Cutis

The Diagnosis: Phytophotodermatitis 

A  more detailed patient history revealed that there was beer with limes on the boat, but the partygoers neglected to bring a knife. The patient volunteered to tear the limes apart with his bare hands. Because he was clad only in swim trunks, lime juice splattered over various regions of his body. 

Phytophotodermatitis is a phototoxic blistering rash that follows topical exposure to plant-derived furocoumarins and sunlight. (Figure) Furocoumarins are photosensitizing substances produced by certain plants, possibly as a defense mechanism against predators.¹ They cause a nonimmunologic phototoxic reaction when deposited on the skin and exposed to UVA radiation. Exposure to limes is the most common precipitant of phytophotodermatitis, but other potential culprits include lemons, grapefruit, figs, carrots, parsnips, celery, and dill.²  

Lesions associated with phytophotodermatitis classically present as painful erythematous patches and bullae in regions of furocoumarin exposure. Affected areas are well demarcated and irregularly shaped and heal with a characteristic hyperpigmented rim. They often have a downward streak pattern from the dripping juice.³ If the furocoumarins are transferred by touch, lesions can appear in the shape of handprints, which may raise alarms for physical abuse in children.⁴ 

Photochemical reactions caused by activated furocoumarins cross-link nuclear DNA and damage cell membranes. These changes lead to cellular death resulting in edema and destruction of the epidermis. Other effects include an increase in keratin and thickening of the stratum corneum. The hyperpigmentation is a result of increased concentration of melanosomes and stimulation of melanocytes by activated furocoumarins.⁵ 

Management of phytophotodermatitis depends on the severity of skin injury. Mild cases may not require any treatment, whereas the most severe ones require admission to a burn unit for wound care. Anti-inflammatory medications are the mainstay of therapy. Our patient was prescribed desonide cream 0.05% for application to the affected areas. Sunscreen should be applied to prevent worsening of hyperpigmentation, which may take months to years to fade naturally. If hyperpigmentation is cosmetically troubling to the patient, bleaching agents such as hydroquinone and retinoids or Nd:YAG laser can be used to accelerate the resolution of pigment.⁵ 

Phototoxicity differs from less common photoallergic reactions caused by preformed antibodies or a delayed cell-mediated response to a trigger. The classic presentation of photoallergy is apruritic, inflammatory, bullous eruption in a sensitized individual.⁶ Allergic contact dermatitis more commonly is associated with pruritus than pain, and it presents as a papulovesicular eruption that evolves into lichenified plaques.⁷ Porphyria cutanea tarda would likely be accompanied by other cutaneous features such as hypertrichosis and sclerodermoid plaques with dystrophic calcification, in addition to wine-colored urine-containing porphyrins.⁸ Bullous fixed drug eruptions develop within 48 hours of exposure to a causative agent. The patient typically would experience pruritus and burning at the site of clearly demarcated erythematous lesions that healed with hyperpigmentation.⁹ Lesions of bullous lupus erythematosus may appear in areas without sun exposure, and they would be more likely to leave behind hypopigmentation rather than hyperpigmentation.¹⁰ 

The Diagnosis: Phytophotodermatitis 

A  more detailed patient history revealed that there was beer with limes on the boat, but the partygoers neglected to bring a knife. The patient volunteered to tear the limes apart with his bare hands. Because he was clad only in swim trunks, lime juice splattered over various regions of his body. 

Phytophotodermatitis is a phototoxic blistering rash that follows topical exposure to plant-derived furocoumarins and sunlight. (Figure) Furocoumarins are photosensitizing substances produced by certain plants, possibly as a defense mechanism against predators.¹ They cause a nonimmunologic phototoxic reaction when deposited on the skin and exposed to UVA radiation. Exposure to limes is the most common precipitant of phytophotodermatitis, but other potential culprits include lemons, grapefruit, figs, carrots, parsnips, celery, and dill.²  

Lesions associated with phytophotodermatitis classically present as painful erythematous patches and bullae in regions of furocoumarin exposure. Affected areas are well demarcated and irregularly shaped and heal with a characteristic hyperpigmented rim. They often have a downward streak pattern from the dripping juice.³ If the furocoumarins are transferred by touch, lesions can appear in the shape of handprints, which may raise alarms for physical abuse in children.⁴ 

Photochemical reactions caused by activated furocoumarins cross-link nuclear DNA and damage cell membranes. These changes lead to cellular death resulting in edema and destruction of the epidermis. Other effects include an increase in keratin and thickening of the stratum corneum. The hyperpigmentation is a result of increased concentration of melanosomes and stimulation of melanocytes by activated furocoumarins.⁵ 

Management of phytophotodermatitis depends on the severity of skin injury. Mild cases may not require any treatment, whereas the most severe ones require admission to a burn unit for wound care. Anti-inflammatory medications are the mainstay of therapy. Our patient was prescribed desonide cream 0.05% for application to the affected areas. Sunscreen should be applied to prevent worsening of hyperpigmentation, which may take months to years to fade naturally. If hyperpigmentation is cosmetically troubling to the patient, bleaching agents such as hydroquinone and retinoids or Nd:YAG laser can be used to accelerate the resolution of pigment.⁵ 

Phototoxicity differs from less common photoallergic reactions caused by preformed antibodies or a delayed cell-mediated response to a trigger. The classic presentation of photoallergy is apruritic, inflammatory, bullous eruption in a sensitized individual.⁶ Allergic contact dermatitis more commonly is associated with pruritus than pain, and it presents as a papulovesicular eruption that evolves into lichenified plaques.⁷ Porphyria cutanea tarda would likely be accompanied by other cutaneous features such as hypertrichosis and sclerodermoid plaques with dystrophic calcification, in addition to wine-colored urine-containing porphyrins.⁸ Bullous fixed drug eruptions develop within 48 hours of exposure to a causative agent. The patient typically would experience pruritus and burning at the site of clearly demarcated erythematous lesions that healed with hyperpigmentation.⁹ Lesions of bullous lupus erythematosus may appear in areas without sun exposure, and they would be more likely to leave behind hypopigmentation rather than hyperpigmentation.¹⁰ 

The Diagnosis: Phytophotodermatitis 

A  more detailed patient history revealed that there was beer with limes on the boat, but the partygoers neglected to bring a knife. The patient volunteered to tear the limes apart with his bare hands. Because he was clad only in swim trunks, lime juice splattered over various regions of his body. 

Phytophotodermatitis is a phototoxic blistering rash that follows topical exposure to plant-derived furocoumarins and sunlight. (Figure) Furocoumarins are photosensitizing substances produced by certain plants, possibly as a defense mechanism against predators.¹ They cause a nonimmunologic phototoxic reaction when deposited on the skin and exposed to UVA radiation. Exposure to limes is the most common precipitant of phytophotodermatitis, but other potential culprits include lemons, grapefruit, figs, carrots, parsnips, celery, and dill.²  

Lesions associated with phytophotodermatitis classically present as painful erythematous patches and bullae in regions of furocoumarin exposure. Affected areas are well demarcated and irregularly shaped and heal with a characteristic hyperpigmented rim. They often have a downward streak pattern from the dripping juice.³ If the furocoumarins are transferred by touch, lesions can appear in the shape of handprints, which may raise alarms for physical abuse in children.⁴ 

Photochemical reactions caused by activated furocoumarins cross-link nuclear DNA and damage cell membranes. These changes lead to cellular death resulting in edema and destruction of the epidermis. Other effects include an increase in keratin and thickening of the stratum corneum. The hyperpigmentation is a result of increased concentration of melanosomes and stimulation of melanocytes by activated furocoumarins.⁵ 

Management of phytophotodermatitis depends on the severity of skin injury. Mild cases may not require any treatment, whereas the most severe ones require admission to a burn unit for wound care. Anti-inflammatory medications are the mainstay of therapy. Our patient was prescribed desonide cream 0.05% for application to the affected areas. Sunscreen should be applied to prevent worsening of hyperpigmentation, which may take months to years to fade naturally. If hyperpigmentation is cosmetically troubling to the patient, bleaching agents such as hydroquinone and retinoids or Nd:YAG laser can be used to accelerate the resolution of pigment.⁵ 

Phototoxicity differs from less common photoallergic reactions caused by preformed antibodies or a delayed cell-mediated response to a trigger. The classic presentation of photoallergy is apruritic, inflammatory, bullous eruption in a sensitized individual.⁶ Allergic contact dermatitis more commonly is associated with pruritus than pain, and it presents as a papulovesicular eruption that evolves into lichenified plaques.⁷ Porphyria cutanea tarda would likely be accompanied by other cutaneous features such as hypertrichosis and sclerodermoid plaques with dystrophic calcification, in addition to wine-colored urine-containing porphyrins.⁸ Bullous fixed drug eruptions develop within 48 hours of exposure to a causative agent. The patient typically would experience pruritus and burning at the site of clearly demarcated erythematous lesions that healed with hyperpigmentation.⁹ Lesions of bullous lupus erythematosus may appear in areas without sun exposure, and they would be more likely to leave behind hypopigmentation rather than hyperpigmentation.¹⁰ 

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. ¹ It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 ^2,3 ; in 1868, the multiple miliary form on the face was described. ⁴ Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.

Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.

A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.^5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.

This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.

Clinical Observations

During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.

In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).

Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).

Comment

Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.

Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins⁵ in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman⁶ also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”

When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).

The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs, which are essential in cross-talk between hair matrix cells and follicular dermal papilla (FDP) cells in the maintenance of the hair cycle, especially during cytodifferentiation.⁷ Follicular dermal papilla cells lose their hair follicle inductive properties in vitro in the absence of BMP signaling. Introducing BMP to the in vitro niche restores these molecular properties of FDP cells.⁸

As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.^8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.¹⁰

Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.⁸ Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.¹¹ Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.¹²

Myllylä et al¹³ described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.¹³

Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.¹⁴ Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,¹⁵ a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.

Conclusion

Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.

The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. ¹ It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 ^2,3 ; in 1868, the multiple miliary form on the face was described. ⁴ Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.

Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.

A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.^5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.

This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.

Clinical Observations

During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.

In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).

Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).

Comment

Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.

Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins⁵ in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman⁶ also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”

When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).

The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs, which are essential in cross-talk between hair matrix cells and follicular dermal papilla (FDP) cells in the maintenance of the hair cycle, especially during cytodifferentiation.⁷ Follicular dermal papilla cells lose their hair follicle inductive properties in vitro in the absence of BMP signaling. Introducing BMP to the in vitro niche restores these molecular properties of FDP cells.⁸

As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.^8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.¹⁰

Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.⁸ Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.¹¹ Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.¹²

Myllylä et al¹³ described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.¹³

Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.¹⁴ Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,¹⁵ a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.

Conclusion

Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.

The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. ¹ It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 ^2,3 ; in 1868, the multiple miliary form on the face was described. ⁴ Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.

Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.

A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.^5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.

This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.

Clinical Observations

During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.

In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).

Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).

Comment

Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.

Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins⁵ in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman⁶ also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”

When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).

The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs, which are essential in cross-talk between hair matrix cells and follicular dermal papilla (FDP) cells in the maintenance of the hair cycle, especially during cytodifferentiation.⁷ Follicular dermal papilla cells lose their hair follicle inductive properties in vitro in the absence of BMP signaling. Introducing BMP to the in vitro niche restores these molecular properties of FDP cells.⁸

As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.^8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.¹⁰

Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.⁸ Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.¹¹ Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.¹²

Myllylä et al¹³ described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.¹³

Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.¹⁴ Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,¹⁵ a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.

Conclusion

Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

Office-based phototherapy practices have closed or are operating below capacity because of the coronavirus disease 2019 (COVID-19) pandemic.¹ Social distancing measures to reduce virus transmission are a significant driving factor.^1-3 In the age of biologics, other options requiring fewer patient visits are available, such as UVB phototherapy. UV phototherapy is considered first line when more than 10% of the body surface area is affected.⁴ Although phototherapy often is performed in the office, it also may be delivered at home.² Home-based phototherapy is safe, effective, and similar in cost to office-based phototherapy.⁴ Currently, there are limited COVID-19–specific guidelines for home-based phototherapy.

The risks and sequelae of COVID-19 are still being investigated, with cases varying by location. As such, local and national public health recommendations are evolving. Dermatologists must make individualized decisions about practice services, as local restrictions differ. As office-based phototherapy services may struggle to implement mitigation strategies, home-based phototherapy is an increasingly viable treatment option.^1,4,5 Patient benefits of home therapy include improved treatment compliance; greater patient satisfaction; reduced travel/waiting time; and reduced long-term cost, including co-pays, depending on insurance coverage.^2,4

We aim to provide recommendations on home-based phototherapy during the pandemic. Throughout the decision-making process, careful consideration of safety, risks, benefits, and treatment options for physicians, staff, and patients will be vital to the successful implementation of home-based phototherapy. Our recommendations are based on maximizing benefits and minimizing risks.

Considerations for Physicians

Physicians should take the following steps when assessing if home phototherapy is an option for each patient.^1,2,4

• Determine patient eligibility for phototherapy treatment if currently not on phototherapy

• Carefully review patient and provider requirements for home phototherapy supplier

• Review patient history of treatment compliance

• Determine insurance coverage and consider exclusion criteria

• Review prior treatments

• Provide education on side effects

• Provide education on signs of adequate treatment response

• Indicate the type of UV light and unit on the prescription

• Consider whether the patient is in the maintenance or initiation phase when providing recommendations

• Work with the supplier if the light therapy unit is denied by submitting an appeal or prescribing a different unit

• Follow up with telemedicine to assess treatment effectiveness and monitor for adverse effects

Considerations for Patients

Counsel patients to weigh the risks and benefits of home phototherapy prescription and usage.^1,2,4

• Evaluate cost

• Carefully review patient and provider requirements for home phototherapy supplier

• Ensure a complete understanding of treatment schedule

• Properly utilize protective equipment (eg, genital shields for men, eye shields for all)

• Avoid sharing phototherapy units with household members

• Disinfect and maintain units

• Maintain proper ventilation of spaces

• Maintain treatment log

• Attend follow-up

Treatment Alternatives

For patients with severe psoriasis, there are alternative treatments to office and home phototherapy. Biologics, immunosuppressive therapies, and other treatment options may be considered on a case-by-case basis.^3,4,6 Currently, recommendations for the risk of COVID-19 with biologics or systemic immunosuppressive therapies remains inconsistent and should be carefully considered when providing alternative treatments.^7-11

Final Thoughts

As restrictions are lifted according to local public health measures, prepandemic office phototherapy practices may resume operations. Home phototherapy is a practical and effective alternative for treatment of psoriasis when access to the office setting is limited.

Office-based phototherapy practices have closed or are operating below capacity because of the coronavirus disease 2019 (COVID-19) pandemic.¹ Social distancing measures to reduce virus transmission are a significant driving factor.^1-3 In the age of biologics, other options requiring fewer patient visits are available, such as UVB phototherapy. UV phototherapy is considered first line when more than 10% of the body surface area is affected.⁴ Although phototherapy often is performed in the office, it also may be delivered at home.² Home-based phototherapy is safe, effective, and similar in cost to office-based phototherapy.⁴ Currently, there are limited COVID-19–specific guidelines for home-based phototherapy.

The risks and sequelae of COVID-19 are still being investigated, with cases varying by location. As such, local and national public health recommendations are evolving. Dermatologists must make individualized decisions about practice services, as local restrictions differ. As office-based phototherapy services may struggle to implement mitigation strategies, home-based phototherapy is an increasingly viable treatment option.^1,4,5 Patient benefits of home therapy include improved treatment compliance; greater patient satisfaction; reduced travel/waiting time; and reduced long-term cost, including co-pays, depending on insurance coverage.^2,4

We aim to provide recommendations on home-based phototherapy during the pandemic. Throughout the decision-making process, careful consideration of safety, risks, benefits, and treatment options for physicians, staff, and patients will be vital to the successful implementation of home-based phototherapy. Our recommendations are based on maximizing benefits and minimizing risks.

Considerations for Physicians

Physicians should take the following steps when assessing if home phototherapy is an option for each patient.^1,2,4

• Determine patient eligibility for phototherapy treatment if currently not on phototherapy

• Carefully review patient and provider requirements for home phototherapy supplier

• Review patient history of treatment compliance

• Determine insurance coverage and consider exclusion criteria

• Review prior treatments

• Provide education on side effects

• Provide education on signs of adequate treatment response

• Indicate the type of UV light and unit on the prescription

• Consider whether the patient is in the maintenance or initiation phase when providing recommendations

• Work with the supplier if the light therapy unit is denied by submitting an appeal or prescribing a different unit

• Follow up with telemedicine to assess treatment effectiveness and monitor for adverse effects

Considerations for Patients

Counsel patients to weigh the risks and benefits of home phototherapy prescription and usage.^1,2,4

• Evaluate cost

• Carefully review patient and provider requirements for home phototherapy supplier

• Ensure a complete understanding of treatment schedule

• Properly utilize protective equipment (eg, genital shields for men, eye shields for all)

• Avoid sharing phototherapy units with household members

• Disinfect and maintain units

• Maintain proper ventilation of spaces

• Maintain treatment log

• Attend follow-up

Treatment Alternatives

For patients with severe psoriasis, there are alternative treatments to office and home phototherapy. Biologics, immunosuppressive therapies, and other treatment options may be considered on a case-by-case basis.^3,4,6 Currently, recommendations for the risk of COVID-19 with biologics or systemic immunosuppressive therapies remains inconsistent and should be carefully considered when providing alternative treatments.^7-11

Final Thoughts

As restrictions are lifted according to local public health measures, prepandemic office phototherapy practices may resume operations. Home phototherapy is a practical and effective alternative for treatment of psoriasis when access to the office setting is limited.

Office-based phototherapy practices have closed or are operating below capacity because of the coronavirus disease 2019 (COVID-19) pandemic.¹ Social distancing measures to reduce virus transmission are a significant driving factor.^1-3 In the age of biologics, other options requiring fewer patient visits are available, such as UVB phototherapy. UV phototherapy is considered first line when more than 10% of the body surface area is affected.⁴ Although phototherapy often is performed in the office, it also may be delivered at home.² Home-based phototherapy is safe, effective, and similar in cost to office-based phototherapy.⁴ Currently, there are limited COVID-19–specific guidelines for home-based phototherapy.

The risks and sequelae of COVID-19 are still being investigated, with cases varying by location. As such, local and national public health recommendations are evolving. Dermatologists must make individualized decisions about practice services, as local restrictions differ. As office-based phototherapy services may struggle to implement mitigation strategies, home-based phototherapy is an increasingly viable treatment option.^1,4,5 Patient benefits of home therapy include improved treatment compliance; greater patient satisfaction; reduced travel/waiting time; and reduced long-term cost, including co-pays, depending on insurance coverage.^2,4

We aim to provide recommendations on home-based phototherapy during the pandemic. Throughout the decision-making process, careful consideration of safety, risks, benefits, and treatment options for physicians, staff, and patients will be vital to the successful implementation of home-based phototherapy. Our recommendations are based on maximizing benefits and minimizing risks.

Considerations for Physicians

Physicians should take the following steps when assessing if home phototherapy is an option for each patient.^1,2,4

• Determine patient eligibility for phototherapy treatment if currently not on phototherapy

• Carefully review patient and provider requirements for home phototherapy supplier

• Review patient history of treatment compliance

• Determine insurance coverage and consider exclusion criteria

• Review prior treatments

• Provide education on side effects

• Provide education on signs of adequate treatment response

• Indicate the type of UV light and unit on the prescription

• Consider whether the patient is in the maintenance or initiation phase when providing recommendations

• Work with the supplier if the light therapy unit is denied by submitting an appeal or prescribing a different unit

• Follow up with telemedicine to assess treatment effectiveness and monitor for adverse effects

Considerations for Patients

Counsel patients to weigh the risks and benefits of home phototherapy prescription and usage.^1,2,4

• Evaluate cost

• Carefully review patient and provider requirements for home phototherapy supplier

• Ensure a complete understanding of treatment schedule

• Properly utilize protective equipment (eg, genital shields for men, eye shields for all)

• Avoid sharing phototherapy units with household members

• Disinfect and maintain units

• Maintain proper ventilation of spaces

• Maintain treatment log

• Attend follow-up

Treatment Alternatives

For patients with severe psoriasis, there are alternative treatments to office and home phototherapy. Biologics, immunosuppressive therapies, and other treatment options may be considered on a case-by-case basis.^3,4,6 Currently, recommendations for the risk of COVID-19 with biologics or systemic immunosuppressive therapies remains inconsistent and should be carefully considered when providing alternative treatments.^7-11

Final Thoughts

As restrictions are lifted according to local public health measures, prepandemic office phototherapy practices may resume operations. Home phototherapy is a practical and effective alternative for treatment of psoriasis when access to the office setting is limited.

The order Lepidoptera (phylum Arthropoda, class Hexapoda) is comprised of moths and butterflies.¹ Lepidopterism refers to a range of adverse medical conditions resulting from contact with these insects, typically during the caterpillar (larval) stage. It involves multiple pathologic mechanisms, including direct toxicity of venom and mechanical irritant effects.² Erucism has been defined as any reaction caused by contact with caterpillars or any reaction limited to the skin caused by contact with caterpillars, butterflies, or moths. Lepidopterism can mean any reaction to caterpillars or moths, referring only to reactions from contact with scales or hairs from adult moths or butterflies, or referring only to cases with systemic signs and symptoms (eg, rhinoconjunctival or asthmatic symptoms, angioedema and anaphylaxis, hemorrhagic diathesis) with or without cutaneous findings, resulting from contact with any lepidopteran source.¹ Strictly speaking, erucism should refer to any reaction from caterpillars and lepidopterism to reactions from moths or butterflies. Because reactions to both larval and adult lepidoptera can cause a variety of either cutaneous and/or systemic symptoms, classifying reactions into erucism or lepidopterism is only of academic interest.¹

We report a documented case of lepidopterism in a patient with acute cutaneous lesions following exposure to an adult-stage black butterfly (Hylesia nigricans).

Case Report

A 21-year-old oil well worker presented with pruritic skin lesions on the right arm and flank of 3 hours’ duration. He reported that a black butterfly had perched on his arm while he was working and left a considerable number of small yellowish hairs on the skin, after which an intense pruritus and skin lesions began to develop. He denied other associated symptoms. Physical examination revealed numerous 1- to 2-mm, nonconfluent, erythematous and edematous papules on the right forearm, arm (Figure 1A), and flank. Some abrasions of the skin due to scratching and crusting were noted (Figure 1B). A skin biopsy from the right arm showed a superficial perivascular dermatitis with a mixed infiltrate of polymorphonuclear predominance with eosinophils (Figure 2A). Importantly, a structure resembling an urticating spicule was identified in the stratum corneum (Figure 2B); spicules are located on the abdomen of arthropods and are associated with an inflammatory response in human skin.

Based on the patient’s history of butterfly exposure, clinical presentation of the lesions, and histopathologic findings demonstrating the presence of the spicules, the diagnosis of lepidopterism was confirmed. The patient was treated with oral antihistamines and topical steroids for 1 week with complete resolution of the lesions.

Comment

Epidemiology of Envenomation
Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, such as dermatitis caused by contact with the skin (erucism or lepidopterism). Caterpillar envenomation is common, but this phenomenon rarely has been studied due to few reported cases, which hinders a complete understanding of the problem.³

The order Lepidoptera comprises 2 suborders: Rhopalocera, with adult specimens that fly during the daytime (butterflies), and Heterocera, which are largely nocturnal (moths). The stages of development include egg, larva (caterpillar), pupa (chrysalis), and adult (imago), constituting a holometabolic life cycle.⁴ Adult butterflies and moths represent the reproductive stage of lepidoptera.

The pathology of lepidopterism is attributed to contact with fluids such as hemolymph and secretions from the spicules, with histamine being identified as the main causative component.³ During the reproductive stage, female insects approach light sources and release clouds of bristles from their abdomens that can penetrate human skin and cause an irritating dermatitis.⁵ Lepidopterism can occur following contact with bristles from insects of the Hylesia genus (Saturniidae family), such as in our patient.^3,6 Epidemic outbreaks have been reported in several countries, mainly Argentina, Brazil, and Venezuela.⁵ The patient was located in Colombia, a country without any reported cases of lepidopterism from the black butterfly (H nigricans). Cutaneous reactions to lepidoptera insects come in many forms, most commonly presenting as a mild stinging reaction with a papular eruption, pruritic urticarial papules and plaques, or scaly erythematous papules and plaques in exposed areas.⁷

Histopathologic Findings
The histology of lepidoptera exposure is nonspecific, typically demonstrating epidermal edema, superficial perivascular lymphocytic infiltrate, and eosinophils. Epidermal necrosis and vasculitis rarely are seen. Embedded spines from Hylesia insects have been described.⁷ The histopathologic examination generally reveals a foreign body reaction in addition to granulomas.³

Therapy
The use of oral antihistamines is indicated for the control of pruritus, and topical treatment with cold compresses, baths, and corticosteroid creams is recommended.^3,8,9

Conclusion

We report the case of a patient with lepidopterism, a rare entity confirmed histologically with documentation of a spicule in the stratum corneum in the patient’s biopsy. Changes due to urbanization and industrialization have a closer relationship with various animal species that are pathogenic to humans; therefore, we encourage dermatologists to be aware of these diseases.

The order Lepidoptera (phylum Arthropoda, class Hexapoda) is comprised of moths and butterflies.¹ Lepidopterism refers to a range of adverse medical conditions resulting from contact with these insects, typically during the caterpillar (larval) stage. It involves multiple pathologic mechanisms, including direct toxicity of venom and mechanical irritant effects.² Erucism has been defined as any reaction caused by contact with caterpillars or any reaction limited to the skin caused by contact with caterpillars, butterflies, or moths. Lepidopterism can mean any reaction to caterpillars or moths, referring only to reactions from contact with scales or hairs from adult moths or butterflies, or referring only to cases with systemic signs and symptoms (eg, rhinoconjunctival or asthmatic symptoms, angioedema and anaphylaxis, hemorrhagic diathesis) with or without cutaneous findings, resulting from contact with any lepidopteran source.¹ Strictly speaking, erucism should refer to any reaction from caterpillars and lepidopterism to reactions from moths or butterflies. Because reactions to both larval and adult lepidoptera can cause a variety of either cutaneous and/or systemic symptoms, classifying reactions into erucism or lepidopterism is only of academic interest.¹

We report a documented case of lepidopterism in a patient with acute cutaneous lesions following exposure to an adult-stage black butterfly (Hylesia nigricans).

Case Report

A 21-year-old oil well worker presented with pruritic skin lesions on the right arm and flank of 3 hours’ duration. He reported that a black butterfly had perched on his arm while he was working and left a considerable number of small yellowish hairs on the skin, after which an intense pruritus and skin lesions began to develop. He denied other associated symptoms. Physical examination revealed numerous 1- to 2-mm, nonconfluent, erythematous and edematous papules on the right forearm, arm (Figure 1A), and flank. Some abrasions of the skin due to scratching and crusting were noted (Figure 1B). A skin biopsy from the right arm showed a superficial perivascular dermatitis with a mixed infiltrate of polymorphonuclear predominance with eosinophils (Figure 2A). Importantly, a structure resembling an urticating spicule was identified in the stratum corneum (Figure 2B); spicules are located on the abdomen of arthropods and are associated with an inflammatory response in human skin.

Based on the patient’s history of butterfly exposure, clinical presentation of the lesions, and histopathologic findings demonstrating the presence of the spicules, the diagnosis of lepidopterism was confirmed. The patient was treated with oral antihistamines and topical steroids for 1 week with complete resolution of the lesions.

Comment

Epidemiology of Envenomation
Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, such as dermatitis caused by contact with the skin (erucism or lepidopterism). Caterpillar envenomation is common, but this phenomenon rarely has been studied due to few reported cases, which hinders a complete understanding of the problem.³

The order Lepidoptera comprises 2 suborders: Rhopalocera, with adult specimens that fly during the daytime (butterflies), and Heterocera, which are largely nocturnal (moths). The stages of development include egg, larva (caterpillar), pupa (chrysalis), and adult (imago), constituting a holometabolic life cycle.⁴ Adult butterflies and moths represent the reproductive stage of lepidoptera.

The pathology of lepidopterism is attributed to contact with fluids such as hemolymph and secretions from the spicules, with histamine being identified as the main causative component.³ During the reproductive stage, female insects approach light sources and release clouds of bristles from their abdomens that can penetrate human skin and cause an irritating dermatitis.⁵ Lepidopterism can occur following contact with bristles from insects of the Hylesia genus (Saturniidae family), such as in our patient.^3,6 Epidemic outbreaks have been reported in several countries, mainly Argentina, Brazil, and Venezuela.⁵ The patient was located in Colombia, a country without any reported cases of lepidopterism from the black butterfly (H nigricans). Cutaneous reactions to lepidoptera insects come in many forms, most commonly presenting as a mild stinging reaction with a papular eruption, pruritic urticarial papules and plaques, or scaly erythematous papules and plaques in exposed areas.⁷

Histopathologic Findings
The histology of lepidoptera exposure is nonspecific, typically demonstrating epidermal edema, superficial perivascular lymphocytic infiltrate, and eosinophils. Epidermal necrosis and vasculitis rarely are seen. Embedded spines from Hylesia insects have been described.⁷ The histopathologic examination generally reveals a foreign body reaction in addition to granulomas.³

Therapy
The use of oral antihistamines is indicated for the control of pruritus, and topical treatment with cold compresses, baths, and corticosteroid creams is recommended.^3,8,9

Conclusion

We report the case of a patient with lepidopterism, a rare entity confirmed histologically with documentation of a spicule in the stratum corneum in the patient’s biopsy. Changes due to urbanization and industrialization have a closer relationship with various animal species that are pathogenic to humans; therefore, we encourage dermatologists to be aware of these diseases.

The order Lepidoptera (phylum Arthropoda, class Hexapoda) is comprised of moths and butterflies.¹ Lepidopterism refers to a range of adverse medical conditions resulting from contact with these insects, typically during the caterpillar (larval) stage. It involves multiple pathologic mechanisms, including direct toxicity of venom and mechanical irritant effects.² Erucism has been defined as any reaction caused by contact with caterpillars or any reaction limited to the skin caused by contact with caterpillars, butterflies, or moths. Lepidopterism can mean any reaction to caterpillars or moths, referring only to reactions from contact with scales or hairs from adult moths or butterflies, or referring only to cases with systemic signs and symptoms (eg, rhinoconjunctival or asthmatic symptoms, angioedema and anaphylaxis, hemorrhagic diathesis) with or without cutaneous findings, resulting from contact with any lepidopteran source.¹ Strictly speaking, erucism should refer to any reaction from caterpillars and lepidopterism to reactions from moths or butterflies. Because reactions to both larval and adult lepidoptera can cause a variety of either cutaneous and/or systemic symptoms, classifying reactions into erucism or lepidopterism is only of academic interest.¹

We report a documented case of lepidopterism in a patient with acute cutaneous lesions following exposure to an adult-stage black butterfly (Hylesia nigricans).

Case Report

A 21-year-old oil well worker presented with pruritic skin lesions on the right arm and flank of 3 hours’ duration. He reported that a black butterfly had perched on his arm while he was working and left a considerable number of small yellowish hairs on the skin, after which an intense pruritus and skin lesions began to develop. He denied other associated symptoms. Physical examination revealed numerous 1- to 2-mm, nonconfluent, erythematous and edematous papules on the right forearm, arm (Figure 1A), and flank. Some abrasions of the skin due to scratching and crusting were noted (Figure 1B). A skin biopsy from the right arm showed a superficial perivascular dermatitis with a mixed infiltrate of polymorphonuclear predominance with eosinophils (Figure 2A). Importantly, a structure resembling an urticating spicule was identified in the stratum corneum (Figure 2B); spicules are located on the abdomen of arthropods and are associated with an inflammatory response in human skin.

Based on the patient’s history of butterfly exposure, clinical presentation of the lesions, and histopathologic findings demonstrating the presence of the spicules, the diagnosis of lepidopterism was confirmed. The patient was treated with oral antihistamines and topical steroids for 1 week with complete resolution of the lesions.

Comment

Epidemiology of Envenomation
Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, such as dermatitis caused by contact with the skin (erucism or lepidopterism). Caterpillar envenomation is common, but this phenomenon rarely has been studied due to few reported cases, which hinders a complete understanding of the problem.³

The order Lepidoptera comprises 2 suborders: Rhopalocera, with adult specimens that fly during the daytime (butterflies), and Heterocera, which are largely nocturnal (moths). The stages of development include egg, larva (caterpillar), pupa (chrysalis), and adult (imago), constituting a holometabolic life cycle.⁴ Adult butterflies and moths represent the reproductive stage of lepidoptera.

The pathology of lepidopterism is attributed to contact with fluids such as hemolymph and secretions from the spicules, with histamine being identified as the main causative component.³ During the reproductive stage, female insects approach light sources and release clouds of bristles from their abdomens that can penetrate human skin and cause an irritating dermatitis.⁵ Lepidopterism can occur following contact with bristles from insects of the Hylesia genus (Saturniidae family), such as in our patient.^3,6 Epidemic outbreaks have been reported in several countries, mainly Argentina, Brazil, and Venezuela.⁵ The patient was located in Colombia, a country without any reported cases of lepidopterism from the black butterfly (H nigricans). Cutaneous reactions to lepidoptera insects come in many forms, most commonly presenting as a mild stinging reaction with a papular eruption, pruritic urticarial papules and plaques, or scaly erythematous papules and plaques in exposed areas.⁷

Histopathologic Findings
The histology of lepidoptera exposure is nonspecific, typically demonstrating epidermal edema, superficial perivascular lymphocytic infiltrate, and eosinophils. Epidermal necrosis and vasculitis rarely are seen. Embedded spines from Hylesia insects have been described.⁷ The histopathologic examination generally reveals a foreign body reaction in addition to granulomas.³

Therapy
The use of oral antihistamines is indicated for the control of pruritus, and topical treatment with cold compresses, baths, and corticosteroid creams is recommended.^3,8,9

Conclusion

We report the case of a patient with lepidopterism, a rare entity confirmed histologically with documentation of a spicule in the stratum corneum in the patient’s biopsy. Changes due to urbanization and industrialization have a closer relationship with various animal species that are pathogenic to humans; therefore, we encourage dermatologists to be aware of these diseases.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

The treatment landscape for psoriasis has evolved rapidly over the last decade. Biologic therapies have demonstrated robust efficacy and acceptable safety profiles among many patients with moderate to severe plaque psoriasis. However, the use of biologics among immunocompromised patients with psoriasis rarely is discussed in the literature. As new biologics for psoriasis are being developed, a critical gap exists in the literature regarding the safety and efficacy of these medications in immunocompromised patients. Per American Academy of Dermatology–National Psoriasis Foundation guidelines, caution should be exercised when using biologics in patients with immunocompromising conditions.¹ In organ transplant recipients, the potential risks of combining systemic medications used for organ transplantation and biologic treatments for psoriasis are unknown.²

In the posttransplant period, the immunosuppressive regimens for transplantation likely will improve psoriasis. However, patients with organ transplant and psoriasis still experience flares that can be challenging to treat.³ Prior treatment modalities to prevent psoriasis flares in organ transplant recipients have relied largely on topical therapies, posttransplant immunosuppressive medications (eg, cyclosporine, tacrolimus, mycophenolate mofetil) that prevent graft rejection, and systemic corticosteroids. We report a case of a 50-year-old man with a recent history of liver transplantation who presented with severe plaque psoriasis and psoriatic arthritis.

Case Report

A 50-year-old man presented to the dermatology clinic with moderate to severe plaque psoriasis and psoriatic arthritis that had been present for 15 years. His plaque psoriasis covered approximately 40% of the body surface area, including the scalp, trunk, arms, and legs. In addition, he had diffuse joint pain in the hands and feet; a radiograph revealed active psoriatic arthritis involving the joints of the fingers and toes.

One year prior to presentation to our dermatology clinic, the patient underwent an an orthotopic liver transplant for history of Child-Pugh class C liver cirrhosis secondary to untreated hepatitis C virus (HCV) and alcohol use that was complicated by hepatocellular carcinoma. He acquired a high-risk donor liver that was HCV positive with HCV genotype 1a. Starting 2 months after the transplant, he underwent 12 weeks of treatment for HCV with glecaprevir-pibrentasvir. Once his HCV treatment course was completed, he achieved a sustained virologic response with an undetectable viral load. To prevent transplant rejection, he was on chronic immunosuppression with tacrolimus, a calcineurin inhibitor, and mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase whose action leads to decreased proliferation of T cells and B cells.

The patient’s psoriasis initially was treated with triamcinolone acetonide ointment 0.1% applied twice daily to the psoriasis lesions for 1 year by another dermatologist. However, his psoriasis progressed to involve 40% of the body surface area. Following our evaluation 1 year posttransplant, the patient was started on subcutaneous brodalumab 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter. Approximately 10 weeks after initiation of brodalumab, the patient’s psoriasis was completely clear, and he was asymptomatic from psoriatic arthritis. The patient’s improvement persisted at 6 months, and his liver enzymes, including alkaline phosphatase, total bilirubin, alanine transaminase, and aspartate transaminase, continued to be within reference range. To date, there has been no evidence of posttransplant complications such as graft-vs-host disease, serious infections, or skin cancers.

Comment

Increased Risk for Infection and Malignancies in Transplant Patients
Transplant patients are on immunosuppressive regimens that increase their risk for infection and malignancies. For example, high doses of immunosuppresants predispose these patients to reactivation of viral infections, including BK and JC viruses.⁴ In addition, the incidence of squamous cell carcinoma is 65- to 250-fold higher in transplant patients compared to the general population.⁵ The risk for Merkel cell carcinoma is increased after solid organ transplantation compared to the general population.⁶ Importantly, transplant patients have a higher mortality from skin cancers than other types of cancers, including breast and colon cancer.⁷

Psoriasis in Organ Transplant Recipients
Psoriasis is a chronic, immune-mediated, inflammatory disease with a prevalence of approximately 3% in the United States.⁸ Approximately one-third of patients with psoriasis develop psoriatic arthritis.⁹ Organ transplant recipients with psoriasis and psoriatic arthritis represent a unique patient population whereby their use of chronic immunosuppressive medications to prevent graft rejection may put them at risk for developing infections and malignancies.

Special Considerations for Brodalumab
Brodalumab is an immunomodulatory biologic that binds to and inhibits IL-17RA, thereby inhibiting the actions of IL-17A, F, E, and C.² The blockade of IL-17RA by brodalumab has been shown to result in reversal of psoriatic phenotype and gene expression patterns.¹⁰ Brodalumab was chosen as the treatment in our patient because it has a rapid onset of action, sustained efficacy, and an acceptable safety profile.¹¹ Brodalumab is well tolerated, with approximately 60% of patients achieving clearance long-term.¹² Candidal infections can occur in patients with brodalumab, but the rates are low and they are reversible with antifungal treatment.¹³ The increased mucocutaneous candidal infections are consistent with medications whose mechanism of action is IL-17 inhibition.^14,15 The most common adverse reactions found were nasopharyngitis and headache.¹⁶ The causal link between brodalumab and suicidality has not been established.¹⁷

The use of brodalumab for psoriasis in organ transplant recipients has not been previously reported in the literature. A few case reports have been published on the successful use of etanercept and ixekizumab as biologic treatment options for psoriasis in transplant patients.^18-23 In addition to choosing an appropriate biologic for psoriasis in transplant patients, transplant providers may evaluate the choice of immunosuppression regimen for the organ transplant in the context of psoriasis. In a retrospective analysis of liver transplant patients with psoriasis, Foroncewicz et al³ found cyclosporine, which was used as an antirejection immunosuppressive agent in the posttransplant period, to be more effective than tacrolimus in treating recurrent psoriasis in liver transplant recipients.

Our case illustrates one example of the successful use of brodalumab in a patient with a solid organ transplant. Our patient’s psoriasis and symptoms of psoriatic arthritis greatly improved after initiation of brodalumab. In the posttransplant period, the patient did not develop graft-vs-host disease, infections, malignancies, depression, or suicidal ideation while taking brodalumab.

Conclusion

It is important that the patient, dermatology team, and transplant team work together to navigate the challenges and relatively unknown landscape of psoriasis treatment in organ transplant recipients. As the number of organ transplant recipients continues to increase, this issue will become more clinically relevant. Case reports and future prospective studies will continue to inform us regarding the role of biologics in psoriasis treatment posttransplantation.

The treatment landscape for psoriasis has evolved rapidly over the last decade. Biologic therapies have demonstrated robust efficacy and acceptable safety profiles among many patients with moderate to severe plaque psoriasis. However, the use of biologics among immunocompromised patients with psoriasis rarely is discussed in the literature. As new biologics for psoriasis are being developed, a critical gap exists in the literature regarding the safety and efficacy of these medications in immunocompromised patients. Per American Academy of Dermatology–National Psoriasis Foundation guidelines, caution should be exercised when using biologics in patients with immunocompromising conditions.¹ In organ transplant recipients, the potential risks of combining systemic medications used for organ transplantation and biologic treatments for psoriasis are unknown.²

In the posttransplant period, the immunosuppressive regimens for transplantation likely will improve psoriasis. However, patients with organ transplant and psoriasis still experience flares that can be challenging to treat.³ Prior treatment modalities to prevent psoriasis flares in organ transplant recipients have relied largely on topical therapies, posttransplant immunosuppressive medications (eg, cyclosporine, tacrolimus, mycophenolate mofetil) that prevent graft rejection, and systemic corticosteroids. We report a case of a 50-year-old man with a recent history of liver transplantation who presented with severe plaque psoriasis and psoriatic arthritis.

Case Report

A 50-year-old man presented to the dermatology clinic with moderate to severe plaque psoriasis and psoriatic arthritis that had been present for 15 years. His plaque psoriasis covered approximately 40% of the body surface area, including the scalp, trunk, arms, and legs. In addition, he had diffuse joint pain in the hands and feet; a radiograph revealed active psoriatic arthritis involving the joints of the fingers and toes.

One year prior to presentation to our dermatology clinic, the patient underwent an an orthotopic liver transplant for history of Child-Pugh class C liver cirrhosis secondary to untreated hepatitis C virus (HCV) and alcohol use that was complicated by hepatocellular carcinoma. He acquired a high-risk donor liver that was HCV positive with HCV genotype 1a. Starting 2 months after the transplant, he underwent 12 weeks of treatment for HCV with glecaprevir-pibrentasvir. Once his HCV treatment course was completed, he achieved a sustained virologic response with an undetectable viral load. To prevent transplant rejection, he was on chronic immunosuppression with tacrolimus, a calcineurin inhibitor, and mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase whose action leads to decreased proliferation of T cells and B cells.

The patient’s psoriasis initially was treated with triamcinolone acetonide ointment 0.1% applied twice daily to the psoriasis lesions for 1 year by another dermatologist. However, his psoriasis progressed to involve 40% of the body surface area. Following our evaluation 1 year posttransplant, the patient was started on subcutaneous brodalumab 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter. Approximately 10 weeks after initiation of brodalumab, the patient’s psoriasis was completely clear, and he was asymptomatic from psoriatic arthritis. The patient’s improvement persisted at 6 months, and his liver enzymes, including alkaline phosphatase, total bilirubin, alanine transaminase, and aspartate transaminase, continued to be within reference range. To date, there has been no evidence of posttransplant complications such as graft-vs-host disease, serious infections, or skin cancers.

Comment

Increased Risk for Infection and Malignancies in Transplant Patients
Transplant patients are on immunosuppressive regimens that increase their risk for infection and malignancies. For example, high doses of immunosuppresants predispose these patients to reactivation of viral infections, including BK and JC viruses.⁴ In addition, the incidence of squamous cell carcinoma is 65- to 250-fold higher in transplant patients compared to the general population.⁵ The risk for Merkel cell carcinoma is increased after solid organ transplantation compared to the general population.⁶ Importantly, transplant patients have a higher mortality from skin cancers than other types of cancers, including breast and colon cancer.⁷

Psoriasis in Organ Transplant Recipients
Psoriasis is a chronic, immune-mediated, inflammatory disease with a prevalence of approximately 3% in the United States.⁸ Approximately one-third of patients with psoriasis develop psoriatic arthritis.⁹ Organ transplant recipients with psoriasis and psoriatic arthritis represent a unique patient population whereby their use of chronic immunosuppressive medications to prevent graft rejection may put them at risk for developing infections and malignancies.

Special Considerations for Brodalumab
Brodalumab is an immunomodulatory biologic that binds to and inhibits IL-17RA, thereby inhibiting the actions of IL-17A, F, E, and C.² The blockade of IL-17RA by brodalumab has been shown to result in reversal of psoriatic phenotype and gene expression patterns.¹⁰ Brodalumab was chosen as the treatment in our patient because it has a rapid onset of action, sustained efficacy, and an acceptable safety profile.¹¹ Brodalumab is well tolerated, with approximately 60% of patients achieving clearance long-term.¹² Candidal infections can occur in patients with brodalumab, but the rates are low and they are reversible with antifungal treatment.¹³ The increased mucocutaneous candidal infections are consistent with medications whose mechanism of action is IL-17 inhibition.^14,15 The most common adverse reactions found were nasopharyngitis and headache.¹⁶ The causal link between brodalumab and suicidality has not been established.¹⁷

The use of brodalumab for psoriasis in organ transplant recipients has not been previously reported in the literature. A few case reports have been published on the successful use of etanercept and ixekizumab as biologic treatment options for psoriasis in transplant patients.^18-23 In addition to choosing an appropriate biologic for psoriasis in transplant patients, transplant providers may evaluate the choice of immunosuppression regimen for the organ transplant in the context of psoriasis. In a retrospective analysis of liver transplant patients with psoriasis, Foroncewicz et al³ found cyclosporine, which was used as an antirejection immunosuppressive agent in the posttransplant period, to be more effective than tacrolimus in treating recurrent psoriasis in liver transplant recipients.

Our case illustrates one example of the successful use of brodalumab in a patient with a solid organ transplant. Our patient’s psoriasis and symptoms of psoriatic arthritis greatly improved after initiation of brodalumab. In the posttransplant period, the patient did not develop graft-vs-host disease, infections, malignancies, depression, or suicidal ideation while taking brodalumab.

Conclusion

It is important that the patient, dermatology team, and transplant team work together to navigate the challenges and relatively unknown landscape of psoriasis treatment in organ transplant recipients. As the number of organ transplant recipients continues to increase, this issue will become more clinically relevant. Case reports and future prospective studies will continue to inform us regarding the role of biologics in psoriasis treatment posttransplantation.

The treatment landscape for psoriasis has evolved rapidly over the last decade. Biologic therapies have demonstrated robust efficacy and acceptable safety profiles among many patients with moderate to severe plaque psoriasis. However, the use of biologics among immunocompromised patients with psoriasis rarely is discussed in the literature. As new biologics for psoriasis are being developed, a critical gap exists in the literature regarding the safety and efficacy of these medications in immunocompromised patients. Per American Academy of Dermatology–National Psoriasis Foundation guidelines, caution should be exercised when using biologics in patients with immunocompromising conditions.¹ In organ transplant recipients, the potential risks of combining systemic medications used for organ transplantation and biologic treatments for psoriasis are unknown.²

In the posttransplant period, the immunosuppressive regimens for transplantation likely will improve psoriasis. However, patients with organ transplant and psoriasis still experience flares that can be challenging to treat.³ Prior treatment modalities to prevent psoriasis flares in organ transplant recipients have relied largely on topical therapies, posttransplant immunosuppressive medications (eg, cyclosporine, tacrolimus, mycophenolate mofetil) that prevent graft rejection, and systemic corticosteroids. We report a case of a 50-year-old man with a recent history of liver transplantation who presented with severe plaque psoriasis and psoriatic arthritis.

Case Report

A 50-year-old man presented to the dermatology clinic with moderate to severe plaque psoriasis and psoriatic arthritis that had been present for 15 years. His plaque psoriasis covered approximately 40% of the body surface area, including the scalp, trunk, arms, and legs. In addition, he had diffuse joint pain in the hands and feet; a radiograph revealed active psoriatic arthritis involving the joints of the fingers and toes.

One year prior to presentation to our dermatology clinic, the patient underwent an an orthotopic liver transplant for history of Child-Pugh class C liver cirrhosis secondary to untreated hepatitis C virus (HCV) and alcohol use that was complicated by hepatocellular carcinoma. He acquired a high-risk donor liver that was HCV positive with HCV genotype 1a. Starting 2 months after the transplant, he underwent 12 weeks of treatment for HCV with glecaprevir-pibrentasvir. Once his HCV treatment course was completed, he achieved a sustained virologic response with an undetectable viral load. To prevent transplant rejection, he was on chronic immunosuppression with tacrolimus, a calcineurin inhibitor, and mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase whose action leads to decreased proliferation of T cells and B cells.

The patient’s psoriasis initially was treated with triamcinolone acetonide ointment 0.1% applied twice daily to the psoriasis lesions for 1 year by another dermatologist. However, his psoriasis progressed to involve 40% of the body surface area. Following our evaluation 1 year posttransplant, the patient was started on subcutaneous brodalumab 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter. Approximately 10 weeks after initiation of brodalumab, the patient’s psoriasis was completely clear, and he was asymptomatic from psoriatic arthritis. The patient’s improvement persisted at 6 months, and his liver enzymes, including alkaline phosphatase, total bilirubin, alanine transaminase, and aspartate transaminase, continued to be within reference range. To date, there has been no evidence of posttransplant complications such as graft-vs-host disease, serious infections, or skin cancers.

Comment

Increased Risk for Infection and Malignancies in Transplant Patients
Transplant patients are on immunosuppressive regimens that increase their risk for infection and malignancies. For example, high doses of immunosuppresants predispose these patients to reactivation of viral infections, including BK and JC viruses.⁴ In addition, the incidence of squamous cell carcinoma is 65- to 250-fold higher in transplant patients compared to the general population.⁵ The risk for Merkel cell carcinoma is increased after solid organ transplantation compared to the general population.⁶ Importantly, transplant patients have a higher mortality from skin cancers than other types of cancers, including breast and colon cancer.⁷

Psoriasis in Organ Transplant Recipients
Psoriasis is a chronic, immune-mediated, inflammatory disease with a prevalence of approximately 3% in the United States.⁸ Approximately one-third of patients with psoriasis develop psoriatic arthritis.⁹ Organ transplant recipients with psoriasis and psoriatic arthritis represent a unique patient population whereby their use of chronic immunosuppressive medications to prevent graft rejection may put them at risk for developing infections and malignancies.

Special Considerations for Brodalumab
Brodalumab is an immunomodulatory biologic that binds to and inhibits IL-17RA, thereby inhibiting the actions of IL-17A, F, E, and C.² The blockade of IL-17RA by brodalumab has been shown to result in reversal of psoriatic phenotype and gene expression patterns.¹⁰ Brodalumab was chosen as the treatment in our patient because it has a rapid onset of action, sustained efficacy, and an acceptable safety profile.¹¹ Brodalumab is well tolerated, with approximately 60% of patients achieving clearance long-term.¹² Candidal infections can occur in patients with brodalumab, but the rates are low and they are reversible with antifungal treatment.¹³ The increased mucocutaneous candidal infections are consistent with medications whose mechanism of action is IL-17 inhibition.^14,15 The most common adverse reactions found were nasopharyngitis and headache.¹⁶ The causal link between brodalumab and suicidality has not been established.¹⁷

The use of brodalumab for psoriasis in organ transplant recipients has not been previously reported in the literature. A few case reports have been published on the successful use of etanercept and ixekizumab as biologic treatment options for psoriasis in transplant patients.^18-23 In addition to choosing an appropriate biologic for psoriasis in transplant patients, transplant providers may evaluate the choice of immunosuppression regimen for the organ transplant in the context of psoriasis. In a retrospective analysis of liver transplant patients with psoriasis, Foroncewicz et al³ found cyclosporine, which was used as an antirejection immunosuppressive agent in the posttransplant period, to be more effective than tacrolimus in treating recurrent psoriasis in liver transplant recipients.

Our case illustrates one example of the successful use of brodalumab in a patient with a solid organ transplant. Our patient’s psoriasis and symptoms of psoriatic arthritis greatly improved after initiation of brodalumab. In the posttransplant period, the patient did not develop graft-vs-host disease, infections, malignancies, depression, or suicidal ideation while taking brodalumab.

Conclusion

It is important that the patient, dermatology team, and transplant team work together to navigate the challenges and relatively unknown landscape of psoriasis treatment in organ transplant recipients. As the number of organ transplant recipients continues to increase, this issue will become more clinically relevant. Case reports and future prospective studies will continue to inform us regarding the role of biologics in psoriasis treatment posttransplantation.

Case Report

An 80-year-old man with a history of hypertension and coronary artery disease presented to the dermatology clinic with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the abdomen, back, and leg (Figure 1). He reported that these “growths” appeared 20 years prior to presentation, shortly after coronary artery bypass surgery with a saphenous vein graft. The patient initially was given a diagnosis of verruca vulgaris and then biopsy-proven psoriasis later that year. At that time, he refused systemic treatment and was treated instead with triamcinolone acetonide ointment, with periodic surgical removal of bothersome lesions.

At the current presentation, physical examination revealed many hyperkeratotic, yellow-gray, verrucous nodules overlying scaly, erythematous, sharply demarcated plaques, exclusively on the left side of the body, including the left side of the abdomen, back, and leg. The differential diagnosis included linear psoriasis and inflammatory linear verrucous epidermal nevus (ILVEN).

Skin biopsy showed irregular psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and papillomatosis, with convergence of the rete ridges, known as buttressing (Figure 2A). There were tortuous dilated blood vessels in the dermal papillae, epidermal neutrophils at the tip of the suprapapillary plates, and Munro microabscesses in the stratum corneum (Figure 2B). Koilocytes were absent, and periodic acid–Schiff staining was negative. Taken together, clinical and histologic features led to a diagnosis of unilateral verrucous psoriasis.

Comment

Presentation and Histology
Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. It typically arises in patients with established psoriasis but can occur de novo.

Histologic features of verrucous psoriasis include epidermal hyperplasia with acanthosis, papillomatosis, and epidermal buttressing.¹ It has been hypothesized that notable hyperkeratosis observed in these lesions is induced by repeat trauma to the extremities in patients with established psoriasis or by anoxia from conditions that predispose to poor circulation, such as diabetes mellitus and pulmonary disease.^1,2

Pathogenesis
Most reported cases of verrucous psoriasis arose atop pre-existing psoriasis lesions.^3,4 The relevance of our patient’s verrucous psoriasis to his prior coronary artery bypass surgery with saphenous vein graft is unknown; however, the distribution of lesions, timing of psoriasis onset in relation to the surgical procedure, and recent data proposing a role for neuropeptide responses to nerve injury in the development of psoriasis, taken together, provide an argument for a role for surgical trauma in the development of our patient’s condition.

Treatment
Although verrucous psoriasis presents both diagnostic and therapeutic challenges, there are some reports of improvement with topical or intralesional corticosteroids in combination with keratolytics,³ coal tar,⁵ and oral methotrexate.⁶ In addition, there are rare reports of successful treatment with biologics. A case report showed successful resolution with adalimumab,⁴ and a case of erythrodermic verrucous psoriasis showed moderate improvement with ustekinumab after other failed treatments.⁷

Differential Diagnosis
Psoriasis typically presents in a symmetric distribution, with rare reported cases of unilateral distribution. Two cases of unilateral psoriasis arising after a surgical procedure have been reported, one after mastectomy and the other after neurosurgery.^8,9 Other cases of unilateral psoriasis are reported to have arisen in adolescents and young adults idiopathically.

A case of linear psoriasis arising in the distribution of the sciatic nerve in a patient with radiculopathy implicated tumor necrosis factor α, neuropeptides, and nerve growth factor released in response to compression as possible etiologic agents.¹⁰ However, none of the reported cases of linear psoriasis, or reported cases of unilateral psoriasis, exhibited verrucous features clinically or histologically. In our patient, distribution of the lesions appeared less typically blaschkoid than in linear psoriasis, and the presence of exophytic wartlike growths throughout the lesions was not characteristic of linear psoriasis.

Late-adulthood onset in this patient in addition to the absence of typical histologic features of ILVEN, including alternating orthokeratosis and parakeratosis,¹¹ make a diagnosis of ILVEN less likely; ILVEN can be distinguished from linear psoriasis based on later age of onset and responsiveness to antipsoriatic therapy of linear psoriasis.¹²

Conclusion

We describe a unique presentation of an already rare variant of psoriasis that can be difficult to diagnose clinically. The unilateral distribution of lesions in this patient can create further diagnostic confusion with other entities, such as ILVEN and linear psoriasis, though it can be distinguished from those diseases based on histologic features. Our aim is that this report improves recognition of this unusual presentation of verrucous psoriasis in clinical settings and decreases delays in diagnosis and treatment.

Case Report

An 80-year-old man with a history of hypertension and coronary artery disease presented to the dermatology clinic with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the abdomen, back, and leg (Figure 1). He reported that these “growths” appeared 20 years prior to presentation, shortly after coronary artery bypass surgery with a saphenous vein graft. The patient initially was given a diagnosis of verruca vulgaris and then biopsy-proven psoriasis later that year. At that time, he refused systemic treatment and was treated instead with triamcinolone acetonide ointment, with periodic surgical removal of bothersome lesions.

At the current presentation, physical examination revealed many hyperkeratotic, yellow-gray, verrucous nodules overlying scaly, erythematous, sharply demarcated plaques, exclusively on the left side of the body, including the left side of the abdomen, back, and leg. The differential diagnosis included linear psoriasis and inflammatory linear verrucous epidermal nevus (ILVEN).

Skin biopsy showed irregular psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and papillomatosis, with convergence of the rete ridges, known as buttressing (Figure 2A). There were tortuous dilated blood vessels in the dermal papillae, epidermal neutrophils at the tip of the suprapapillary plates, and Munro microabscesses in the stratum corneum (Figure 2B). Koilocytes were absent, and periodic acid–Schiff staining was negative. Taken together, clinical and histologic features led to a diagnosis of unilateral verrucous psoriasis.

Comment

Presentation and Histology
Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. It typically arises in patients with established psoriasis but can occur de novo.

Histologic features of verrucous psoriasis include epidermal hyperplasia with acanthosis, papillomatosis, and epidermal buttressing.¹ It has been hypothesized that notable hyperkeratosis observed in these lesions is induced by repeat trauma to the extremities in patients with established psoriasis or by anoxia from conditions that predispose to poor circulation, such as diabetes mellitus and pulmonary disease.^1,2

Pathogenesis
Most reported cases of verrucous psoriasis arose atop pre-existing psoriasis lesions.^3,4 The relevance of our patient’s verrucous psoriasis to his prior coronary artery bypass surgery with saphenous vein graft is unknown; however, the distribution of lesions, timing of psoriasis onset in relation to the surgical procedure, and recent data proposing a role for neuropeptide responses to nerve injury in the development of psoriasis, taken together, provide an argument for a role for surgical trauma in the development of our patient’s condition.

Treatment
Although verrucous psoriasis presents both diagnostic and therapeutic challenges, there are some reports of improvement with topical or intralesional corticosteroids in combination with keratolytics,³ coal tar,⁵ and oral methotrexate.⁶ In addition, there are rare reports of successful treatment with biologics. A case report showed successful resolution with adalimumab,⁴ and a case of erythrodermic verrucous psoriasis showed moderate improvement with ustekinumab after other failed treatments.⁷

Differential Diagnosis
Psoriasis typically presents in a symmetric distribution, with rare reported cases of unilateral distribution. Two cases of unilateral psoriasis arising after a surgical procedure have been reported, one after mastectomy and the other after neurosurgery.^8,9 Other cases of unilateral psoriasis are reported to have arisen in adolescents and young adults idiopathically.

A case of linear psoriasis arising in the distribution of the sciatic nerve in a patient with radiculopathy implicated tumor necrosis factor α, neuropeptides, and nerve growth factor released in response to compression as possible etiologic agents.¹⁰ However, none of the reported cases of linear psoriasis, or reported cases of unilateral psoriasis, exhibited verrucous features clinically or histologically. In our patient, distribution of the lesions appeared less typically blaschkoid than in linear psoriasis, and the presence of exophytic wartlike growths throughout the lesions was not characteristic of linear psoriasis.

Late-adulthood onset in this patient in addition to the absence of typical histologic features of ILVEN, including alternating orthokeratosis and parakeratosis,¹¹ make a diagnosis of ILVEN less likely; ILVEN can be distinguished from linear psoriasis based on later age of onset and responsiveness to antipsoriatic therapy of linear psoriasis.¹²

Conclusion

We describe a unique presentation of an already rare variant of psoriasis that can be difficult to diagnose clinically. The unilateral distribution of lesions in this patient can create further diagnostic confusion with other entities, such as ILVEN and linear psoriasis, though it can be distinguished from those diseases based on histologic features. Our aim is that this report improves recognition of this unusual presentation of verrucous psoriasis in clinical settings and decreases delays in diagnosis and treatment.

Case Report

An 80-year-old man with a history of hypertension and coronary artery disease presented to the dermatology clinic with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the abdomen, back, and leg (Figure 1). He reported that these “growths” appeared 20 years prior to presentation, shortly after coronary artery bypass surgery with a saphenous vein graft. The patient initially was given a diagnosis of verruca vulgaris and then biopsy-proven psoriasis later that year. At that time, he refused systemic treatment and was treated instead with triamcinolone acetonide ointment, with periodic surgical removal of bothersome lesions.

At the current presentation, physical examination revealed many hyperkeratotic, yellow-gray, verrucous nodules overlying scaly, erythematous, sharply demarcated plaques, exclusively on the left side of the body, including the left side of the abdomen, back, and leg. The differential diagnosis included linear psoriasis and inflammatory linear verrucous epidermal nevus (ILVEN).

Skin biopsy showed irregular psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and papillomatosis, with convergence of the rete ridges, known as buttressing (Figure 2A). There were tortuous dilated blood vessels in the dermal papillae, epidermal neutrophils at the tip of the suprapapillary plates, and Munro microabscesses in the stratum corneum (Figure 2B). Koilocytes were absent, and periodic acid–Schiff staining was negative. Taken together, clinical and histologic features led to a diagnosis of unilateral verrucous psoriasis.

Comment

Presentation and Histology
Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. It typically arises in patients with established psoriasis but can occur de novo.

Histologic features of verrucous psoriasis include epidermal hyperplasia with acanthosis, papillomatosis, and epidermal buttressing.¹ It has been hypothesized that notable hyperkeratosis observed in these lesions is induced by repeat trauma to the extremities in patients with established psoriasis or by anoxia from conditions that predispose to poor circulation, such as diabetes mellitus and pulmonary disease.^1,2

Pathogenesis
Most reported cases of verrucous psoriasis arose atop pre-existing psoriasis lesions.^3,4 The relevance of our patient’s verrucous psoriasis to his prior coronary artery bypass surgery with saphenous vein graft is unknown; however, the distribution of lesions, timing of psoriasis onset in relation to the surgical procedure, and recent data proposing a role for neuropeptide responses to nerve injury in the development of psoriasis, taken together, provide an argument for a role for surgical trauma in the development of our patient’s condition.

Treatment
Although verrucous psoriasis presents both diagnostic and therapeutic challenges, there are some reports of improvement with topical or intralesional corticosteroids in combination with keratolytics,³ coal tar,⁵ and oral methotrexate.⁶ In addition, there are rare reports of successful treatment with biologics. A case report showed successful resolution with adalimumab,⁴ and a case of erythrodermic verrucous psoriasis showed moderate improvement with ustekinumab after other failed treatments.⁷

Differential Diagnosis
Psoriasis typically presents in a symmetric distribution, with rare reported cases of unilateral distribution. Two cases of unilateral psoriasis arising after a surgical procedure have been reported, one after mastectomy and the other after neurosurgery.^8,9 Other cases of unilateral psoriasis are reported to have arisen in adolescents and young adults idiopathically.

A case of linear psoriasis arising in the distribution of the sciatic nerve in a patient with radiculopathy implicated tumor necrosis factor α, neuropeptides, and nerve growth factor released in response to compression as possible etiologic agents.¹⁰ However, none of the reported cases of linear psoriasis, or reported cases of unilateral psoriasis, exhibited verrucous features clinically or histologically. In our patient, distribution of the lesions appeared less typically blaschkoid than in linear psoriasis, and the presence of exophytic wartlike growths throughout the lesions was not characteristic of linear psoriasis.

Late-adulthood onset in this patient in addition to the absence of typical histologic features of ILVEN, including alternating orthokeratosis and parakeratosis,¹¹ make a diagnosis of ILVEN less likely; ILVEN can be distinguished from linear psoriasis based on later age of onset and responsiveness to antipsoriatic therapy of linear psoriasis.¹²

Conclusion

We describe a unique presentation of an already rare variant of psoriasis that can be difficult to diagnose clinically. The unilateral distribution of lesions in this patient can create further diagnostic confusion with other entities, such as ILVEN and linear psoriasis, though it can be distinguished from those diseases based on histologic features. Our aim is that this report improves recognition of this unusual presentation of verrucous psoriasis in clinical settings and decreases delays in diagnosis and treatment.