Norwegian scabies.^1-4 Peripheral eosinophilia has been reported in eczematous dermatoses such as atopic dermatitis and contact dermatitis,^5,6 but our review of the literature did not find it described in the context of id reactions. We report the case of a patient who developed a rupioid id reaction with peripheral eosinophilia.

An otherwise healthy 40-year-old woman presented with a generalized pruritic eruption of 1 month’s duration. Prior to onset, she was bitten by a bug on the left arm and covered the site with a bandage. She subsequently noticed an erythematous papulopustular rash corresponding to the shape of the bandage adhesive. Shortly thereafter, a generalized eruption developed, prompting the patient to present for evaluation 1 month later. A review of systems was negative for fevers, chills, headaches, vision changes, and joint symptoms. She denied having a history of atopy.

Physical examination revealed numerous pink papules and plaques with rupioid scale scattered over the trunk and extremities (Figure). The palms, soles, and mucous membranes were spared. Laboratory studies revealed peripheral eosinophilia (9% eosinophils [reference range, 1%-6%] and an absolute eosinophil count of 600/µL [reference range, 0-400/µL]). A 3-mm punch biopsy of a representative lesion revealed a superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils along with epidermal hyperplasia, spongiosis, and mounds of parakeratosis. Clinicopathologic correlation led to the diagnosis of a rupioid id reaction secondary to an arthropod assault and/or a reaction to the bandage adhesive.

Treatment with topical corticosteroids was avoided at the patient’s request. Instead, a ceramide-based emollient and oral antihistamines (fexofenadine 180 mg in the morning and cetirizine 10 mg in the evening) were recommended and resulted in resolution of the eruption with postinflammatory hyperpigmentation at 2-week follow-up. The patient was advised to avoid further exposure to bandage adhesives.

An id reaction, or autoeczematization, is a cutaneous immunologic response to antigen(s) released from an initial, often distant site of inflammation.^7,8 Clinically, it typically manifests as a pruritic, symmetrically distributed papulovesicular eruption. Although the pathogenesis of id reactions is uncertain, overactivation of T lymphocytes responding to the initial inflammatory insult has been implicated.⁷ A variety of noninfectious (eg, stasis dermatitis, contact dermatitis) and infectious dermatoses (eg, fungal, bacterial, viral, parasitic) may trigger id reactions.^7,9-13 In this case, we believe an arthropod assault and/or reaction to the bandage adhesive was the primary insult, and the id reaction that ensued was so exuberant that it resulted not only in rupioid scale but also in peripheral eosinophilia—similar to how more severe forms of atopic dermatitis have been associated with peripheral eosinophilia.⁵ As such presentations of id reactions not have been widely described in the literature, this report expands our understanding of this condition to include rupioid scale and peripheral eosinophilia.

To the Editor:

In dermatology, rupioid describes ­dirty-appearing scale. The term is derived from the Greek word rhupos, which translates to “dirty” or “filthy.” This type of scale also is called ostraceous, owing to its resemblance to an oyster shell. Histopathologically, rupioid or ostraceous scale corresponds to epidermal hyperplasia and hyperkeratosis. Therefore, the presence of rupioid scale is believed to reflect an exuberant inflammatory response. Several dermatologic conditions have been associated with rupioid scale, including psoriasis, secondary syphilis, reactive arthritis, histoplasmosis, and Norwegian scabies.^1-4 Peripheral eosinophilia has been reported in eczematous dermatoses such as atopic dermatitis and contact dermatitis,^5,6 but our review of the literature did not find it described in the context of id reactions. We report the case of a patient who developed a rupioid id reaction with peripheral eosinophilia.

An otherwise healthy 40-year-old woman presented with a generalized pruritic eruption of 1 month’s duration. Prior to onset, she was bitten by a bug on the left arm and covered the site with a bandage. She subsequently noticed an erythematous papulopustular rash corresponding to the shape of the bandage adhesive. Shortly thereafter, a generalized eruption developed, prompting the patient to present for evaluation 1 month later. A review of systems was negative for fevers, chills, headaches, vision changes, and joint symptoms. She denied having a history of atopy.

Physical examination revealed numerous pink papules and plaques with rupioid scale scattered over the trunk and extremities (Figure). The palms, soles, and mucous membranes were spared. Laboratory studies revealed peripheral eosinophilia (9% eosinophils [reference range, 1%-6%] and an absolute eosinophil count of 600/µL [reference range, 0-400/µL]). A 3-mm punch biopsy of a representative lesion revealed a superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils along with epidermal hyperplasia, spongiosis, and mounds of parakeratosis. Clinicopathologic correlation led to the diagnosis of a rupioid id reaction secondary to an arthropod assault and/or a reaction to the bandage adhesive.

Treatment with topical corticosteroids was avoided at the patient’s request. Instead, a ceramide-based emollient and oral antihistamines (fexofenadine 180 mg in the morning and cetirizine 10 mg in the evening) were recommended and resulted in resolution of the eruption with postinflammatory hyperpigmentation at 2-week follow-up. The patient was advised to avoid further exposure to bandage adhesives.

An id reaction, or autoeczematization, is a cutaneous immunologic response to antigen(s) released from an initial, often distant site of inflammation.^7,8 Clinically, it typically manifests as a pruritic, symmetrically distributed papulovesicular eruption. Although the pathogenesis of id reactions is uncertain, overactivation of T lymphocytes responding to the initial inflammatory insult has been implicated.⁷ A variety of noninfectious (eg, stasis dermatitis, contact dermatitis) and infectious dermatoses (eg, fungal, bacterial, viral, parasitic) may trigger id reactions.^7,9-13 In this case, we believe an arthropod assault and/or reaction to the bandage adhesive was the primary insult, and the id reaction that ensued was so exuberant that it resulted not only in rupioid scale but also in peripheral eosinophilia—similar to how more severe forms of atopic dermatitis have been associated with peripheral eosinophilia.⁵ As such presentations of id reactions not have been widely described in the literature, this report expands our understanding of this condition to include rupioid scale and peripheral eosinophilia.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

What clinical signs suggest antimicrobial resistance is affecting acne treatment response, and how can dermatologists identify them early? 

DR. ROSAMILIA: Antibiotic resistance is a difficult phenomenon to define clinically for acne due to many pathogenic contributors, namely the increase in sebum production stoked by hormonal changes, which further provokes Cutibacterium acnes biofilms, follicular plugs, and various inflammatory cascades. The sequence and primacy of these steps are enigmatic in each patient, therefore the role and extent of true antimicrobial therapy are debatable. Acne is more complex than other conditions that utilize antimicrobials, such as tinea corporis. In acne, lack of treatment response may be due to various factors, including long-term adherence challenges (such as inconsistent home dosing and trending complex over-the-counter [OTC] regimens), hormonal fluctuation, and confounders such as gram-negative or pityrosporum folliculitis. Therefore, determining if resistant bacteria are “causal” in acne recalcitrance or exacerbation is vague. In older patients (or younger patients with chronic conditions), proof of bacterial resistance from wound, pulmonary, or gastrointestinal studies might be available, but a typical acne patient would not present with these data. 

Do you routinely rotate patients off oral antibiotics after a fixed treatment period, or is it symptom based? How do you balance the risk for disease recurrence with resistance concerns? 

DR. ROSAMILIA: For my patients, the typical “triple threat” for moderate acne—oral antibiotics, topical benzoyl peroxide, and topical retinoids—still is tried and true. I typically prescribe 6 weeks of low-dose antibiotic therapy (doxycycline 50 mg daily) and arrange a telemedicine visit at 4 to 6 weeks to assess progress and adherence. Subsequently, I might substitute topical for oral antibiotics, with long-term plans to discontinue all antibiotics. In females, I might add spironolactone and/or oral contraceptive pills, and for recalcitrant or progressive acne, I would discuss isotretinoin. If the patient’s acne is under good control without antibiotics but they still experience intermittent deeper papules, I consider adding burst therapy of low-dose doxycycline for 1 week as needed, or for instance, during sports seasons. I try to maintain the lowest possible dosage of doxycycline while toeing the line between short-term antibacterial and longer-term anti-inflammatory control. In fact, I typically recommend that patients take it with their morning meal to absorb slightly less than the full 50-mg dosage, mitigate adverse effects, and increase adherence. All of these regimens include a benzoyl peroxide wash for its many anti-acne properties and in the context of this discussion to mitigate C acnes on acne-prone skin without creating antibiotic resistance. 

Do you see a future for point-of-care microbiome or resistance testing in acne management? 

DR. ROSAMILIA: I think we should be receptive to the evolution of these tests, and depending on the patient’s insurance coverage, efficient collection methods, and applicability to all patients, we someday may approach antimicrobial pharmacotherapy in a more personalized way. The microbiome is a broad topic with protean approaches to testing and prebiotic/probiotic supplementation, so openminded but cautious and well-studied utilization is key. 

What language do you find effective when setting expectations for acne treatment that avoids overreliance on antibiotics? 

DR. ROSAMILIA: I find it important to first determine the patient’s prior therapies. Many patients with acne present to dermatology after taking a full dosage of various antibiotics for broad amounts of time, and they may have experienced acne exacerbation (or at least perception of such) when the refills ran out. Also, I ask them to outline their past and current OTC regimens, which provides context for where and how the patient gets their information and advice. I like providing the patient’s next steps in written form, even telling them to tape the instructions to their bathroom mirror. It is just as vital to take time at the first office visit to explain the expected time to improvement and why acne is a multifactorial condition for which antibiotics are only part of the approach with benzoyl peroxide and retinoids. 

What are your top practical tips for incoming dermatologists to practice antibiotic stewardship in acne management? 

DR. ROSAMILIA: The American Academy of Dermatology (AAD) guidelines recommend 3 to 4 months as the maximum threshold for systemic antibiotics for moderate to severe acne, with tetracyclines having the best evidence for efficacy and safety. The AAD recommends never utilizing these as monotherapy and always including concomitant benzoyl peroxide to avoid bacterial resistance and topicals such as retinoids to provide a bridge to a maintenance phase without antibiotics. Starting there gives trainees structure within which to build their own acne management approach and style for their patient population. Some dermatologists might prescribe middle to high antibiotic dosages at first followed by a taper or initiate low antibiotic dosages with a standard 3- to 4-month follow-up, or a bit of a hybrid of these, as outlined in my approach. As mentioned, standardized testing for resistance to guide our dosing is not mainstream. There are countless ways to apply these guardrails, consider a place for hormonal or future isotretinoin therapy, and include the many varieties of OTC and prescription acne topicals to round out a personalized regimen for each patient based on their schedule, medication intolerances, skin type, fertility plans, and lifestyle. 

What’s the single most impactful change a busy dermatology clinic could make right now to reduce antibiotic overuse in acne care? 

DR. ROSAMILIA: I think telemedicine or in-person check-ins at the 1- or 2-month mark are vital to the assessment of the patient’s and/or family’s understanding of the treatment schedule, their ability to procure the prescription and OTC products successfully, and their consistency in using them. This is a good opportunity to remind them that our goal is to see true acne improvement; take fewer medications, not more; and create a reality where their acne regimen is intuitive and safe.

What clinical signs suggest antimicrobial resistance is affecting acne treatment response, and how can dermatologists identify them early? 

DR. ROSAMILIA: Antibiotic resistance is a difficult phenomenon to define clinically for acne due to many pathogenic contributors, namely the increase in sebum production stoked by hormonal changes, which further provokes Cutibacterium acnes biofilms, follicular plugs, and various inflammatory cascades. The sequence and primacy of these steps are enigmatic in each patient, therefore the role and extent of true antimicrobial therapy are debatable. Acne is more complex than other conditions that utilize antimicrobials, such as tinea corporis. In acne, lack of treatment response may be due to various factors, including long-term adherence challenges (such as inconsistent home dosing and trending complex over-the-counter [OTC] regimens), hormonal fluctuation, and confounders such as gram-negative or pityrosporum folliculitis. Therefore, determining if resistant bacteria are “causal” in acne recalcitrance or exacerbation is vague. In older patients (or younger patients with chronic conditions), proof of bacterial resistance from wound, pulmonary, or gastrointestinal studies might be available, but a typical acne patient would not present with these data. 

Do you routinely rotate patients off oral antibiotics after a fixed treatment period, or is it symptom based? How do you balance the risk for disease recurrence with resistance concerns? 

DR. ROSAMILIA: For my patients, the typical “triple threat” for moderate acne—oral antibiotics, topical benzoyl peroxide, and topical retinoids—still is tried and true. I typically prescribe 6 weeks of low-dose antibiotic therapy (doxycycline 50 mg daily) and arrange a telemedicine visit at 4 to 6 weeks to assess progress and adherence. Subsequently, I might substitute topical for oral antibiotics, with long-term plans to discontinue all antibiotics. In females, I might add spironolactone and/or oral contraceptive pills, and for recalcitrant or progressive acne, I would discuss isotretinoin. If the patient’s acne is under good control without antibiotics but they still experience intermittent deeper papules, I consider adding burst therapy of low-dose doxycycline for 1 week as needed, or for instance, during sports seasons. I try to maintain the lowest possible dosage of doxycycline while toeing the line between short-term antibacterial and longer-term anti-inflammatory control. In fact, I typically recommend that patients take it with their morning meal to absorb slightly less than the full 50-mg dosage, mitigate adverse effects, and increase adherence. All of these regimens include a benzoyl peroxide wash for its many anti-acne properties and in the context of this discussion to mitigate C acnes on acne-prone skin without creating antibiotic resistance. 

Do you see a future for point-of-care microbiome or resistance testing in acne management? 

DR. ROSAMILIA: I think we should be receptive to the evolution of these tests, and depending on the patient’s insurance coverage, efficient collection methods, and applicability to all patients, we someday may approach antimicrobial pharmacotherapy in a more personalized way. The microbiome is a broad topic with protean approaches to testing and prebiotic/probiotic supplementation, so openminded but cautious and well-studied utilization is key. 

What language do you find effective when setting expectations for acne treatment that avoids overreliance on antibiotics? 

DR. ROSAMILIA: I find it important to first determine the patient’s prior therapies. Many patients with acne present to dermatology after taking a full dosage of various antibiotics for broad amounts of time, and they may have experienced acne exacerbation (or at least perception of such) when the refills ran out. Also, I ask them to outline their past and current OTC regimens, which provides context for where and how the patient gets their information and advice. I like providing the patient’s next steps in written form, even telling them to tape the instructions to their bathroom mirror. It is just as vital to take time at the first office visit to explain the expected time to improvement and why acne is a multifactorial condition for which antibiotics are only part of the approach with benzoyl peroxide and retinoids. 

What are your top practical tips for incoming dermatologists to practice antibiotic stewardship in acne management? 

DR. ROSAMILIA: The American Academy of Dermatology (AAD) guidelines recommend 3 to 4 months as the maximum threshold for systemic antibiotics for moderate to severe acne, with tetracyclines having the best evidence for efficacy and safety. The AAD recommends never utilizing these as monotherapy and always including concomitant benzoyl peroxide to avoid bacterial resistance and topicals such as retinoids to provide a bridge to a maintenance phase without antibiotics. Starting there gives trainees structure within which to build their own acne management approach and style for their patient population. Some dermatologists might prescribe middle to high antibiotic dosages at first followed by a taper or initiate low antibiotic dosages with a standard 3- to 4-month follow-up, or a bit of a hybrid of these, as outlined in my approach. As mentioned, standardized testing for resistance to guide our dosing is not mainstream. There are countless ways to apply these guardrails, consider a place for hormonal or future isotretinoin therapy, and include the many varieties of OTC and prescription acne topicals to round out a personalized regimen for each patient based on their schedule, medication intolerances, skin type, fertility plans, and lifestyle. 

What’s the single most impactful change a busy dermatology clinic could make right now to reduce antibiotic overuse in acne care? 

DR. ROSAMILIA: I think telemedicine or in-person check-ins at the 1- or 2-month mark are vital to the assessment of the patient’s and/or family’s understanding of the treatment schedule, their ability to procure the prescription and OTC products successfully, and their consistency in using them. This is a good opportunity to remind them that our goal is to see true acne improvement; take fewer medications, not more; and create a reality where their acne regimen is intuitive and safe.

What clinical signs suggest antimicrobial resistance is affecting acne treatment response, and how can dermatologists identify them early? 

DR. ROSAMILIA: Antibiotic resistance is a difficult phenomenon to define clinically for acne due to many pathogenic contributors, namely the increase in sebum production stoked by hormonal changes, which further provokes Cutibacterium acnes biofilms, follicular plugs, and various inflammatory cascades. The sequence and primacy of these steps are enigmatic in each patient, therefore the role and extent of true antimicrobial therapy are debatable. Acne is more complex than other conditions that utilize antimicrobials, such as tinea corporis. In acne, lack of treatment response may be due to various factors, including long-term adherence challenges (such as inconsistent home dosing and trending complex over-the-counter [OTC] regimens), hormonal fluctuation, and confounders such as gram-negative or pityrosporum folliculitis. Therefore, determining if resistant bacteria are “causal” in acne recalcitrance or exacerbation is vague. In older patients (or younger patients with chronic conditions), proof of bacterial resistance from wound, pulmonary, or gastrointestinal studies might be available, but a typical acne patient would not present with these data. 

Do you routinely rotate patients off oral antibiotics after a fixed treatment period, or is it symptom based? How do you balance the risk for disease recurrence with resistance concerns? 

DR. ROSAMILIA: For my patients, the typical “triple threat” for moderate acne—oral antibiotics, topical benzoyl peroxide, and topical retinoids—still is tried and true. I typically prescribe 6 weeks of low-dose antibiotic therapy (doxycycline 50 mg daily) and arrange a telemedicine visit at 4 to 6 weeks to assess progress and adherence. Subsequently, I might substitute topical for oral antibiotics, with long-term plans to discontinue all antibiotics. In females, I might add spironolactone and/or oral contraceptive pills, and for recalcitrant or progressive acne, I would discuss isotretinoin. If the patient’s acne is under good control without antibiotics but they still experience intermittent deeper papules, I consider adding burst therapy of low-dose doxycycline for 1 week as needed, or for instance, during sports seasons. I try to maintain the lowest possible dosage of doxycycline while toeing the line between short-term antibacterial and longer-term anti-inflammatory control. In fact, I typically recommend that patients take it with their morning meal to absorb slightly less than the full 50-mg dosage, mitigate adverse effects, and increase adherence. All of these regimens include a benzoyl peroxide wash for its many anti-acne properties and in the context of this discussion to mitigate C acnes on acne-prone skin without creating antibiotic resistance. 

Do you see a future for point-of-care microbiome or resistance testing in acne management? 

DR. ROSAMILIA: I think we should be receptive to the evolution of these tests, and depending on the patient’s insurance coverage, efficient collection methods, and applicability to all patients, we someday may approach antimicrobial pharmacotherapy in a more personalized way. The microbiome is a broad topic with protean approaches to testing and prebiotic/probiotic supplementation, so openminded but cautious and well-studied utilization is key. 

What language do you find effective when setting expectations for acne treatment that avoids overreliance on antibiotics? 

DR. ROSAMILIA: I find it important to first determine the patient’s prior therapies. Many patients with acne present to dermatology after taking a full dosage of various antibiotics for broad amounts of time, and they may have experienced acne exacerbation (or at least perception of such) when the refills ran out. Also, I ask them to outline their past and current OTC regimens, which provides context for where and how the patient gets their information and advice. I like providing the patient’s next steps in written form, even telling them to tape the instructions to their bathroom mirror. It is just as vital to take time at the first office visit to explain the expected time to improvement and why acne is a multifactorial condition for which antibiotics are only part of the approach with benzoyl peroxide and retinoids. 

What are your top practical tips for incoming dermatologists to practice antibiotic stewardship in acne management? 

DR. ROSAMILIA: The American Academy of Dermatology (AAD) guidelines recommend 3 to 4 months as the maximum threshold for systemic antibiotics for moderate to severe acne, with tetracyclines having the best evidence for efficacy and safety. The AAD recommends never utilizing these as monotherapy and always including concomitant benzoyl peroxide to avoid bacterial resistance and topicals such as retinoids to provide a bridge to a maintenance phase without antibiotics. Starting there gives trainees structure within which to build their own acne management approach and style for their patient population. Some dermatologists might prescribe middle to high antibiotic dosages at first followed by a taper or initiate low antibiotic dosages with a standard 3- to 4-month follow-up, or a bit of a hybrid of these, as outlined in my approach. As mentioned, standardized testing for resistance to guide our dosing is not mainstream. There are countless ways to apply these guardrails, consider a place for hormonal or future isotretinoin therapy, and include the many varieties of OTC and prescription acne topicals to round out a personalized regimen for each patient based on their schedule, medication intolerances, skin type, fertility plans, and lifestyle. 

What’s the single most impactful change a busy dermatology clinic could make right now to reduce antibiotic overuse in acne care? 

DR. ROSAMILIA: I think telemedicine or in-person check-ins at the 1- or 2-month mark are vital to the assessment of the patient’s and/or family’s understanding of the treatment schedule, their ability to procure the prescription and OTC products successfully, and their consistency in using them. This is a good opportunity to remind them that our goal is to see true acne improvement; take fewer medications, not more; and create a reality where their acne regimen is intuitive and safe.