Cutis

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

On November 2, 2021, the Centers for Medicare & Medicaid Services (CMS) released its final rule for the 2022 Medicare Physician Fee Schedule (PFS) and the Quality Payment Program (QPP).^1,2 These guidelines contain updates that will remarkably impact the field of medicine—and dermatology in particular—in 2022. This article will walk you through some of the updates most relevant to dermatology and how they may affect your practice.

Process for the Final Rule

The CMS releases an annual rule for the PFS and QPP. The interim rule generally is released over the summer with preliminary guidelines for the upcoming payment year. There is then a period of open comment where those affected by these changes, including physicians and medical associations, can submit comments to support what has been proposed or advocate for any changes. This input is then reviewed, and a final rule generally is published in the fall.

For this calendar year, the interim 2022 rule was released on July 13, 2021,³ and included many of guidelines that will be discussed in more detail in this article. Many associations that represent medicine overall and specifically dermatology, including the American Medical Association and the American Academy of Dermatology, submitted comments in response to these proposals.^4,5

PFS Conversion Factor

The PFS conversion factor is updated annually to ensure budget neutrality in the setting of changes in relative value units. For 2022, the PFS conversion factor is $34.6062, representing a reduction of approximately $0.29 from the 2021 PFS conversion factor of $34.8931.⁶ This reduction does not take into account other payment adjustments due to legislative changes.

In combination, these changes previously were estimated to represent an overall payment cut of 10% or higher for dermatology, with those practitioners doing more procedural work or dermatopathology likely being impacted more heavily. However, with the passing of the Protecting Medicare and American Farmers from Sequester Cuts Act, it is estimated that the reductions in payment to dermatology will begin at 0.75% and reach 2.75% in the second half of the year with the phased-in reinstatement of the Medicare sequester.^4,5,7

Clinical Labor Pricing Updates

Starting in 2022, the CMS will utilize updated wage rates from the US Bureau of Labor Statistics to revise clinical labor costs over a 4-year period. Clinical labor rates are important, as they are used to calculate practice expense within the PFS. These clinical labor rates were last updated in 2002.⁸ Median wage data, as opposed to mean data, from the US Bureau of Labor Statistics will be utilized to calculate the updated clinical labor rates.

A multiyear implementation plan was put into place by CMS due to multiple concerns, including that current wage rates are inadequate and may not reflect current labor rate information. Additionally, comments on this proposal voiced concern that updating the supply and equipment pricing without updating the clinical labor pricing could create distortions in the allocation of direct practice expense, which also factored into the implementation of a multiyear plan.⁸

Evaluation and Management Visits

The biggest update in this area primarily is related to refining policies for split (shared) evaluation and management (E/M) visits and teaching physician activities. Split E/M visits are defined by the CMS as visits provided in the facility setting by a physician and nonphysician practitioner in the same group, with the visit billed by whomever provides the substantive portion of the visit. For 2022, the term substantive portion will be defined by the CMS as history, physical examination, medical decision-making, or more than half of the total time; for 2023, it will be defined as more than half of the total time spent.³ A split visit also can apply to an E/M visit provided in part by both a teaching physician and resident. Split visits can be reported for new or established patients. For proper reimbursement, the 2 practitioners who performed the services must be documented in the medical record, and the practitioner who provided the substantive portion must sign and date the encounter in the medical record. Additionally, the CMS has indicated the modifier FS must be included on the claim to indicate the split visit.⁹

For dermatologists who act as teaching physicians, it is important to note that many of the existing CMS policies for billing E/M services are still in place, specifically that if a resident participates in a service in a teaching setting, the teaching physician can bill for the service only if they are present for the key or critical portion of the service. A primary care exception does exist, in which teaching physicians at certain teaching hospital primary care centers can bill for some services performed independently by a resident without the physical presence of the teaching physician; however, this often is not applicable within dermatology.

With updated outpatient E/M guidelines, if time is being selected to bill, only the time that the teaching physician was present can be included to determine the overall E/M level.

Billing for Physician Assistant Services

Currently Medicare can only make payments to the employer or independent contractor of a physician assistant (PA); however, starting January 1, 2022, the CMS has authorized Medicare to make direct payments to PAs for qualifying professional services, in the same manner that nurse practitioners can currently bill. This also will allow PAs to incorporate as a group and bill Medicare for PA services. This stems from a congressional mandate within the Consolidated Appropriations Act of 2021.⁸ As a result, in states where PAs can practice independently, they can opt out of physician-led care teams and furnish services independently, including dermatologic services.

Several changes were made to the Merit-Based Incentive Payment System (MIPS). Some of these changes include:

• Increase the MIPS performance threshold to 75 points from 60 points.
• Set the performance threshold at 89 points.
• Reduce the quality performance category weight from 40% to 30% of the final MIPS score.
• Increase the cost performance category weight from 20% to 30% of the final MIPS score.
• The extreme and uncontrollable circumstances application also has been extended to the end of 2022, allowing those remarkably impacted by the COVID-19 public health emergency to request for reweighting on any or all MIPS performance categories.

Cost Measures and MIPS Value Pathways

The melanoma resection cost measure will be implemented in 2022, representing the first dermatology cost measure, which will include the cost to Medicare over a 1-year period for all patient care for the excision of a melanoma. Although cost measures will be part of the MIPS value pathways (MVPs) reporting, dermatology currently is not part of the MVP; however, with the CMS moving forward with an initial set of MVPs that physicians can voluntarily report on in 2023, there is a possibility that dermatology will be asked to be part of the program in the future.¹⁰

Final Thoughts

There are many upcoming changes as part of the 2022 final rule, including to the conversion factor, E/M split visits, PA billing, and the QPP. Advocacy in these areas to the CMS and lawmakers, either directly or through dermatologic and other medical societies, is critical to help influence eventual recommendations.

On November 2, 2021, the Centers for Medicare & Medicaid Services (CMS) released its final rule for the 2022 Medicare Physician Fee Schedule (PFS) and the Quality Payment Program (QPP).^1,2 These guidelines contain updates that will remarkably impact the field of medicine—and dermatology in particular—in 2022. This article will walk you through some of the updates most relevant to dermatology and how they may affect your practice.

Process for the Final Rule

The CMS releases an annual rule for the PFS and QPP. The interim rule generally is released over the summer with preliminary guidelines for the upcoming payment year. There is then a period of open comment where those affected by these changes, including physicians and medical associations, can submit comments to support what has been proposed or advocate for any changes. This input is then reviewed, and a final rule generally is published in the fall.

For this calendar year, the interim 2022 rule was released on July 13, 2021,³ and included many of guidelines that will be discussed in more detail in this article. Many associations that represent medicine overall and specifically dermatology, including the American Medical Association and the American Academy of Dermatology, submitted comments in response to these proposals.^4,5

PFS Conversion Factor

The PFS conversion factor is updated annually to ensure budget neutrality in the setting of changes in relative value units. For 2022, the PFS conversion factor is $34.6062, representing a reduction of approximately $0.29 from the 2021 PFS conversion factor of $34.8931.⁶ This reduction does not take into account other payment adjustments due to legislative changes.

In combination, these changes previously were estimated to represent an overall payment cut of 10% or higher for dermatology, with those practitioners doing more procedural work or dermatopathology likely being impacted more heavily. However, with the passing of the Protecting Medicare and American Farmers from Sequester Cuts Act, it is estimated that the reductions in payment to dermatology will begin at 0.75% and reach 2.75% in the second half of the year with the phased-in reinstatement of the Medicare sequester.^4,5,7

Clinical Labor Pricing Updates

Starting in 2022, the CMS will utilize updated wage rates from the US Bureau of Labor Statistics to revise clinical labor costs over a 4-year period. Clinical labor rates are important, as they are used to calculate practice expense within the PFS. These clinical labor rates were last updated in 2002.⁸ Median wage data, as opposed to mean data, from the US Bureau of Labor Statistics will be utilized to calculate the updated clinical labor rates.

A multiyear implementation plan was put into place by CMS due to multiple concerns, including that current wage rates are inadequate and may not reflect current labor rate information. Additionally, comments on this proposal voiced concern that updating the supply and equipment pricing without updating the clinical labor pricing could create distortions in the allocation of direct practice expense, which also factored into the implementation of a multiyear plan.⁸

Evaluation and Management Visits

The biggest update in this area primarily is related to refining policies for split (shared) evaluation and management (E/M) visits and teaching physician activities. Split E/M visits are defined by the CMS as visits provided in the facility setting by a physician and nonphysician practitioner in the same group, with the visit billed by whomever provides the substantive portion of the visit. For 2022, the term substantive portion will be defined by the CMS as history, physical examination, medical decision-making, or more than half of the total time; for 2023, it will be defined as more than half of the total time spent.³ A split visit also can apply to an E/M visit provided in part by both a teaching physician and resident. Split visits can be reported for new or established patients. For proper reimbursement, the 2 practitioners who performed the services must be documented in the medical record, and the practitioner who provided the substantive portion must sign and date the encounter in the medical record. Additionally, the CMS has indicated the modifier FS must be included on the claim to indicate the split visit.⁹

For dermatologists who act as teaching physicians, it is important to note that many of the existing CMS policies for billing E/M services are still in place, specifically that if a resident participates in a service in a teaching setting, the teaching physician can bill for the service only if they are present for the key or critical portion of the service. A primary care exception does exist, in which teaching physicians at certain teaching hospital primary care centers can bill for some services performed independently by a resident without the physical presence of the teaching physician; however, this often is not applicable within dermatology.

With updated outpatient E/M guidelines, if time is being selected to bill, only the time that the teaching physician was present can be included to determine the overall E/M level.

Billing for Physician Assistant Services

Currently Medicare can only make payments to the employer or independent contractor of a physician assistant (PA); however, starting January 1, 2022, the CMS has authorized Medicare to make direct payments to PAs for qualifying professional services, in the same manner that nurse practitioners can currently bill. This also will allow PAs to incorporate as a group and bill Medicare for PA services. This stems from a congressional mandate within the Consolidated Appropriations Act of 2021.⁸ As a result, in states where PAs can practice independently, they can opt out of physician-led care teams and furnish services independently, including dermatologic services.

Several changes were made to the Merit-Based Incentive Payment System (MIPS). Some of these changes include:

• Increase the MIPS performance threshold to 75 points from 60 points.
• Set the performance threshold at 89 points.
• Reduce the quality performance category weight from 40% to 30% of the final MIPS score.
• Increase the cost performance category weight from 20% to 30% of the final MIPS score.
• The extreme and uncontrollable circumstances application also has been extended to the end of 2022, allowing those remarkably impacted by the COVID-19 public health emergency to request for reweighting on any or all MIPS performance categories.

Cost Measures and MIPS Value Pathways

The melanoma resection cost measure will be implemented in 2022, representing the first dermatology cost measure, which will include the cost to Medicare over a 1-year period for all patient care for the excision of a melanoma. Although cost measures will be part of the MIPS value pathways (MVPs) reporting, dermatology currently is not part of the MVP; however, with the CMS moving forward with an initial set of MVPs that physicians can voluntarily report on in 2023, there is a possibility that dermatology will be asked to be part of the program in the future.¹⁰

Final Thoughts

There are many upcoming changes as part of the 2022 final rule, including to the conversion factor, E/M split visits, PA billing, and the QPP. Advocacy in these areas to the CMS and lawmakers, either directly or through dermatologic and other medical societies, is critical to help influence eventual recommendations.

On November 2, 2021, the Centers for Medicare & Medicaid Services (CMS) released its final rule for the 2022 Medicare Physician Fee Schedule (PFS) and the Quality Payment Program (QPP).^1,2 These guidelines contain updates that will remarkably impact the field of medicine—and dermatology in particular—in 2022. This article will walk you through some of the updates most relevant to dermatology and how they may affect your practice.

Process for the Final Rule

The CMS releases an annual rule for the PFS and QPP. The interim rule generally is released over the summer with preliminary guidelines for the upcoming payment year. There is then a period of open comment where those affected by these changes, including physicians and medical associations, can submit comments to support what has been proposed or advocate for any changes. This input is then reviewed, and a final rule generally is published in the fall.

For this calendar year, the interim 2022 rule was released on July 13, 2021,³ and included many of guidelines that will be discussed in more detail in this article. Many associations that represent medicine overall and specifically dermatology, including the American Medical Association and the American Academy of Dermatology, submitted comments in response to these proposals.^4,5

PFS Conversion Factor

The PFS conversion factor is updated annually to ensure budget neutrality in the setting of changes in relative value units. For 2022, the PFS conversion factor is $34.6062, representing a reduction of approximately $0.29 from the 2021 PFS conversion factor of $34.8931.⁶ This reduction does not take into account other payment adjustments due to legislative changes.

In combination, these changes previously were estimated to represent an overall payment cut of 10% or higher for dermatology, with those practitioners doing more procedural work or dermatopathology likely being impacted more heavily. However, with the passing of the Protecting Medicare and American Farmers from Sequester Cuts Act, it is estimated that the reductions in payment to dermatology will begin at 0.75% and reach 2.75% in the second half of the year with the phased-in reinstatement of the Medicare sequester.^4,5,7

Clinical Labor Pricing Updates

Starting in 2022, the CMS will utilize updated wage rates from the US Bureau of Labor Statistics to revise clinical labor costs over a 4-year period. Clinical labor rates are important, as they are used to calculate practice expense within the PFS. These clinical labor rates were last updated in 2002.⁸ Median wage data, as opposed to mean data, from the US Bureau of Labor Statistics will be utilized to calculate the updated clinical labor rates.

A multiyear implementation plan was put into place by CMS due to multiple concerns, including that current wage rates are inadequate and may not reflect current labor rate information. Additionally, comments on this proposal voiced concern that updating the supply and equipment pricing without updating the clinical labor pricing could create distortions in the allocation of direct practice expense, which also factored into the implementation of a multiyear plan.⁸

Evaluation and Management Visits

The biggest update in this area primarily is related to refining policies for split (shared) evaluation and management (E/M) visits and teaching physician activities. Split E/M visits are defined by the CMS as visits provided in the facility setting by a physician and nonphysician practitioner in the same group, with the visit billed by whomever provides the substantive portion of the visit. For 2022, the term substantive portion will be defined by the CMS as history, physical examination, medical decision-making, or more than half of the total time; for 2023, it will be defined as more than half of the total time spent.³ A split visit also can apply to an E/M visit provided in part by both a teaching physician and resident. Split visits can be reported for new or established patients. For proper reimbursement, the 2 practitioners who performed the services must be documented in the medical record, and the practitioner who provided the substantive portion must sign and date the encounter in the medical record. Additionally, the CMS has indicated the modifier FS must be included on the claim to indicate the split visit.⁹

For dermatologists who act as teaching physicians, it is important to note that many of the existing CMS policies for billing E/M services are still in place, specifically that if a resident participates in a service in a teaching setting, the teaching physician can bill for the service only if they are present for the key or critical portion of the service. A primary care exception does exist, in which teaching physicians at certain teaching hospital primary care centers can bill for some services performed independently by a resident without the physical presence of the teaching physician; however, this often is not applicable within dermatology.

With updated outpatient E/M guidelines, if time is being selected to bill, only the time that the teaching physician was present can be included to determine the overall E/M level.

Billing for Physician Assistant Services

Currently Medicare can only make payments to the employer or independent contractor of a physician assistant (PA); however, starting January 1, 2022, the CMS has authorized Medicare to make direct payments to PAs for qualifying professional services, in the same manner that nurse practitioners can currently bill. This also will allow PAs to incorporate as a group and bill Medicare for PA services. This stems from a congressional mandate within the Consolidated Appropriations Act of 2021.⁸ As a result, in states where PAs can practice independently, they can opt out of physician-led care teams and furnish services independently, including dermatologic services.

Several changes were made to the Merit-Based Incentive Payment System (MIPS). Some of these changes include:

• Increase the MIPS performance threshold to 75 points from 60 points.
• Set the performance threshold at 89 points.
• Reduce the quality performance category weight from 40% to 30% of the final MIPS score.
• Increase the cost performance category weight from 20% to 30% of the final MIPS score.
• The extreme and uncontrollable circumstances application also has been extended to the end of 2022, allowing those remarkably impacted by the COVID-19 public health emergency to request for reweighting on any or all MIPS performance categories.

Cost Measures and MIPS Value Pathways

The melanoma resection cost measure will be implemented in 2022, representing the first dermatology cost measure, which will include the cost to Medicare over a 1-year period for all patient care for the excision of a melanoma. Although cost measures will be part of the MIPS value pathways (MVPs) reporting, dermatology currently is not part of the MVP; however, with the CMS moving forward with an initial set of MVPs that physicians can voluntarily report on in 2023, there is a possibility that dermatology will be asked to be part of the program in the future.¹⁰

Final Thoughts

There are many upcoming changes as part of the 2022 final rule, including to the conversion factor, E/M split visits, PA billing, and the QPP. Advocacy in these areas to the CMS and lawmakers, either directly or through dermatologic and other medical societies, is critical to help influence eventual recommendations.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

Acne vulgaris is an extremely common dermatologic disease affecting 40 to 50 million individuals in the United States each year, with a prevalence of 85% in adolescents and young adults aged 12 to 24 years. For some patients, the disease may persist well into adulthood, affecting 8% of adults aged 25 and 34 years.¹ Acne negatively impacts patients’ quality of life and productivity, with an estimated direct and indirect cost of over $3 billion per year.²

Oral isotretinoin, a vitamin A derivative, is approved by the US Food and Drug Administration for the treatment of severe nodulocystic acne. Isotretinoin reduces the size and secretions of sebaceous glands, inhibits growth and resulting inflammation of Cutibacterium acnes, and normalizes the differentiation of follicular keratinocytes, resulting in permanent changes in the pathogenesis of acne that may lead to remission.³ The use of oral isotretinoin in the active-duty US Military population may cause service members to be nondeployable or limit their ability to function in special roles (eg, pilot, submariner).⁴ Treatment regimens that minimize the course duration of isotretinoin and reduce the risk for relapse that requires a retrial of isotretinoin may, in turn, increase a service member’s readiness, deployment availability, and ability to perform unique occupational roles.

Additionally, teledermatology has been increasingly utilized to maintain treatment continuity for patients on isotretinoin during the COVID-19 pandemic.⁵ Application of this technology in the military also may be used to facilitate timely isotretinoin treatment regimens in active-duty service members to minimize course duration and increase readiness.

In this article, we discuss an accelerated course of oral isotretinoin as a safe and effective option for military service members bound by duty restrictions and operational timelines and explore the role of teledermatology for the treatment of acne in military service members.

Isotretinoin for Acne

Isotretinoin typically is initiated at a dosage of 0.5 mg/kg daily, increasing to 1 mg/kg daily with a goal cumulative dose between 120 and 150 mg/kg. Relapse may occur after completing a treatment course and is associated with cumulative dosing less than 120 mg/kg.⁶ The average duration of acne treatment with oral isotretinoin is approximately 6 months.⁷ At therapeutic doses, nearly all patients experience side effects, most commonly dryness and desquamation of the skin and mucous membranes, as well as possible involvement of the lips, eyes, and nose. Notable extracutaneous side effects include headache, visual disturbances at night, idiopathic intracranial hypertension, and myalgia. Serum cholesterol, triglycerides, and transaminases may be increased in patients taking isotretinoin, which requires routine monitoring using serum lipid profiles and liver function studies. A potential association between isotretinoin and inflammatory bowel disease and changes in mood have been reported, but current data do not suggest an evidence-based link.^6,8 Isotretinoin is a potent teratogen, and in the United States, all patients are required to enroll in iPLEDGE, a US Food and Drug Administration–approved pregnancy prevention program that monitors prescribing and dispensing of the medication. For patients who can become pregnant, iPLEDGE requires use of 2 forms of contraception as well as monthly pregnancy tests prior to dispensing the medication.

Acne in Military Service Members

Acne is exceedingly common in the active-duty military population. In 2018, more than 40% of soldiers, sailors, airmen, and marines were 25 years or younger, and 75% of all US service members were 35 years or younger, corresponding to acne peak incidences.^1,9 Management of acne in this population requires unique treatment considerations due to distinctive occupational requirements of and hazards faced by military personnel. Use of personal protective equipment, including gas masks, safety restraints, parachute rigging, and flak jackets, may be limiting in individuals with moderate to severe acne.¹⁰ For example, severe nodulocystic acne on the chin and jawline can interfere with proper wear of the chin strap on a Kevlar helmet. The severity of acne often necessitates the use of oral isotretinoin therapy, which is considered disqualifying for many special military assignments, including submarine duty, nuclear field duty, and diving duty.¹¹ In military aviation communities, oral isotretinoin requires grounding for the duration of therapy plus 3 months after cessation. Slit-lamp examination, triglycerides, and transaminase levels must be normal prior to returning to unrestricted duty.¹² Furthermore, use of oral isotretinoin may limit overseas assignments or deployment eligibility.⁴

The high prevalence of acne and the operationally limiting consequences of isotretinoin therapy present a unique challenge for dermatologists treating military personnel. The average duration of isotretinoin treatment is approximately 6 months,⁷ which represents a considerable amount of time during an average 4-year enlistment contract. Therapeutic treatment strategies that (1) reduce the duration of oral isotretinoin therapy, (2) reduce the risk for relapse, and (3) increase medication compliance can reduce the operational impact of this acne treatment. Such treatment strategies are discussed below.

An optimal isotretinoin dosing regimen would achieve swift resolution of acne lesions and reduce the overall relapse rate requiring retrial of isotretinoin, thereby minimizing the operational- and duty-limiting impacts of the medication. Cyrulnik et al¹³ studied treatment outcomes of high-dose isotretinoin for acne vulgaris using a mean dosage of 1.6 mg/kg daily with an average cumulative dosage of 290 mg/kg. They demonstrated 100% clearance of lesions over 6 months, with a 12.5% relapse rate at 3 years. Aside from an increased rate of elevated transaminases, incidence of adverse effects and laboratory abnormalities were not significantly increased compared to conventional dosing regimens.¹³ The goal cumulative dosing of 120 to 150 mg/kg can be achieved 1 to 2 months earlier using a dosage of 1.6 mg/kg daily vs a conventional dosage of 1 mg/kg daily.

It has been hypothesized that higher cumulative doses of oral isotretinoin reduce the risk for relapse of acne and retrial of oral isotretinoin.¹⁴ Blasiak et al¹⁵ studied relapse and retrial of oral isotretinoin in acne patients who received cumulative dosing higher or lower than 220 mg/kg. A clinically but not statistically significant reduced relapse rate was observed in the cohort that received cumulative dosing higher than 220 mg/kg. No statistically significant difference in rates of adverse advents was observed aside from an increase in retinoid dermatitis in the cohort that received cumulative dosing higher than 220 mg/kg. Higher but not statistically significant rates of adverse events were seen in the group that received dosing higher than 220 mg/kg.¹⁵ Cumulative doses of oral isotretinoin higher than the 120 to 150 mg/kg range may decrease the risk for acne relapse and the need for an additional course of oral isotretinoin, which would reduce a service member’s total time away from deployment and full duty.

Relapse requiring a retrial of oral isotretinoin not only increases the operational cost of acne treatment but also considerably increases the monetary cost to the health care system. In a cost-analysis model, cumulative doses of oral isotretinoin higher than 230 mg/kg have a decreased overall cost compared to traditional cumulative dosing of less than 150 mg/kg due to the cost of relapse.¹⁶

Limitations of high daily and cumulative dosing regimens of oral isotretinoin are chiefly the dose-dependent rate of adverse effects. Low-dose regimens are associated with a reduced risk of isotretinoin-related side effects.^6,17 Acute acne flares may be seen following initial administration of oral isotretinoin and are aggravated by increases in dosage.¹⁸ Isotretinoin-induced acne fulminans is a rare but devastating complication observed with high initial doses of oral isotretinoin in patients with severe acne.¹⁹ The risks and benefits of high daily and cumulatively dosed isotretinoin must be carefully considered in patients with severe acne.

Teledermatology: A Force for Readiness

The COVID-19 pandemic drastically changed the dermatology practice landscape with recommendations to cancel all elective outpatient visits in favor of teledermatology encounters.²⁰ This decreased access to care, which resulted in an increase in drug interruption for dermatology patients, including patients on oral isotretinoin.²¹ Teledermatology has been increasingly utilized to maintain continuity of care for the management of patients taking isotretinoin.⁵ Routine utilization of teledermatology evaluation in military practices could expedite care, decrease patient travel time, and allow for in-clinic visits to be utilized for higher-acuity concerns.²²

The use of teledermatology for uncomplicated oral isotretinoin management has the potential to increase medication compliance and decrease the amount of travel time for active-duty service members; for example, consider a military dermatology practice based in San Diego, California, that accepts referrals from military bases 3 hours away by car. After an initial consultation for consideration and initiation of oral isotretinoin, teledermatology appointments can save the active-duty service member 3 hours of travel time for each follow-up visit per month. This ultimately increases operational productivity, reduces barriers to accessing care, and improves patient satisfaction.²³

Although military personnel usually are located at duty stations for 2 to 4 years, training exercises and military vocational schools often temporarily take personnel away from their home station. These temporary-duty assignments have the potential to interrupt medical follow-up appointments and may cause delays in treatment for individuals who miss monthly isotretinoin visits. When deemed appropriate by the prescribing dermatologist, teledermatology allows for increased continuity of care for active-duty service members and maintenance of a therapeutic isotretinoin course despite temporary geographic displacement.

By facilitating regular follow-up appointments, teledermatology can minimize the amount of time an active-duty service member is on a course of oral isotretinoin, thereby reducing the operational and duty-limiting implications of the medication.

Final Thoughts

Acne is a common dermatologic concern within the active-duty military population. Oral isotretinoin is indicated for treatment-resistant moderate or severe acne; however, it limits the ability of service members to deploy and is disqualifying for special military assignments. High daily- and cumulative-dose isotretinoin treatment strategies can reduce the duration of therapy and may be associated with a decrease in acne relapse and the need for retrial. Teledermatology can increase access to care and facilitate the completion of oral isotretinoin courses in a timely manner. These treatment strategies may help mitigate the duty-limiting impact of oral isotretinoin therapy in military service members.

The Diagnosis: Histiocytoid Sweet Syndrome

The patient was admitted for clinical study and treatment monitoring. During the first 72 hours of admittance, the lesions and general malaise further developed along with C-reactive protein elevation (126 mg/L). Administration of intravenous prednisone at a dosage of 1 mg/kg daily was accompanied by substantial improvement after 1 week of treatment, with subsequent follow-up and outpatient monitoring. An underlying neoplasia was ruled out after review of medical history, physical examination, complete blood cell count, chest radiography, abdominal ultrasonography, colonoscopy, and bone marrow aspiration.

A 4-mm skin biopsy was performed from a lesion on the neck (Figure 1). Histology revealed a dermis with prominent edema alongside superficial, deep, and periadnexal perivascular inflammatory infiltrates, as well as predominant lymphocytes and cells with a histiocytoid profile (Figure 2). These findings were accompanied by isolated neutrophil foci. The absence of leukocytoclastic vasculitis was noted. Immunohistochemistry demonstrated that the histiocyte population was positive for myeloperoxidase and CD68, which categorized them as immature cells of myeloid origin (Figure 3). Clinical and histopathologic findings led to a definitive diagnosis of histiocytoid Sweet syndrome (SS). Sweet syndrome consists of a neutrophilic dermatosis profile. Clinically, it manifests as a sudden onset of painful nodules and plaques accompanied by fever, malaise, and leukocytosis.

Histiocytoid SS is a rare histologic variant of SS initially described by Requena et al1 in 2005. In histiocytoid SS, the main inflammatory infiltrates are promyelocytes and myelocytes.² Immunohistochemistry shows positivity for myeloperoxidase, CD15, CD43, CD45, CD68, MAC-386, and HAM56.¹ The diagnosis is determined by exclusion after adequate clinical and histopathologic correlation, which also should exclude other diagnoses such as leukemia cutis and interstitial granulomatous dermatitis.³ Histiocytoid SS may be related to an increased risk for underlying malignancy. Haber et al⁴ performed a systematic review in which they concluded that approximately 40% of patients newly diagnosed with histiocytoid SS subsequently were diagnosed or already were diagnosed with a hematologic or solid cancer vs 21% in the classical neutrophilic infiltrate of SS (NSS). Histiocytoid SS more commonly was associated with myelodysplastic syndrome (46% vs 2.5% in NSS) and hematologic malignancies (42.5% vs 25% in SS).

The initial differential diagnoses include inflammatory dermatoses, infections, neoplasms, and systemic diseases. In exudative erythema multiforme, early lesions are composed of typical target lesions with mucosal involvement in 25% to 60% of patients.⁵ Erythema elevatum diutinum is a chronic dermatosis characterized by asymptomatic papules and red-violet nodules. The most characteristic histologic finding is leukocytoclastic vasculitis.⁶ The absence of vasculitis is part of the major diagnostic criteria for SS.⁷ Wells syndrome is associated with general malaise, and edematous and erythematous-violet plaques or nodules appear on the limbs; however, it frequently is associated with eosinophilia in peripheral blood, and histology shows that the main cell population of the inflammatory infiltrate also is eosinophilic.⁸ Painful, superficial, and erosive blisters appear preferentially on the face and backs of the arms in bullous pyoderma gangrenosum. It usually is not associated with the typical systemic manifestations of SS (ie, fever, arthralgia, damage to target organs). On histopathology, the neutrophilic infiltrate is accompanied by subepidermal vesicles.⁹

Histiocytoid SS responds dramatically to corticosteroids. Other first-line treatments that avoid use of corticosteroids are colchicine, dapsone, and potassium iodide. Multiple treatments were attempted in our patient, including corticosteroids, methotrexate, dapsone, colchicine, and anakinra. Despite patients responding well to treatment, a possible underlying neoplasm, most frequently of hematologic origin, must be excluded.¹⁰

The Diagnosis: Histiocytoid Sweet Syndrome

The patient was admitted for clinical study and treatment monitoring. During the first 72 hours of admittance, the lesions and general malaise further developed along with C-reactive protein elevation (126 mg/L). Administration of intravenous prednisone at a dosage of 1 mg/kg daily was accompanied by substantial improvement after 1 week of treatment, with subsequent follow-up and outpatient monitoring. An underlying neoplasia was ruled out after review of medical history, physical examination, complete blood cell count, chest radiography, abdominal ultrasonography, colonoscopy, and bone marrow aspiration.

A 4-mm skin biopsy was performed from a lesion on the neck (Figure 1). Histology revealed a dermis with prominent edema alongside superficial, deep, and periadnexal perivascular inflammatory infiltrates, as well as predominant lymphocytes and cells with a histiocytoid profile (Figure 2). These findings were accompanied by isolated neutrophil foci. The absence of leukocytoclastic vasculitis was noted. Immunohistochemistry demonstrated that the histiocyte population was positive for myeloperoxidase and CD68, which categorized them as immature cells of myeloid origin (Figure 3). Clinical and histopathologic findings led to a definitive diagnosis of histiocytoid Sweet syndrome (SS). Sweet syndrome consists of a neutrophilic dermatosis profile. Clinically, it manifests as a sudden onset of painful nodules and plaques accompanied by fever, malaise, and leukocytosis.

Histiocytoid SS is a rare histologic variant of SS initially described by Requena et al1 in 2005. In histiocytoid SS, the main inflammatory infiltrates are promyelocytes and myelocytes.² Immunohistochemistry shows positivity for myeloperoxidase, CD15, CD43, CD45, CD68, MAC-386, and HAM56.¹ The diagnosis is determined by exclusion after adequate clinical and histopathologic correlation, which also should exclude other diagnoses such as leukemia cutis and interstitial granulomatous dermatitis.³ Histiocytoid SS may be related to an increased risk for underlying malignancy. Haber et al⁴ performed a systematic review in which they concluded that approximately 40% of patients newly diagnosed with histiocytoid SS subsequently were diagnosed or already were diagnosed with a hematologic or solid cancer vs 21% in the classical neutrophilic infiltrate of SS (NSS). Histiocytoid SS more commonly was associated with myelodysplastic syndrome (46% vs 2.5% in NSS) and hematologic malignancies (42.5% vs 25% in SS).

The initial differential diagnoses include inflammatory dermatoses, infections, neoplasms, and systemic diseases. In exudative erythema multiforme, early lesions are composed of typical target lesions with mucosal involvement in 25% to 60% of patients.⁵ Erythema elevatum diutinum is a chronic dermatosis characterized by asymptomatic papules and red-violet nodules. The most characteristic histologic finding is leukocytoclastic vasculitis.⁶ The absence of vasculitis is part of the major diagnostic criteria for SS.⁷ Wells syndrome is associated with general malaise, and edematous and erythematous-violet plaques or nodules appear on the limbs; however, it frequently is associated with eosinophilia in peripheral blood, and histology shows that the main cell population of the inflammatory infiltrate also is eosinophilic.⁸ Painful, superficial, and erosive blisters appear preferentially on the face and backs of the arms in bullous pyoderma gangrenosum. It usually is not associated with the typical systemic manifestations of SS (ie, fever, arthralgia, damage to target organs). On histopathology, the neutrophilic infiltrate is accompanied by subepidermal vesicles.⁹

Histiocytoid SS responds dramatically to corticosteroids. Other first-line treatments that avoid use of corticosteroids are colchicine, dapsone, and potassium iodide. Multiple treatments were attempted in our patient, including corticosteroids, methotrexate, dapsone, colchicine, and anakinra. Despite patients responding well to treatment, a possible underlying neoplasm, most frequently of hematologic origin, must be excluded.¹⁰

The Diagnosis: Histiocytoid Sweet Syndrome

The patient was admitted for clinical study and treatment monitoring. During the first 72 hours of admittance, the lesions and general malaise further developed along with C-reactive protein elevation (126 mg/L). Administration of intravenous prednisone at a dosage of 1 mg/kg daily was accompanied by substantial improvement after 1 week of treatment, with subsequent follow-up and outpatient monitoring. An underlying neoplasia was ruled out after review of medical history, physical examination, complete blood cell count, chest radiography, abdominal ultrasonography, colonoscopy, and bone marrow aspiration.

A 4-mm skin biopsy was performed from a lesion on the neck (Figure 1). Histology revealed a dermis with prominent edema alongside superficial, deep, and periadnexal perivascular inflammatory infiltrates, as well as predominant lymphocytes and cells with a histiocytoid profile (Figure 2). These findings were accompanied by isolated neutrophil foci. The absence of leukocytoclastic vasculitis was noted. Immunohistochemistry demonstrated that the histiocyte population was positive for myeloperoxidase and CD68, which categorized them as immature cells of myeloid origin (Figure 3). Clinical and histopathologic findings led to a definitive diagnosis of histiocytoid Sweet syndrome (SS). Sweet syndrome consists of a neutrophilic dermatosis profile. Clinically, it manifests as a sudden onset of painful nodules and plaques accompanied by fever, malaise, and leukocytosis.

Histiocytoid SS is a rare histologic variant of SS initially described by Requena et al1 in 2005. In histiocytoid SS, the main inflammatory infiltrates are promyelocytes and myelocytes.² Immunohistochemistry shows positivity for myeloperoxidase, CD15, CD43, CD45, CD68, MAC-386, and HAM56.¹ The diagnosis is determined by exclusion after adequate clinical and histopathologic correlation, which also should exclude other diagnoses such as leukemia cutis and interstitial granulomatous dermatitis.³ Histiocytoid SS may be related to an increased risk for underlying malignancy. Haber et al⁴ performed a systematic review in which they concluded that approximately 40% of patients newly diagnosed with histiocytoid SS subsequently were diagnosed or already were diagnosed with a hematologic or solid cancer vs 21% in the classical neutrophilic infiltrate of SS (NSS). Histiocytoid SS more commonly was associated with myelodysplastic syndrome (46% vs 2.5% in NSS) and hematologic malignancies (42.5% vs 25% in SS).

The initial differential diagnoses include inflammatory dermatoses, infections, neoplasms, and systemic diseases. In exudative erythema multiforme, early lesions are composed of typical target lesions with mucosal involvement in 25% to 60% of patients.⁵ Erythema elevatum diutinum is a chronic dermatosis characterized by asymptomatic papules and red-violet nodules. The most characteristic histologic finding is leukocytoclastic vasculitis.⁶ The absence of vasculitis is part of the major diagnostic criteria for SS.⁷ Wells syndrome is associated with general malaise, and edematous and erythematous-violet plaques or nodules appear on the limbs; however, it frequently is associated with eosinophilia in peripheral blood, and histology shows that the main cell population of the inflammatory infiltrate also is eosinophilic.⁸ Painful, superficial, and erosive blisters appear preferentially on the face and backs of the arms in bullous pyoderma gangrenosum. It usually is not associated with the typical systemic manifestations of SS (ie, fever, arthralgia, damage to target organs). On histopathology, the neutrophilic infiltrate is accompanied by subepidermal vesicles.⁹

Histiocytoid SS responds dramatically to corticosteroids. Other first-line treatments that avoid use of corticosteroids are colchicine, dapsone, and potassium iodide. Multiple treatments were attempted in our patient, including corticosteroids, methotrexate, dapsone, colchicine, and anakinra. Despite patients responding well to treatment, a possible underlying neoplasm, most frequently of hematologic origin, must be excluded.¹⁰

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at cutis@mdedge.com.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at cutis@mdedge.com.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at cutis@mdedge.com.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

When I finished my dermatology training in 1986, the only moving parts in the skin that I recall were keratinocytes moving upward from the basal layer of the epidermis until they were desquamated 4 or 5 weeks later and hairs growing within their follicles until they were shed. Now we are learning about countless cytokines, chemokines, interleukins, antibodies, receptors, enzymes, and cell types, as well as their associated pathways, at an endless pace. Every day I am looking in my inbox to sign up for the “Cytokine of the Month” club! Despite the challenges of sorting through what is relevant clinically, it is a very exciting time. Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis. Importantly, there also is hope for patients with notoriously refractory skin disorders, such as hidradenitis suppurativa, alopecia areata, and vitiligo, as newer therapies are being thoroughly studied in clinical trials.

Despite the best advances in therapy that we currently have available and those anticipated in the foreseeable future, patients with chronic dermatoses such as psoriasis and atopic dermatitis still require prolonged constant or frequently used intermittent therapies to adequately control their disease. Fortunately, as dermatologists we understand the importance of proper skin care and topical medications as well as how to incorporate them in the management plan. To date, specifically with psoriasis, we have a variety of brand and generic topical corticosteroids, calcipotriene (vitamin D analogue), and tazarotene (retinoid), as well as combination formulations, in our toolbox to help manage localized areas of involvement.¹ This includes both patients with more limited psoriasis and those responding favorably to systemic therapy but who still develop some new or persistent areas of localized psoriatic lesions. New data with the brand formulation of calcipotriene–betamethasone dipropionate (Cal-BDP) foam applied once daily shows that after adequate control is achieved, continued application to the affected sites twice weekly is superior to vehicle in preventing relapse of psoriasis.² A highly cosmetically acceptable Cal-BDP cream incorporating a unique vehicle technology has been US Food and Drug Administration (FDA) approved for once-daily use for plaque psoriasis, overcoming the compatibility difficulties encountered in combining both active ingredients in an aqueous-based formulation and also optimizing the delivery of the active ingredients into the skin. This Cal-BDP cream demonstrated efficacy superior to a brand Cal-BDP suspension, rapid reduction in pruritus, and favorable tolerability and safety.³ Another combination formulation that is FDA approved for plaque psoriasis with once-daily application that has been shown to be effective and safe is halobetasol propionate–tazarotene lotion. This formulation contains lower concentrations of both active ingredients than those normally used in a barrier-friendly polymeric emulsion vehicle, allowing for augmented delivery of both active ingredients into the skin than with the individual agents applied separately and sequentially.^4,5 In the best of circumstances, most patients with psoriasis still require use of topical therapy and appreciate its availability. Just like on any menu, it is good to have multiple good options.

What else does this psoriasis management story need? A pipeline! I am happy to tell you that with topical therapy, 2 nonsteroidal agents are under development with completion of phase 2 and phase 3 trials submitted to the FDA to evaluate for approval for psoriasis. They are tapinarof cream, an aryl hydrocarbon receptor agonist, and roflumilast cream, a phosphodiesterase 4 (PDE4) inhibitor. Both of these modes of action involve intracellular pathways that are highly conserved in humans and are ubiquitously present in structural and hematopoietic cells.

Topical application of tapinarof cream once daily has been shown to be effective and safe for plaque psoriasis, is well tolerated with some reports of folliculitis observed that did not typically interfere with use, exhibits a remittive effect in patients achieving clearance on therapy, and is devoid of any systemic safety signals with both short-term and long-term use.^6-8 It also is currently under evaluation for atopic dermatitis. Topical roflumilast cream once daily has been shown to be effective and safe for plaque psoriasis as well as intertriginous psoriasis; is well tolerated including negligible rates of skin tolerability reactions such as stinging and burning; and is devoid of systemic safety signals, including those often observed with oral PDE4 inhibitor therapy (apremilast).^9,10 In addition, roflumilast has been shown to be more inherently potent in PDE4 inhibition activity than crisaborole and apremilast.¹¹ Roflumilast cream also is being studied for atopic dermatitis and a foam formulation is being evaluated for seborrheic dermatitis. Importantly, both tapinarof and roflumilast are not corticosteroids and are not associated with adverse effects observed with topical corticosteroid therapy, such as atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal axis suppression. This provides a sense of comfort for clinicians and patients, as potential side effects associated with more prolonged topical corticosteroid therapy are common and lingering concerns.

To summarize, topical therapy for psoriasis is here to stay, just like all the rock and roll we have more access to than ever through expanded modern-day radio access and several music streaming sources, most of which are on demand. Also available to us are some viable current options, including a few newer brand formulations. New nonsteroidal agents with favorable data thus far are on the horizon, providing their own inherent efficacy and safety, which appear to be advantageous thus far. As the late Ric Ocasek of the Cars sang, “Let the good times roll.”

When I finished my dermatology training in 1986, the only moving parts in the skin that I recall were keratinocytes moving upward from the basal layer of the epidermis until they were desquamated 4 or 5 weeks later and hairs growing within their follicles until they were shed. Now we are learning about countless cytokines, chemokines, interleukins, antibodies, receptors, enzymes, and cell types, as well as their associated pathways, at an endless pace. Every day I am looking in my inbox to sign up for the “Cytokine of the Month” club! Despite the challenges of sorting through what is relevant clinically, it is a very exciting time. Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis. Importantly, there also is hope for patients with notoriously refractory skin disorders, such as hidradenitis suppurativa, alopecia areata, and vitiligo, as newer therapies are being thoroughly studied in clinical trials.

Despite the best advances in therapy that we currently have available and those anticipated in the foreseeable future, patients with chronic dermatoses such as psoriasis and atopic dermatitis still require prolonged constant or frequently used intermittent therapies to adequately control their disease. Fortunately, as dermatologists we understand the importance of proper skin care and topical medications as well as how to incorporate them in the management plan. To date, specifically with psoriasis, we have a variety of brand and generic topical corticosteroids, calcipotriene (vitamin D analogue), and tazarotene (retinoid), as well as combination formulations, in our toolbox to help manage localized areas of involvement.¹ This includes both patients with more limited psoriasis and those responding favorably to systemic therapy but who still develop some new or persistent areas of localized psoriatic lesions. New data with the brand formulation of calcipotriene–betamethasone dipropionate (Cal-BDP) foam applied once daily shows that after adequate control is achieved, continued application to the affected sites twice weekly is superior to vehicle in preventing relapse of psoriasis.² A highly cosmetically acceptable Cal-BDP cream incorporating a unique vehicle technology has been US Food and Drug Administration (FDA) approved for once-daily use for plaque psoriasis, overcoming the compatibility difficulties encountered in combining both active ingredients in an aqueous-based formulation and also optimizing the delivery of the active ingredients into the skin. This Cal-BDP cream demonstrated efficacy superior to a brand Cal-BDP suspension, rapid reduction in pruritus, and favorable tolerability and safety.³ Another combination formulation that is FDA approved for plaque psoriasis with once-daily application that has been shown to be effective and safe is halobetasol propionate–tazarotene lotion. This formulation contains lower concentrations of both active ingredients than those normally used in a barrier-friendly polymeric emulsion vehicle, allowing for augmented delivery of both active ingredients into the skin than with the individual agents applied separately and sequentially.^4,5 In the best of circumstances, most patients with psoriasis still require use of topical therapy and appreciate its availability. Just like on any menu, it is good to have multiple good options.

What else does this psoriasis management story need? A pipeline! I am happy to tell you that with topical therapy, 2 nonsteroidal agents are under development with completion of phase 2 and phase 3 trials submitted to the FDA to evaluate for approval for psoriasis. They are tapinarof cream, an aryl hydrocarbon receptor agonist, and roflumilast cream, a phosphodiesterase 4 (PDE4) inhibitor. Both of these modes of action involve intracellular pathways that are highly conserved in humans and are ubiquitously present in structural and hematopoietic cells.

Topical application of tapinarof cream once daily has been shown to be effective and safe for plaque psoriasis, is well tolerated with some reports of folliculitis observed that did not typically interfere with use, exhibits a remittive effect in patients achieving clearance on therapy, and is devoid of any systemic safety signals with both short-term and long-term use.^6-8 It also is currently under evaluation for atopic dermatitis. Topical roflumilast cream once daily has been shown to be effective and safe for plaque psoriasis as well as intertriginous psoriasis; is well tolerated including negligible rates of skin tolerability reactions such as stinging and burning; and is devoid of systemic safety signals, including those often observed with oral PDE4 inhibitor therapy (apremilast).^9,10 In addition, roflumilast has been shown to be more inherently potent in PDE4 inhibition activity than crisaborole and apremilast.¹¹ Roflumilast cream also is being studied for atopic dermatitis and a foam formulation is being evaluated for seborrheic dermatitis. Importantly, both tapinarof and roflumilast are not corticosteroids and are not associated with adverse effects observed with topical corticosteroid therapy, such as atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal axis suppression. This provides a sense of comfort for clinicians and patients, as potential side effects associated with more prolonged topical corticosteroid therapy are common and lingering concerns.

To summarize, topical therapy for psoriasis is here to stay, just like all the rock and roll we have more access to than ever through expanded modern-day radio access and several music streaming sources, most of which are on demand. Also available to us are some viable current options, including a few newer brand formulations. New nonsteroidal agents with favorable data thus far are on the horizon, providing their own inherent efficacy and safety, which appear to be advantageous thus far. As the late Ric Ocasek of the Cars sang, “Let the good times roll.”

When I finished my dermatology training in 1986, the only moving parts in the skin that I recall were keratinocytes moving upward from the basal layer of the epidermis until they were desquamated 4 or 5 weeks later and hairs growing within their follicles until they were shed. Now we are learning about countless cytokines, chemokines, interleukins, antibodies, receptors, enzymes, and cell types, as well as their associated pathways, at an endless pace. Every day I am looking in my inbox to sign up for the “Cytokine of the Month” club! Despite the challenges of sorting through what is relevant clinically, it is a very exciting time. Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis. Importantly, there also is hope for patients with notoriously refractory skin disorders, such as hidradenitis suppurativa, alopecia areata, and vitiligo, as newer therapies are being thoroughly studied in clinical trials.

Despite the best advances in therapy that we currently have available and those anticipated in the foreseeable future, patients with chronic dermatoses such as psoriasis and atopic dermatitis still require prolonged constant or frequently used intermittent therapies to adequately control their disease. Fortunately, as dermatologists we understand the importance of proper skin care and topical medications as well as how to incorporate them in the management plan. To date, specifically with psoriasis, we have a variety of brand and generic topical corticosteroids, calcipotriene (vitamin D analogue), and tazarotene (retinoid), as well as combination formulations, in our toolbox to help manage localized areas of involvement.¹ This includes both patients with more limited psoriasis and those responding favorably to systemic therapy but who still develop some new or persistent areas of localized psoriatic lesions. New data with the brand formulation of calcipotriene–betamethasone dipropionate (Cal-BDP) foam applied once daily shows that after adequate control is achieved, continued application to the affected sites twice weekly is superior to vehicle in preventing relapse of psoriasis.² A highly cosmetically acceptable Cal-BDP cream incorporating a unique vehicle technology has been US Food and Drug Administration (FDA) approved for once-daily use for plaque psoriasis, overcoming the compatibility difficulties encountered in combining both active ingredients in an aqueous-based formulation and also optimizing the delivery of the active ingredients into the skin. This Cal-BDP cream demonstrated efficacy superior to a brand Cal-BDP suspension, rapid reduction in pruritus, and favorable tolerability and safety.³ Another combination formulation that is FDA approved for plaque psoriasis with once-daily application that has been shown to be effective and safe is halobetasol propionate–tazarotene lotion. This formulation contains lower concentrations of both active ingredients than those normally used in a barrier-friendly polymeric emulsion vehicle, allowing for augmented delivery of both active ingredients into the skin than with the individual agents applied separately and sequentially.^4,5 In the best of circumstances, most patients with psoriasis still require use of topical therapy and appreciate its availability. Just like on any menu, it is good to have multiple good options.

What else does this psoriasis management story need? A pipeline! I am happy to tell you that with topical therapy, 2 nonsteroidal agents are under development with completion of phase 2 and phase 3 trials submitted to the FDA to evaluate for approval for psoriasis. They are tapinarof cream, an aryl hydrocarbon receptor agonist, and roflumilast cream, a phosphodiesterase 4 (PDE4) inhibitor. Both of these modes of action involve intracellular pathways that are highly conserved in humans and are ubiquitously present in structural and hematopoietic cells.

Topical application of tapinarof cream once daily has been shown to be effective and safe for plaque psoriasis, is well tolerated with some reports of folliculitis observed that did not typically interfere with use, exhibits a remittive effect in patients achieving clearance on therapy, and is devoid of any systemic safety signals with both short-term and long-term use.^6-8 It also is currently under evaluation for atopic dermatitis. Topical roflumilast cream once daily has been shown to be effective and safe for plaque psoriasis as well as intertriginous psoriasis; is well tolerated including negligible rates of skin tolerability reactions such as stinging and burning; and is devoid of systemic safety signals, including those often observed with oral PDE4 inhibitor therapy (apremilast).^9,10 In addition, roflumilast has been shown to be more inherently potent in PDE4 inhibition activity than crisaborole and apremilast.¹¹ Roflumilast cream also is being studied for atopic dermatitis and a foam formulation is being evaluated for seborrheic dermatitis. Importantly, both tapinarof and roflumilast are not corticosteroids and are not associated with adverse effects observed with topical corticosteroid therapy, such as atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal axis suppression. This provides a sense of comfort for clinicians and patients, as potential side effects associated with more prolonged topical corticosteroid therapy are common and lingering concerns.

To summarize, topical therapy for psoriasis is here to stay, just like all the rock and roll we have more access to than ever through expanded modern-day radio access and several music streaming sources, most of which are on demand. Also available to us are some viable current options, including a few newer brand formulations. New nonsteroidal agents with favorable data thus far are on the horizon, providing their own inherent efficacy and safety, which appear to be advantageous thus far. As the late Ric Ocasek of the Cars sang, “Let the good times roll.”

Psoriasis is a common chronic immunologic skin disease that affects approximately 7.4 million adults in the United States¹ and more than 100 million individuals worldwide.² Patients with psoriasis have a potentially heightened risk for cardiometabolic diseases, psychiatric disorders, and psoriatic arthritis,³ as well as impaired quality of life (QOL).⁴ Psoriasis also is associated with increased health care costs⁵ and may result in substantial socioeconomic repercussions for affected patients.^6,7

Psoriasis treatments focus on relieving symptoms and improving patient QOL. Systemic therapy has been the mainstay of treatment for moderate to severe psoriasis.⁸ Although topical therapy usually is applied to treat mild symptoms, it also can be used as an adjunct to enhance efficacy of other treatment approaches.⁹ The National Psoriasis Foundation (NPF) recommends a treat-to-target (TTT) strategy for plaque psoriasis, the most common form of psoriasis, with a target response of attaining affected body surface area (BSA) of 1% or lower at 3 months after treatment initiation, allowing for regular assessments of treatment responses.¹⁰

Not all patients with moderate to severe psoriasis can achieve a satisfactory response with systemic biologic monotherapy.¹¹ Switching to a new biologic improves responses in some but not all cases¹² and could be associated with new safety issues and additional costs. Combinations of biologics with phototherapy, nonbiologic systemic agents, or topical medications were found to be more effective than biologics alone,^9,11 though long-term safety studies are needed for biologics combined with other systemic inverventions.¹¹

A lotion containing a fixed combination of halobetasol propionate (HP) 0.01%, a corticosteroid, and tazarotene (TAZ) 0.045%, a retinoid, is indicated for plaque psoriasis in adults.¹³ Two randomized, controlled, phase 3 trials demonstrated the rapid and sustained efficacy of HP-TAZ in treating moderate to severe plaque psoriasis without any safety concerns.^14,15 However, combining HP-TAZ lotion with biologics has not been examined yet, to our knowledge.

This open-label study evaluated the effectiveness and safety of adjunctive HP-TAZ lotion in adult patients with moderate to severe plaque psoriasis who were being treated with biologics in a real-world setting. Potential cost savings with the addition of topical HP-TAZ to ongoing biologics vs switching to a new biologic also were assessed.

Methods

Study Design and Participants—A single-center, institutional review board–approved, open-label study evaluated adjunctive therapy with HP 0.01%–TAZ 0.045% lotion in patients with psoriasis being treated with biologic agents. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practices. All patients provided written informed consent before enrollment.

Male and nonpregnant female patients (aged ≥18 years)with moderate to severe chronic plaque psoriasis and a BSA of 2% to 10% who were being treated with biologics for at least 24 weeks at baseline were enrolled. Patients were excluded if they had used oral systemic medications for psoriasis (≤4 weeks), other topical antipsoriatic therapies (≤14 days), UVB phototherapy (≤2 weeks), and psoralen plus UVA phototherapy (≤4 weeks) prior to study initiation. Concomitant use of steroid-free topical emollients or low-potency topical steroids and appropriate interventions deemed necessary by the investigator were allowed.

Although participants maintained their prescribed biologics for the duration of the study, HP-TAZ lotion also was applied once daily for 8 weeks, followed by once every other day for an additional 4 weeks. Participants then continued with biologics only for the last 4 weeks of the study.

Study Outcome Measures—Disease severity and treatment efficacy were assessed by affected BSA, Physician Global Assessment (PGA) score, composite BSA×PGA score, and participant-reported Dermatology Life Quality Index (DLQI). The primary end point was the proportion of participants achieving a BSA of 0% to 1% (NPF TTT status) at week 8. Secondary end points included the proportions of participants with BSA of 0% to 1% at weeks 12 and 16; BSA×PGA score at weeks 8, 12, and 16; and improvements in BSA, PGA, and DLQI at weeks 8, 12, and 16.

Adverse events (AEs) that occurred after the signing of the informed consent and for the duration of the participant’s participation were recorded, regardless of causality. Physical examinations were performed at screening; baseline; and weeks 8, 12, and 16 to document any clinically significant abnormalities. Localized skin reactions were assessed for tolerability of the study drug, with any reaction requiring concomitant therapy recorded as an AE.

The likelihood of switching to a new biologic regimen was assessed by the investigator for each participant at baseline and weeks 8, 12, and 16. Participants with unacceptable responses to their treatments (BSA >3%) were reported as likely to be considered for switching biologics by the investigator.

Pharmacoeconomic Evaluation—Potential cost savings were evaluated for the addition of HP-TAZ lotion to ongoing biologics vs switching to a new biologic. Cost comparisons were made in participants for whom the investigator would likely have switched biologics at baseline but not at the end of the study. For maintaining the same biologic with adjunctive topical HP-TAZ, total cost was estimated by adding the cost for 12 weeks (once daily for 8 weeks and once every other day for 4 weeks) of the HP-TAZ lotion to that of 16-week maintenance dosing with the biologic. The projected cost for switching to a new biologic for 16 weeks of treatment was based on both induction and maintenance dosing as recommended in its product label. Prices were obtained from the 2020 average wholesale price specialty pharmacy reports (BioPlus Specialty Pharmacy Services [https://www.bioplusrx.com]).

Data Handling—Enrollment of approximately 25 participants was desired for the study. Data on disease severity and participant-reported outcomes were assessed using descriptive statistics. Adverse events were summarized descriptively by incidence, severity, and relationship to the study drug. All participants with data available at a measured time point were included in the analyses for that time point.

Results

Participant Disposition and Demographics—Twenty-five participants (15 male and 10 female) were included in the study (Table 1). Seven participants discontinued the study for the following reasons: AEs (n=4), patient choice (n=2), and noncompliance (n=1).

The average age of the participants was 50 years, the majority were White (76.0% [19/25]) andnon-Hispanic (88.0% [22/25]), and the mean duration of chronic plaque psoriasis was 18.9 years (Table 1). Participants had been receiving biologic monotherapy for at least 24 weeks prior to enrollment, most commonly ustekinumab (32.0% [8/25])(Table 1). None had achieved the NPF TTT status with their biologics. At baseline, mean (SD) affected BSA, PGA, BSA×PGA, and participant-reported DLQI were 4.16% (2.04%), 2.84 (0.55), 11.88 (6.39), and 4.00 (4.74), respectively.

Efficacy Assessment—Application of HP-TAZ lotion in addition to the participants’ existing biologic therapy reduced severity of the disease, as evidenced by the reductions in mean BSA, PGA, and BSA×PGA. After 8 weeks of once-daily concomitant HP-TAZ use with biologic, mean BSA and PGA dropped by approximately 40% and 37%, respectively (Figures 1A and 1B). A greater reduction (54%) was found for mean BSA×PGA (Figure 1C). Disease severity continued to improve when the application schedule for HP-TAZ was changed to once every other day for 4 weeks, as mean BSA, PGA, and BSA×PGA decreased further at week 12. These beneficial effects were sustained during the last 4 weeks of the study after HP-TAZ was discontinued, with reductions of 57%, 43%, and 70% from baseline for mean BSA, PGA, and BSA×PGA, respectively (Figure 1).

The proportion of participants who achieved NPF TTT status increased from 0% at baseline to 20.0% (5/20) at week 8 with once-daily use of HP-TAZ plus biologic for 8 weeks (Figure 2). At week 12, more participants (64.7% [11/17]) achieved the treatment goal after application of HP-TAZ once every other day with biologic for 4 weeks. Most participants maintained NPF TTT status after HP-TAZ was discontinued; at week 16, 50.0% (9/18) attained the NPF treatment goal (Figure 2).

The mean DLQI score decreased from 4.00 at baseline to 2.45 after 8 weeks of concomitant use of once-daily HP-TAZ with biologic, reflecting a 39% score reduction. An additional 4 weeks of adjunctive HP-TAZ applied once every other day with biologic further decreased the DLQI score to 2.18 at week 12. Mean DLQI remained similar (2.33) after another 4 weeks of biologics alone. The proportion of participants reporting a DLQI score of 0 to 1 increased from 40% (10/25) at baseline to 60% (12/20) at week 8 and 76.5% (13/17) at week 12 with adjunctive HP-TAZ lotion use with biologic. At week 16, a DLQI score of 0 to 1 was reported in 61.1% (11/18) of participants after receiving only biologics for 4 weeks.

Safety Assessment—A total of 19 AEs were reported in 11 participants during the study; 16 AEs were considered treatment related in 8 participants (Table 2). The most common AEs were retinoid dermatitis (28% [7/25]), burning at the application site (8% [2/25]), and pruritus at the application site (8% [2/25]), all of which were considered related to the treatment. Among all AEs, 12 were mild in severity, and the remaining 7 were moderate. Adverse events led to early study termination in 4 participants, all with retinoid dermatitis as the primary reason.

Likelihood of Switching Biologics—At baseline, almost 90% (22/25) of participants were rated as likely to switch biologics by the investigator due to unacceptable responses to their currently prescribed biologics (BSA >3%)(Figure 3). The likelihood was greatly reduced by concomitant HP-TAZ, as the proportion of participants defined as nonresponders to their biologic decreased to 35% (7/20) with 8-week adjunctive application of once-daily HP-TAZ with biologic and further decreased to 23.5% (4/17) with another 4 weeks of adjunctive HP-TAZ applied every other day plus biologic. At week 16, after 4 weeks of biologics alone, the proportion was maintained at 33.3% (6/18).

Pharmacoeconomics of Adding Topical HP-TAZ vs Switching Biologics—In the participants whom the investigator reported as likely to switch biologics at baseline, 9 had improvements in disease control such that switching biologics was no longer considered necessary for them at week 16. Potential cost savings with adjunctive therapy of HP-TAZ plus biologic vs switching biologics were therefore evaluated in these 9 participants, who were receiving ustekinumab, adalimumab, guselkumab, ixekizumab, and secukinumab during the study (Table 3). The estimated total cost of 16-week maintenance dosing of biologics plus adjunct HP-TAZ lotion ranged from $14,675 (ustekinumab 45 mg) to $54,025 (secukinumab 300 mg), while switching to other most commonly prescribed biologics for 16 weeks would cost an estimated $33,340 to $106,400 (induction and subsequent maintenance phases)(Table 3). Most biologic plus HP-TAZ combinations were estimated to cost less than $30,000, potentially saving $4816 to $91,725 compared with switching to any of the other 7 biologics (Table 3). The relatively more expensive maintenance combination containing secukinumab plus HP-TAZ ($54,025) appeared to be a less expensive option when compared with switching to ustekinumab (90 mg)($83,097), ixekizumab (80 mg)($61,452), or risankizumab (150 mg)($57,030) as an alternative biologic.

Comment

Adjunctive Use of HP-TAZ Lotion—In the present study, we showed that adjunctive HP-TAZ lotion improved biologic treatment response and reduced disease severity in participants with moderate to severe psoriasis whose symptoms could not be adequately controlled by 24 weeks or more of biologic monotherapy in a real-world setting. Disease activity decreased as evidenced by reductions in all assessed effectiveness variables, including BSA involvement, PGA score, composite BSA×PGA score, and participant-reported DLQI score. Half of the participants achieved NPF TTT status at the end of the study. The treatment was well tolerated with no unexpected safety concerns. Compared with switching to a new biologic, adding topical HP-TAZ to ongoing biologics appeared to be a more cost-effective approach to enhance treatment effects. Our results suggest that adjunctive use of HP-TAZ lotion may be a safe, effective, and economical option for patients with psoriasis who are failing their ongoing biologic monotherapy.

Treat-to-Target Status—The NPF-recommended target response to a treatment for plaque psoriasis is BSA of 1% or lower at 3 months postinitiation.¹⁰ Patients in the current study had major psoriasis activity at study entry despite being treated with a biologic for at least 24 weeks, as none had attained NPF TTT status at baseline. Because the time period of prior biologic treatment (at least 24 weeks) is much longer than the 3 months suggested by NPF, we believe that we were observing a true failure of the biologic rather than a slow onset of treatment effects in these patients at the time of enrollment. By week 12, with the addition of HP-TAZ lotion to the biologic, a high rate of participants achieved NPF TTT status (64.7%), with most participants being able to maintain this TTT status at study end after 4 weeks of biologic alone. Most participants also reported no impact of psoriasis on their QOL (DLQI, 0–1¹⁶; 76.5%) at week 12. Improvements we found in disease control with adjunctive HP-TAZ lotion plus biologic support prior reports showing enhanced responses when a topical medication was added to a biologic.^17,18 Reductions in psoriasis activity after 8 weeks of combined biologics plus once-daily HP-TAZ also are consistent with 2 phase 3 RCTs in which a monotherapy of HP-TAZ lotion used once daily for 8 weeks reduced BSA and DLQI.¹⁵ Notably, in the current study, disease severity continued to decrease when dosing of HP-TAZ was reduced to once every other day for 4 weeks, and the improvements were maintained even after the adjunct topical therapy was discontinued.

Safety Profile of HP-TAZ Lotion—The overall safety profile in our study also was consistent with that previously reported for HP-TAZ lotion,^15,19-21 with no new safety signals observed. The combination treatment was well tolerated, with most reported AEs being mild in severity. Adverse events were mostly related to application-site reactions, the most common being dermatitis (28%), which was likely attributable to the TAZ component of the topical regimen.¹⁵

Likelihood of Switching Biologics—Reduced disease activity was reflected by a decrease in the percentage of participants the investigator considered likely to change biologics, which was 88.0% at baseline but only 33.3% at the end of the study. Although switching to a different biologic agent can improve treatment effect,²² it could lead to a substantial increase in health care costs and use of resources compared with no switch.⁵ We found that switching to one of the other most commonly prescribed biologics could incur $4816 to $91,725 in additional costs in most cases when compared with the combination strategy we evaluated over the 16-week treatment period. Therefore, concomitant use of HP-TAZ lotion with the ongoing biologics would be a potentially more economical alternative for patients to achieve acceptable responses or the NPF TTT goal. Moreover, combination with an adjunctive topical medication could avoid potential risks associated with switching, such as new AEs with new biologic regimens or disease flare during any washout period sometimes adopted for switching biologics.

Study Limitations—Our estimated costs were based on average wholesale prices and did not reflect net prices paid by patients or health plans due to the lack of known discount rates. Inherent to the nature of its design, the study also had a relatively small patient population and lacked control groups. Although lack of a control group may limit the conclusions of our study, our goal was to examine real-world patient experience, and the efficacy of HP-TAZ lotion as well as the baseline disease state for each participant using a biologic was well known. Statistical inference on the differences in efficacy between biologics with and without adjunctive HP-TAZ lotion, or between combination therapy and a new biologic monotherapy, was not possible. Additionally, a longer follow-up after discontinuation of HP-TAZ is needed to evaluate the long-term maintenance of responses. Nevertheless, the results here demonstrated that participants responded better when adjunctive HP-TAZ lotion was added to the ongoing biologics in a clinical practice setting.

Conclusion

In this real-world study, patients with psoriasis that failed to respond to biologic monotherapy had improved disease control and QOL and reported no new safety concerns with adjunctive use of HP-TAZ lotion. Adding HP-TAZ to the ongoing biologics could be a more cost-effective option vs switching biologics for patients whose psoriasis symptoms could not be controlled with biologic monotherapy. Taken together, our results support the use of HP-TAZ lotion as an effective and safe adjunctive topical therapy in combination with biologics for psoriasis treatment.

Acknowledgments—We acknowledge the medical writing assistance provided by Hui Zhang, PhD, and Kathleen Ohleth, PhD, from Precise Publications LLC (Far Hills, New Jersey), which was funded by Ortho Dermatologics.

Psoriasis is a common chronic immunologic skin disease that affects approximately 7.4 million adults in the United States¹ and more than 100 million individuals worldwide.² Patients with psoriasis have a potentially heightened risk for cardiometabolic diseases, psychiatric disorders, and psoriatic arthritis,³ as well as impaired quality of life (QOL).⁴ Psoriasis also is associated with increased health care costs⁵ and may result in substantial socioeconomic repercussions for affected patients.^6,7

Psoriasis treatments focus on relieving symptoms and improving patient QOL. Systemic therapy has been the mainstay of treatment for moderate to severe psoriasis.⁸ Although topical therapy usually is applied to treat mild symptoms, it also can be used as an adjunct to enhance efficacy of other treatment approaches.⁹ The National Psoriasis Foundation (NPF) recommends a treat-to-target (TTT) strategy for plaque psoriasis, the most common form of psoriasis, with a target response of attaining affected body surface area (BSA) of 1% or lower at 3 months after treatment initiation, allowing for regular assessments of treatment responses.¹⁰

Not all patients with moderate to severe psoriasis can achieve a satisfactory response with systemic biologic monotherapy.¹¹ Switching to a new biologic improves responses in some but not all cases¹² and could be associated with new safety issues and additional costs. Combinations of biologics with phototherapy, nonbiologic systemic agents, or topical medications were found to be more effective than biologics alone,^9,11 though long-term safety studies are needed for biologics combined with other systemic inverventions.¹¹

A lotion containing a fixed combination of halobetasol propionate (HP) 0.01%, a corticosteroid, and tazarotene (TAZ) 0.045%, a retinoid, is indicated for plaque psoriasis in adults.¹³ Two randomized, controlled, phase 3 trials demonstrated the rapid and sustained efficacy of HP-TAZ in treating moderate to severe plaque psoriasis without any safety concerns.^14,15 However, combining HP-TAZ lotion with biologics has not been examined yet, to our knowledge.

This open-label study evaluated the effectiveness and safety of adjunctive HP-TAZ lotion in adult patients with moderate to severe plaque psoriasis who were being treated with biologics in a real-world setting. Potential cost savings with the addition of topical HP-TAZ to ongoing biologics vs switching to a new biologic also were assessed.

Methods

Study Design and Participants—A single-center, institutional review board–approved, open-label study evaluated adjunctive therapy with HP 0.01%–TAZ 0.045% lotion in patients with psoriasis being treated with biologic agents. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practices. All patients provided written informed consent before enrollment.

Male and nonpregnant female patients (aged ≥18 years)with moderate to severe chronic plaque psoriasis and a BSA of 2% to 10% who were being treated with biologics for at least 24 weeks at baseline were enrolled. Patients were excluded if they had used oral systemic medications for psoriasis (≤4 weeks), other topical antipsoriatic therapies (≤14 days), UVB phototherapy (≤2 weeks), and psoralen plus UVA phototherapy (≤4 weeks) prior to study initiation. Concomitant use of steroid-free topical emollients or low-potency topical steroids and appropriate interventions deemed necessary by the investigator were allowed.

Although participants maintained their prescribed biologics for the duration of the study, HP-TAZ lotion also was applied once daily for 8 weeks, followed by once every other day for an additional 4 weeks. Participants then continued with biologics only for the last 4 weeks of the study.

Study Outcome Measures—Disease severity and treatment efficacy were assessed by affected BSA, Physician Global Assessment (PGA) score, composite BSA×PGA score, and participant-reported Dermatology Life Quality Index (DLQI). The primary end point was the proportion of participants achieving a BSA of 0% to 1% (NPF TTT status) at week 8. Secondary end points included the proportions of participants with BSA of 0% to 1% at weeks 12 and 16; BSA×PGA score at weeks 8, 12, and 16; and improvements in BSA, PGA, and DLQI at weeks 8, 12, and 16.

Adverse events (AEs) that occurred after the signing of the informed consent and for the duration of the participant’s participation were recorded, regardless of causality. Physical examinations were performed at screening; baseline; and weeks 8, 12, and 16 to document any clinically significant abnormalities. Localized skin reactions were assessed for tolerability of the study drug, with any reaction requiring concomitant therapy recorded as an AE.

The likelihood of switching to a new biologic regimen was assessed by the investigator for each participant at baseline and weeks 8, 12, and 16. Participants with unacceptable responses to their treatments (BSA >3%) were reported as likely to be considered for switching biologics by the investigator.

Pharmacoeconomic Evaluation—Potential cost savings were evaluated for the addition of HP-TAZ lotion to ongoing biologics vs switching to a new biologic. Cost comparisons were made in participants for whom the investigator would likely have switched biologics at baseline but not at the end of the study. For maintaining the same biologic with adjunctive topical HP-TAZ, total cost was estimated by adding the cost for 12 weeks (once daily for 8 weeks and once every other day for 4 weeks) of the HP-TAZ lotion to that of 16-week maintenance dosing with the biologic. The projected cost for switching to a new biologic for 16 weeks of treatment was based on both induction and maintenance dosing as recommended in its product label. Prices were obtained from the 2020 average wholesale price specialty pharmacy reports (BioPlus Specialty Pharmacy Services [https://www.bioplusrx.com]).

Data Handling—Enrollment of approximately 25 participants was desired for the study. Data on disease severity and participant-reported outcomes were assessed using descriptive statistics. Adverse events were summarized descriptively by incidence, severity, and relationship to the study drug. All participants with data available at a measured time point were included in the analyses for that time point.

Results

Participant Disposition and Demographics—Twenty-five participants (15 male and 10 female) were included in the study (Table 1). Seven participants discontinued the study for the following reasons: AEs (n=4), patient choice (n=2), and noncompliance (n=1).

The average age of the participants was 50 years, the majority were White (76.0% [19/25]) andnon-Hispanic (88.0% [22/25]), and the mean duration of chronic plaque psoriasis was 18.9 years (Table 1). Participants had been receiving biologic monotherapy for at least 24 weeks prior to enrollment, most commonly ustekinumab (32.0% [8/25])(Table 1). None had achieved the NPF TTT status with their biologics. At baseline, mean (SD) affected BSA, PGA, BSA×PGA, and participant-reported DLQI were 4.16% (2.04%), 2.84 (0.55), 11.88 (6.39), and 4.00 (4.74), respectively.

Efficacy Assessment—Application of HP-TAZ lotion in addition to the participants’ existing biologic therapy reduced severity of the disease, as evidenced by the reductions in mean BSA, PGA, and BSA×PGA. After 8 weeks of once-daily concomitant HP-TAZ use with biologic, mean BSA and PGA dropped by approximately 40% and 37%, respectively (Figures 1A and 1B). A greater reduction (54%) was found for mean BSA×PGA (Figure 1C). Disease severity continued to improve when the application schedule for HP-TAZ was changed to once every other day for 4 weeks, as mean BSA, PGA, and BSA×PGA decreased further at week 12. These beneficial effects were sustained during the last 4 weeks of the study after HP-TAZ was discontinued, with reductions of 57%, 43%, and 70% from baseline for mean BSA, PGA, and BSA×PGA, respectively (Figure 1).

The proportion of participants who achieved NPF TTT status increased from 0% at baseline to 20.0% (5/20) at week 8 with once-daily use of HP-TAZ plus biologic for 8 weeks (Figure 2). At week 12, more participants (64.7% [11/17]) achieved the treatment goal after application of HP-TAZ once every other day with biologic for 4 weeks. Most participants maintained NPF TTT status after HP-TAZ was discontinued; at week 16, 50.0% (9/18) attained the NPF treatment goal (Figure 2).

The mean DLQI score decreased from 4.00 at baseline to 2.45 after 8 weeks of concomitant use of once-daily HP-TAZ with biologic, reflecting a 39% score reduction. An additional 4 weeks of adjunctive HP-TAZ applied once every other day with biologic further decreased the DLQI score to 2.18 at week 12. Mean DLQI remained similar (2.33) after another 4 weeks of biologics alone. The proportion of participants reporting a DLQI score of 0 to 1 increased from 40% (10/25) at baseline to 60% (12/20) at week 8 and 76.5% (13/17) at week 12 with adjunctive HP-TAZ lotion use with biologic. At week 16, a DLQI score of 0 to 1 was reported in 61.1% (11/18) of participants after receiving only biologics for 4 weeks.

Safety Assessment—A total of 19 AEs were reported in 11 participants during the study; 16 AEs were considered treatment related in 8 participants (Table 2). The most common AEs were retinoid dermatitis (28% [7/25]), burning at the application site (8% [2/25]), and pruritus at the application site (8% [2/25]), all of which were considered related to the treatment. Among all AEs, 12 were mild in severity, and the remaining 7 were moderate. Adverse events led to early study termination in 4 participants, all with retinoid dermatitis as the primary reason.

Likelihood of Switching Biologics—At baseline, almost 90% (22/25) of participants were rated as likely to switch biologics by the investigator due to unacceptable responses to their currently prescribed biologics (BSA >3%)(Figure 3). The likelihood was greatly reduced by concomitant HP-TAZ, as the proportion of participants defined as nonresponders to their biologic decreased to 35% (7/20) with 8-week adjunctive application of once-daily HP-TAZ with biologic and further decreased to 23.5% (4/17) with another 4 weeks of adjunctive HP-TAZ applied every other day plus biologic. At week 16, after 4 weeks of biologics alone, the proportion was maintained at 33.3% (6/18).

Pharmacoeconomics of Adding Topical HP-TAZ vs Switching Biologics—In the participants whom the investigator reported as likely to switch biologics at baseline, 9 had improvements in disease control such that switching biologics was no longer considered necessary for them at week 16. Potential cost savings with adjunctive therapy of HP-TAZ plus biologic vs switching biologics were therefore evaluated in these 9 participants, who were receiving ustekinumab, adalimumab, guselkumab, ixekizumab, and secukinumab during the study (Table 3). The estimated total cost of 16-week maintenance dosing of biologics plus adjunct HP-TAZ lotion ranged from $14,675 (ustekinumab 45 mg) to $54,025 (secukinumab 300 mg), while switching to other most commonly prescribed biologics for 16 weeks would cost an estimated $33,340 to $106,400 (induction and subsequent maintenance phases)(Table 3). Most biologic plus HP-TAZ combinations were estimated to cost less than $30,000, potentially saving $4816 to $91,725 compared with switching to any of the other 7 biologics (Table 3). The relatively more expensive maintenance combination containing secukinumab plus HP-TAZ ($54,025) appeared to be a less expensive option when compared with switching to ustekinumab (90 mg)($83,097), ixekizumab (80 mg)($61,452), or risankizumab (150 mg)($57,030) as an alternative biologic.

Comment

Adjunctive Use of HP-TAZ Lotion—In the present study, we showed that adjunctive HP-TAZ lotion improved biologic treatment response and reduced disease severity in participants with moderate to severe psoriasis whose symptoms could not be adequately controlled by 24 weeks or more of biologic monotherapy in a real-world setting. Disease activity decreased as evidenced by reductions in all assessed effectiveness variables, including BSA involvement, PGA score, composite BSA×PGA score, and participant-reported DLQI score. Half of the participants achieved NPF TTT status at the end of the study. The treatment was well tolerated with no unexpected safety concerns. Compared with switching to a new biologic, adding topical HP-TAZ to ongoing biologics appeared to be a more cost-effective approach to enhance treatment effects. Our results suggest that adjunctive use of HP-TAZ lotion may be a safe, effective, and economical option for patients with psoriasis who are failing their ongoing biologic monotherapy.

Treat-to-Target Status—The NPF-recommended target response to a treatment for plaque psoriasis is BSA of 1% or lower at 3 months postinitiation.¹⁰ Patients in the current study had major psoriasis activity at study entry despite being treated with a biologic for at least 24 weeks, as none had attained NPF TTT status at baseline. Because the time period of prior biologic treatment (at least 24 weeks) is much longer than the 3 months suggested by NPF, we believe that we were observing a true failure of the biologic rather than a slow onset of treatment effects in these patients at the time of enrollment. By week 12, with the addition of HP-TAZ lotion to the biologic, a high rate of participants achieved NPF TTT status (64.7%), with most participants being able to maintain this TTT status at study end after 4 weeks of biologic alone. Most participants also reported no impact of psoriasis on their QOL (DLQI, 0–1¹⁶; 76.5%) at week 12. Improvements we found in disease control with adjunctive HP-TAZ lotion plus biologic support prior reports showing enhanced responses when a topical medication was added to a biologic.^17,18 Reductions in psoriasis activity after 8 weeks of combined biologics plus once-daily HP-TAZ also are consistent with 2 phase 3 RCTs in which a monotherapy of HP-TAZ lotion used once daily for 8 weeks reduced BSA and DLQI.¹⁵ Notably, in the current study, disease severity continued to decrease when dosing of HP-TAZ was reduced to once every other day for 4 weeks, and the improvements were maintained even after the adjunct topical therapy was discontinued.

Safety Profile of HP-TAZ Lotion—The overall safety profile in our study also was consistent with that previously reported for HP-TAZ lotion,^15,19-21 with no new safety signals observed. The combination treatment was well tolerated, with most reported AEs being mild in severity. Adverse events were mostly related to application-site reactions, the most common being dermatitis (28%), which was likely attributable to the TAZ component of the topical regimen.¹⁵

Likelihood of Switching Biologics—Reduced disease activity was reflected by a decrease in the percentage of participants the investigator considered likely to change biologics, which was 88.0% at baseline but only 33.3% at the end of the study. Although switching to a different biologic agent can improve treatment effect,²² it could lead to a substantial increase in health care costs and use of resources compared with no switch.⁵ We found that switching to one of the other most commonly prescribed biologics could incur $4816 to $91,725 in additional costs in most cases when compared with the combination strategy we evaluated over the 16-week treatment period. Therefore, concomitant use of HP-TAZ lotion with the ongoing biologics would be a potentially more economical alternative for patients to achieve acceptable responses or the NPF TTT goal. Moreover, combination with an adjunctive topical medication could avoid potential risks associated with switching, such as new AEs with new biologic regimens or disease flare during any washout period sometimes adopted for switching biologics.

Study Limitations—Our estimated costs were based on average wholesale prices and did not reflect net prices paid by patients or health plans due to the lack of known discount rates. Inherent to the nature of its design, the study also had a relatively small patient population and lacked control groups. Although lack of a control group may limit the conclusions of our study, our goal was to examine real-world patient experience, and the efficacy of HP-TAZ lotion as well as the baseline disease state for each participant using a biologic was well known. Statistical inference on the differences in efficacy between biologics with and without adjunctive HP-TAZ lotion, or between combination therapy and a new biologic monotherapy, was not possible. Additionally, a longer follow-up after discontinuation of HP-TAZ is needed to evaluate the long-term maintenance of responses. Nevertheless, the results here demonstrated that participants responded better when adjunctive HP-TAZ lotion was added to the ongoing biologics in a clinical practice setting.

Conclusion

In this real-world study, patients with psoriasis that failed to respond to biologic monotherapy had improved disease control and QOL and reported no new safety concerns with adjunctive use of HP-TAZ lotion. Adding HP-TAZ to the ongoing biologics could be a more cost-effective option vs switching biologics for patients whose psoriasis symptoms could not be controlled with biologic monotherapy. Taken together, our results support the use of HP-TAZ lotion as an effective and safe adjunctive topical therapy in combination with biologics for psoriasis treatment.

Acknowledgments—We acknowledge the medical writing assistance provided by Hui Zhang, PhD, and Kathleen Ohleth, PhD, from Precise Publications LLC (Far Hills, New Jersey), which was funded by Ortho Dermatologics.

Psoriasis is a common chronic immunologic skin disease that affects approximately 7.4 million adults in the United States¹ and more than 100 million individuals worldwide.² Patients with psoriasis have a potentially heightened risk for cardiometabolic diseases, psychiatric disorders, and psoriatic arthritis,³ as well as impaired quality of life (QOL).⁴ Psoriasis also is associated with increased health care costs⁵ and may result in substantial socioeconomic repercussions for affected patients.^6,7

Psoriasis treatments focus on relieving symptoms and improving patient QOL. Systemic therapy has been the mainstay of treatment for moderate to severe psoriasis.⁸ Although topical therapy usually is applied to treat mild symptoms, it also can be used as an adjunct to enhance efficacy of other treatment approaches.⁹ The National Psoriasis Foundation (NPF) recommends a treat-to-target (TTT) strategy for plaque psoriasis, the most common form of psoriasis, with a target response of attaining affected body surface area (BSA) of 1% or lower at 3 months after treatment initiation, allowing for regular assessments of treatment responses.¹⁰

Not all patients with moderate to severe psoriasis can achieve a satisfactory response with systemic biologic monotherapy.¹¹ Switching to a new biologic improves responses in some but not all cases¹² and could be associated with new safety issues and additional costs. Combinations of biologics with phototherapy, nonbiologic systemic agents, or topical medications were found to be more effective than biologics alone,^9,11 though long-term safety studies are needed for biologics combined with other systemic inverventions.¹¹

A lotion containing a fixed combination of halobetasol propionate (HP) 0.01%, a corticosteroid, and tazarotene (TAZ) 0.045%, a retinoid, is indicated for plaque psoriasis in adults.¹³ Two randomized, controlled, phase 3 trials demonstrated the rapid and sustained efficacy of HP-TAZ in treating moderate to severe plaque psoriasis without any safety concerns.^14,15 However, combining HP-TAZ lotion with biologics has not been examined yet, to our knowledge.

This open-label study evaluated the effectiveness and safety of adjunctive HP-TAZ lotion in adult patients with moderate to severe plaque psoriasis who were being treated with biologics in a real-world setting. Potential cost savings with the addition of topical HP-TAZ to ongoing biologics vs switching to a new biologic also were assessed.

Methods

Study Design and Participants—A single-center, institutional review board–approved, open-label study evaluated adjunctive therapy with HP 0.01%–TAZ 0.045% lotion in patients with psoriasis being treated with biologic agents. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practices. All patients provided written informed consent before enrollment.

Male and nonpregnant female patients (aged ≥18 years)with moderate to severe chronic plaque psoriasis and a BSA of 2% to 10% who were being treated with biologics for at least 24 weeks at baseline were enrolled. Patients were excluded if they had used oral systemic medications for psoriasis (≤4 weeks), other topical antipsoriatic therapies (≤14 days), UVB phototherapy (≤2 weeks), and psoralen plus UVA phototherapy (≤4 weeks) prior to study initiation. Concomitant use of steroid-free topical emollients or low-potency topical steroids and appropriate interventions deemed necessary by the investigator were allowed.

Although participants maintained their prescribed biologics for the duration of the study, HP-TAZ lotion also was applied once daily for 8 weeks, followed by once every other day for an additional 4 weeks. Participants then continued with biologics only for the last 4 weeks of the study.

Study Outcome Measures—Disease severity and treatment efficacy were assessed by affected BSA, Physician Global Assessment (PGA) score, composite BSA×PGA score, and participant-reported Dermatology Life Quality Index (DLQI). The primary end point was the proportion of participants achieving a BSA of 0% to 1% (NPF TTT status) at week 8. Secondary end points included the proportions of participants with BSA of 0% to 1% at weeks 12 and 16; BSA×PGA score at weeks 8, 12, and 16; and improvements in BSA, PGA, and DLQI at weeks 8, 12, and 16.

Adverse events (AEs) that occurred after the signing of the informed consent and for the duration of the participant’s participation were recorded, regardless of causality. Physical examinations were performed at screening; baseline; and weeks 8, 12, and 16 to document any clinically significant abnormalities. Localized skin reactions were assessed for tolerability of the study drug, with any reaction requiring concomitant therapy recorded as an AE.

The likelihood of switching to a new biologic regimen was assessed by the investigator for each participant at baseline and weeks 8, 12, and 16. Participants with unacceptable responses to their treatments (BSA >3%) were reported as likely to be considered for switching biologics by the investigator.

Pharmacoeconomic Evaluation—Potential cost savings were evaluated for the addition of HP-TAZ lotion to ongoing biologics vs switching to a new biologic. Cost comparisons were made in participants for whom the investigator would likely have switched biologics at baseline but not at the end of the study. For maintaining the same biologic with adjunctive topical HP-TAZ, total cost was estimated by adding the cost for 12 weeks (once daily for 8 weeks and once every other day for 4 weeks) of the HP-TAZ lotion to that of 16-week maintenance dosing with the biologic. The projected cost for switching to a new biologic for 16 weeks of treatment was based on both induction and maintenance dosing as recommended in its product label. Prices were obtained from the 2020 average wholesale price specialty pharmacy reports (BioPlus Specialty Pharmacy Services [https://www.bioplusrx.com]).

Data Handling—Enrollment of approximately 25 participants was desired for the study. Data on disease severity and participant-reported outcomes were assessed using descriptive statistics. Adverse events were summarized descriptively by incidence, severity, and relationship to the study drug. All participants with data available at a measured time point were included in the analyses for that time point.

Results

Participant Disposition and Demographics—Twenty-five participants (15 male and 10 female) were included in the study (Table 1). Seven participants discontinued the study for the following reasons: AEs (n=4), patient choice (n=2), and noncompliance (n=1).

The average age of the participants was 50 years, the majority were White (76.0% [19/25]) andnon-Hispanic (88.0% [22/25]), and the mean duration of chronic plaque psoriasis was 18.9 years (Table 1). Participants had been receiving biologic monotherapy for at least 24 weeks prior to enrollment, most commonly ustekinumab (32.0% [8/25])(Table 1). None had achieved the NPF TTT status with their biologics. At baseline, mean (SD) affected BSA, PGA, BSA×PGA, and participant-reported DLQI were 4.16% (2.04%), 2.84 (0.55), 11.88 (6.39), and 4.00 (4.74), respectively.

Efficacy Assessment—Application of HP-TAZ lotion in addition to the participants’ existing biologic therapy reduced severity of the disease, as evidenced by the reductions in mean BSA, PGA, and BSA×PGA. After 8 weeks of once-daily concomitant HP-TAZ use with biologic, mean BSA and PGA dropped by approximately 40% and 37%, respectively (Figures 1A and 1B). A greater reduction (54%) was found for mean BSA×PGA (Figure 1C). Disease severity continued to improve when the application schedule for HP-TAZ was changed to once every other day for 4 weeks, as mean BSA, PGA, and BSA×PGA decreased further at week 12. These beneficial effects were sustained during the last 4 weeks of the study after HP-TAZ was discontinued, with reductions of 57%, 43%, and 70% from baseline for mean BSA, PGA, and BSA×PGA, respectively (Figure 1).

The proportion of participants who achieved NPF TTT status increased from 0% at baseline to 20.0% (5/20) at week 8 with once-daily use of HP-TAZ plus biologic for 8 weeks (Figure 2). At week 12, more participants (64.7% [11/17]) achieved the treatment goal after application of HP-TAZ once every other day with biologic for 4 weeks. Most participants maintained NPF TTT status after HP-TAZ was discontinued; at week 16, 50.0% (9/18) attained the NPF treatment goal (Figure 2).

The mean DLQI score decreased from 4.00 at baseline to 2.45 after 8 weeks of concomitant use of once-daily HP-TAZ with biologic, reflecting a 39% score reduction. An additional 4 weeks of adjunctive HP-TAZ applied once every other day with biologic further decreased the DLQI score to 2.18 at week 12. Mean DLQI remained similar (2.33) after another 4 weeks of biologics alone. The proportion of participants reporting a DLQI score of 0 to 1 increased from 40% (10/25) at baseline to 60% (12/20) at week 8 and 76.5% (13/17) at week 12 with adjunctive HP-TAZ lotion use with biologic. At week 16, a DLQI score of 0 to 1 was reported in 61.1% (11/18) of participants after receiving only biologics for 4 weeks.

Safety Assessment—A total of 19 AEs were reported in 11 participants during the study; 16 AEs were considered treatment related in 8 participants (Table 2). The most common AEs were retinoid dermatitis (28% [7/25]), burning at the application site (8% [2/25]), and pruritus at the application site (8% [2/25]), all of which were considered related to the treatment. Among all AEs, 12 were mild in severity, and the remaining 7 were moderate. Adverse events led to early study termination in 4 participants, all with retinoid dermatitis as the primary reason.

Likelihood of Switching Biologics—At baseline, almost 90% (22/25) of participants were rated as likely to switch biologics by the investigator due to unacceptable responses to their currently prescribed biologics (BSA >3%)(Figure 3). The likelihood was greatly reduced by concomitant HP-TAZ, as the proportion of participants defined as nonresponders to their biologic decreased to 35% (7/20) with 8-week adjunctive application of once-daily HP-TAZ with biologic and further decreased to 23.5% (4/17) with another 4 weeks of adjunctive HP-TAZ applied every other day plus biologic. At week 16, after 4 weeks of biologics alone, the proportion was maintained at 33.3% (6/18).

Pharmacoeconomics of Adding Topical HP-TAZ vs Switching Biologics—In the participants whom the investigator reported as likely to switch biologics at baseline, 9 had improvements in disease control such that switching biologics was no longer considered necessary for them at week 16. Potential cost savings with adjunctive therapy of HP-TAZ plus biologic vs switching biologics were therefore evaluated in these 9 participants, who were receiving ustekinumab, adalimumab, guselkumab, ixekizumab, and secukinumab during the study (Table 3). The estimated total cost of 16-week maintenance dosing of biologics plus adjunct HP-TAZ lotion ranged from $14,675 (ustekinumab 45 mg) to $54,025 (secukinumab 300 mg), while switching to other most commonly prescribed biologics for 16 weeks would cost an estimated $33,340 to $106,400 (induction and subsequent maintenance phases)(Table 3). Most biologic plus HP-TAZ combinations were estimated to cost less than $30,000, potentially saving $4816 to $91,725 compared with switching to any of the other 7 biologics (Table 3). The relatively more expensive maintenance combination containing secukinumab plus HP-TAZ ($54,025) appeared to be a less expensive option when compared with switching to ustekinumab (90 mg)($83,097), ixekizumab (80 mg)($61,452), or risankizumab (150 mg)($57,030) as an alternative biologic.

Comment

Adjunctive Use of HP-TAZ Lotion—In the present study, we showed that adjunctive HP-TAZ lotion improved biologic treatment response and reduced disease severity in participants with moderate to severe psoriasis whose symptoms could not be adequately controlled by 24 weeks or more of biologic monotherapy in a real-world setting. Disease activity decreased as evidenced by reductions in all assessed effectiveness variables, including BSA involvement, PGA score, composite BSA×PGA score, and participant-reported DLQI score. Half of the participants achieved NPF TTT status at the end of the study. The treatment was well tolerated with no unexpected safety concerns. Compared with switching to a new biologic, adding topical HP-TAZ to ongoing biologics appeared to be a more cost-effective approach to enhance treatment effects. Our results suggest that adjunctive use of HP-TAZ lotion may be a safe, effective, and economical option for patients with psoriasis who are failing their ongoing biologic monotherapy.

Treat-to-Target Status—The NPF-recommended target response to a treatment for plaque psoriasis is BSA of 1% or lower at 3 months postinitiation.¹⁰ Patients in the current study had major psoriasis activity at study entry despite being treated with a biologic for at least 24 weeks, as none had attained NPF TTT status at baseline. Because the time period of prior biologic treatment (at least 24 weeks) is much longer than the 3 months suggested by NPF, we believe that we were observing a true failure of the biologic rather than a slow onset of treatment effects in these patients at the time of enrollment. By week 12, with the addition of HP-TAZ lotion to the biologic, a high rate of participants achieved NPF TTT status (64.7%), with most participants being able to maintain this TTT status at study end after 4 weeks of biologic alone. Most participants also reported no impact of psoriasis on their QOL (DLQI, 0–1¹⁶; 76.5%) at week 12. Improvements we found in disease control with adjunctive HP-TAZ lotion plus biologic support prior reports showing enhanced responses when a topical medication was added to a biologic.^17,18 Reductions in psoriasis activity after 8 weeks of combined biologics plus once-daily HP-TAZ also are consistent with 2 phase 3 RCTs in which a monotherapy of HP-TAZ lotion used once daily for 8 weeks reduced BSA and DLQI.¹⁵ Notably, in the current study, disease severity continued to decrease when dosing of HP-TAZ was reduced to once every other day for 4 weeks, and the improvements were maintained even after the adjunct topical therapy was discontinued.

Safety Profile of HP-TAZ Lotion—The overall safety profile in our study also was consistent with that previously reported for HP-TAZ lotion,^15,19-21 with no new safety signals observed. The combination treatment was well tolerated, with most reported AEs being mild in severity. Adverse events were mostly related to application-site reactions, the most common being dermatitis (28%), which was likely attributable to the TAZ component of the topical regimen.¹⁵

Likelihood of Switching Biologics—Reduced disease activity was reflected by a decrease in the percentage of participants the investigator considered likely to change biologics, which was 88.0% at baseline but only 33.3% at the end of the study. Although switching to a different biologic agent can improve treatment effect,²² it could lead to a substantial increase in health care costs and use of resources compared with no switch.⁵ We found that switching to one of the other most commonly prescribed biologics could incur $4816 to $91,725 in additional costs in most cases when compared with the combination strategy we evaluated over the 16-week treatment period. Therefore, concomitant use of HP-TAZ lotion with the ongoing biologics would be a potentially more economical alternative for patients to achieve acceptable responses or the NPF TTT goal. Moreover, combination with an adjunctive topical medication could avoid potential risks associated with switching, such as new AEs with new biologic regimens or disease flare during any washout period sometimes adopted for switching biologics.

Study Limitations—Our estimated costs were based on average wholesale prices and did not reflect net prices paid by patients or health plans due to the lack of known discount rates. Inherent to the nature of its design, the study also had a relatively small patient population and lacked control groups. Although lack of a control group may limit the conclusions of our study, our goal was to examine real-world patient experience, and the efficacy of HP-TAZ lotion as well as the baseline disease state for each participant using a biologic was well known. Statistical inference on the differences in efficacy between biologics with and without adjunctive HP-TAZ lotion, or between combination therapy and a new biologic monotherapy, was not possible. Additionally, a longer follow-up after discontinuation of HP-TAZ is needed to evaluate the long-term maintenance of responses. Nevertheless, the results here demonstrated that participants responded better when adjunctive HP-TAZ lotion was added to the ongoing biologics in a clinical practice setting.

Conclusion

In this real-world study, patients with psoriasis that failed to respond to biologic monotherapy had improved disease control and QOL and reported no new safety concerns with adjunctive use of HP-TAZ lotion. Adding HP-TAZ to the ongoing biologics could be a more cost-effective option vs switching biologics for patients whose psoriasis symptoms could not be controlled with biologic monotherapy. Taken together, our results support the use of HP-TAZ lotion as an effective and safe adjunctive topical therapy in combination with biologics for psoriasis treatment.

Acknowledgments—We acknowledge the medical writing assistance provided by Hui Zhang, PhD, and Kathleen Ohleth, PhD, from Precise Publications LLC (Far Hills, New Jersey), which was funded by Ortho Dermatologics.