Clinical Review

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.¹⁶
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace, which leads to hairstyling practices that may increase the risk for AKN.²¹

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.¹⁶
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace, which leads to hairstyling practices that may increase the risk for AKN.²¹

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.¹⁶
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace, which leads to hairstyling practices that may increase the risk for AKN.²¹

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Skin grafting is a surgical technique used to cover skin defects resulting from the removal of skin tumors, ulcers, or burn injuries.^1-3 Complications can occur at both donor and recipient sites and may include bleeding, hematoma/seroma formation, postoperative pain, infection, scarring, paresthesia, skin pigmentation, graft contracture, and graft failure.^1,2,4,5 The development of epidermal tumors is not commonly reported among the complications of skin grafting; however, cases of epidermal tumor development on skin graft donor sites during the postoperative period have been reported.^6-12

We performed a systematic review of the literature for cases of epidermal tumor development on skin graft donor sites in patients undergoing autologous skin graft surgery. We present the clinical characteristics of these cases and discuss the nature of these tumors.

Methods

Search Strategy and Study Selection—A literature search was conducted by 2 independent researchers (Z.P. and V.P.) for articles published before December 2022 in the following databases: MEDLINE/PubMed, Web of Science, Scopus, Cochrane Library, OpenGrey, Google Scholar, and WorldCat. Search terms included all possible combinations of the following: keratoacanthoma, molluscum sebaceum, basal cell carcinoma, squamous cell carcinoma, acanthoma, wart, Merkel cell carcinoma, verruca, Bowen disease, keratosis, skin cancer, cutaneous cancer, skin neoplasia, cutaneous neoplasia, and skin tumor. The literature search terms were selected based on the World Health Organization classification of skin tumors.¹³ Manual bibliography checks were performed on all eligible search results for possible relevant studies. Discrepancies were resolved through discussion and, if needed, mediation by a third researcher (N.C.). To be included, a study had to report a case(s) of epidermal tumor(s) that was confirmed by histopathology and arose on a graft donor site in a patient receiving autologous skin grafts for any reason. No language, geographic, or report date restrictions were set.

Data Extraction, Quality Assessment, and Statistical Analysis—We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁴ Two independent researchers (Z.P. and V.P.) retrieved the data from the included studies. We have used the terms case and patient interchangeably, and 1 month was measured as 4 weeks for simplicity. Disagreements were resolved by discussion and mediation by a third researcher (N.C.). The quality of the included studies was assessed by 2 researchers (M.P. and V.P.) using the tool proposed by Murad et al.¹⁵

We used descriptive statistical analysis to analyze clinical characteristics of the included cases. We performed separate descriptive analyses based on the most frequently reported types of epidermal tumors and compared the differences between different groups using the Mann-Whitney U test, χ2 test, and Fisher exact test. The level of significance was set at P<.05. All statistical analyses were conducted using SPSS (version 29).

Results

Literature Search and Characteristics of Included Studies—The initial literature search identified 1378 studies, which were screened based on title and abstract. After removing duplicate and irrelevant studies and evaluating the full text of eligible studies, 31 studies (4 case series and 27 case reports) were included in the systematic review (Figure).^6-12,16-39 Quality assessment of the included studies is presented in Table 1.

Clinical Characteristics of Included Patients—Our systematic review included 36 patients with a mean age of 63 years and a male to female ratio of 2:1. The 2 most common causes for skin grafting were burn wounds and surgical excision of skin tumors. Most grafts were harvested from the thighs. The development of a solitary lesion on the donor area was reported in two-thirds of the patients, while more than 1 lesion developed in the remaining one-third of patients. The median time to tumor development was 6.5 weeks. In most cases, a split-thickness skin graft was used.

Cutaneous squamous cell carcinomas (CSCCs) were found in 23 patients, with well-differentiated CSCCs in 19 of these cases. Additionally, keratoacanthomas (KAs) were found in 10 patients. The majority of patients underwent surgical excision of the tumor. The median follow-up time was 12 months, during which recurrences were noted in a small percentage of cases. Clinical characteristics of included patients are presented in Table 2.

Comment

Reasons for Tumor Development on Skin Graft Donor Sites—The etiology behind epidermal tumor development on graft donor sites is unclear. According to one theory, iatrogenic contamination of the donor site during the removal of a primary epidermal tumor could be responsible. However, contemporary surgical procedures dictate the use of different sets of instruments for separate surgical sites. Moreover, this theory cannot explain the occurrence of epidermal tumors on donor sites in patients who have undergone skin grafting for the repair of burn wounds.³⁷

Another theory suggests that hematogenous and/or lymphatic spread can occur from the site of the primary epidermal tumor to the donor site, which has increased vascularization.^16,37 However, this theory also fails to provide an explanation for the development of epidermal tumors in patients who receive skin grafts for burn wounds.

A third theory states that the microenvironment of the donor site is key to tumor development. The donor site undergoes acute inflammation due to the trauma from harvesting the skin graft. According to this theory, acute inflammation could promote neoplastic growth and thus explain the development of epidermal tumors on the donor site.^8,26 However, the relationship between acute inflammation and carcinogenesis remains unclear. What is known to date is that the development of CSCC has been documented primarily in chronically inflamed tissues, whereas the development of KA—a variant of CSCC with distinctive and more benign clinical characteristics—can be expected in the setting of acute trauma-related inflammation.^13,40,41

Based on our systematic review, we propose that well-differentiated CSCC on graft donor sites might actually be misdiagnosed KA, given that the histopathologic differential diagnosis between CSCC and KA is extremely challenging.⁴² This hypothesis could explain the development of well-differentiated CSCC and KA on graft donor sites.

Conclusion

Development of CSCC and KA on graft donor sites can be listed among the postoperative complications of autologous skin grafting. Patients and physicians should be aware of this potential complication, and donor sites should be monitored for the occurrence of epidermal tumors.

Skin grafting is a surgical technique used to cover skin defects resulting from the removal of skin tumors, ulcers, or burn injuries.^1-3 Complications can occur at both donor and recipient sites and may include bleeding, hematoma/seroma formation, postoperative pain, infection, scarring, paresthesia, skin pigmentation, graft contracture, and graft failure.^1,2,4,5 The development of epidermal tumors is not commonly reported among the complications of skin grafting; however, cases of epidermal tumor development on skin graft donor sites during the postoperative period have been reported.^6-12

We performed a systematic review of the literature for cases of epidermal tumor development on skin graft donor sites in patients undergoing autologous skin graft surgery. We present the clinical characteristics of these cases and discuss the nature of these tumors.

Methods

Search Strategy and Study Selection—A literature search was conducted by 2 independent researchers (Z.P. and V.P.) for articles published before December 2022 in the following databases: MEDLINE/PubMed, Web of Science, Scopus, Cochrane Library, OpenGrey, Google Scholar, and WorldCat. Search terms included all possible combinations of the following: keratoacanthoma, molluscum sebaceum, basal cell carcinoma, squamous cell carcinoma, acanthoma, wart, Merkel cell carcinoma, verruca, Bowen disease, keratosis, skin cancer, cutaneous cancer, skin neoplasia, cutaneous neoplasia, and skin tumor. The literature search terms were selected based on the World Health Organization classification of skin tumors.¹³ Manual bibliography checks were performed on all eligible search results for possible relevant studies. Discrepancies were resolved through discussion and, if needed, mediation by a third researcher (N.C.). To be included, a study had to report a case(s) of epidermal tumor(s) that was confirmed by histopathology and arose on a graft donor site in a patient receiving autologous skin grafts for any reason. No language, geographic, or report date restrictions were set.

Data Extraction, Quality Assessment, and Statistical Analysis—We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁴ Two independent researchers (Z.P. and V.P.) retrieved the data from the included studies. We have used the terms case and patient interchangeably, and 1 month was measured as 4 weeks for simplicity. Disagreements were resolved by discussion and mediation by a third researcher (N.C.). The quality of the included studies was assessed by 2 researchers (M.P. and V.P.) using the tool proposed by Murad et al.¹⁵

We used descriptive statistical analysis to analyze clinical characteristics of the included cases. We performed separate descriptive analyses based on the most frequently reported types of epidermal tumors and compared the differences between different groups using the Mann-Whitney U test, χ2 test, and Fisher exact test. The level of significance was set at P<.05. All statistical analyses were conducted using SPSS (version 29).

Results

Literature Search and Characteristics of Included Studies—The initial literature search identified 1378 studies, which were screened based on title and abstract. After removing duplicate and irrelevant studies and evaluating the full text of eligible studies, 31 studies (4 case series and 27 case reports) were included in the systematic review (Figure).^6-12,16-39 Quality assessment of the included studies is presented in Table 1.

Clinical Characteristics of Included Patients—Our systematic review included 36 patients with a mean age of 63 years and a male to female ratio of 2:1. The 2 most common causes for skin grafting were burn wounds and surgical excision of skin tumors. Most grafts were harvested from the thighs. The development of a solitary lesion on the donor area was reported in two-thirds of the patients, while more than 1 lesion developed in the remaining one-third of patients. The median time to tumor development was 6.5 weeks. In most cases, a split-thickness skin graft was used.

Cutaneous squamous cell carcinomas (CSCCs) were found in 23 patients, with well-differentiated CSCCs in 19 of these cases. Additionally, keratoacanthomas (KAs) were found in 10 patients. The majority of patients underwent surgical excision of the tumor. The median follow-up time was 12 months, during which recurrences were noted in a small percentage of cases. Clinical characteristics of included patients are presented in Table 2.

Comment

Reasons for Tumor Development on Skin Graft Donor Sites—The etiology behind epidermal tumor development on graft donor sites is unclear. According to one theory, iatrogenic contamination of the donor site during the removal of a primary epidermal tumor could be responsible. However, contemporary surgical procedures dictate the use of different sets of instruments for separate surgical sites. Moreover, this theory cannot explain the occurrence of epidermal tumors on donor sites in patients who have undergone skin grafting for the repair of burn wounds.³⁷

Another theory suggests that hematogenous and/or lymphatic spread can occur from the site of the primary epidermal tumor to the donor site, which has increased vascularization.^16,37 However, this theory also fails to provide an explanation for the development of epidermal tumors in patients who receive skin grafts for burn wounds.

A third theory states that the microenvironment of the donor site is key to tumor development. The donor site undergoes acute inflammation due to the trauma from harvesting the skin graft. According to this theory, acute inflammation could promote neoplastic growth and thus explain the development of epidermal tumors on the donor site.^8,26 However, the relationship between acute inflammation and carcinogenesis remains unclear. What is known to date is that the development of CSCC has been documented primarily in chronically inflamed tissues, whereas the development of KA—a variant of CSCC with distinctive and more benign clinical characteristics—can be expected in the setting of acute trauma-related inflammation.^13,40,41

Based on our systematic review, we propose that well-differentiated CSCC on graft donor sites might actually be misdiagnosed KA, given that the histopathologic differential diagnosis between CSCC and KA is extremely challenging.⁴² This hypothesis could explain the development of well-differentiated CSCC and KA on graft donor sites.

Conclusion

Development of CSCC and KA on graft donor sites can be listed among the postoperative complications of autologous skin grafting. Patients and physicians should be aware of this potential complication, and donor sites should be monitored for the occurrence of epidermal tumors.

Skin grafting is a surgical technique used to cover skin defects resulting from the removal of skin tumors, ulcers, or burn injuries.^1-3 Complications can occur at both donor and recipient sites and may include bleeding, hematoma/seroma formation, postoperative pain, infection, scarring, paresthesia, skin pigmentation, graft contracture, and graft failure.^1,2,4,5 The development of epidermal tumors is not commonly reported among the complications of skin grafting; however, cases of epidermal tumor development on skin graft donor sites during the postoperative period have been reported.^6-12

We performed a systematic review of the literature for cases of epidermal tumor development on skin graft donor sites in patients undergoing autologous skin graft surgery. We present the clinical characteristics of these cases and discuss the nature of these tumors.

Methods

Search Strategy and Study Selection—A literature search was conducted by 2 independent researchers (Z.P. and V.P.) for articles published before December 2022 in the following databases: MEDLINE/PubMed, Web of Science, Scopus, Cochrane Library, OpenGrey, Google Scholar, and WorldCat. Search terms included all possible combinations of the following: keratoacanthoma, molluscum sebaceum, basal cell carcinoma, squamous cell carcinoma, acanthoma, wart, Merkel cell carcinoma, verruca, Bowen disease, keratosis, skin cancer, cutaneous cancer, skin neoplasia, cutaneous neoplasia, and skin tumor. The literature search terms were selected based on the World Health Organization classification of skin tumors.¹³ Manual bibliography checks were performed on all eligible search results for possible relevant studies. Discrepancies were resolved through discussion and, if needed, mediation by a third researcher (N.C.). To be included, a study had to report a case(s) of epidermal tumor(s) that was confirmed by histopathology and arose on a graft donor site in a patient receiving autologous skin grafts for any reason. No language, geographic, or report date restrictions were set.

Data Extraction, Quality Assessment, and Statistical Analysis—We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁴ Two independent researchers (Z.P. and V.P.) retrieved the data from the included studies. We have used the terms case and patient interchangeably, and 1 month was measured as 4 weeks for simplicity. Disagreements were resolved by discussion and mediation by a third researcher (N.C.). The quality of the included studies was assessed by 2 researchers (M.P. and V.P.) using the tool proposed by Murad et al.¹⁵

We used descriptive statistical analysis to analyze clinical characteristics of the included cases. We performed separate descriptive analyses based on the most frequently reported types of epidermal tumors and compared the differences between different groups using the Mann-Whitney U test, χ2 test, and Fisher exact test. The level of significance was set at P<.05. All statistical analyses were conducted using SPSS (version 29).

Results

Literature Search and Characteristics of Included Studies—The initial literature search identified 1378 studies, which were screened based on title and abstract. After removing duplicate and irrelevant studies and evaluating the full text of eligible studies, 31 studies (4 case series and 27 case reports) were included in the systematic review (Figure).^6-12,16-39 Quality assessment of the included studies is presented in Table 1.

Clinical Characteristics of Included Patients—Our systematic review included 36 patients with a mean age of 63 years and a male to female ratio of 2:1. The 2 most common causes for skin grafting were burn wounds and surgical excision of skin tumors. Most grafts were harvested from the thighs. The development of a solitary lesion on the donor area was reported in two-thirds of the patients, while more than 1 lesion developed in the remaining one-third of patients. The median time to tumor development was 6.5 weeks. In most cases, a split-thickness skin graft was used.

Cutaneous squamous cell carcinomas (CSCCs) were found in 23 patients, with well-differentiated CSCCs in 19 of these cases. Additionally, keratoacanthomas (KAs) were found in 10 patients. The majority of patients underwent surgical excision of the tumor. The median follow-up time was 12 months, during which recurrences were noted in a small percentage of cases. Clinical characteristics of included patients are presented in Table 2.

Comment

Reasons for Tumor Development on Skin Graft Donor Sites—The etiology behind epidermal tumor development on graft donor sites is unclear. According to one theory, iatrogenic contamination of the donor site during the removal of a primary epidermal tumor could be responsible. However, contemporary surgical procedures dictate the use of different sets of instruments for separate surgical sites. Moreover, this theory cannot explain the occurrence of epidermal tumors on donor sites in patients who have undergone skin grafting for the repair of burn wounds.³⁷

Another theory suggests that hematogenous and/or lymphatic spread can occur from the site of the primary epidermal tumor to the donor site, which has increased vascularization.^16,37 However, this theory also fails to provide an explanation for the development of epidermal tumors in patients who receive skin grafts for burn wounds.

A third theory states that the microenvironment of the donor site is key to tumor development. The donor site undergoes acute inflammation due to the trauma from harvesting the skin graft. According to this theory, acute inflammation could promote neoplastic growth and thus explain the development of epidermal tumors on the donor site.^8,26 However, the relationship between acute inflammation and carcinogenesis remains unclear. What is known to date is that the development of CSCC has been documented primarily in chronically inflamed tissues, whereas the development of KA—a variant of CSCC with distinctive and more benign clinical characteristics—can be expected in the setting of acute trauma-related inflammation.^13,40,41

Based on our systematic review, we propose that well-differentiated CSCC on graft donor sites might actually be misdiagnosed KA, given that the histopathologic differential diagnosis between CSCC and KA is extremely challenging.⁴² This hypothesis could explain the development of well-differentiated CSCC and KA on graft donor sites.

Conclusion

Development of CSCC and KA on graft donor sites can be listed among the postoperative complications of autologous skin grafting. Patients and physicians should be aware of this potential complication, and donor sites should be monitored for the occurrence of epidermal tumors.

Illicit use of the veterinary tranquilizer xylazine continues to spread across the United States. The drug, which is increasingly mixed with fentanyl, often fails to respond to the opioid overdose reversal medication naloxone and can cause severe necrotic lesions.

A report released by Millennium Health, a specialty lab that provides medication monitoring for pain management, drug treatment, and behavioral and substance use disorder treatment centers across the country, showed the number of urine specimens collected and tested at the US drug treatment centers were positive for xylazine in the most recent 6 months.

As previously reported by this news organization, in late 2022, the US Food and Drug Administration (FDA) issued a communication alerting clinicians about the special management required for opioid overdoses tainted with xylazine, which is also known as “tranq” or “tranq dope.”

Subsequently, in early 2023, The White House Office of National Drug Control Policy designated xylazine combined with fentanyl as an emerging threat to the United States.

Both the FDA and the Drug Enforcement Administration have taken steps to try to stop trafficking of the combination. However, despite these efforts, xylazine use has continued to spread.

The Millennium Health Signals report showed that the greatest increase in xylazine use was largely in the western United States. In the first 6 months of 2023, 3% of urine drug tests (UDTs) in Washington, Oregon, California, Hawaii, and Alaska were positive for xylazine. From November 2023 to April 2024, this rose to 8%, a 147% increase. In the Mountain West, xylazine-positive UDTs increased from 2% in 2023 to 4% in 2024, an increase of 94%. In addition to growth in the West, the report showed that xylazine use increased by more than 100% in New England — from 14% in 2023 to 28% in 2024.

Nationally, 16% of all urine specimens were positive for xylazine from late 2023 to April 2024, up slightly from 14% from April to October 2023.

Xylazine use was highest in the East and in the mid-Atlantic United States. Still, positivity rates in the mid-Atlantic dropped from 44% to 33%. The states included in that group were New York, Pennsylvania, Delaware, and New Jersey. East North Central states (Ohio, Michigan, Wisconsin, Indiana, and Illinois) also experienced a decline in positive tests from 32% to 30%.

The South Atlantic states, which include Maryland, Virginia, West Virginia, North and South Carolina, Georgia, and Florida, had a 17% increase in positivity — from 22% to 26%.

From April 2023 to April 2024 state-level UDT positivity rates were 40% in Pennsylvania, 37% in New York, and 35% in Ohio. But rates vary by locality. In Clermont and Hamilton counties in Ohio — both in the Cincinnati area — about 70% of specimens were positive for xylazine.

About one third of specimens in Maryland and South Carolina contained xylazine.

“Because xylazine exposure remains a significant challenge in the East and is a growing concern in the West, clinicians across the US need to be prepared to recognize and address the consequences of xylazine use — like diminished responses to naloxone and severe skin wounds that may lead to amputation — among people who use fentanyl,” Millennium Health Chief Clinical Officer Angela Huskey, PharmD, said in a press release.

The Health Signals Alert analyzed more than 50,000 fentanyl-positive UDT specimens collected between April 12, 2023, and April 11, 2024. Millennium Health researchers analyzed xylazine positivity rates in fentanyl-positive UDT specimens by the US Census Division and state.

A version of this article first appeared on Medscape.com.

Illicit use of the veterinary tranquilizer xylazine continues to spread across the United States. The drug, which is increasingly mixed with fentanyl, often fails to respond to the opioid overdose reversal medication naloxone and can cause severe necrotic lesions.

A report released by Millennium Health, a specialty lab that provides medication monitoring for pain management, drug treatment, and behavioral and substance use disorder treatment centers across the country, showed the number of urine specimens collected and tested at the US drug treatment centers were positive for xylazine in the most recent 6 months.

As previously reported by this news organization, in late 2022, the US Food and Drug Administration (FDA) issued a communication alerting clinicians about the special management required for opioid overdoses tainted with xylazine, which is also known as “tranq” or “tranq dope.”

Subsequently, in early 2023, The White House Office of National Drug Control Policy designated xylazine combined with fentanyl as an emerging threat to the United States.

Both the FDA and the Drug Enforcement Administration have taken steps to try to stop trafficking of the combination. However, despite these efforts, xylazine use has continued to spread.

The Millennium Health Signals report showed that the greatest increase in xylazine use was largely in the western United States. In the first 6 months of 2023, 3% of urine drug tests (UDTs) in Washington, Oregon, California, Hawaii, and Alaska were positive for xylazine. From November 2023 to April 2024, this rose to 8%, a 147% increase. In the Mountain West, xylazine-positive UDTs increased from 2% in 2023 to 4% in 2024, an increase of 94%. In addition to growth in the West, the report showed that xylazine use increased by more than 100% in New England — from 14% in 2023 to 28% in 2024.

Nationally, 16% of all urine specimens were positive for xylazine from late 2023 to April 2024, up slightly from 14% from April to October 2023.

Xylazine use was highest in the East and in the mid-Atlantic United States. Still, positivity rates in the mid-Atlantic dropped from 44% to 33%. The states included in that group were New York, Pennsylvania, Delaware, and New Jersey. East North Central states (Ohio, Michigan, Wisconsin, Indiana, and Illinois) also experienced a decline in positive tests from 32% to 30%.

The South Atlantic states, which include Maryland, Virginia, West Virginia, North and South Carolina, Georgia, and Florida, had a 17% increase in positivity — from 22% to 26%.

From April 2023 to April 2024 state-level UDT positivity rates were 40% in Pennsylvania, 37% in New York, and 35% in Ohio. But rates vary by locality. In Clermont and Hamilton counties in Ohio — both in the Cincinnati area — about 70% of specimens were positive for xylazine.

About one third of specimens in Maryland and South Carolina contained xylazine.

“Because xylazine exposure remains a significant challenge in the East and is a growing concern in the West, clinicians across the US need to be prepared to recognize and address the consequences of xylazine use — like diminished responses to naloxone and severe skin wounds that may lead to amputation — among people who use fentanyl,” Millennium Health Chief Clinical Officer Angela Huskey, PharmD, said in a press release.

The Health Signals Alert analyzed more than 50,000 fentanyl-positive UDT specimens collected between April 12, 2023, and April 11, 2024. Millennium Health researchers analyzed xylazine positivity rates in fentanyl-positive UDT specimens by the US Census Division and state.

A version of this article first appeared on Medscape.com.

Illicit use of the veterinary tranquilizer xylazine continues to spread across the United States. The drug, which is increasingly mixed with fentanyl, often fails to respond to the opioid overdose reversal medication naloxone and can cause severe necrotic lesions.

A report released by Millennium Health, a specialty lab that provides medication monitoring for pain management, drug treatment, and behavioral and substance use disorder treatment centers across the country, showed the number of urine specimens collected and tested at the US drug treatment centers were positive for xylazine in the most recent 6 months.

As previously reported by this news organization, in late 2022, the US Food and Drug Administration (FDA) issued a communication alerting clinicians about the special management required for opioid overdoses tainted with xylazine, which is also known as “tranq” or “tranq dope.”

Subsequently, in early 2023, The White House Office of National Drug Control Policy designated xylazine combined with fentanyl as an emerging threat to the United States.

Both the FDA and the Drug Enforcement Administration have taken steps to try to stop trafficking of the combination. However, despite these efforts, xylazine use has continued to spread.

The Millennium Health Signals report showed that the greatest increase in xylazine use was largely in the western United States. In the first 6 months of 2023, 3% of urine drug tests (UDTs) in Washington, Oregon, California, Hawaii, and Alaska were positive for xylazine. From November 2023 to April 2024, this rose to 8%, a 147% increase. In the Mountain West, xylazine-positive UDTs increased from 2% in 2023 to 4% in 2024, an increase of 94%. In addition to growth in the West, the report showed that xylazine use increased by more than 100% in New England — from 14% in 2023 to 28% in 2024.

Nationally, 16% of all urine specimens were positive for xylazine from late 2023 to April 2024, up slightly from 14% from April to October 2023.

Xylazine use was highest in the East and in the mid-Atlantic United States. Still, positivity rates in the mid-Atlantic dropped from 44% to 33%. The states included in that group were New York, Pennsylvania, Delaware, and New Jersey. East North Central states (Ohio, Michigan, Wisconsin, Indiana, and Illinois) also experienced a decline in positive tests from 32% to 30%.

The South Atlantic states, which include Maryland, Virginia, West Virginia, North and South Carolina, Georgia, and Florida, had a 17% increase in positivity — from 22% to 26%.

From April 2023 to April 2024 state-level UDT positivity rates were 40% in Pennsylvania, 37% in New York, and 35% in Ohio. But rates vary by locality. In Clermont and Hamilton counties in Ohio — both in the Cincinnati area — about 70% of specimens were positive for xylazine.

About one third of specimens in Maryland and South Carolina contained xylazine.

“Because xylazine exposure remains a significant challenge in the East and is a growing concern in the West, clinicians across the US need to be prepared to recognize and address the consequences of xylazine use — like diminished responses to naloxone and severe skin wounds that may lead to amputation — among people who use fentanyl,” Millennium Health Chief Clinical Officer Angela Huskey, PharmD, said in a press release.

The Health Signals Alert analyzed more than 50,000 fentanyl-positive UDT specimens collected between April 12, 2023, and April 11, 2024. Millennium Health researchers analyzed xylazine positivity rates in fentanyl-positive UDT specimens by the US Census Division and state.

A version of this article first appeared on Medscape.com.

Nail disorders are common among pediatric patients but often are underdiagnosed or misdiagnosed because of their unique disease manifestations. These conditions may severely impact quality of life. There are few nail disease clinical trials that include children. Consequently, most treatment recommendations are based on case series and expert consensus recommendations. We review inflammatory and infectious nail disorders in pediatric patients. By describing characteristics, clinical manifestations, and management approaches for these conditions, we aim to provide guidance to dermatologists in their diagnosis and treatment.

INFLAMMATORY NAIL DISORDERS

Nail Psoriasis

Nail involvement in children with psoriasis is common, with prevalence estimates ranging from 17% to 39.2%.¹ Nail matrix psoriasis may manifest with pitting (large irregular pits) and leukonychia as well as chromonychia and nail plate crumbling. Onycholysis, oil drop spots (salmon patches), and subungual hyperkeratosis can be seen in nail bed psoriasis. Nail pitting is the most frequently observed clinical finding (Figure 1).^2,3 In a cross-sectional multicenter study of 313 children with cutaneous psoriasis in France, nail findings were present in 101 patients (32.3%). There were associations between nail findings and presence of psoriatic arthritis (P=.03), palmoplantar psoriasis (P<.001), and severity of psoriatic disease, defined as use of systemic treatment with phototherapy (psoralen plus UVA, UVB), traditional systemic treatment (acitretin, methotrexate, cyclosporine), or a biologic (P=.003).⁴

Topical steroids and vitamin D analogues may be used with or without occlusion and may be efficacious.⁵ Several case reports describe systemic treatments for psoriasis in children, including methotrexate, acitretin, and apremilast (approved for children 6 years and older for plaque psoriasis by the US Food and Drug Administration [FDA]).² There are 5 biologic drugs currently approved for the treatment of pediatric psoriasis—adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab—and 6 drugs currently undergoing phase 3 studies—brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib (Table 1).^6-15 Adalimumab is specifically approved for moderate to severe nail psoriasis in adults 18 years and older.

Intralesional steroid injections are sometimes useful in the management of nail matrix psoriasis; however, appropriate patient selection is critical due to the pain associated with the procedure. In a prospective study of 16 children (age range, 9–17 years) with nail psoriasis treated with intralesional triamcinolone (ILTAC) 2.5 to 5 mg/mL every 4 to 8 weeks for a minimum of 3 to 6 months, 9 patients achieved resolution and 6 had improvement of clinical findings.¹⁶ Local adverse events were mild, including injection-site pain (66%), subungual hematoma (n=1), Beau lines (n=1), proximal nail fold hypopigmentation (n=2), and proximal nail fold atrophy (n=2). Because the proximal nail fold in children is thinner than in adults, there may be an increased risk for nail fold hypopigmentation and atrophy in children. Therefore, a maximum ILTAC concentration of 2.5 mg/mL with 0.2 mL maximum volume per nail per session is recommended for children younger than 15 years.¹⁶

Nail Lichen Planus

Nail lichen planus (NLP) is uncommon in children, with few biopsy-proven cases documented in the literature.¹⁷ Common clinical findings are onychorrhexis, nail plate thinning, fissuring, splitting, and atrophy with koilonychia.⁵ Although pterygium development (irreversible nail matrix scarring) is uncommon in pediatric patients, NLP can be progressive and may cause irreversible destruction of the nail matrix and subsequent nail loss, warranting therapeutic intervention.¹⁸

Treatment of NLP may be difficult, as there are no options that work in all patients. Current literature supports the use of systemic corticosteroids or ILTAC for the treatment of NLP; however, recurrence rates can be high. According to an expert consensus paper on NLP treatment, ILTAC may be injected in a concentration of 2.5, 5, or 10 mg/mL according to disease severity.¹⁹ In severe or resistant cases, intramuscular (IM) triamcinolone may be considered, especially if more than 3 nails are affected. A dosage of 0.5 to 1 mg/kg/mo for at least 3 to 6 months is recommended for both children and adults, with 1 mg/kg/mo recommended in the active treatment phase (first 2–3 months).¹⁹ In a retrospective review of 5 pediatric patients with NLP treated with IM triamcinolone 0.5 mg/kg/mo, 3 patients had resolution and 2 improved with treatment.²⁰ In a prospective study of 10 children with NLP, IM triamcinolone at a dosage of 0.5 to 1 mg/kg every 30 days for 3 to 6 months resulted in resolution of nail findings in 9 patients.¹⁷ In a prospective study of 14 pediatric patients with NLP treated with 2.5 to 5 mg/mL of ILTAC, 10 achieved resolution and 3 improved.¹⁶

Intralesional triamcinolone injections may be better suited for teenagers compared to younger children who may be more apprehensive of needles. To minimize pain, it is recommended to inject ILTAC slowly at room temperature, with use of “talkesthesia” and vibration devices, 1% lidocaine, or ethyl chloride spray.¹⁸

Trachyonychia

Trachyonychia is characterized by the presence of sandpaperlike nails. It manifests with brittle thin nails with longitudinal ridging, onychoschizia, and thickened hyperkeratotic cuticles. Trachyonychia typically involves multiple nails, with a peak age of onset between 3 and 12 years.^21,22 There are 2 variants: the opaque type with rough longitudinal ridging, and the shiny variant with opalescent nails and pits that reflect light. The opaque variant is more common and is associated with psoriasis, whereas the shiny variant is less common and is associated with alopecia areata.²³ Although most cases are idiopathic, some are associated with psoriasis and alopecia areata, as previously noted, as well as atopic dermatitis (AD) and lichen planus.^22,24

Fortunately, trachyonychia does not lead to permanent nail damage or pterygium, making treatment primarily focused on addressing functional and cosmetic concerns.²⁴ Spontaneous resolution occurs in approximately 50% of patients. In a prospective study of 11 patients with idiopathic trachyonychia, there was partial improvement in 5 of 9 patients treated with topical steroids, 1 with only petrolatum, and 1 with vitamin supplements. Complete resolution was reported in 1 patient treated with topical steroids.²⁵ Because trachyonychia often is self-resolving, no treatment is required and a conservative approach is strongly recommended.²⁶ Treatment options include topical corticosteroids, tazarotene, and 5-fluorouracil. Intralesional triamcinolone, systemic cyclosporine, retinoids, systemic corticosteroids, and tofacitinib have been described in case reports, though none of these have been shown to be 100% efficacious.²⁴

Nail Lichen Striatus

Lichen striatus involving the nail is uncommon and is characterized by onycholysis, longitudinal ridging, ­splitting, and fraying, as well as what appears to be a subungual tumor. It can encompass the entire nail or may be isolated to a portion of the nail (Figure 2). Usually, a Blaschko-linear array of flesh-colored papules on the more proximal digit directly adjacent to the nail dystrophy will be seen, though nail findings can occur in ­isolation.^27-29 The underlying pathophysiology is not clear; however, one hypothesis is that a triggering event, such as trauma, induces the expression of antigens that elicit a self-limiting immune-mediated response by CD8 T lymphocytes.³⁰

Generally, nail lichen striatus spontaneously resolves in 1 to 2 years without treatment. In a prospective study of 5 patients with nail lichen striatus, the median time to resolution was 22.6 months (range, 10–30 months).³¹ Topical steroids may be used for pruritus. In one case report, a 3-year-old boy with nail lichen striatus of 4 months’ duration was treated with tacrolimus ointment 0.03% daily for 3 months.²⁸

Nail AD

Nail changes with AD may be more common in adults than children or are underreported. In a study of 777 adults with AD, nail dystrophy was present in 124 patients (16%), whereas in a study of 250 pediatric patients with AD (aged 0-2 years), nail dystrophy was present in only 4 patients.^32,33

Periungual inflammation from AD causes the nail changes.³⁴ In a cross-sectional study of 24 pediatric patients with nail dystrophy due to AD, transverse grooves (Beau lines) were present in 25% (6/24), nail pitting in 16.7% (4/24), koilonychia in 16.7% (4/24), trachyonychia in 12.5% (3/24), leukonychia in 12.5% (3/24), brachyonychia in 8.3% (2/24), melanonychia in 8.3% (2/24), onychomadesis in 8.3% (2/24), onychoschizia in 8.3% (2/24), and onycholysis in 8.3% (2/24). There was an association between disease severity and presence of toenail dystrophy (P=.03).³⁵

Topical steroids with or without occlusion can be used to treat nail changes. Although there is limited literature describing the treatment of nail AD in children, a 61-year-old man with nail changes associated with AD achieved resolution with 3 months of treatment with dupilumab.³⁶ Anecdotally, most patients will improve with usual cutaneous AD management.

INFECTIOUS NAIL DISORDERS

Viral Infections

Hand, Foot, and Mouth Disease—Hand, foot, and mouth disease (HFMD) is a common childhood viral infection caused by various enteroviruses, most commonly coxsackievirus A16, with the A6 variant causing more severe disease. Fever and painful vesicles involving the oral mucosa as well as palms and soles give the disease its name. Nail changes are common. In a prospective study involving 130 patients with laboratory-confirmed coxsackievirus CA6 serotype infection, 37% developed onychomadesis vs only 5% of 145 cases with non-CA6 enterovirus infection who developed nail findings. There was an association between CA6 infection and presence of nail changes (P<.001).³⁷

Findings ranging from transverse grooves (Beau lines) to complete nail shedding (onychomadesis)(Figure 3) may be seen.^38,39 Nail findings in HFMD are due to transient inhibition of nail growth and present approximately 3 to 6 weeks after infection.⁴⁰ Onychomadesis is seen in 30% to 68% of patients with HFMD.^37,41,42 Nail findings in HFMD spontaneously resolve with nail growth (2–3 mm per month for fingernails and 1 mm per month for toenails) and do not require specific treatment. Although the appearance of nail changes associated with HFMD can be disturbing, dermatologists can reassure children and their parents that the nails will resolve with the next cycle of growth.

Kawasaki Disease—Kawasaki disease (KD) is a vasculitis primarily affecting children and infants. Although the specific pathogen and pathophysiology is not entirely clear, clinical observations have suggested an infectious cause, most likely a virus.⁴³ In Japan, more than 15,000 cases of KD are documented annually, while approximately 4200 cases are seen in the United States.⁴⁴ In a prospective study from 1984 to 1990, 4 of 26 (15.4%) patients with KD presented with nail manifestations during the late acute phase or early convalescent phase of disease. There were no significant associations between nail dystrophy and severity of KD, such as coronary artery aneurysm.⁴⁵

Nail changes reported in children with KD include onychomadesis, onycholysis, orange-brown chromonychia, splinter hemorrhages, Beau lines, and pincer nails. In a review of nail changes associated with KD from 1980 to 2021, orange-brown transverse chromonychia, which may evolve into transverse leukonychia, was the most common nail finding reported, occurring in 17 of 31 (54.8%) patients.⁴⁴ It has been hypothesized that nail changes may result from blood flow disturbance due to the underlying vasculitis.⁴⁶ Nail changes appear several weeks after the onset of fever and are self-limited. Resolution occurs with nail growth, with no treatment required.

FUNGAL INFECTIONS

Onychomycosis

Onychomycosis is a fungal infection of the nails that occurs in 0.2% to 5.5% of pediatric patients, and its prevalence may be increasing, which may be due to environmental factors or increased rates of diabetes mellitus and obesity in the pediatric population.⁴⁷ Onychomycosis represents 15.5% of nail dystrophies in pediatric patients.⁴⁸ Some dermatologists treat presumptive onychomycosis without confirmation; however, we do not recommend that approach. Because the differential is broad and the duration of treatment is long, mycologic examination (potassium hydroxide preparation, fungal culture, polymerase chain reaction, and/or histopathology) should be obtained to confirm onychomycosis prior to initiation of antifungal management. Family members of affected individuals should be evaluated and treated, if indicated, for onychomycosis and tinea pedis, as household transmission is common.

Currently, there are 2 topical FDA-approved treatments for pediatric onychomycosis in children 6 years and older (Table 2).^49,50 There is a discussion of the need for confirmatory testing for onychomycosis in children, particularly when systemic treatment is prescribed. In a retrospective review of 269 pediatric patients with onychomycosis prescribed terbinafine, 53.5% (n=144) underwent laboratory monitoring of liver function and complete blood cell counts, and 12.5% had grade 1 laboratory abnormalities either prior to (12/144 [8.3%]) or during (6/144 [4.2%]) therapy.⁵¹ Baseline transaminase monitoring is recommended, though subsequent routine laboratory monitoring in healthy children may have limited utility with associated increased costs, incidental findings, and patient discomfort and likely is not needed.⁵¹

Pediatric onychomycosis responds better to topical therapy than adult disease, and pediatric patients do not always require systemic treatment.⁵² Ciclopirox is not FDA approved for the treatment of pediatric onychomycosis, but in a 32-week clinical trial of ciclopirox lacquer 8% use in 40 patients, 77% (27/35) of treated patients achieved mycologic cure. Overall, 71% of treated patients (25/35) vs 22% (2/9) of controls achieved efficacy (defined as investigator global assessment score of 2 or lower).⁵² In an open-label, single-arm clinical trial assessing tavaborole solution 5% applied once daily for 48 weeks for the treatment of toenail onychomycosis in pediatric patients (aged 6–17 years), 36.2% (20/55) of patients achieved mycologic cure, and 8.5% (5/55) achieved complete cure at week 52 with mild or minimal adverse effects.⁵³ In an open-label, phase 4 study of the safety and efficacy of efinaconazole solution 10% applied once daily for 48 weeks in pediatric patients (aged 6 to 16 years) (n=60), 65% (35/60) achieved mycologic cure, 42% (25/60) achieved clinical cure, and 40% (24/60) achieved complete cure at 52 weeks. The most common adverse effects of efina­conazole were local and included ingrown toenail (1/60), application-site dermatitis (1/60), application-site vesicles (1/60), and application-site pain (1/60).⁵⁴

In a systematic review of systemic antifungals for onychomycosis in 151 pediatric patients, itraconazole, fluconazole, griseofulvin, and terbinafine resulted in complete cure rates similar to those of the adult population, with excellent safety profiles.⁵⁵ Depending on the situation, initiation of treatment with topical medications followed by addition of systemic antifungal agents only if needed may be an appropriate course of action.

BACTERIAL INFECTIONS

Acute Paronychia

Acute paronychia is a nail-fold infection that develops after the protective nail barrier has been compromised.⁵⁶ In children, thumb-sucking, nail-biting, frequent oral manipulation of the digits, and poor skin hygiene are risk factors. Acute paronychia also may develop in association with congenital malalignment of the great toenails.⁵⁷

Clinical manifestations include localized pain, erythema, and nail fold edema (Figure 4). Purulent material and abscess formation may ensue. Staphylococcus aureus as well as methicillin-resistant S aureus and Streptococcus pyogenes are classically the most common causes of acute paronychia. Treatment of paronychia is based on severity. In mild cases, warm soaks with topical antibiotics are indicated. Oral antibiotics should be prescribed for more severe presentations. If there is no improvement after 48 hours, surgical drainage is required to facilitate healing.⁵⁶

FINAL THOUGHTS

Inflammatory and infectious nail disorders in children are relatively common and may impact the physical and emotional well-being of young patients. By understanding the distinctive features of these nail disorders in pediatric patients, dermatologists can provide anticipatory guidance and informed treatment options to children and their parents. Further research is needed to expand our understanding of pediatric nail disorders and create targeted therapeutic interventions, particularly for NLP and psoriasis.

Nail disorders are common among pediatric patients but often are underdiagnosed or misdiagnosed because of their unique disease manifestations. These conditions may severely impact quality of life. There are few nail disease clinical trials that include children. Consequently, most treatment recommendations are based on case series and expert consensus recommendations. We review inflammatory and infectious nail disorders in pediatric patients. By describing characteristics, clinical manifestations, and management approaches for these conditions, we aim to provide guidance to dermatologists in their diagnosis and treatment.

INFLAMMATORY NAIL DISORDERS

Nail Psoriasis

Nail involvement in children with psoriasis is common, with prevalence estimates ranging from 17% to 39.2%.¹ Nail matrix psoriasis may manifest with pitting (large irregular pits) and leukonychia as well as chromonychia and nail plate crumbling. Onycholysis, oil drop spots (salmon patches), and subungual hyperkeratosis can be seen in nail bed psoriasis. Nail pitting is the most frequently observed clinical finding (Figure 1).^2,3 In a cross-sectional multicenter study of 313 children with cutaneous psoriasis in France, nail findings were present in 101 patients (32.3%). There were associations between nail findings and presence of psoriatic arthritis (P=.03), palmoplantar psoriasis (P<.001), and severity of psoriatic disease, defined as use of systemic treatment with phototherapy (psoralen plus UVA, UVB), traditional systemic treatment (acitretin, methotrexate, cyclosporine), or a biologic (P=.003).⁴

Topical steroids and vitamin D analogues may be used with or without occlusion and may be efficacious.⁵ Several case reports describe systemic treatments for psoriasis in children, including methotrexate, acitretin, and apremilast (approved for children 6 years and older for plaque psoriasis by the US Food and Drug Administration [FDA]).² There are 5 biologic drugs currently approved for the treatment of pediatric psoriasis—adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab—and 6 drugs currently undergoing phase 3 studies—brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib (Table 1).^6-15 Adalimumab is specifically approved for moderate to severe nail psoriasis in adults 18 years and older.

Intralesional steroid injections are sometimes useful in the management of nail matrix psoriasis; however, appropriate patient selection is critical due to the pain associated with the procedure. In a prospective study of 16 children (age range, 9–17 years) with nail psoriasis treated with intralesional triamcinolone (ILTAC) 2.5 to 5 mg/mL every 4 to 8 weeks for a minimum of 3 to 6 months, 9 patients achieved resolution and 6 had improvement of clinical findings.¹⁶ Local adverse events were mild, including injection-site pain (66%), subungual hematoma (n=1), Beau lines (n=1), proximal nail fold hypopigmentation (n=2), and proximal nail fold atrophy (n=2). Because the proximal nail fold in children is thinner than in adults, there may be an increased risk for nail fold hypopigmentation and atrophy in children. Therefore, a maximum ILTAC concentration of 2.5 mg/mL with 0.2 mL maximum volume per nail per session is recommended for children younger than 15 years.¹⁶

Nail Lichen Planus

Nail lichen planus (NLP) is uncommon in children, with few biopsy-proven cases documented in the literature.¹⁷ Common clinical findings are onychorrhexis, nail plate thinning, fissuring, splitting, and atrophy with koilonychia.⁵ Although pterygium development (irreversible nail matrix scarring) is uncommon in pediatric patients, NLP can be progressive and may cause irreversible destruction of the nail matrix and subsequent nail loss, warranting therapeutic intervention.¹⁸

Treatment of NLP may be difficult, as there are no options that work in all patients. Current literature supports the use of systemic corticosteroids or ILTAC for the treatment of NLP; however, recurrence rates can be high. According to an expert consensus paper on NLP treatment, ILTAC may be injected in a concentration of 2.5, 5, or 10 mg/mL according to disease severity.¹⁹ In severe or resistant cases, intramuscular (IM) triamcinolone may be considered, especially if more than 3 nails are affected. A dosage of 0.5 to 1 mg/kg/mo for at least 3 to 6 months is recommended for both children and adults, with 1 mg/kg/mo recommended in the active treatment phase (first 2–3 months).¹⁹ In a retrospective review of 5 pediatric patients with NLP treated with IM triamcinolone 0.5 mg/kg/mo, 3 patients had resolution and 2 improved with treatment.²⁰ In a prospective study of 10 children with NLP, IM triamcinolone at a dosage of 0.5 to 1 mg/kg every 30 days for 3 to 6 months resulted in resolution of nail findings in 9 patients.¹⁷ In a prospective study of 14 pediatric patients with NLP treated with 2.5 to 5 mg/mL of ILTAC, 10 achieved resolution and 3 improved.¹⁶

Intralesional triamcinolone injections may be better suited for teenagers compared to younger children who may be more apprehensive of needles. To minimize pain, it is recommended to inject ILTAC slowly at room temperature, with use of “talkesthesia” and vibration devices, 1% lidocaine, or ethyl chloride spray.¹⁸

Trachyonychia

Trachyonychia is characterized by the presence of sandpaperlike nails. It manifests with brittle thin nails with longitudinal ridging, onychoschizia, and thickened hyperkeratotic cuticles. Trachyonychia typically involves multiple nails, with a peak age of onset between 3 and 12 years.^21,22 There are 2 variants: the opaque type with rough longitudinal ridging, and the shiny variant with opalescent nails and pits that reflect light. The opaque variant is more common and is associated with psoriasis, whereas the shiny variant is less common and is associated with alopecia areata.²³ Although most cases are idiopathic, some are associated with psoriasis and alopecia areata, as previously noted, as well as atopic dermatitis (AD) and lichen planus.^22,24

Fortunately, trachyonychia does not lead to permanent nail damage or pterygium, making treatment primarily focused on addressing functional and cosmetic concerns.²⁴ Spontaneous resolution occurs in approximately 50% of patients. In a prospective study of 11 patients with idiopathic trachyonychia, there was partial improvement in 5 of 9 patients treated with topical steroids, 1 with only petrolatum, and 1 with vitamin supplements. Complete resolution was reported in 1 patient treated with topical steroids.²⁵ Because trachyonychia often is self-resolving, no treatment is required and a conservative approach is strongly recommended.²⁶ Treatment options include topical corticosteroids, tazarotene, and 5-fluorouracil. Intralesional triamcinolone, systemic cyclosporine, retinoids, systemic corticosteroids, and tofacitinib have been described in case reports, though none of these have been shown to be 100% efficacious.²⁴

Nail Lichen Striatus

Lichen striatus involving the nail is uncommon and is characterized by onycholysis, longitudinal ridging, ­splitting, and fraying, as well as what appears to be a subungual tumor. It can encompass the entire nail or may be isolated to a portion of the nail (Figure 2). Usually, a Blaschko-linear array of flesh-colored papules on the more proximal digit directly adjacent to the nail dystrophy will be seen, though nail findings can occur in ­isolation.^27-29 The underlying pathophysiology is not clear; however, one hypothesis is that a triggering event, such as trauma, induces the expression of antigens that elicit a self-limiting immune-mediated response by CD8 T lymphocytes.³⁰

Generally, nail lichen striatus spontaneously resolves in 1 to 2 years without treatment. In a prospective study of 5 patients with nail lichen striatus, the median time to resolution was 22.6 months (range, 10–30 months).³¹ Topical steroids may be used for pruritus. In one case report, a 3-year-old boy with nail lichen striatus of 4 months’ duration was treated with tacrolimus ointment 0.03% daily for 3 months.²⁸

Nail AD

Nail changes with AD may be more common in adults than children or are underreported. In a study of 777 adults with AD, nail dystrophy was present in 124 patients (16%), whereas in a study of 250 pediatric patients with AD (aged 0-2 years), nail dystrophy was present in only 4 patients.^32,33

Periungual inflammation from AD causes the nail changes.³⁴ In a cross-sectional study of 24 pediatric patients with nail dystrophy due to AD, transverse grooves (Beau lines) were present in 25% (6/24), nail pitting in 16.7% (4/24), koilonychia in 16.7% (4/24), trachyonychia in 12.5% (3/24), leukonychia in 12.5% (3/24), brachyonychia in 8.3% (2/24), melanonychia in 8.3% (2/24), onychomadesis in 8.3% (2/24), onychoschizia in 8.3% (2/24), and onycholysis in 8.3% (2/24). There was an association between disease severity and presence of toenail dystrophy (P=.03).³⁵

Topical steroids with or without occlusion can be used to treat nail changes. Although there is limited literature describing the treatment of nail AD in children, a 61-year-old man with nail changes associated with AD achieved resolution with 3 months of treatment with dupilumab.³⁶ Anecdotally, most patients will improve with usual cutaneous AD management.

INFECTIOUS NAIL DISORDERS

Viral Infections

Hand, Foot, and Mouth Disease—Hand, foot, and mouth disease (HFMD) is a common childhood viral infection caused by various enteroviruses, most commonly coxsackievirus A16, with the A6 variant causing more severe disease. Fever and painful vesicles involving the oral mucosa as well as palms and soles give the disease its name. Nail changes are common. In a prospective study involving 130 patients with laboratory-confirmed coxsackievirus CA6 serotype infection, 37% developed onychomadesis vs only 5% of 145 cases with non-CA6 enterovirus infection who developed nail findings. There was an association between CA6 infection and presence of nail changes (P<.001).³⁷

Findings ranging from transverse grooves (Beau lines) to complete nail shedding (onychomadesis)(Figure 3) may be seen.^38,39 Nail findings in HFMD are due to transient inhibition of nail growth and present approximately 3 to 6 weeks after infection.⁴⁰ Onychomadesis is seen in 30% to 68% of patients with HFMD.^37,41,42 Nail findings in HFMD spontaneously resolve with nail growth (2–3 mm per month for fingernails and 1 mm per month for toenails) and do not require specific treatment. Although the appearance of nail changes associated with HFMD can be disturbing, dermatologists can reassure children and their parents that the nails will resolve with the next cycle of growth.

Kawasaki Disease—Kawasaki disease (KD) is a vasculitis primarily affecting children and infants. Although the specific pathogen and pathophysiology is not entirely clear, clinical observations have suggested an infectious cause, most likely a virus.⁴³ In Japan, more than 15,000 cases of KD are documented annually, while approximately 4200 cases are seen in the United States.⁴⁴ In a prospective study from 1984 to 1990, 4 of 26 (15.4%) patients with KD presented with nail manifestations during the late acute phase or early convalescent phase of disease. There were no significant associations between nail dystrophy and severity of KD, such as coronary artery aneurysm.⁴⁵

Nail changes reported in children with KD include onychomadesis, onycholysis, orange-brown chromonychia, splinter hemorrhages, Beau lines, and pincer nails. In a review of nail changes associated with KD from 1980 to 2021, orange-brown transverse chromonychia, which may evolve into transverse leukonychia, was the most common nail finding reported, occurring in 17 of 31 (54.8%) patients.⁴⁴ It has been hypothesized that nail changes may result from blood flow disturbance due to the underlying vasculitis.⁴⁶ Nail changes appear several weeks after the onset of fever and are self-limited. Resolution occurs with nail growth, with no treatment required.

FUNGAL INFECTIONS

Onychomycosis

Onychomycosis is a fungal infection of the nails that occurs in 0.2% to 5.5% of pediatric patients, and its prevalence may be increasing, which may be due to environmental factors or increased rates of diabetes mellitus and obesity in the pediatric population.⁴⁷ Onychomycosis represents 15.5% of nail dystrophies in pediatric patients.⁴⁸ Some dermatologists treat presumptive onychomycosis without confirmation; however, we do not recommend that approach. Because the differential is broad and the duration of treatment is long, mycologic examination (potassium hydroxide preparation, fungal culture, polymerase chain reaction, and/or histopathology) should be obtained to confirm onychomycosis prior to initiation of antifungal management. Family members of affected individuals should be evaluated and treated, if indicated, for onychomycosis and tinea pedis, as household transmission is common.

Currently, there are 2 topical FDA-approved treatments for pediatric onychomycosis in children 6 years and older (Table 2).^49,50 There is a discussion of the need for confirmatory testing for onychomycosis in children, particularly when systemic treatment is prescribed. In a retrospective review of 269 pediatric patients with onychomycosis prescribed terbinafine, 53.5% (n=144) underwent laboratory monitoring of liver function and complete blood cell counts, and 12.5% had grade 1 laboratory abnormalities either prior to (12/144 [8.3%]) or during (6/144 [4.2%]) therapy.⁵¹ Baseline transaminase monitoring is recommended, though subsequent routine laboratory monitoring in healthy children may have limited utility with associated increased costs, incidental findings, and patient discomfort and likely is not needed.⁵¹

Pediatric onychomycosis responds better to topical therapy than adult disease, and pediatric patients do not always require systemic treatment.⁵² Ciclopirox is not FDA approved for the treatment of pediatric onychomycosis, but in a 32-week clinical trial of ciclopirox lacquer 8% use in 40 patients, 77% (27/35) of treated patients achieved mycologic cure. Overall, 71% of treated patients (25/35) vs 22% (2/9) of controls achieved efficacy (defined as investigator global assessment score of 2 or lower).⁵² In an open-label, single-arm clinical trial assessing tavaborole solution 5% applied once daily for 48 weeks for the treatment of toenail onychomycosis in pediatric patients (aged 6–17 years), 36.2% (20/55) of patients achieved mycologic cure, and 8.5% (5/55) achieved complete cure at week 52 with mild or minimal adverse effects.⁵³ In an open-label, phase 4 study of the safety and efficacy of efinaconazole solution 10% applied once daily for 48 weeks in pediatric patients (aged 6 to 16 years) (n=60), 65% (35/60) achieved mycologic cure, 42% (25/60) achieved clinical cure, and 40% (24/60) achieved complete cure at 52 weeks. The most common adverse effects of efina­conazole were local and included ingrown toenail (1/60), application-site dermatitis (1/60), application-site vesicles (1/60), and application-site pain (1/60).⁵⁴

In a systematic review of systemic antifungals for onychomycosis in 151 pediatric patients, itraconazole, fluconazole, griseofulvin, and terbinafine resulted in complete cure rates similar to those of the adult population, with excellent safety profiles.⁵⁵ Depending on the situation, initiation of treatment with topical medications followed by addition of systemic antifungal agents only if needed may be an appropriate course of action.

BACTERIAL INFECTIONS

Acute Paronychia

Acute paronychia is a nail-fold infection that develops after the protective nail barrier has been compromised.⁵⁶ In children, thumb-sucking, nail-biting, frequent oral manipulation of the digits, and poor skin hygiene are risk factors. Acute paronychia also may develop in association with congenital malalignment of the great toenails.⁵⁷

Clinical manifestations include localized pain, erythema, and nail fold edema (Figure 4). Purulent material and abscess formation may ensue. Staphylococcus aureus as well as methicillin-resistant S aureus and Streptococcus pyogenes are classically the most common causes of acute paronychia. Treatment of paronychia is based on severity. In mild cases, warm soaks with topical antibiotics are indicated. Oral antibiotics should be prescribed for more severe presentations. If there is no improvement after 48 hours, surgical drainage is required to facilitate healing.⁵⁶

FINAL THOUGHTS

Inflammatory and infectious nail disorders in children are relatively common and may impact the physical and emotional well-being of young patients. By understanding the distinctive features of these nail disorders in pediatric patients, dermatologists can provide anticipatory guidance and informed treatment options to children and their parents. Further research is needed to expand our understanding of pediatric nail disorders and create targeted therapeutic interventions, particularly for NLP and psoriasis.

Nail disorders are common among pediatric patients but often are underdiagnosed or misdiagnosed because of their unique disease manifestations. These conditions may severely impact quality of life. There are few nail disease clinical trials that include children. Consequently, most treatment recommendations are based on case series and expert consensus recommendations. We review inflammatory and infectious nail disorders in pediatric patients. By describing characteristics, clinical manifestations, and management approaches for these conditions, we aim to provide guidance to dermatologists in their diagnosis and treatment.

INFLAMMATORY NAIL DISORDERS

Nail Psoriasis

Nail involvement in children with psoriasis is common, with prevalence estimates ranging from 17% to 39.2%.¹ Nail matrix psoriasis may manifest with pitting (large irregular pits) and leukonychia as well as chromonychia and nail plate crumbling. Onycholysis, oil drop spots (salmon patches), and subungual hyperkeratosis can be seen in nail bed psoriasis. Nail pitting is the most frequently observed clinical finding (Figure 1).^2,3 In a cross-sectional multicenter study of 313 children with cutaneous psoriasis in France, nail findings were present in 101 patients (32.3%). There were associations between nail findings and presence of psoriatic arthritis (P=.03), palmoplantar psoriasis (P<.001), and severity of psoriatic disease, defined as use of systemic treatment with phototherapy (psoralen plus UVA, UVB), traditional systemic treatment (acitretin, methotrexate, cyclosporine), or a biologic (P=.003).⁴

Topical steroids and vitamin D analogues may be used with or without occlusion and may be efficacious.⁵ Several case reports describe systemic treatments for psoriasis in children, including methotrexate, acitretin, and apremilast (approved for children 6 years and older for plaque psoriasis by the US Food and Drug Administration [FDA]).² There are 5 biologic drugs currently approved for the treatment of pediatric psoriasis—adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab—and 6 drugs currently undergoing phase 3 studies—brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib (Table 1).^6-15 Adalimumab is specifically approved for moderate to severe nail psoriasis in adults 18 years and older.

Intralesional steroid injections are sometimes useful in the management of nail matrix psoriasis; however, appropriate patient selection is critical due to the pain associated with the procedure. In a prospective study of 16 children (age range, 9–17 years) with nail psoriasis treated with intralesional triamcinolone (ILTAC) 2.5 to 5 mg/mL every 4 to 8 weeks for a minimum of 3 to 6 months, 9 patients achieved resolution and 6 had improvement of clinical findings.¹⁶ Local adverse events were mild, including injection-site pain (66%), subungual hematoma (n=1), Beau lines (n=1), proximal nail fold hypopigmentation (n=2), and proximal nail fold atrophy (n=2). Because the proximal nail fold in children is thinner than in adults, there may be an increased risk for nail fold hypopigmentation and atrophy in children. Therefore, a maximum ILTAC concentration of 2.5 mg/mL with 0.2 mL maximum volume per nail per session is recommended for children younger than 15 years.¹⁶

Nail Lichen Planus

Nail lichen planus (NLP) is uncommon in children, with few biopsy-proven cases documented in the literature.¹⁷ Common clinical findings are onychorrhexis, nail plate thinning, fissuring, splitting, and atrophy with koilonychia.⁵ Although pterygium development (irreversible nail matrix scarring) is uncommon in pediatric patients, NLP can be progressive and may cause irreversible destruction of the nail matrix and subsequent nail loss, warranting therapeutic intervention.¹⁸

Treatment of NLP may be difficult, as there are no options that work in all patients. Current literature supports the use of systemic corticosteroids or ILTAC for the treatment of NLP; however, recurrence rates can be high. According to an expert consensus paper on NLP treatment, ILTAC may be injected in a concentration of 2.5, 5, or 10 mg/mL according to disease severity.¹⁹ In severe or resistant cases, intramuscular (IM) triamcinolone may be considered, especially if more than 3 nails are affected. A dosage of 0.5 to 1 mg/kg/mo for at least 3 to 6 months is recommended for both children and adults, with 1 mg/kg/mo recommended in the active treatment phase (first 2–3 months).¹⁹ In a retrospective review of 5 pediatric patients with NLP treated with IM triamcinolone 0.5 mg/kg/mo, 3 patients had resolution and 2 improved with treatment.²⁰ In a prospective study of 10 children with NLP, IM triamcinolone at a dosage of 0.5 to 1 mg/kg every 30 days for 3 to 6 months resulted in resolution of nail findings in 9 patients.¹⁷ In a prospective study of 14 pediatric patients with NLP treated with 2.5 to 5 mg/mL of ILTAC, 10 achieved resolution and 3 improved.¹⁶

Intralesional triamcinolone injections may be better suited for teenagers compared to younger children who may be more apprehensive of needles. To minimize pain, it is recommended to inject ILTAC slowly at room temperature, with use of “talkesthesia” and vibration devices, 1% lidocaine, or ethyl chloride spray.¹⁸

Trachyonychia

Trachyonychia is characterized by the presence of sandpaperlike nails. It manifests with brittle thin nails with longitudinal ridging, onychoschizia, and thickened hyperkeratotic cuticles. Trachyonychia typically involves multiple nails, with a peak age of onset between 3 and 12 years.^21,22 There are 2 variants: the opaque type with rough longitudinal ridging, and the shiny variant with opalescent nails and pits that reflect light. The opaque variant is more common and is associated with psoriasis, whereas the shiny variant is less common and is associated with alopecia areata.²³ Although most cases are idiopathic, some are associated with psoriasis and alopecia areata, as previously noted, as well as atopic dermatitis (AD) and lichen planus.^22,24

Fortunately, trachyonychia does not lead to permanent nail damage or pterygium, making treatment primarily focused on addressing functional and cosmetic concerns.²⁴ Spontaneous resolution occurs in approximately 50% of patients. In a prospective study of 11 patients with idiopathic trachyonychia, there was partial improvement in 5 of 9 patients treated with topical steroids, 1 with only petrolatum, and 1 with vitamin supplements. Complete resolution was reported in 1 patient treated with topical steroids.²⁵ Because trachyonychia often is self-resolving, no treatment is required and a conservative approach is strongly recommended.²⁶ Treatment options include topical corticosteroids, tazarotene, and 5-fluorouracil. Intralesional triamcinolone, systemic cyclosporine, retinoids, systemic corticosteroids, and tofacitinib have been described in case reports, though none of these have been shown to be 100% efficacious.²⁴

Nail Lichen Striatus

Lichen striatus involving the nail is uncommon and is characterized by onycholysis, longitudinal ridging, ­splitting, and fraying, as well as what appears to be a subungual tumor. It can encompass the entire nail or may be isolated to a portion of the nail (Figure 2). Usually, a Blaschko-linear array of flesh-colored papules on the more proximal digit directly adjacent to the nail dystrophy will be seen, though nail findings can occur in ­isolation.^27-29 The underlying pathophysiology is not clear; however, one hypothesis is that a triggering event, such as trauma, induces the expression of antigens that elicit a self-limiting immune-mediated response by CD8 T lymphocytes.³⁰

Generally, nail lichen striatus spontaneously resolves in 1 to 2 years without treatment. In a prospective study of 5 patients with nail lichen striatus, the median time to resolution was 22.6 months (range, 10–30 months).³¹ Topical steroids may be used for pruritus. In one case report, a 3-year-old boy with nail lichen striatus of 4 months’ duration was treated with tacrolimus ointment 0.03% daily for 3 months.²⁸

Nail AD

Nail changes with AD may be more common in adults than children or are underreported. In a study of 777 adults with AD, nail dystrophy was present in 124 patients (16%), whereas in a study of 250 pediatric patients with AD (aged 0-2 years), nail dystrophy was present in only 4 patients.^32,33

Periungual inflammation from AD causes the nail changes.³⁴ In a cross-sectional study of 24 pediatric patients with nail dystrophy due to AD, transverse grooves (Beau lines) were present in 25% (6/24), nail pitting in 16.7% (4/24), koilonychia in 16.7% (4/24), trachyonychia in 12.5% (3/24), leukonychia in 12.5% (3/24), brachyonychia in 8.3% (2/24), melanonychia in 8.3% (2/24), onychomadesis in 8.3% (2/24), onychoschizia in 8.3% (2/24), and onycholysis in 8.3% (2/24). There was an association between disease severity and presence of toenail dystrophy (P=.03).³⁵

Topical steroids with or without occlusion can be used to treat nail changes. Although there is limited literature describing the treatment of nail AD in children, a 61-year-old man with nail changes associated with AD achieved resolution with 3 months of treatment with dupilumab.³⁶ Anecdotally, most patients will improve with usual cutaneous AD management.

INFECTIOUS NAIL DISORDERS

Viral Infections

Hand, Foot, and Mouth Disease—Hand, foot, and mouth disease (HFMD) is a common childhood viral infection caused by various enteroviruses, most commonly coxsackievirus A16, with the A6 variant causing more severe disease. Fever and painful vesicles involving the oral mucosa as well as palms and soles give the disease its name. Nail changes are common. In a prospective study involving 130 patients with laboratory-confirmed coxsackievirus CA6 serotype infection, 37% developed onychomadesis vs only 5% of 145 cases with non-CA6 enterovirus infection who developed nail findings. There was an association between CA6 infection and presence of nail changes (P<.001).³⁷

Findings ranging from transverse grooves (Beau lines) to complete nail shedding (onychomadesis)(Figure 3) may be seen.^38,39 Nail findings in HFMD are due to transient inhibition of nail growth and present approximately 3 to 6 weeks after infection.⁴⁰ Onychomadesis is seen in 30% to 68% of patients with HFMD.^37,41,42 Nail findings in HFMD spontaneously resolve with nail growth (2–3 mm per month for fingernails and 1 mm per month for toenails) and do not require specific treatment. Although the appearance of nail changes associated with HFMD can be disturbing, dermatologists can reassure children and their parents that the nails will resolve with the next cycle of growth.

Kawasaki Disease—Kawasaki disease (KD) is a vasculitis primarily affecting children and infants. Although the specific pathogen and pathophysiology is not entirely clear, clinical observations have suggested an infectious cause, most likely a virus.⁴³ In Japan, more than 15,000 cases of KD are documented annually, while approximately 4200 cases are seen in the United States.⁴⁴ In a prospective study from 1984 to 1990, 4 of 26 (15.4%) patients with KD presented with nail manifestations during the late acute phase or early convalescent phase of disease. There were no significant associations between nail dystrophy and severity of KD, such as coronary artery aneurysm.⁴⁵

Nail changes reported in children with KD include onychomadesis, onycholysis, orange-brown chromonychia, splinter hemorrhages, Beau lines, and pincer nails. In a review of nail changes associated with KD from 1980 to 2021, orange-brown transverse chromonychia, which may evolve into transverse leukonychia, was the most common nail finding reported, occurring in 17 of 31 (54.8%) patients.⁴⁴ It has been hypothesized that nail changes may result from blood flow disturbance due to the underlying vasculitis.⁴⁶ Nail changes appear several weeks after the onset of fever and are self-limited. Resolution occurs with nail growth, with no treatment required.

FUNGAL INFECTIONS

Onychomycosis

Onychomycosis is a fungal infection of the nails that occurs in 0.2% to 5.5% of pediatric patients, and its prevalence may be increasing, which may be due to environmental factors or increased rates of diabetes mellitus and obesity in the pediatric population.⁴⁷ Onychomycosis represents 15.5% of nail dystrophies in pediatric patients.⁴⁸ Some dermatologists treat presumptive onychomycosis without confirmation; however, we do not recommend that approach. Because the differential is broad and the duration of treatment is long, mycologic examination (potassium hydroxide preparation, fungal culture, polymerase chain reaction, and/or histopathology) should be obtained to confirm onychomycosis prior to initiation of antifungal management. Family members of affected individuals should be evaluated and treated, if indicated, for onychomycosis and tinea pedis, as household transmission is common.

Currently, there are 2 topical FDA-approved treatments for pediatric onychomycosis in children 6 years and older (Table 2).^49,50 There is a discussion of the need for confirmatory testing for onychomycosis in children, particularly when systemic treatment is prescribed. In a retrospective review of 269 pediatric patients with onychomycosis prescribed terbinafine, 53.5% (n=144) underwent laboratory monitoring of liver function and complete blood cell counts, and 12.5% had grade 1 laboratory abnormalities either prior to (12/144 [8.3%]) or during (6/144 [4.2%]) therapy.⁵¹ Baseline transaminase monitoring is recommended, though subsequent routine laboratory monitoring in healthy children may have limited utility with associated increased costs, incidental findings, and patient discomfort and likely is not needed.⁵¹

Pediatric onychomycosis responds better to topical therapy than adult disease, and pediatric patients do not always require systemic treatment.⁵² Ciclopirox is not FDA approved for the treatment of pediatric onychomycosis, but in a 32-week clinical trial of ciclopirox lacquer 8% use in 40 patients, 77% (27/35) of treated patients achieved mycologic cure. Overall, 71% of treated patients (25/35) vs 22% (2/9) of controls achieved efficacy (defined as investigator global assessment score of 2 or lower).⁵² In an open-label, single-arm clinical trial assessing tavaborole solution 5% applied once daily for 48 weeks for the treatment of toenail onychomycosis in pediatric patients (aged 6–17 years), 36.2% (20/55) of patients achieved mycologic cure, and 8.5% (5/55) achieved complete cure at week 52 with mild or minimal adverse effects.⁵³ In an open-label, phase 4 study of the safety and efficacy of efinaconazole solution 10% applied once daily for 48 weeks in pediatric patients (aged 6 to 16 years) (n=60), 65% (35/60) achieved mycologic cure, 42% (25/60) achieved clinical cure, and 40% (24/60) achieved complete cure at 52 weeks. The most common adverse effects of efina­conazole were local and included ingrown toenail (1/60), application-site dermatitis (1/60), application-site vesicles (1/60), and application-site pain (1/60).⁵⁴

In a systematic review of systemic antifungals for onychomycosis in 151 pediatric patients, itraconazole, fluconazole, griseofulvin, and terbinafine resulted in complete cure rates similar to those of the adult population, with excellent safety profiles.⁵⁵ Depending on the situation, initiation of treatment with topical medications followed by addition of systemic antifungal agents only if needed may be an appropriate course of action.

BACTERIAL INFECTIONS

Acute Paronychia

Acute paronychia is a nail-fold infection that develops after the protective nail barrier has been compromised.⁵⁶ In children, thumb-sucking, nail-biting, frequent oral manipulation of the digits, and poor skin hygiene are risk factors. Acute paronychia also may develop in association with congenital malalignment of the great toenails.⁵⁷

Clinical manifestations include localized pain, erythema, and nail fold edema (Figure 4). Purulent material and abscess formation may ensue. Staphylococcus aureus as well as methicillin-resistant S aureus and Streptococcus pyogenes are classically the most common causes of acute paronychia. Treatment of paronychia is based on severity. In mild cases, warm soaks with topical antibiotics are indicated. Oral antibiotics should be prescribed for more severe presentations. If there is no improvement after 48 hours, surgical drainage is required to facilitate healing.⁵⁶

FINAL THOUGHTS

Inflammatory and infectious nail disorders in children are relatively common and may impact the physical and emotional well-being of young patients. By understanding the distinctive features of these nail disorders in pediatric patients, dermatologists can provide anticipatory guidance and informed treatment options to children and their parents. Further research is needed to expand our understanding of pediatric nail disorders and create targeted therapeutic interventions, particularly for NLP and psoriasis.