Cutis

To improve patient care and outcomes, leading dermatologists offered their recommendations on redness-reducing products. Consideration must be given to:

• Avène Antirougeurs FORT Relief Concentrate
  Pierre Fabre Dermo-Cosmetique USA
  “This formula has medical-grade ruscus extract to support microcirculation and soothe skin reactivity and redness, as well as soothing Avène Thermal Spring Water.” — Jeannette Graf, MD, New York, New York
   
• Eucerin Redness Relief
  Beiersdorf Inc
  “Eucerin’s Redness Relief product line has worked well for some of my patients.” — Gary Goldenberg, MD, New York, New York
   
• Redness Solutions Daily Protective Base Broad Spectrum SPF 15
  Clinique Laboratories, LLC
  “This oil-free makeup primer has a sheer green tint that camouflages redness while also protecting from UV rays.” — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and men’s products will be featured in upcoming editions of Cosmetic Corner. Please email your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on redness-reducing products. Consideration must be given to:

• Avène Antirougeurs FORT Relief Concentrate
  Pierre Fabre Dermo-Cosmetique USA
  “This formula has medical-grade ruscus extract to support microcirculation and soothe skin reactivity and redness, as well as soothing Avène Thermal Spring Water.” — Jeannette Graf, MD, New York, New York
   
• Eucerin Redness Relief
  Beiersdorf Inc
  “Eucerin’s Redness Relief product line has worked well for some of my patients.” — Gary Goldenberg, MD, New York, New York
   
• Redness Solutions Daily Protective Base Broad Spectrum SPF 15
  Clinique Laboratories, LLC
  “This oil-free makeup primer has a sheer green tint that camouflages redness while also protecting from UV rays.” — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and men’s products will be featured in upcoming editions of Cosmetic Corner. Please email your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on redness-reducing products. Consideration must be given to:

• Avène Antirougeurs FORT Relief Concentrate
  Pierre Fabre Dermo-Cosmetique USA
  “This formula has medical-grade ruscus extract to support microcirculation and soothe skin reactivity and redness, as well as soothing Avène Thermal Spring Water.” — Jeannette Graf, MD, New York, New York
   
• Eucerin Redness Relief
  Beiersdorf Inc
  “Eucerin’s Redness Relief product line has worked well for some of my patients.” — Gary Goldenberg, MD, New York, New York
   
• Redness Solutions Daily Protective Base Broad Spectrum SPF 15
  Clinique Laboratories, LLC
  “This oil-free makeup primer has a sheer green tint that camouflages redness while also protecting from UV rays.” — Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and men’s products will be featured in upcoming editions of Cosmetic Corner. Please email your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

Glytone Sunscreen Lotion Broad Spectrum SPF 40

Pierre Fabre Dermo-Cosmetique USA introduces Glytone Sunscreen Lotion Broad Spectrum SPF 40, a mineral-based formula for face and body with micronized zinc oxide, octinoxate, and octisalate. The lightweight formula is water resistant for up to 40 minutes and contains hyaluronic acid to nourish the skin and help boost natural moisture levels to visibly reduce the appearance of fine lines and wrinkles. For more information, visit www.glytone-usa.com.

proactivMD

The Proactiv Company launches the proactivMD Essentials System, a 3-step acne regimen that has been reformulated to include the topical retinoid adapalene. Step 1 is the Deep Cleansing Face Wash formulated to help clear dirt and debris from deep within the pores. Step 2 is the Balancing Toner, an alcohol-free formula that contains a light astringent to sweep away impurities leaving the skin feeling fresh and balanced. Step 3 consists of the Daily Oil Control Moisturizer (morning), which protects the skin and controls shine, and Adapalene Gel 0.1% (evening) to speed acne healing and prevent new acne from forming. For more information, visit www.proactiv.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Glytone Sunscreen Lotion Broad Spectrum SPF 40

Pierre Fabre Dermo-Cosmetique USA introduces Glytone Sunscreen Lotion Broad Spectrum SPF 40, a mineral-based formula for face and body with micronized zinc oxide, octinoxate, and octisalate. The lightweight formula is water resistant for up to 40 minutes and contains hyaluronic acid to nourish the skin and help boost natural moisture levels to visibly reduce the appearance of fine lines and wrinkles. For more information, visit www.glytone-usa.com.

proactivMD

The Proactiv Company launches the proactivMD Essentials System, a 3-step acne regimen that has been reformulated to include the topical retinoid adapalene. Step 1 is the Deep Cleansing Face Wash formulated to help clear dirt and debris from deep within the pores. Step 2 is the Balancing Toner, an alcohol-free formula that contains a light astringent to sweep away impurities leaving the skin feeling fresh and balanced. Step 3 consists of the Daily Oil Control Moisturizer (morning), which protects the skin and controls shine, and Adapalene Gel 0.1% (evening) to speed acne healing and prevent new acne from forming. For more information, visit www.proactiv.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Glytone Sunscreen Lotion Broad Spectrum SPF 40

Pierre Fabre Dermo-Cosmetique USA introduces Glytone Sunscreen Lotion Broad Spectrum SPF 40, a mineral-based formula for face and body with micronized zinc oxide, octinoxate, and octisalate. The lightweight formula is water resistant for up to 40 minutes and contains hyaluronic acid to nourish the skin and help boost natural moisture levels to visibly reduce the appearance of fine lines and wrinkles. For more information, visit www.glytone-usa.com.

proactivMD

The Proactiv Company launches the proactivMD Essentials System, a 3-step acne regimen that has been reformulated to include the topical retinoid adapalene. Step 1 is the Deep Cleansing Face Wash formulated to help clear dirt and debris from deep within the pores. Step 2 is the Balancing Toner, an alcohol-free formula that contains a light astringent to sweep away impurities leaving the skin feeling fresh and balanced. Step 3 consists of the Daily Oil Control Moisturizer (morning), which protects the skin and controls shine, and Adapalene Gel 0.1% (evening) to speed acne healing and prevent new acne from forming. For more information, visit www.proactiv.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

One of the most common concerns among black patients is hair- and scalp-related disease. As increasing numbers of black patients opt to see dermatologists, it is imperative that all dermatologists be adequately trained to address the concerns of this patient population. When patients ask for help with common skin diseases of the hair and scalp, there are details that must be included in diagnosis, treatment, and hair care recommendations to reach goals for excellence in patient care. Herein, we provide must-know information to effectively approach this patient population.

Seborrheic Dermatitis

A study utilizing data from the National Ambulatory Medical Care Survey from 1993 to 2009 revealed seborrheic dermatitis (SD) as the second most common diagnosis for black patients who visit a dermatologist.¹ Prevalence data from a population of 1408 white, black, and Chinese patients from the United States and China revealed scalp flaking in 81% to 95% of black patients, 66% to 82% in white patients, and 30% to 42% in Chinese patients.² Seborrheic dermatitis has a notable prevalence in black women and often is considered normal by patients. It can be exacerbated by infrequent shampooing (ranging from once per month or longer in between shampoos) and the inappropriate use of hair oils and pomades; it also has been associated with hair breakage, lichen simplex chronicus, and folliculitis. Seborrheic dermatitis must be distinguished from other disorders including sarcoidosis, psoriasis, discoid lupus erythematosus, tinea capitis, and lichen simplex chronicus.

Although there is a paucity of literature on the treatment of SD in black patients, components of treatment are similar to those recommended for other populations. Black women are advised to carefully utilize antidandruff shampoos containing zinc pyrithione, selenium sulfide, or tar to avoid hair shaft damage and dryness. Ketoconazole shampoo rarely is recommended and may be more appropriately used in men and boys, as hair fragility is less of a concern for them. The shampoo should be applied directly to the scalp rather than the hair shafts to minimize dryness, with no particular elongated contact time needed for these medicated shampoos to be effective. Because conditioners can wash off the active ingredients in therapeutic shampoos, antidandruff conditioners are recommended. Potent or ultrapotent topical corticosteroids applied to the scalp 3 to 4 times weekly initially will control the symptoms of itching as well as scaling, and mid-potency topical corticosteroid oil may be used at weekly intervals.

Hairline and facial involvement of SD often co-occurs, and low-potency topical steroids may be applied to the affected areas twice daily for 3 to 4 weeks, which may be repeated for flares. Topical calcineurin inhibitors or antifungal creams such as ketoconazole or econazole may then provide effective control. Encouraging patients to increase shampooing to once weekly or every 2 weeks and discontinue use of scalp pomades and oils also is recommended. Patients must know that an itchy scaly scalp represents a treatable disorder. 

Acquired Trichorrhexis Nodosa

Hair fragility and breakage is common and multifactorial in black patients. Hair shaft breakage can occur on the vertex scalp in central centrifugal cicatricial alopecia (CCCA), with random localized breakage due to scratching in SD. Heat, hair colorants, and chemical relaxers may result in diffuse damage and breakage.³ Sodium-, potassium-, and guanine hydroxide–containing chemical relaxers change the physical properties of the hair by rearranging disulfide bonds. They remove the monomolecular layer of fatty acids covalently bound to the cuticle that help prevent penetration of water into the hair shaft. Additionally, chemical relaxers weaken the hair shaft and decrease tensile strength.

Unlike hair relaxers, colorants are less likely to lead to catastrophic hair breakage after a single use and require frequent use, which leads to cumulative damage. Thermal straightening is another cause of hair-shaft weakening in black patients.^4,5 Flat irons and curling irons can cause substantially more damage than blow-dryers due to the amount of heat generated. Flat irons may reach a high temperature of 230ºC (450ºF) as compared to 100°C (210°F) for a blow-dryer. Even the simple act of combing the hair can cause hair breakage, as demonstrated in African volunteers whose hair remained short in contrast to white and Asian volunteers, despite the fact that they had not cut their hair for 1 or more years.^6,7 These volunteers had many hair strand knots that led to breakage during combing and hair grooming.⁶

There is no known prevalence data for acquired trichorrhexis nodosa, though a study of 30 white and black women demonstrated that broken hairs were significantly increased in black women (P=.0001).⁸ Another study by Hall et al⁹ of 103 black women showed that 55% of the women reported breakage of hair shafts with normal styling. Khumalo et al⁶ investigated hair shaft fragility and reported no trichothiodystrophy; the authors concluded that the cause of the hair fragility likely was physical trauma or an undiscovered structural abnormality. Franbourg et al¹⁰ examined the structure of hair fibers in white, Asian, and black patients and found no differences, but microfractures were only present in black patients and were determined to be the cause of hair breakage. These studies underscore the need for specific questioning of the patient on hair care including combing, washing, drying, and using products and chemicals.

The approach to the treatment of hair breakage involves correcting underlying abnormalities (eg, iron deficiency, hypothyroidism, nutritional deficiencies). Patients should “give their hair a rest” by discontinuing use of heat, colorants, and chemical relaxers. For patients who are unable to comply, advising them to stop these processes for 6 to 12 months will allow for repair of the hair shaft. To minimize damage from colorants, recommend semipermanent, demipermanent, or temporary dyes. Patients should be counseled to stop bleaching their hair or using permanent colorants. The use of heat protectant products on the hair before styling as well as layering moisturizing regimens starting with a moisturizing shampoo followed by a leave-in, dimethicone-containing conditioner marketed for dry damaged hair is suggested. Dimethicone thinly coats the hair shaft to restore hydrophobicity, smoothes cuticular scales, decreases frizz, and protects the hair from damage. Use of a 2-in-1 shampoo and conditioner containing anionic surfactants and wide-toothed, smooth (no jagged edges in the grooves) combs along with rare brushing are recommended. The hair may be worn in its natural state, but straightening with heat should be avoided. Air drying the hair can minimize breakage, but if thermal styling is necessary, patients should turn the temperature setting of the flat or curling iron down. Protective hair care practices may include placing a loosely sewn-in hair weave that will allow for good hair care, wearing loose braids, or using a wig. Serial trimming of the hair every 6 to 8 weeks is recommended. Improvement may take time, and patients should be advised of this timeline to prevent frustration.

Acne Keloidalis Nuchae

Acne keloidalis nuchae (AKN) is characterized by papules and pustules located on the occipital scalp and/or the nape of the neck, which may result in keloidal papules and plaques. The etiology is unknown, but ingrown hairs, genetics, trauma, infection, inflammation, and androgen hormones have been proposed to play a role.¹¹ Although AKN may occur in black women, it is primarily a disorder in black men. The diagnosis is made based primarily on clinical findings, and a history of short haircuts may support the diagnosis. Treatment is tailored to the severity of the disease (Table 1). Avoidance of short haircuts and irritation from shirt collars may be helpful. Patients should be advised that the condition is controllable but not curable.

Pseudofolliculitis Barbae

Pseudofolliculitis barbae (PFB) is characterized by papules and pustules in the beard region that may result in postinflammatory hyperpigmentation, keloidal scar formation, and/or linear scarring. The coarse curled hairs characteristic of black men penetrate the follicle before exiting the skin and penetrate the skin after exiting the follicle, resulting in inflammation. Shaving methods and genetics also may contribute to the development of PFB. As with AKN, diagnosis is made clinically and does not require a skin biopsy. Important components of the patient’s history that should be obtained are hair removal practices and the use of over-the-counter products (eg, shave [pre and post] moisturizers, exfoliants, shaving creams or gels, keratin-softening agents containing α- or β-hydroxy acids). A bacterial culture may be appropriate if a notable pustular component is present. The patient should be advised to discontinue shaving if possible, which may require a physician’s letter explaining the necessity to the patient’s employer. Pseudofolliculitis barbae often can be prevented or lessened with the right hair removal strategy. Because there is not one optimal hair removal strategy that suits every patient, encourage the patient to experiment with different hair removal techniques, from depilatories to electric shavers, foil-guard razors, and multiple-blade razors. Preshave hydration and postshave moisturiza-tion also should be encouraged.¹² Benzoyl peroxide–containing shave gels and cleansers, as well as moisturizers containing glycolic, salicylic, and phytic acids, may minimize ingrown hairs, papules, and inflammation.

Other useful topical agents include eflornithine hydrochloride to decrease hair growth, retinoids to soften hair fibers, mild topical steroids to reduce inflammation, and/or topical erythromycin or clindamycin if pustules are present.¹³ Oral antibiotics such as doxycycline, minocycline, or erythromycin can be added for more severe cases of inflammation or infection. Procedural interventions include laser hair removal to prevent PFB and intralesional triamcinolone 10 to 40 mg/cc every 4 to 6 weeks, with the total volume depending on the size and number of lesions.

Alopecia

Alopecia is the sixth most common diagnosis seen in black patients visiting a dermatologist.¹⁴ The physician’s response to the patient’s chief concern of hair loss is key to building a relationship of confidence and trust. Trivializing the concern or dismissing it will undermine the physician-patient relationship. A survey by Gathers and Mahan¹⁵ revealed that 68% of patients thought that physicians did not understand their hair.

Hair loss negatively impacts quality of life, and a study of 50 black South African women with alopecia demonstrated a notable disease burden. Factors with the highest impact were those related to self-image, relationships, and interactions with others.¹⁶

It is not unusual for black women to have multiple types of alopecia identified in one biopsy specimen. Wohltmann and Sperling¹⁷ demonstrated 2 or more different types of alopecia in more than 10% of biopsy specimens of alopecia, including CCCA, androgenetic alopecia, end-stage traction alopecia, telogen effluvium, and tinea capitis. A complete history, physical examination, and appropriate procedures (eg, hair pull test, dermatoscopic examination and scalp biopsy) likely will yield an accurate diagnosis. Table 2 highlights important questions that should be asked about the patient’s history.

Physical examination of the scalp including dermatoscopic examination and a hair pull test as well as an evaluation of other hair-bearing areas may suggest a diagnosis that can be confirmed with a scalp biopsy.^18,19 Selection of a biopsy site at the periphery of the alopecic area that includes hair and consultation with a dermatopathologist familiar with features of CCCA, traction, and traumatic alopecia are important for making an accurate diagnosis.

Tinea Capitis in Black Pediatric Patients

Tinea capitis, a fungal infection of the scalp and hair, is one of the most common issues in children with skin of color. Clinical presentation may include widely distributed scaling, annular scaly plaques, annular patches of alopecia studded with black dots (broken hairs), and/or annular inflammatory plaques. Although scalp hyperkeratosis often is a hallmark of pediatric tinea capitis, it is not diagnostic. The differential diagnosis of pediatric scalp hyperkeratosis/scaling includes tinea capitis, SD, atopic dermatitis, psoriasis, and sebopsoriasis.^20,21 Clues to accurate diagnosis of tinea capitis may be found by examination of the adult who combs the child’s hair, as erythematous annular scaly plaques representing tinea corporis may be observed on the forearms or thighs. Although the thighs are a seemingly unusual location, the frequent practice of the child sitting on the floor between the legs of the adult during hairstyling provides a point of contact for the transmission of tinea from the child’s scalp to the thighs or forearms of the adult. Once tinea capitis is clinically suspected, the diagnosis is confirmed by a fungal culture. Adequate sampling is obtained by clipping hairs in an area of scaling for submission and vigorously rubbing the area of black dots or hyperkeratosis with a cotton swab.

Hubbard²² shed light on the decision to treat tinea capitis empirically or await the culture results. One hundred consecutive children (98 were black) presented with the constellation of scalp alopecia, scaling, pruritus, and occipital lymphadenopathy. Sixty-eight of those children had positive fungal cultures, and of them, 60 had both occipital lymphadenopathy and scaling and 55 had both occipital lymphadenopathy and alopecia.²² Thus, occipital lymphadenopathy in conjunction with alopecia and/or scaling is predictive of tinea capitis in this population and suggests that the initiation of treatment prior to confirmative culture results is appropriate.

The mainstay of treatment for tinea capitis is griseofulvin, but it is often underdosed and not continued for an adequate period of time to ensure clearance of the infection. Griseofulvin microsize (125 mg/5 mL) at the dosage of 20 to 25 mg/kg once daily for 8 to 12 weeks is recommended instead of a lower-dosed 4- to 6-week course.^23,24

Options for treating a child with residual disease include increasing and/or extending the griseofulvin dosage, encouraging ingestion of fatty foods to enhance absorption, dividing the dosage of griseofulvin from once daily to twice daily, changing therapy to oral terbinafine due to resistance to griseofulvin, examining siblings as a source of reinfection, and reviewing the positive fungal culture report to distinguish Trichophyton tonsurans versus Microsporum canis as the causative agent and adjust treatment accordingly. Although griseofulvin is the first-line treatment for M canis, terbinafine, which is approved for children 4 years and older for tineacapitis, is most efficacious for T tonsurans.²⁵ Treatment with terbinafine is weight based and should extend for 2 to 4 weeksfor T tonsurans and 8 to 12 weeks for M canis.

Antifungal shampoos may help reduce household spread of tinea and decrease transmissible fungal spores, but they may cause hair dryness and breakage.^26,27 Antifungal shampoos can be applied directly onto the scalp for a 5- to 10-minute contact time and rinsed, and then the hair should be shampooed with a moisturizing shampoo followed by a moisturizing conditioner. Hair conditioners may decrease household spread of tinea capitis and should be used by the patient and other members of the household.²⁸ Infection control may be enhanced by advising parents to dispose of hair pomades and washing hair accessories, combs, and brushes in hot soapy water, preferably in the dishwasher.

Hair Growth

The inability of the hair of black children to grow long is a common concern for parents of toddlers and preschool-aged children. Although the hair does grow, it grows more slowly than hair in white children (0.259 vs 0.330 mm per day), and it is likely to break faster than it is growing in black versus white children (146.6 vs 13.13 total broken hairs).⁸ Reassurance that the hair is indeed growing and that the length will increase as the child matures is important. Avoidance of hairstyles that promote traction and use of hair extensions, as well as use of moisturizing shampoos and conditioners, may minimize breakage and support the growth of healthy hair.

Conclusion

Hair- and scalp-related disease in black adults and children is commonly encountered in dermatology practice. It is important to understand the intrinsic characteristics of facial and scalp hair as well as hair care practices in this patient population that differ from those of white and Asian populations, such as frequency of shampooing, products, and styling. Familiarity with these differences may aid in effective diagnosis, treatment, and hair care recommendations in patients with these conditions.

One of the most common concerns among black patients is hair- and scalp-related disease. As increasing numbers of black patients opt to see dermatologists, it is imperative that all dermatologists be adequately trained to address the concerns of this patient population. When patients ask for help with common skin diseases of the hair and scalp, there are details that must be included in diagnosis, treatment, and hair care recommendations to reach goals for excellence in patient care. Herein, we provide must-know information to effectively approach this patient population.

Seborrheic Dermatitis

A study utilizing data from the National Ambulatory Medical Care Survey from 1993 to 2009 revealed seborrheic dermatitis (SD) as the second most common diagnosis for black patients who visit a dermatologist.¹ Prevalence data from a population of 1408 white, black, and Chinese patients from the United States and China revealed scalp flaking in 81% to 95% of black patients, 66% to 82% in white patients, and 30% to 42% in Chinese patients.² Seborrheic dermatitis has a notable prevalence in black women and often is considered normal by patients. It can be exacerbated by infrequent shampooing (ranging from once per month or longer in between shampoos) and the inappropriate use of hair oils and pomades; it also has been associated with hair breakage, lichen simplex chronicus, and folliculitis. Seborrheic dermatitis must be distinguished from other disorders including sarcoidosis, psoriasis, discoid lupus erythematosus, tinea capitis, and lichen simplex chronicus.

Although there is a paucity of literature on the treatment of SD in black patients, components of treatment are similar to those recommended for other populations. Black women are advised to carefully utilize antidandruff shampoos containing zinc pyrithione, selenium sulfide, or tar to avoid hair shaft damage and dryness. Ketoconazole shampoo rarely is recommended and may be more appropriately used in men and boys, as hair fragility is less of a concern for them. The shampoo should be applied directly to the scalp rather than the hair shafts to minimize dryness, with no particular elongated contact time needed for these medicated shampoos to be effective. Because conditioners can wash off the active ingredients in therapeutic shampoos, antidandruff conditioners are recommended. Potent or ultrapotent topical corticosteroids applied to the scalp 3 to 4 times weekly initially will control the symptoms of itching as well as scaling, and mid-potency topical corticosteroid oil may be used at weekly intervals.

Hairline and facial involvement of SD often co-occurs, and low-potency topical steroids may be applied to the affected areas twice daily for 3 to 4 weeks, which may be repeated for flares. Topical calcineurin inhibitors or antifungal creams such as ketoconazole or econazole may then provide effective control. Encouraging patients to increase shampooing to once weekly or every 2 weeks and discontinue use of scalp pomades and oils also is recommended. Patients must know that an itchy scaly scalp represents a treatable disorder. 

Acquired Trichorrhexis Nodosa

Hair fragility and breakage is common and multifactorial in black patients. Hair shaft breakage can occur on the vertex scalp in central centrifugal cicatricial alopecia (CCCA), with random localized breakage due to scratching in SD. Heat, hair colorants, and chemical relaxers may result in diffuse damage and breakage.³ Sodium-, potassium-, and guanine hydroxide–containing chemical relaxers change the physical properties of the hair by rearranging disulfide bonds. They remove the monomolecular layer of fatty acids covalently bound to the cuticle that help prevent penetration of water into the hair shaft. Additionally, chemical relaxers weaken the hair shaft and decrease tensile strength.

Unlike hair relaxers, colorants are less likely to lead to catastrophic hair breakage after a single use and require frequent use, which leads to cumulative damage. Thermal straightening is another cause of hair-shaft weakening in black patients.^4,5 Flat irons and curling irons can cause substantially more damage than blow-dryers due to the amount of heat generated. Flat irons may reach a high temperature of 230ºC (450ºF) as compared to 100°C (210°F) for a blow-dryer. Even the simple act of combing the hair can cause hair breakage, as demonstrated in African volunteers whose hair remained short in contrast to white and Asian volunteers, despite the fact that they had not cut their hair for 1 or more years.^6,7 These volunteers had many hair strand knots that led to breakage during combing and hair grooming.⁶

There is no known prevalence data for acquired trichorrhexis nodosa, though a study of 30 white and black women demonstrated that broken hairs were significantly increased in black women (P=.0001).⁸ Another study by Hall et al⁹ of 103 black women showed that 55% of the women reported breakage of hair shafts with normal styling. Khumalo et al⁶ investigated hair shaft fragility and reported no trichothiodystrophy; the authors concluded that the cause of the hair fragility likely was physical trauma or an undiscovered structural abnormality. Franbourg et al¹⁰ examined the structure of hair fibers in white, Asian, and black patients and found no differences, but microfractures were only present in black patients and were determined to be the cause of hair breakage. These studies underscore the need for specific questioning of the patient on hair care including combing, washing, drying, and using products and chemicals.

The approach to the treatment of hair breakage involves correcting underlying abnormalities (eg, iron deficiency, hypothyroidism, nutritional deficiencies). Patients should “give their hair a rest” by discontinuing use of heat, colorants, and chemical relaxers. For patients who are unable to comply, advising them to stop these processes for 6 to 12 months will allow for repair of the hair shaft. To minimize damage from colorants, recommend semipermanent, demipermanent, or temporary dyes. Patients should be counseled to stop bleaching their hair or using permanent colorants. The use of heat protectant products on the hair before styling as well as layering moisturizing regimens starting with a moisturizing shampoo followed by a leave-in, dimethicone-containing conditioner marketed for dry damaged hair is suggested. Dimethicone thinly coats the hair shaft to restore hydrophobicity, smoothes cuticular scales, decreases frizz, and protects the hair from damage. Use of a 2-in-1 shampoo and conditioner containing anionic surfactants and wide-toothed, smooth (no jagged edges in the grooves) combs along with rare brushing are recommended. The hair may be worn in its natural state, but straightening with heat should be avoided. Air drying the hair can minimize breakage, but if thermal styling is necessary, patients should turn the temperature setting of the flat or curling iron down. Protective hair care practices may include placing a loosely sewn-in hair weave that will allow for good hair care, wearing loose braids, or using a wig. Serial trimming of the hair every 6 to 8 weeks is recommended. Improvement may take time, and patients should be advised of this timeline to prevent frustration.

Acne Keloidalis Nuchae

Acne keloidalis nuchae (AKN) is characterized by papules and pustules located on the occipital scalp and/or the nape of the neck, which may result in keloidal papules and plaques. The etiology is unknown, but ingrown hairs, genetics, trauma, infection, inflammation, and androgen hormones have been proposed to play a role.¹¹ Although AKN may occur in black women, it is primarily a disorder in black men. The diagnosis is made based primarily on clinical findings, and a history of short haircuts may support the diagnosis. Treatment is tailored to the severity of the disease (Table 1). Avoidance of short haircuts and irritation from shirt collars may be helpful. Patients should be advised that the condition is controllable but not curable.

Pseudofolliculitis Barbae

Pseudofolliculitis barbae (PFB) is characterized by papules and pustules in the beard region that may result in postinflammatory hyperpigmentation, keloidal scar formation, and/or linear scarring. The coarse curled hairs characteristic of black men penetrate the follicle before exiting the skin and penetrate the skin after exiting the follicle, resulting in inflammation. Shaving methods and genetics also may contribute to the development of PFB. As with AKN, diagnosis is made clinically and does not require a skin biopsy. Important components of the patient’s history that should be obtained are hair removal practices and the use of over-the-counter products (eg, shave [pre and post] moisturizers, exfoliants, shaving creams or gels, keratin-softening agents containing α- or β-hydroxy acids). A bacterial culture may be appropriate if a notable pustular component is present. The patient should be advised to discontinue shaving if possible, which may require a physician’s letter explaining the necessity to the patient’s employer. Pseudofolliculitis barbae often can be prevented or lessened with the right hair removal strategy. Because there is not one optimal hair removal strategy that suits every patient, encourage the patient to experiment with different hair removal techniques, from depilatories to electric shavers, foil-guard razors, and multiple-blade razors. Preshave hydration and postshave moisturiza-tion also should be encouraged.¹² Benzoyl peroxide–containing shave gels and cleansers, as well as moisturizers containing glycolic, salicylic, and phytic acids, may minimize ingrown hairs, papules, and inflammation.

Other useful topical agents include eflornithine hydrochloride to decrease hair growth, retinoids to soften hair fibers, mild topical steroids to reduce inflammation, and/or topical erythromycin or clindamycin if pustules are present.¹³ Oral antibiotics such as doxycycline, minocycline, or erythromycin can be added for more severe cases of inflammation or infection. Procedural interventions include laser hair removal to prevent PFB and intralesional triamcinolone 10 to 40 mg/cc every 4 to 6 weeks, with the total volume depending on the size and number of lesions.

Alopecia

Alopecia is the sixth most common diagnosis seen in black patients visiting a dermatologist.¹⁴ The physician’s response to the patient’s chief concern of hair loss is key to building a relationship of confidence and trust. Trivializing the concern or dismissing it will undermine the physician-patient relationship. A survey by Gathers and Mahan¹⁵ revealed that 68% of patients thought that physicians did not understand their hair.

Hair loss negatively impacts quality of life, and a study of 50 black South African women with alopecia demonstrated a notable disease burden. Factors with the highest impact were those related to self-image, relationships, and interactions with others.¹⁶

It is not unusual for black women to have multiple types of alopecia identified in one biopsy specimen. Wohltmann and Sperling¹⁷ demonstrated 2 or more different types of alopecia in more than 10% of biopsy specimens of alopecia, including CCCA, androgenetic alopecia, end-stage traction alopecia, telogen effluvium, and tinea capitis. A complete history, physical examination, and appropriate procedures (eg, hair pull test, dermatoscopic examination and scalp biopsy) likely will yield an accurate diagnosis. Table 2 highlights important questions that should be asked about the patient’s history.

Physical examination of the scalp including dermatoscopic examination and a hair pull test as well as an evaluation of other hair-bearing areas may suggest a diagnosis that can be confirmed with a scalp biopsy.^18,19 Selection of a biopsy site at the periphery of the alopecic area that includes hair and consultation with a dermatopathologist familiar with features of CCCA, traction, and traumatic alopecia are important for making an accurate diagnosis.

Tinea Capitis in Black Pediatric Patients

Tinea capitis, a fungal infection of the scalp and hair, is one of the most common issues in children with skin of color. Clinical presentation may include widely distributed scaling, annular scaly plaques, annular patches of alopecia studded with black dots (broken hairs), and/or annular inflammatory plaques. Although scalp hyperkeratosis often is a hallmark of pediatric tinea capitis, it is not diagnostic. The differential diagnosis of pediatric scalp hyperkeratosis/scaling includes tinea capitis, SD, atopic dermatitis, psoriasis, and sebopsoriasis.^20,21 Clues to accurate diagnosis of tinea capitis may be found by examination of the adult who combs the child’s hair, as erythematous annular scaly plaques representing tinea corporis may be observed on the forearms or thighs. Although the thighs are a seemingly unusual location, the frequent practice of the child sitting on the floor between the legs of the adult during hairstyling provides a point of contact for the transmission of tinea from the child’s scalp to the thighs or forearms of the adult. Once tinea capitis is clinically suspected, the diagnosis is confirmed by a fungal culture. Adequate sampling is obtained by clipping hairs in an area of scaling for submission and vigorously rubbing the area of black dots or hyperkeratosis with a cotton swab.

Hubbard²² shed light on the decision to treat tinea capitis empirically or await the culture results. One hundred consecutive children (98 were black) presented with the constellation of scalp alopecia, scaling, pruritus, and occipital lymphadenopathy. Sixty-eight of those children had positive fungal cultures, and of them, 60 had both occipital lymphadenopathy and scaling and 55 had both occipital lymphadenopathy and alopecia.²² Thus, occipital lymphadenopathy in conjunction with alopecia and/or scaling is predictive of tinea capitis in this population and suggests that the initiation of treatment prior to confirmative culture results is appropriate.

The mainstay of treatment for tinea capitis is griseofulvin, but it is often underdosed and not continued for an adequate period of time to ensure clearance of the infection. Griseofulvin microsize (125 mg/5 mL) at the dosage of 20 to 25 mg/kg once daily for 8 to 12 weeks is recommended instead of a lower-dosed 4- to 6-week course.^23,24

Options for treating a child with residual disease include increasing and/or extending the griseofulvin dosage, encouraging ingestion of fatty foods to enhance absorption, dividing the dosage of griseofulvin from once daily to twice daily, changing therapy to oral terbinafine due to resistance to griseofulvin, examining siblings as a source of reinfection, and reviewing the positive fungal culture report to distinguish Trichophyton tonsurans versus Microsporum canis as the causative agent and adjust treatment accordingly. Although griseofulvin is the first-line treatment for M canis, terbinafine, which is approved for children 4 years and older for tineacapitis, is most efficacious for T tonsurans.²⁵ Treatment with terbinafine is weight based and should extend for 2 to 4 weeksfor T tonsurans and 8 to 12 weeks for M canis.

Antifungal shampoos may help reduce household spread of tinea and decrease transmissible fungal spores, but they may cause hair dryness and breakage.^26,27 Antifungal shampoos can be applied directly onto the scalp for a 5- to 10-minute contact time and rinsed, and then the hair should be shampooed with a moisturizing shampoo followed by a moisturizing conditioner. Hair conditioners may decrease household spread of tinea capitis and should be used by the patient and other members of the household.²⁸ Infection control may be enhanced by advising parents to dispose of hair pomades and washing hair accessories, combs, and brushes in hot soapy water, preferably in the dishwasher.

Hair Growth

The inability of the hair of black children to grow long is a common concern for parents of toddlers and preschool-aged children. Although the hair does grow, it grows more slowly than hair in white children (0.259 vs 0.330 mm per day), and it is likely to break faster than it is growing in black versus white children (146.6 vs 13.13 total broken hairs).⁸ Reassurance that the hair is indeed growing and that the length will increase as the child matures is important. Avoidance of hairstyles that promote traction and use of hair extensions, as well as use of moisturizing shampoos and conditioners, may minimize breakage and support the growth of healthy hair.

Conclusion

Hair- and scalp-related disease in black adults and children is commonly encountered in dermatology practice. It is important to understand the intrinsic characteristics of facial and scalp hair as well as hair care practices in this patient population that differ from those of white and Asian populations, such as frequency of shampooing, products, and styling. Familiarity with these differences may aid in effective diagnosis, treatment, and hair care recommendations in patients with these conditions.

One of the most common concerns among black patients is hair- and scalp-related disease. As increasing numbers of black patients opt to see dermatologists, it is imperative that all dermatologists be adequately trained to address the concerns of this patient population. When patients ask for help with common skin diseases of the hair and scalp, there are details that must be included in diagnosis, treatment, and hair care recommendations to reach goals for excellence in patient care. Herein, we provide must-know information to effectively approach this patient population.

Seborrheic Dermatitis

A study utilizing data from the National Ambulatory Medical Care Survey from 1993 to 2009 revealed seborrheic dermatitis (SD) as the second most common diagnosis for black patients who visit a dermatologist.¹ Prevalence data from a population of 1408 white, black, and Chinese patients from the United States and China revealed scalp flaking in 81% to 95% of black patients, 66% to 82% in white patients, and 30% to 42% in Chinese patients.² Seborrheic dermatitis has a notable prevalence in black women and often is considered normal by patients. It can be exacerbated by infrequent shampooing (ranging from once per month or longer in between shampoos) and the inappropriate use of hair oils and pomades; it also has been associated with hair breakage, lichen simplex chronicus, and folliculitis. Seborrheic dermatitis must be distinguished from other disorders including sarcoidosis, psoriasis, discoid lupus erythematosus, tinea capitis, and lichen simplex chronicus.

Although there is a paucity of literature on the treatment of SD in black patients, components of treatment are similar to those recommended for other populations. Black women are advised to carefully utilize antidandruff shampoos containing zinc pyrithione, selenium sulfide, or tar to avoid hair shaft damage and dryness. Ketoconazole shampoo rarely is recommended and may be more appropriately used in men and boys, as hair fragility is less of a concern for them. The shampoo should be applied directly to the scalp rather than the hair shafts to minimize dryness, with no particular elongated contact time needed for these medicated shampoos to be effective. Because conditioners can wash off the active ingredients in therapeutic shampoos, antidandruff conditioners are recommended. Potent or ultrapotent topical corticosteroids applied to the scalp 3 to 4 times weekly initially will control the symptoms of itching as well as scaling, and mid-potency topical corticosteroid oil may be used at weekly intervals.

Hairline and facial involvement of SD often co-occurs, and low-potency topical steroids may be applied to the affected areas twice daily for 3 to 4 weeks, which may be repeated for flares. Topical calcineurin inhibitors or antifungal creams such as ketoconazole or econazole may then provide effective control. Encouraging patients to increase shampooing to once weekly or every 2 weeks and discontinue use of scalp pomades and oils also is recommended. Patients must know that an itchy scaly scalp represents a treatable disorder. 

Acquired Trichorrhexis Nodosa

Hair fragility and breakage is common and multifactorial in black patients. Hair shaft breakage can occur on the vertex scalp in central centrifugal cicatricial alopecia (CCCA), with random localized breakage due to scratching in SD. Heat, hair colorants, and chemical relaxers may result in diffuse damage and breakage.³ Sodium-, potassium-, and guanine hydroxide–containing chemical relaxers change the physical properties of the hair by rearranging disulfide bonds. They remove the monomolecular layer of fatty acids covalently bound to the cuticle that help prevent penetration of water into the hair shaft. Additionally, chemical relaxers weaken the hair shaft and decrease tensile strength.

Unlike hair relaxers, colorants are less likely to lead to catastrophic hair breakage after a single use and require frequent use, which leads to cumulative damage. Thermal straightening is another cause of hair-shaft weakening in black patients.^4,5 Flat irons and curling irons can cause substantially more damage than blow-dryers due to the amount of heat generated. Flat irons may reach a high temperature of 230ºC (450ºF) as compared to 100°C (210°F) for a blow-dryer. Even the simple act of combing the hair can cause hair breakage, as demonstrated in African volunteers whose hair remained short in contrast to white and Asian volunteers, despite the fact that they had not cut their hair for 1 or more years.^6,7 These volunteers had many hair strand knots that led to breakage during combing and hair grooming.⁶

There is no known prevalence data for acquired trichorrhexis nodosa, though a study of 30 white and black women demonstrated that broken hairs were significantly increased in black women (P=.0001).⁸ Another study by Hall et al⁹ of 103 black women showed that 55% of the women reported breakage of hair shafts with normal styling. Khumalo et al⁶ investigated hair shaft fragility and reported no trichothiodystrophy; the authors concluded that the cause of the hair fragility likely was physical trauma or an undiscovered structural abnormality. Franbourg et al¹⁰ examined the structure of hair fibers in white, Asian, and black patients and found no differences, but microfractures were only present in black patients and were determined to be the cause of hair breakage. These studies underscore the need for specific questioning of the patient on hair care including combing, washing, drying, and using products and chemicals.

The approach to the treatment of hair breakage involves correcting underlying abnormalities (eg, iron deficiency, hypothyroidism, nutritional deficiencies). Patients should “give their hair a rest” by discontinuing use of heat, colorants, and chemical relaxers. For patients who are unable to comply, advising them to stop these processes for 6 to 12 months will allow for repair of the hair shaft. To minimize damage from colorants, recommend semipermanent, demipermanent, or temporary dyes. Patients should be counseled to stop bleaching their hair or using permanent colorants. The use of heat protectant products on the hair before styling as well as layering moisturizing regimens starting with a moisturizing shampoo followed by a leave-in, dimethicone-containing conditioner marketed for dry damaged hair is suggested. Dimethicone thinly coats the hair shaft to restore hydrophobicity, smoothes cuticular scales, decreases frizz, and protects the hair from damage. Use of a 2-in-1 shampoo and conditioner containing anionic surfactants and wide-toothed, smooth (no jagged edges in the grooves) combs along with rare brushing are recommended. The hair may be worn in its natural state, but straightening with heat should be avoided. Air drying the hair can minimize breakage, but if thermal styling is necessary, patients should turn the temperature setting of the flat or curling iron down. Protective hair care practices may include placing a loosely sewn-in hair weave that will allow for good hair care, wearing loose braids, or using a wig. Serial trimming of the hair every 6 to 8 weeks is recommended. Improvement may take time, and patients should be advised of this timeline to prevent frustration.

Acne Keloidalis Nuchae

Acne keloidalis nuchae (AKN) is characterized by papules and pustules located on the occipital scalp and/or the nape of the neck, which may result in keloidal papules and plaques. The etiology is unknown, but ingrown hairs, genetics, trauma, infection, inflammation, and androgen hormones have been proposed to play a role.¹¹ Although AKN may occur in black women, it is primarily a disorder in black men. The diagnosis is made based primarily on clinical findings, and a history of short haircuts may support the diagnosis. Treatment is tailored to the severity of the disease (Table 1). Avoidance of short haircuts and irritation from shirt collars may be helpful. Patients should be advised that the condition is controllable but not curable.

Pseudofolliculitis Barbae

Pseudofolliculitis barbae (PFB) is characterized by papules and pustules in the beard region that may result in postinflammatory hyperpigmentation, keloidal scar formation, and/or linear scarring. The coarse curled hairs characteristic of black men penetrate the follicle before exiting the skin and penetrate the skin after exiting the follicle, resulting in inflammation. Shaving methods and genetics also may contribute to the development of PFB. As with AKN, diagnosis is made clinically and does not require a skin biopsy. Important components of the patient’s history that should be obtained are hair removal practices and the use of over-the-counter products (eg, shave [pre and post] moisturizers, exfoliants, shaving creams or gels, keratin-softening agents containing α- or β-hydroxy acids). A bacterial culture may be appropriate if a notable pustular component is present. The patient should be advised to discontinue shaving if possible, which may require a physician’s letter explaining the necessity to the patient’s employer. Pseudofolliculitis barbae often can be prevented or lessened with the right hair removal strategy. Because there is not one optimal hair removal strategy that suits every patient, encourage the patient to experiment with different hair removal techniques, from depilatories to electric shavers, foil-guard razors, and multiple-blade razors. Preshave hydration and postshave moisturiza-tion also should be encouraged.¹² Benzoyl peroxide–containing shave gels and cleansers, as well as moisturizers containing glycolic, salicylic, and phytic acids, may minimize ingrown hairs, papules, and inflammation.

Other useful topical agents include eflornithine hydrochloride to decrease hair growth, retinoids to soften hair fibers, mild topical steroids to reduce inflammation, and/or topical erythromycin or clindamycin if pustules are present.¹³ Oral antibiotics such as doxycycline, minocycline, or erythromycin can be added for more severe cases of inflammation or infection. Procedural interventions include laser hair removal to prevent PFB and intralesional triamcinolone 10 to 40 mg/cc every 4 to 6 weeks, with the total volume depending on the size and number of lesions.

Alopecia

Alopecia is the sixth most common diagnosis seen in black patients visiting a dermatologist.¹⁴ The physician’s response to the patient’s chief concern of hair loss is key to building a relationship of confidence and trust. Trivializing the concern or dismissing it will undermine the physician-patient relationship. A survey by Gathers and Mahan¹⁵ revealed that 68% of patients thought that physicians did not understand their hair.

Hair loss negatively impacts quality of life, and a study of 50 black South African women with alopecia demonstrated a notable disease burden. Factors with the highest impact were those related to self-image, relationships, and interactions with others.¹⁶

It is not unusual for black women to have multiple types of alopecia identified in one biopsy specimen. Wohltmann and Sperling¹⁷ demonstrated 2 or more different types of alopecia in more than 10% of biopsy specimens of alopecia, including CCCA, androgenetic alopecia, end-stage traction alopecia, telogen effluvium, and tinea capitis. A complete history, physical examination, and appropriate procedures (eg, hair pull test, dermatoscopic examination and scalp biopsy) likely will yield an accurate diagnosis. Table 2 highlights important questions that should be asked about the patient’s history.

Physical examination of the scalp including dermatoscopic examination and a hair pull test as well as an evaluation of other hair-bearing areas may suggest a diagnosis that can be confirmed with a scalp biopsy.^18,19 Selection of a biopsy site at the periphery of the alopecic area that includes hair and consultation with a dermatopathologist familiar with features of CCCA, traction, and traumatic alopecia are important for making an accurate diagnosis.

Tinea Capitis in Black Pediatric Patients

Tinea capitis, a fungal infection of the scalp and hair, is one of the most common issues in children with skin of color. Clinical presentation may include widely distributed scaling, annular scaly plaques, annular patches of alopecia studded with black dots (broken hairs), and/or annular inflammatory plaques. Although scalp hyperkeratosis often is a hallmark of pediatric tinea capitis, it is not diagnostic. The differential diagnosis of pediatric scalp hyperkeratosis/scaling includes tinea capitis, SD, atopic dermatitis, psoriasis, and sebopsoriasis.^20,21 Clues to accurate diagnosis of tinea capitis may be found by examination of the adult who combs the child’s hair, as erythematous annular scaly plaques representing tinea corporis may be observed on the forearms or thighs. Although the thighs are a seemingly unusual location, the frequent practice of the child sitting on the floor between the legs of the adult during hairstyling provides a point of contact for the transmission of tinea from the child’s scalp to the thighs or forearms of the adult. Once tinea capitis is clinically suspected, the diagnosis is confirmed by a fungal culture. Adequate sampling is obtained by clipping hairs in an area of scaling for submission and vigorously rubbing the area of black dots or hyperkeratosis with a cotton swab.

Hubbard²² shed light on the decision to treat tinea capitis empirically or await the culture results. One hundred consecutive children (98 were black) presented with the constellation of scalp alopecia, scaling, pruritus, and occipital lymphadenopathy. Sixty-eight of those children had positive fungal cultures, and of them, 60 had both occipital lymphadenopathy and scaling and 55 had both occipital lymphadenopathy and alopecia.²² Thus, occipital lymphadenopathy in conjunction with alopecia and/or scaling is predictive of tinea capitis in this population and suggests that the initiation of treatment prior to confirmative culture results is appropriate.

The mainstay of treatment for tinea capitis is griseofulvin, but it is often underdosed and not continued for an adequate period of time to ensure clearance of the infection. Griseofulvin microsize (125 mg/5 mL) at the dosage of 20 to 25 mg/kg once daily for 8 to 12 weeks is recommended instead of a lower-dosed 4- to 6-week course.^23,24

Options for treating a child with residual disease include increasing and/or extending the griseofulvin dosage, encouraging ingestion of fatty foods to enhance absorption, dividing the dosage of griseofulvin from once daily to twice daily, changing therapy to oral terbinafine due to resistance to griseofulvin, examining siblings as a source of reinfection, and reviewing the positive fungal culture report to distinguish Trichophyton tonsurans versus Microsporum canis as the causative agent and adjust treatment accordingly. Although griseofulvin is the first-line treatment for M canis, terbinafine, which is approved for children 4 years and older for tineacapitis, is most efficacious for T tonsurans.²⁵ Treatment with terbinafine is weight based and should extend for 2 to 4 weeksfor T tonsurans and 8 to 12 weeks for M canis.

Antifungal shampoos may help reduce household spread of tinea and decrease transmissible fungal spores, but they may cause hair dryness and breakage.^26,27 Antifungal shampoos can be applied directly onto the scalp for a 5- to 10-minute contact time and rinsed, and then the hair should be shampooed with a moisturizing shampoo followed by a moisturizing conditioner. Hair conditioners may decrease household spread of tinea capitis and should be used by the patient and other members of the household.²⁸ Infection control may be enhanced by advising parents to dispose of hair pomades and washing hair accessories, combs, and brushes in hot soapy water, preferably in the dishwasher.

Hair Growth

The inability of the hair of black children to grow long is a common concern for parents of toddlers and preschool-aged children. Although the hair does grow, it grows more slowly than hair in white children (0.259 vs 0.330 mm per day), and it is likely to break faster than it is growing in black versus white children (146.6 vs 13.13 total broken hairs).⁸ Reassurance that the hair is indeed growing and that the length will increase as the child matures is important. Avoidance of hairstyles that promote traction and use of hair extensions, as well as use of moisturizing shampoos and conditioners, may minimize breakage and support the growth of healthy hair.

Conclusion

Hair- and scalp-related disease in black adults and children is commonly encountered in dermatology practice. It is important to understand the intrinsic characteristics of facial and scalp hair as well as hair care practices in this patient population that differ from those of white and Asian populations, such as frequency of shampooing, products, and styling. Familiarity with these differences may aid in effective diagnosis, treatment, and hair care recommendations in patients with these conditions.

Hypertrophic scarring secondary to trauma, burns, and surgical interventions is a major source of morbidity worldwide and often is mechanically, aesthetically, and symptomatically debilitating. Modern advances in acute trauma care protocols have resulted in survival rates greater than 90% in both civilian and military populations.^1,2 Patients with wounds that have historically proven fatal are now surviving and are confronted with the long-term sequelae of their injuries. With more than 52,000 service members injured in military engagements from 2001 to 2015 and 8.5 million civilians presenting annually with injury patterns at risk for hypertrophic scarring, it is paramount that we ensure access to safe and effective long-term scar care.^2,3

At its simplest level, hypertrophic scarring is believed to result from a disequilibrium between collagen production and degradation. This failure to properly transition through the stages of wound healing results in bothersome symptoms, a disfigured appearance, and mechanical dysfunction of the skin (Figure, A). Decreased elasticity and extensibility, increased dermal thickness, and scar contractures impair patient range of motion and functional mobility. Those affected commonly experience varying degrees of pruritus and dysesthesia along the scar. Combined with aesthetic variations in pigmentation, erythema, texture, and thickness, hypertrophic scarring often leads to long-term psychosocial impairment and decreased health-related quality of life.⁴

Treatment Approach

Treatment of hypertrophic scars requires a multimodal approach due to the spectrum of associated concerns and the natural recalcitrance of the scar to therapy. Protocols should be tailored to the individual but generally begin with tissue-conserving surgical interventions followed by selective photothermolysis of the scar vasculature. Subsequently, deep and superficial ablative fractional laser (AFL) treatment and local pharmacotherapy also are employed. Treatment can be accomplished in the outpatient setting under local anesthesia in a serial fashion. In the authors’ experience, these therapies behave in a synergistic fashion, achieving outcomes that far exceed the sum of their parts, often obviating the need for scar excision in the majority of cases (Figure, B).

Tissue-Conserving Surgical Intervention

Z-plasty is an indispensable surgical tool due to its ability to lengthen scars and reduce wound tension. Treatment is easily customizable to the patient and can be performed using the individual or multiple Z-plasty techniques. Undermining and step-off correction while suturing allow the physician to lower raised scars, elevate depressed scars, and obscure scar presence by minimizing the straight lines that draw the eye to the scar. Z-plasties rely on the creation and transposition of 2 triangular flaps and permit a 75% increase in length along the desired tension vector. As such, Z-plasties decrease wound tension and facilitate scar maturation.

Selective Photothermolysis of the Vasculature

Although there are several devices available to treat vascular and immature hypertrophic scars, the majority of studies have been conducted with the 595-nm pulsed dye laser. By preferentially heating oxyhemoglobin within the dermal microvasculature, the pulsed dye laser irreparably injures the vascular endothelium. The subsequent tissue hypoxia and collagen fiber heating results in collagen fiber realignment, normalization of collagen subtypes, and neocollagenesis.⁵ Pulsed dye laser therapy most effectively reduces erythema and pruritus; however, improvements in scar volume, pliability, and elasticity also have been reported.⁵ When targeting the fine vasculature of the scar, thermal confinement is critical to prevent injury to the surrounding dermis. As such, pulse widths of 0.45 to 1.5 milliseconds are routinely utilized with a fluence just sufficient to elicit transient purpura lasting 3 to 5 seconds. Employing a spot size of 7 to 10 mm, typical fluences range from 4.5 to 6.5 J/cm². Engagement of the dynamic cooling device reduces the risk for complications, allowing the patient to proceed to the next step in their therapy regimen: the AFL.

Ablative Fractional Laser

The AFL creates a pixilated pattern of injury throughout the epidermis and dermis of the treatment area. Ablative fractional laser platforms include the 10,600-nm CO₂ and 2940-nm erbium-doped YAG lasers, both targeting intracellular water. The AFL vaporizes columns of tissue, leaving minute vertical channels with narrow rims of protein coagulation referred to as microscopic treatment zones (MTZs).⁶ Scar collagen analysis after AFL treatment has shown a profile resembling unaffected skin.⁷ Consistently, patients report improvements in stiffness, range of motion, pain, pruritus, pigmentation, and erythema.Physician observers also have reported similar improvements in these end points.^8,9 Recently, interim data from a prospective controlled trial were presented showing objective improvements in dermal thickness, elasticity, and extensibility after 3 treatments with the CO₂ AFL.⁶ The UltraPulse CO₂ laser (Lumenis) is the most well-studied and widely available AFL for scar therapy and as such we will outline common treatment parameters with this device. Of note, treatment end points may be generalized to any AFL.

The DeepFX UltraPulse configuration is utilized to achieve deep AFL therapy and has a fixed pulse width of 0.8 milliseconds, slightly less than the thermal relaxation time of the skin. The diameter of the MTZs is 120 µm, and MTZ density for scar treatment ranges from 1% to 10% with a goal depth of at least 80% of scar thickness. Maximal penetration of the AFL is 4 mm, which is directly proportional to fluence. The goal of deep AFL is the removal of scar tissue to facilitate remodeling and neocollagenesis. Superficial fractional ablation can then be achieved utilizing the ActiveFX UltraPulse configuration generating a 1.3-mm MTZ spot size. We commonly use a treatment level of 3 (82% density). Typical treatment energy ranges from 80 to 125 mJ, which correlates with depths of approximately 50 to 115 µm. With both configurations, the size and shape of the treatment area can be customized to the scar. In addition, frequency may be adjusted to control the speed of treatment while balancing the risk of bulk heating. The goal of superficial AFL is to minimize scar surface irregularities and ensure blending of deep AFL treatment. Once AFL treatment is complete, local pharmacotherapy can then be employed.

Pharmacotherapy

Intralesional corticosteroids have long represented the standard of care for hypertrophic scars, with concentrations between 2.5 and 40 mg/mL that are titrated to scar thickness and location to avoid unwanted atrophy. Visual blanching of the scar represents the clinical end point for treatment. Corticosteroids act by inhibiting fibroblast proliferation and enhancing collagen degradation.¹⁰ 5-Fluorouracil (5-FU) also is used in scar management. In addition to inhibiting fibroblast proliferation and inducing fibroblast apoptosis, 5-FU inhibits myofibroblast proliferation, which is helpful in the prevention and treatment of scar contracture.¹¹ As monotherapy, weekly injections with 1 to 3 mL of 50 mg/mL 5-FU has been safe and effective. Combination intralesional corticosteroid and 5-FU therapy has been reported and is associated with improved scar regression, reduced reoccurrence, and fewer side effects.¹¹ In our experience, a 1:1 suspension is effective with appropriate titration of the corticosteroid component. Although less well defined, topical application of pharmacotherapy and massage to the newly created MTZs appears beneficial and offers another option for delivery of corticosteroids and 5-FU, in addition to a number of promising medications such as bimatoprost, poly-L-lactic acid, timolol, and rapamycin.¹²

Conclusion

Advances in laser surgery and our understanding of wound healing have created a paradigm shift in the treatment approach to trauma and burn scars. In lieu of extensive scar excisions, the summarized multimodal regimen emphasizing tissue conservation and autologous remodeling is gaining favor in the military, academic medical centers, and scar centers of excellence, but patients are finding local access to care difficult. Dermatologists are uniquely positioned to cost-effectively deliver this care in the outpatient setting utilizing devices and techniques they already possess. With the end goal of optimization of functional, symptomatic, and aesthetic state of the patient, it is critical that dermatologists seize this opportunity to truly make a difference for the military and civilian patients that need it most.

Hypertrophic scarring secondary to trauma, burns, and surgical interventions is a major source of morbidity worldwide and often is mechanically, aesthetically, and symptomatically debilitating. Modern advances in acute trauma care protocols have resulted in survival rates greater than 90% in both civilian and military populations.^1,2 Patients with wounds that have historically proven fatal are now surviving and are confronted with the long-term sequelae of their injuries. With more than 52,000 service members injured in military engagements from 2001 to 2015 and 8.5 million civilians presenting annually with injury patterns at risk for hypertrophic scarring, it is paramount that we ensure access to safe and effective long-term scar care.^2,3

At its simplest level, hypertrophic scarring is believed to result from a disequilibrium between collagen production and degradation. This failure to properly transition through the stages of wound healing results in bothersome symptoms, a disfigured appearance, and mechanical dysfunction of the skin (Figure, A). Decreased elasticity and extensibility, increased dermal thickness, and scar contractures impair patient range of motion and functional mobility. Those affected commonly experience varying degrees of pruritus and dysesthesia along the scar. Combined with aesthetic variations in pigmentation, erythema, texture, and thickness, hypertrophic scarring often leads to long-term psychosocial impairment and decreased health-related quality of life.⁴

Treatment Approach

Treatment of hypertrophic scars requires a multimodal approach due to the spectrum of associated concerns and the natural recalcitrance of the scar to therapy. Protocols should be tailored to the individual but generally begin with tissue-conserving surgical interventions followed by selective photothermolysis of the scar vasculature. Subsequently, deep and superficial ablative fractional laser (AFL) treatment and local pharmacotherapy also are employed. Treatment can be accomplished in the outpatient setting under local anesthesia in a serial fashion. In the authors’ experience, these therapies behave in a synergistic fashion, achieving outcomes that far exceed the sum of their parts, often obviating the need for scar excision in the majority of cases (Figure, B).

Tissue-Conserving Surgical Intervention

Z-plasty is an indispensable surgical tool due to its ability to lengthen scars and reduce wound tension. Treatment is easily customizable to the patient and can be performed using the individual or multiple Z-plasty techniques. Undermining and step-off correction while suturing allow the physician to lower raised scars, elevate depressed scars, and obscure scar presence by minimizing the straight lines that draw the eye to the scar. Z-plasties rely on the creation and transposition of 2 triangular flaps and permit a 75% increase in length along the desired tension vector. As such, Z-plasties decrease wound tension and facilitate scar maturation.

Selective Photothermolysis of the Vasculature

Although there are several devices available to treat vascular and immature hypertrophic scars, the majority of studies have been conducted with the 595-nm pulsed dye laser. By preferentially heating oxyhemoglobin within the dermal microvasculature, the pulsed dye laser irreparably injures the vascular endothelium. The subsequent tissue hypoxia and collagen fiber heating results in collagen fiber realignment, normalization of collagen subtypes, and neocollagenesis.⁵ Pulsed dye laser therapy most effectively reduces erythema and pruritus; however, improvements in scar volume, pliability, and elasticity also have been reported.⁵ When targeting the fine vasculature of the scar, thermal confinement is critical to prevent injury to the surrounding dermis. As such, pulse widths of 0.45 to 1.5 milliseconds are routinely utilized with a fluence just sufficient to elicit transient purpura lasting 3 to 5 seconds. Employing a spot size of 7 to 10 mm, typical fluences range from 4.5 to 6.5 J/cm². Engagement of the dynamic cooling device reduces the risk for complications, allowing the patient to proceed to the next step in their therapy regimen: the AFL.

Ablative Fractional Laser

The AFL creates a pixilated pattern of injury throughout the epidermis and dermis of the treatment area. Ablative fractional laser platforms include the 10,600-nm CO₂ and 2940-nm erbium-doped YAG lasers, both targeting intracellular water. The AFL vaporizes columns of tissue, leaving minute vertical channels with narrow rims of protein coagulation referred to as microscopic treatment zones (MTZs).⁶ Scar collagen analysis after AFL treatment has shown a profile resembling unaffected skin.⁷ Consistently, patients report improvements in stiffness, range of motion, pain, pruritus, pigmentation, and erythema.Physician observers also have reported similar improvements in these end points.^8,9 Recently, interim data from a prospective controlled trial were presented showing objective improvements in dermal thickness, elasticity, and extensibility after 3 treatments with the CO₂ AFL.⁶ The UltraPulse CO₂ laser (Lumenis) is the most well-studied and widely available AFL for scar therapy and as such we will outline common treatment parameters with this device. Of note, treatment end points may be generalized to any AFL.

The DeepFX UltraPulse configuration is utilized to achieve deep AFL therapy and has a fixed pulse width of 0.8 milliseconds, slightly less than the thermal relaxation time of the skin. The diameter of the MTZs is 120 µm, and MTZ density for scar treatment ranges from 1% to 10% with a goal depth of at least 80% of scar thickness. Maximal penetration of the AFL is 4 mm, which is directly proportional to fluence. The goal of deep AFL is the removal of scar tissue to facilitate remodeling and neocollagenesis. Superficial fractional ablation can then be achieved utilizing the ActiveFX UltraPulse configuration generating a 1.3-mm MTZ spot size. We commonly use a treatment level of 3 (82% density). Typical treatment energy ranges from 80 to 125 mJ, which correlates with depths of approximately 50 to 115 µm. With both configurations, the size and shape of the treatment area can be customized to the scar. In addition, frequency may be adjusted to control the speed of treatment while balancing the risk of bulk heating. The goal of superficial AFL is to minimize scar surface irregularities and ensure blending of deep AFL treatment. Once AFL treatment is complete, local pharmacotherapy can then be employed.

Pharmacotherapy

Intralesional corticosteroids have long represented the standard of care for hypertrophic scars, with concentrations between 2.5 and 40 mg/mL that are titrated to scar thickness and location to avoid unwanted atrophy. Visual blanching of the scar represents the clinical end point for treatment. Corticosteroids act by inhibiting fibroblast proliferation and enhancing collagen degradation.¹⁰ 5-Fluorouracil (5-FU) also is used in scar management. In addition to inhibiting fibroblast proliferation and inducing fibroblast apoptosis, 5-FU inhibits myofibroblast proliferation, which is helpful in the prevention and treatment of scar contracture.¹¹ As monotherapy, weekly injections with 1 to 3 mL of 50 mg/mL 5-FU has been safe and effective. Combination intralesional corticosteroid and 5-FU therapy has been reported and is associated with improved scar regression, reduced reoccurrence, and fewer side effects.¹¹ In our experience, a 1:1 suspension is effective with appropriate titration of the corticosteroid component. Although less well defined, topical application of pharmacotherapy and massage to the newly created MTZs appears beneficial and offers another option for delivery of corticosteroids and 5-FU, in addition to a number of promising medications such as bimatoprost, poly-L-lactic acid, timolol, and rapamycin.¹²

Conclusion

Advances in laser surgery and our understanding of wound healing have created a paradigm shift in the treatment approach to trauma and burn scars. In lieu of extensive scar excisions, the summarized multimodal regimen emphasizing tissue conservation and autologous remodeling is gaining favor in the military, academic medical centers, and scar centers of excellence, but patients are finding local access to care difficult. Dermatologists are uniquely positioned to cost-effectively deliver this care in the outpatient setting utilizing devices and techniques they already possess. With the end goal of optimization of functional, symptomatic, and aesthetic state of the patient, it is critical that dermatologists seize this opportunity to truly make a difference for the military and civilian patients that need it most.

Hypertrophic scarring secondary to trauma, burns, and surgical interventions is a major source of morbidity worldwide and often is mechanically, aesthetically, and symptomatically debilitating. Modern advances in acute trauma care protocols have resulted in survival rates greater than 90% in both civilian and military populations.^1,2 Patients with wounds that have historically proven fatal are now surviving and are confronted with the long-term sequelae of their injuries. With more than 52,000 service members injured in military engagements from 2001 to 2015 and 8.5 million civilians presenting annually with injury patterns at risk for hypertrophic scarring, it is paramount that we ensure access to safe and effective long-term scar care.^2,3

At its simplest level, hypertrophic scarring is believed to result from a disequilibrium between collagen production and degradation. This failure to properly transition through the stages of wound healing results in bothersome symptoms, a disfigured appearance, and mechanical dysfunction of the skin (Figure, A). Decreased elasticity and extensibility, increased dermal thickness, and scar contractures impair patient range of motion and functional mobility. Those affected commonly experience varying degrees of pruritus and dysesthesia along the scar. Combined with aesthetic variations in pigmentation, erythema, texture, and thickness, hypertrophic scarring often leads to long-term psychosocial impairment and decreased health-related quality of life.⁴

Treatment Approach

Treatment of hypertrophic scars requires a multimodal approach due to the spectrum of associated concerns and the natural recalcitrance of the scar to therapy. Protocols should be tailored to the individual but generally begin with tissue-conserving surgical interventions followed by selective photothermolysis of the scar vasculature. Subsequently, deep and superficial ablative fractional laser (AFL) treatment and local pharmacotherapy also are employed. Treatment can be accomplished in the outpatient setting under local anesthesia in a serial fashion. In the authors’ experience, these therapies behave in a synergistic fashion, achieving outcomes that far exceed the sum of their parts, often obviating the need for scar excision in the majority of cases (Figure, B).

Tissue-Conserving Surgical Intervention

Z-plasty is an indispensable surgical tool due to its ability to lengthen scars and reduce wound tension. Treatment is easily customizable to the patient and can be performed using the individual or multiple Z-plasty techniques. Undermining and step-off correction while suturing allow the physician to lower raised scars, elevate depressed scars, and obscure scar presence by minimizing the straight lines that draw the eye to the scar. Z-plasties rely on the creation and transposition of 2 triangular flaps and permit a 75% increase in length along the desired tension vector. As such, Z-plasties decrease wound tension and facilitate scar maturation.

Selective Photothermolysis of the Vasculature

Although there are several devices available to treat vascular and immature hypertrophic scars, the majority of studies have been conducted with the 595-nm pulsed dye laser. By preferentially heating oxyhemoglobin within the dermal microvasculature, the pulsed dye laser irreparably injures the vascular endothelium. The subsequent tissue hypoxia and collagen fiber heating results in collagen fiber realignment, normalization of collagen subtypes, and neocollagenesis.⁵ Pulsed dye laser therapy most effectively reduces erythema and pruritus; however, improvements in scar volume, pliability, and elasticity also have been reported.⁵ When targeting the fine vasculature of the scar, thermal confinement is critical to prevent injury to the surrounding dermis. As such, pulse widths of 0.45 to 1.5 milliseconds are routinely utilized with a fluence just sufficient to elicit transient purpura lasting 3 to 5 seconds. Employing a spot size of 7 to 10 mm, typical fluences range from 4.5 to 6.5 J/cm². Engagement of the dynamic cooling device reduces the risk for complications, allowing the patient to proceed to the next step in their therapy regimen: the AFL.

Ablative Fractional Laser

The AFL creates a pixilated pattern of injury throughout the epidermis and dermis of the treatment area. Ablative fractional laser platforms include the 10,600-nm CO₂ and 2940-nm erbium-doped YAG lasers, both targeting intracellular water. The AFL vaporizes columns of tissue, leaving minute vertical channels with narrow rims of protein coagulation referred to as microscopic treatment zones (MTZs).⁶ Scar collagen analysis after AFL treatment has shown a profile resembling unaffected skin.⁷ Consistently, patients report improvements in stiffness, range of motion, pain, pruritus, pigmentation, and erythema.Physician observers also have reported similar improvements in these end points.^8,9 Recently, interim data from a prospective controlled trial were presented showing objective improvements in dermal thickness, elasticity, and extensibility after 3 treatments with the CO₂ AFL.⁶ The UltraPulse CO₂ laser (Lumenis) is the most well-studied and widely available AFL for scar therapy and as such we will outline common treatment parameters with this device. Of note, treatment end points may be generalized to any AFL.

The DeepFX UltraPulse configuration is utilized to achieve deep AFL therapy and has a fixed pulse width of 0.8 milliseconds, slightly less than the thermal relaxation time of the skin. The diameter of the MTZs is 120 µm, and MTZ density for scar treatment ranges from 1% to 10% with a goal depth of at least 80% of scar thickness. Maximal penetration of the AFL is 4 mm, which is directly proportional to fluence. The goal of deep AFL is the removal of scar tissue to facilitate remodeling and neocollagenesis. Superficial fractional ablation can then be achieved utilizing the ActiveFX UltraPulse configuration generating a 1.3-mm MTZ spot size. We commonly use a treatment level of 3 (82% density). Typical treatment energy ranges from 80 to 125 mJ, which correlates with depths of approximately 50 to 115 µm. With both configurations, the size and shape of the treatment area can be customized to the scar. In addition, frequency may be adjusted to control the speed of treatment while balancing the risk of bulk heating. The goal of superficial AFL is to minimize scar surface irregularities and ensure blending of deep AFL treatment. Once AFL treatment is complete, local pharmacotherapy can then be employed.

Pharmacotherapy

Intralesional corticosteroids have long represented the standard of care for hypertrophic scars, with concentrations between 2.5 and 40 mg/mL that are titrated to scar thickness and location to avoid unwanted atrophy. Visual blanching of the scar represents the clinical end point for treatment. Corticosteroids act by inhibiting fibroblast proliferation and enhancing collagen degradation.¹⁰ 5-Fluorouracil (5-FU) also is used in scar management. In addition to inhibiting fibroblast proliferation and inducing fibroblast apoptosis, 5-FU inhibits myofibroblast proliferation, which is helpful in the prevention and treatment of scar contracture.¹¹ As monotherapy, weekly injections with 1 to 3 mL of 50 mg/mL 5-FU has been safe and effective. Combination intralesional corticosteroid and 5-FU therapy has been reported and is associated with improved scar regression, reduced reoccurrence, and fewer side effects.¹¹ In our experience, a 1:1 suspension is effective with appropriate titration of the corticosteroid component. Although less well defined, topical application of pharmacotherapy and massage to the newly created MTZs appears beneficial and offers another option for delivery of corticosteroids and 5-FU, in addition to a number of promising medications such as bimatoprost, poly-L-lactic acid, timolol, and rapamycin.¹²

Conclusion

Advances in laser surgery and our understanding of wound healing have created a paradigm shift in the treatment approach to trauma and burn scars. In lieu of extensive scar excisions, the summarized multimodal regimen emphasizing tissue conservation and autologous remodeling is gaining favor in the military, academic medical centers, and scar centers of excellence, but patients are finding local access to care difficult. Dermatologists are uniquely positioned to cost-effectively deliver this care in the outpatient setting utilizing devices and techniques they already possess. With the end goal of optimization of functional, symptomatic, and aesthetic state of the patient, it is critical that dermatologists seize this opportunity to truly make a difference for the military and civilian patients that need it most.

When tasked with outlining updated therapy regimens for rosacea, specific patient vignettes come to mind.

A 53-year-old male golfer presents with years of central facial flushing, prominent telangiectases, erythema, and scattered pink papules. He attempted various over-the-counter topical products indicated for acne, such as salicylic acid scrub and benzoyl peroxide cream, with no improvement and much irritation. Recently, his wife has been helping him apply redness-concealing makeup in the morning and over-the-counter hydrocortisone cream in the evening, which has been slightly helpful.

This patient’s rosacea could conceivably be labeled under the papulopustular rosacea subtype; however, the conventional categories are fluid with subtype overlap and imprecise diagnostic criteria. He also seemed to display features of the erythematotelangiectatic subtype, perhaps with underlying photodamage as well as steroid rebound erythema and/or atrophy.¹ Nevertheless, it is a common presentation, and certain baseline tenets should be applied. First, all steroid products and irritants (eg, benzoyl peroxide and salicylic acid ingredients, any scrub vehicle) should be discontinued. Education about avoidance of triggers (ie, sun, heat, spicy food, alcohol, stress is paramount. Because barrier inadequacy is a recent insight into rosacea pathogenesis, mild syndet- or lipid-free cleansers, daily sunscreen, and evening emollients dictate baseline skin care, as does meticulous situation-specific sun protection.^2,3 The papular component and immediate erythema in and around the papules can be managed topically (prior to sunscreen or emollient application) with metronidazole gel or cream up to twice daily, ivermectin cream once daily, or azelaic acid gel or foam up to twice daily. Oral doxycycline 40 mg (delayed release) on an empty stomach or 50 mg (immediate release) with food to avert antimicrobial dosing and antibiotic resistance also could be considered if topical therapy is inadequate or irritating, though gastrointestinal comorbidities with rosacea also should be delineated before initiating oral antibiotics.^4-6 (Management of this patient’s nonlesional fixed erythema, telangiectases, and flushing is discussed after the next vignette.)

What if a woman presented in a similar fashion as above, only without papules? Her family physician prescribed metronidazole gel twice daily for years with no improvement in flushing, redness, or telangiectases.

Background erythema in rosacea often is persistent with trigger-specific intensification, with or without episodic facial flushing; undoubtedly, these symptoms can be difficult to compartmentalize depending on the clarity of the patient’s history and frequency of clinic visits. The aforementioned baseline skin care and sun-protection regimen applies, and newer topical agents such as α-adrenergics (daily oxymetazoline cream or brimonidine gel) may be considered for persistent erythema; however, irritant potential and rebound erythema are common.^7-9 Topical therapies such as metronidazole gel, as in this case, are inadequate for persistent background erythema or flushing. Persistent erythema and telangiectases can be reduced with pulsed dye laser or intense pulsed light modalities, particularly following conservative management of acute inflammation.⁵ Episodic flushing is poorly controlled with the above tactics, but anecdotally, topical or oral α-adrenergics or oral nonselective beta-blockers could be considered; the latter is also applicable to migraine therapy, which is perhaps comorbid with rosacea.^5,10

A 35-year-old Hispanic woman states that the scalp, forehead, and cheeks have been flaky, pink, and pruritic for years. She saw several aestheticians for it and the admixed “acne” on the face, receiving salicylic acid chemical peels with no improvement and much dyspigmentation.

Although underreported, the commingling of rosacea with seborrheic dermatitis is common, perhaps with mutual Demodex mite overpopulation, assigning topical therapies to its management such as daily ivermectin cream or steroid-sparing pimecrolimus cream for inflammatory papules and scaly regions of the face and scalp.^11-13 Further, this case exemplifies the increasing incidence and awareness of rosacea in darker skin types, along with its postinflammatory pigmentary perturbations, which necessitate repeated education about barrier control and sun protection.¹⁴

A 72-year-old male farmer presents with his wife whoinsists that his nose has been increasing in size for years; she procures a prior driver’s license photograph as proof. She also notes that he has been snoring at night and having more trouble breathing while working outdoors. The patient had not noticed.

Phymatous rosacea may exist as an additional feature of any rosacea subtype or as a singular finding, presenting as actively inflamed, fibrotic/noninflamed, or both. Management, particularly if inflamed, involves baseline gentle skin care and sun protection, avoidance of rosacea triggers, and implementation of oral therapy such as doxycycline or isotretinoin. Many cases, particularly those with a fibrotic component, warrant surgical methods such as fractionated CO₂ laser or Shaw scalpel surgical sculpting. These cases frequently demonstrate varying degrees of airway compromise, validating surgery as a legitimate medical, not merely cosmetic, presentation.^5,15

Final Thoughts

The Table, constructed as a concise therapy compendium by the ROSacea COnsensus (ROSCO) international panel of dermatologists and ophthalmologists, outlines data-driven and expert experience-based therapies for rosacea.⁵ This panel asserts that phenotypical features, not rigid subtypes, oblige patient-specific treatment schema. Also, as these cases outline, an evolving understanding of rosacea’s multifaceted pathogenesis, assorted presentations, and frequent pitfalls in daily skin care and initial management require individualized care.

When tasked with outlining updated therapy regimens for rosacea, specific patient vignettes come to mind.

A 53-year-old male golfer presents with years of central facial flushing, prominent telangiectases, erythema, and scattered pink papules. He attempted various over-the-counter topical products indicated for acne, such as salicylic acid scrub and benzoyl peroxide cream, with no improvement and much irritation. Recently, his wife has been helping him apply redness-concealing makeup in the morning and over-the-counter hydrocortisone cream in the evening, which has been slightly helpful.

This patient’s rosacea could conceivably be labeled under the papulopustular rosacea subtype; however, the conventional categories are fluid with subtype overlap and imprecise diagnostic criteria. He also seemed to display features of the erythematotelangiectatic subtype, perhaps with underlying photodamage as well as steroid rebound erythema and/or atrophy.¹ Nevertheless, it is a common presentation, and certain baseline tenets should be applied. First, all steroid products and irritants (eg, benzoyl peroxide and salicylic acid ingredients, any scrub vehicle) should be discontinued. Education about avoidance of triggers (ie, sun, heat, spicy food, alcohol, stress is paramount. Because barrier inadequacy is a recent insight into rosacea pathogenesis, mild syndet- or lipid-free cleansers, daily sunscreen, and evening emollients dictate baseline skin care, as does meticulous situation-specific sun protection.^2,3 The papular component and immediate erythema in and around the papules can be managed topically (prior to sunscreen or emollient application) with metronidazole gel or cream up to twice daily, ivermectin cream once daily, or azelaic acid gel or foam up to twice daily. Oral doxycycline 40 mg (delayed release) on an empty stomach or 50 mg (immediate release) with food to avert antimicrobial dosing and antibiotic resistance also could be considered if topical therapy is inadequate or irritating, though gastrointestinal comorbidities with rosacea also should be delineated before initiating oral antibiotics.^4-6 (Management of this patient’s nonlesional fixed erythema, telangiectases, and flushing is discussed after the next vignette.)

What if a woman presented in a similar fashion as above, only without papules? Her family physician prescribed metronidazole gel twice daily for years with no improvement in flushing, redness, or telangiectases.

Background erythema in rosacea often is persistent with trigger-specific intensification, with or without episodic facial flushing; undoubtedly, these symptoms can be difficult to compartmentalize depending on the clarity of the patient’s history and frequency of clinic visits. The aforementioned baseline skin care and sun-protection regimen applies, and newer topical agents such as α-adrenergics (daily oxymetazoline cream or brimonidine gel) may be considered for persistent erythema; however, irritant potential and rebound erythema are common.^7-9 Topical therapies such as metronidazole gel, as in this case, are inadequate for persistent background erythema or flushing. Persistent erythema and telangiectases can be reduced with pulsed dye laser or intense pulsed light modalities, particularly following conservative management of acute inflammation.⁵ Episodic flushing is poorly controlled with the above tactics, but anecdotally, topical or oral α-adrenergics or oral nonselective beta-blockers could be considered; the latter is also applicable to migraine therapy, which is perhaps comorbid with rosacea.^5,10

A 35-year-old Hispanic woman states that the scalp, forehead, and cheeks have been flaky, pink, and pruritic for years. She saw several aestheticians for it and the admixed “acne” on the face, receiving salicylic acid chemical peels with no improvement and much dyspigmentation.

Although underreported, the commingling of rosacea with seborrheic dermatitis is common, perhaps with mutual Demodex mite overpopulation, assigning topical therapies to its management such as daily ivermectin cream or steroid-sparing pimecrolimus cream for inflammatory papules and scaly regions of the face and scalp.^11-13 Further, this case exemplifies the increasing incidence and awareness of rosacea in darker skin types, along with its postinflammatory pigmentary perturbations, which necessitate repeated education about barrier control and sun protection.¹⁴

A 72-year-old male farmer presents with his wife whoinsists that his nose has been increasing in size for years; she procures a prior driver’s license photograph as proof. She also notes that he has been snoring at night and having more trouble breathing while working outdoors. The patient had not noticed.

Phymatous rosacea may exist as an additional feature of any rosacea subtype or as a singular finding, presenting as actively inflamed, fibrotic/noninflamed, or both. Management, particularly if inflamed, involves baseline gentle skin care and sun protection, avoidance of rosacea triggers, and implementation of oral therapy such as doxycycline or isotretinoin. Many cases, particularly those with a fibrotic component, warrant surgical methods such as fractionated CO₂ laser or Shaw scalpel surgical sculpting. These cases frequently demonstrate varying degrees of airway compromise, validating surgery as a legitimate medical, not merely cosmetic, presentation.^5,15

Final Thoughts

The Table, constructed as a concise therapy compendium by the ROSacea COnsensus (ROSCO) international panel of dermatologists and ophthalmologists, outlines data-driven and expert experience-based therapies for rosacea.⁵ This panel asserts that phenotypical features, not rigid subtypes, oblige patient-specific treatment schema. Also, as these cases outline, an evolving understanding of rosacea’s multifaceted pathogenesis, assorted presentations, and frequent pitfalls in daily skin care and initial management require individualized care.

When tasked with outlining updated therapy regimens for rosacea, specific patient vignettes come to mind.

A 53-year-old male golfer presents with years of central facial flushing, prominent telangiectases, erythema, and scattered pink papules. He attempted various over-the-counter topical products indicated for acne, such as salicylic acid scrub and benzoyl peroxide cream, with no improvement and much irritation. Recently, his wife has been helping him apply redness-concealing makeup in the morning and over-the-counter hydrocortisone cream in the evening, which has been slightly helpful.

This patient’s rosacea could conceivably be labeled under the papulopustular rosacea subtype; however, the conventional categories are fluid with subtype overlap and imprecise diagnostic criteria. He also seemed to display features of the erythematotelangiectatic subtype, perhaps with underlying photodamage as well as steroid rebound erythema and/or atrophy.¹ Nevertheless, it is a common presentation, and certain baseline tenets should be applied. First, all steroid products and irritants (eg, benzoyl peroxide and salicylic acid ingredients, any scrub vehicle) should be discontinued. Education about avoidance of triggers (ie, sun, heat, spicy food, alcohol, stress is paramount. Because barrier inadequacy is a recent insight into rosacea pathogenesis, mild syndet- or lipid-free cleansers, daily sunscreen, and evening emollients dictate baseline skin care, as does meticulous situation-specific sun protection.^2,3 The papular component and immediate erythema in and around the papules can be managed topically (prior to sunscreen or emollient application) with metronidazole gel or cream up to twice daily, ivermectin cream once daily, or azelaic acid gel or foam up to twice daily. Oral doxycycline 40 mg (delayed release) on an empty stomach or 50 mg (immediate release) with food to avert antimicrobial dosing and antibiotic resistance also could be considered if topical therapy is inadequate or irritating, though gastrointestinal comorbidities with rosacea also should be delineated before initiating oral antibiotics.^4-6 (Management of this patient’s nonlesional fixed erythema, telangiectases, and flushing is discussed after the next vignette.)

What if a woman presented in a similar fashion as above, only without papules? Her family physician prescribed metronidazole gel twice daily for years with no improvement in flushing, redness, or telangiectases.

Background erythema in rosacea often is persistent with trigger-specific intensification, with or without episodic facial flushing; undoubtedly, these symptoms can be difficult to compartmentalize depending on the clarity of the patient’s history and frequency of clinic visits. The aforementioned baseline skin care and sun-protection regimen applies, and newer topical agents such as α-adrenergics (daily oxymetazoline cream or brimonidine gel) may be considered for persistent erythema; however, irritant potential and rebound erythema are common.^7-9 Topical therapies such as metronidazole gel, as in this case, are inadequate for persistent background erythema or flushing. Persistent erythema and telangiectases can be reduced with pulsed dye laser or intense pulsed light modalities, particularly following conservative management of acute inflammation.⁵ Episodic flushing is poorly controlled with the above tactics, but anecdotally, topical or oral α-adrenergics or oral nonselective beta-blockers could be considered; the latter is also applicable to migraine therapy, which is perhaps comorbid with rosacea.^5,10

A 35-year-old Hispanic woman states that the scalp, forehead, and cheeks have been flaky, pink, and pruritic for years. She saw several aestheticians for it and the admixed “acne” on the face, receiving salicylic acid chemical peels with no improvement and much dyspigmentation.

Although underreported, the commingling of rosacea with seborrheic dermatitis is common, perhaps with mutual Demodex mite overpopulation, assigning topical therapies to its management such as daily ivermectin cream or steroid-sparing pimecrolimus cream for inflammatory papules and scaly regions of the face and scalp.^11-13 Further, this case exemplifies the increasing incidence and awareness of rosacea in darker skin types, along with its postinflammatory pigmentary perturbations, which necessitate repeated education about barrier control and sun protection.¹⁴

A 72-year-old male farmer presents with his wife whoinsists that his nose has been increasing in size for years; she procures a prior driver’s license photograph as proof. She also notes that he has been snoring at night and having more trouble breathing while working outdoors. The patient had not noticed.

Phymatous rosacea may exist as an additional feature of any rosacea subtype or as a singular finding, presenting as actively inflamed, fibrotic/noninflamed, or both. Management, particularly if inflamed, involves baseline gentle skin care and sun protection, avoidance of rosacea triggers, and implementation of oral therapy such as doxycycline or isotretinoin. Many cases, particularly those with a fibrotic component, warrant surgical methods such as fractionated CO₂ laser or Shaw scalpel surgical sculpting. These cases frequently demonstrate varying degrees of airway compromise, validating surgery as a legitimate medical, not merely cosmetic, presentation.^5,15

Final Thoughts

The Table, constructed as a concise therapy compendium by the ROSacea COnsensus (ROSCO) international panel of dermatologists and ophthalmologists, outlines data-driven and expert experience-based therapies for rosacea.⁵ This panel asserts that phenotypical features, not rigid subtypes, oblige patient-specific treatment schema. Also, as these cases outline, an evolving understanding of rosacea’s multifaceted pathogenesis, assorted presentations, and frequent pitfalls in daily skin care and initial management require individualized care.

The prevalence of topical cannabinoids has risen sharply in recent years. Commercial advertisers promote their usage as a safe means to treat a multitude of skin disorders, including atopic dermatitis (AD), psoriasis, and acne. Topical compounds have garnered interest in laboratory studies, but the purchase of commercial formulations is limited to over-the-counter products from unregulated suppliers. In this article, we review the scientific evidence behind topical cannabinoids and evaluate their role in clinical dermatology.

Background

Cannabis is designated as a Schedule I drug, according to the Controlled Substances Act of 1970. This listing is given to substances with no therapeutic value and a high potential for abuse. However, as of 2017, 29 states and the District of Columbia have laws legalizing cannabis in some capacity. These regulations typically apply to medicinal use, though several states have now legalized recreational use.

Cannabinoids represent a broad class of chemical compounds derived from the cannabis plant. Originally, this class only comprised phytocannabinoids, cannabinoids produced by the cannabis plant. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and leads to the psychoactive effects typically associated with cannabis use. Later investigation led to the discovery of endocannabinoids, cannabinoids that are naturally produced by human and animal bodies, as well as synthetic cannabinoids.¹ Cannabidiol is a phytocannabinoid that has been investigated in neurologic and anti-inflammatory conditions.^2-4

Cannabinoids act as agonists on 2 principal receptors— cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)—which are both G protein–coupled receptors (Figure).⁵ Both have distinct distributions throughout different organ systems, to which cannabinoids (eg, THC, cannabidiol, endocannabinoids) show differential binding.^6,7 Importantly, the expression of CB1 and CB2 has been identified on sensory nerve fibers, inflammatory cells, and adnexal structures of human skin.⁸ Based on these associations, topical application of cannabinoids has become a modality of interest for dermatological disorders. These formulations aim to influence cutaneous morphology without producing psychoactive effects.

Topical Cannabinoids in Inflammatory Disorders

Atopic dermatitis has emerged as an active area of investigation for cannabinoid receptors and topical agonists (Table 1). In an animal model, Kim et al⁹ examined the effects of CB1 agonism on skin inflammation. Mice treated with topical CB1 agonists showed greater recovery of epidermal barrier function in acutely abrogated skin relative to those treated with a vehicle preparation. In addition, agonism of CB1 led to significant (P<.001) decreases in skin fold thickness among models of acute and chronic skin inflammation.⁹

Nam et al¹⁰ also examined the role of topical CB1 agonists in mice with induced AD-like symptoms. Relative to treatment with vehicle, CB1 agonists significantly reduced the recruitment of mast cells (P<.01) and lowered the blood concentration of histamine (P<.05). Given the noted decrease in the release of inflammatory mediators, the authors speculated that topical agonsim of CB1 may prove useful in several conditions related to mast cell activation, such as AD, contact dermatitis, and psoriasis.¹⁰

The anti-inflammatory properties of topical THC were evaluated by Gaffal et al.¹¹ In a mouse model of allergic contact dermatitis, mice treated with topical THC showed decreases in myeloid immune cell infiltration, with these beneficial effects existing even in mice with deficient CB1 and CB2 receptors. These results support a potentially wide anti-inflammatory activity of topical THC.¹¹

Topical Cannabinoids in Pain Management

The effects of smoked cannabis in treating pain have undergone thorough investigation over recent years. Benefits have been noted in treating neuropathic pain, particularly in human immunodeficiency virus–associated sensory neuropathy.^12-15 Smoked cannabis also may provide value as a synergistic therapy with opioids, thereby allowing for lower opioid doses.¹⁶

In contrast, research into the relationship between topical application of cannabinoids and nociception remains in preliminary stages (Table 2). In a mouse model, Dogrul et al¹⁷ assessed the topical antinociceptive potential of a mixed CB1-CB2 agonist. Results showed significant (P<.01) and dose-dependent antinociceptive effects relative to treatment with a vehicle.¹⁷ In a related study, Yesilyurt et al¹⁸ evaluated whether a mixed CB1-CB2 agonist could enhance the antinociceptive effects of topical opioids. Among mice treated with the combination of a cannabinoid agonist and topical morphine, a significantly (P<.05) greater analgesic effect was demonstrated relative to topical morphine alone.¹⁸

Studies in humans have been far more limited. Phan et al¹⁹ conducted a small, nonrandomized, open-label trial of a topical cannabinoid cream in patients with facial postherpetic neuralgia. Of 8 patients treated, 5 noted a mean pain reduction of 87.8%. No comparison vehicle was used. Based on this narrow study design, it is difficult to extrapolate these positive results to a broader patient population.¹⁹

Commercial Products

Although preliminary models with topical cannabinoids have shown potential, large-scale clinical trials in humans have yet to be performed. Despite this lack of investigation, commercial formulations of topical cannabinoids are available to dermatology patients. These formulations are nonstandardized, and no safety data exists regarding their use. Topical cannabinoids on the market may contain various amounts of active ingredient and may be combined with a range of other compounds.

In dermatology offices, it is not uncommon for patients to express an intention to use topical cannabinoid products following their planned treatment or procedure. Patients also have been known to use topical cannabinoid products prior to dermatologic procedures, sometimes in place of an approved topical anesthetic, without consulting the physician performing the procedure. With interventions that lead to active areas of wound healing, the application of such products may increase the risk for contamination and infection. Therefore, patients should be counseled that the use of commercial topical cannabinoids could jeopardize the success of their planned procedure, put them at risk for infection, and possibly lead to systemic absorption and/or changes in wound-healing capacities.

Conclusion

Based on the results from recent animal models, cannabinoids may have a role in future treatment algorithms for several inflammatory conditions. However, current efficacy and safety data are almost entirely limited to preliminary animal studies in rodents. In addition, the formulation of topical cannabinoid products is nonstandardized and poorly regulated. As such, the present evidence does not support the use of topical cannabinoids in dermatology practices. Dermatologists should ask patients about the use of any cannabinoid products as part of a treatment program, especially given the unsubstantiated claims often made by unscrupulous advertisers. This issue highlights the need for further research and regulation.

The prevalence of topical cannabinoids has risen sharply in recent years. Commercial advertisers promote their usage as a safe means to treat a multitude of skin disorders, including atopic dermatitis (AD), psoriasis, and acne. Topical compounds have garnered interest in laboratory studies, but the purchase of commercial formulations is limited to over-the-counter products from unregulated suppliers. In this article, we review the scientific evidence behind topical cannabinoids and evaluate their role in clinical dermatology.

Background

Cannabis is designated as a Schedule I drug, according to the Controlled Substances Act of 1970. This listing is given to substances with no therapeutic value and a high potential for abuse. However, as of 2017, 29 states and the District of Columbia have laws legalizing cannabis in some capacity. These regulations typically apply to medicinal use, though several states have now legalized recreational use.

Cannabinoids represent a broad class of chemical compounds derived from the cannabis plant. Originally, this class only comprised phytocannabinoids, cannabinoids produced by the cannabis plant. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and leads to the psychoactive effects typically associated with cannabis use. Later investigation led to the discovery of endocannabinoids, cannabinoids that are naturally produced by human and animal bodies, as well as synthetic cannabinoids.¹ Cannabidiol is a phytocannabinoid that has been investigated in neurologic and anti-inflammatory conditions.^2-4

Cannabinoids act as agonists on 2 principal receptors— cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)—which are both G protein–coupled receptors (Figure).⁵ Both have distinct distributions throughout different organ systems, to which cannabinoids (eg, THC, cannabidiol, endocannabinoids) show differential binding.^6,7 Importantly, the expression of CB1 and CB2 has been identified on sensory nerve fibers, inflammatory cells, and adnexal structures of human skin.⁸ Based on these associations, topical application of cannabinoids has become a modality of interest for dermatological disorders. These formulations aim to influence cutaneous morphology without producing psychoactive effects.

Topical Cannabinoids in Inflammatory Disorders

Atopic dermatitis has emerged as an active area of investigation for cannabinoid receptors and topical agonists (Table 1). In an animal model, Kim et al⁹ examined the effects of CB1 agonism on skin inflammation. Mice treated with topical CB1 agonists showed greater recovery of epidermal barrier function in acutely abrogated skin relative to those treated with a vehicle preparation. In addition, agonism of CB1 led to significant (P<.001) decreases in skin fold thickness among models of acute and chronic skin inflammation.⁹

Nam et al¹⁰ also examined the role of topical CB1 agonists in mice with induced AD-like symptoms. Relative to treatment with vehicle, CB1 agonists significantly reduced the recruitment of mast cells (P<.01) and lowered the blood concentration of histamine (P<.05). Given the noted decrease in the release of inflammatory mediators, the authors speculated that topical agonsim of CB1 may prove useful in several conditions related to mast cell activation, such as AD, contact dermatitis, and psoriasis.¹⁰

The anti-inflammatory properties of topical THC were evaluated by Gaffal et al.¹¹ In a mouse model of allergic contact dermatitis, mice treated with topical THC showed decreases in myeloid immune cell infiltration, with these beneficial effects existing even in mice with deficient CB1 and CB2 receptors. These results support a potentially wide anti-inflammatory activity of topical THC.¹¹

Topical Cannabinoids in Pain Management

The effects of smoked cannabis in treating pain have undergone thorough investigation over recent years. Benefits have been noted in treating neuropathic pain, particularly in human immunodeficiency virus–associated sensory neuropathy.^12-15 Smoked cannabis also may provide value as a synergistic therapy with opioids, thereby allowing for lower opioid doses.¹⁶

In contrast, research into the relationship between topical application of cannabinoids and nociception remains in preliminary stages (Table 2). In a mouse model, Dogrul et al¹⁷ assessed the topical antinociceptive potential of a mixed CB1-CB2 agonist. Results showed significant (P<.01) and dose-dependent antinociceptive effects relative to treatment with a vehicle.¹⁷ In a related study, Yesilyurt et al¹⁸ evaluated whether a mixed CB1-CB2 agonist could enhance the antinociceptive effects of topical opioids. Among mice treated with the combination of a cannabinoid agonist and topical morphine, a significantly (P<.05) greater analgesic effect was demonstrated relative to topical morphine alone.¹⁸

Studies in humans have been far more limited. Phan et al¹⁹ conducted a small, nonrandomized, open-label trial of a topical cannabinoid cream in patients with facial postherpetic neuralgia. Of 8 patients treated, 5 noted a mean pain reduction of 87.8%. No comparison vehicle was used. Based on this narrow study design, it is difficult to extrapolate these positive results to a broader patient population.¹⁹

Commercial Products

Although preliminary models with topical cannabinoids have shown potential, large-scale clinical trials in humans have yet to be performed. Despite this lack of investigation, commercial formulations of topical cannabinoids are available to dermatology patients. These formulations are nonstandardized, and no safety data exists regarding their use. Topical cannabinoids on the market may contain various amounts of active ingredient and may be combined with a range of other compounds.

In dermatology offices, it is not uncommon for patients to express an intention to use topical cannabinoid products following their planned treatment or procedure. Patients also have been known to use topical cannabinoid products prior to dermatologic procedures, sometimes in place of an approved topical anesthetic, without consulting the physician performing the procedure. With interventions that lead to active areas of wound healing, the application of such products may increase the risk for contamination and infection. Therefore, patients should be counseled that the use of commercial topical cannabinoids could jeopardize the success of their planned procedure, put them at risk for infection, and possibly lead to systemic absorption and/or changes in wound-healing capacities.

Conclusion

Based on the results from recent animal models, cannabinoids may have a role in future treatment algorithms for several inflammatory conditions. However, current efficacy and safety data are almost entirely limited to preliminary animal studies in rodents. In addition, the formulation of topical cannabinoid products is nonstandardized and poorly regulated. As such, the present evidence does not support the use of topical cannabinoids in dermatology practices. Dermatologists should ask patients about the use of any cannabinoid products as part of a treatment program, especially given the unsubstantiated claims often made by unscrupulous advertisers. This issue highlights the need for further research and regulation.

The prevalence of topical cannabinoids has risen sharply in recent years. Commercial advertisers promote their usage as a safe means to treat a multitude of skin disorders, including atopic dermatitis (AD), psoriasis, and acne. Topical compounds have garnered interest in laboratory studies, but the purchase of commercial formulations is limited to over-the-counter products from unregulated suppliers. In this article, we review the scientific evidence behind topical cannabinoids and evaluate their role in clinical dermatology.

Background

Cannabis is designated as a Schedule I drug, according to the Controlled Substances Act of 1970. This listing is given to substances with no therapeutic value and a high potential for abuse. However, as of 2017, 29 states and the District of Columbia have laws legalizing cannabis in some capacity. These regulations typically apply to medicinal use, though several states have now legalized recreational use.

Cannabinoids represent a broad class of chemical compounds derived from the cannabis plant. Originally, this class only comprised phytocannabinoids, cannabinoids produced by the cannabis plant. Tetrahydrocannabinol (THC) is the most well-known phytocannabinoid and leads to the psychoactive effects typically associated with cannabis use. Later investigation led to the discovery of endocannabinoids, cannabinoids that are naturally produced by human and animal bodies, as well as synthetic cannabinoids.¹ Cannabidiol is a phytocannabinoid that has been investigated in neurologic and anti-inflammatory conditions.^2-4

Cannabinoids act as agonists on 2 principal receptors— cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2)—which are both G protein–coupled receptors (Figure).⁵ Both have distinct distributions throughout different organ systems, to which cannabinoids (eg, THC, cannabidiol, endocannabinoids) show differential binding.^6,7 Importantly, the expression of CB1 and CB2 has been identified on sensory nerve fibers, inflammatory cells, and adnexal structures of human skin.⁸ Based on these associations, topical application of cannabinoids has become a modality of interest for dermatological disorders. These formulations aim to influence cutaneous morphology without producing psychoactive effects.

Topical Cannabinoids in Inflammatory Disorders

Atopic dermatitis has emerged as an active area of investigation for cannabinoid receptors and topical agonists (Table 1). In an animal model, Kim et al⁹ examined the effects of CB1 agonism on skin inflammation. Mice treated with topical CB1 agonists showed greater recovery of epidermal barrier function in acutely abrogated skin relative to those treated with a vehicle preparation. In addition, agonism of CB1 led to significant (P<.001) decreases in skin fold thickness among models of acute and chronic skin inflammation.⁹

Nam et al¹⁰ also examined the role of topical CB1 agonists in mice with induced AD-like symptoms. Relative to treatment with vehicle, CB1 agonists significantly reduced the recruitment of mast cells (P<.01) and lowered the blood concentration of histamine (P<.05). Given the noted decrease in the release of inflammatory mediators, the authors speculated that topical agonsim of CB1 may prove useful in several conditions related to mast cell activation, such as AD, contact dermatitis, and psoriasis.¹⁰

The anti-inflammatory properties of topical THC were evaluated by Gaffal et al.¹¹ In a mouse model of allergic contact dermatitis, mice treated with topical THC showed decreases in myeloid immune cell infiltration, with these beneficial effects existing even in mice with deficient CB1 and CB2 receptors. These results support a potentially wide anti-inflammatory activity of topical THC.¹¹

Topical Cannabinoids in Pain Management

The effects of smoked cannabis in treating pain have undergone thorough investigation over recent years. Benefits have been noted in treating neuropathic pain, particularly in human immunodeficiency virus–associated sensory neuropathy.^12-15 Smoked cannabis also may provide value as a synergistic therapy with opioids, thereby allowing for lower opioid doses.¹⁶

In contrast, research into the relationship between topical application of cannabinoids and nociception remains in preliminary stages (Table 2). In a mouse model, Dogrul et al¹⁷ assessed the topical antinociceptive potential of a mixed CB1-CB2 agonist. Results showed significant (P<.01) and dose-dependent antinociceptive effects relative to treatment with a vehicle.¹⁷ In a related study, Yesilyurt et al¹⁸ evaluated whether a mixed CB1-CB2 agonist could enhance the antinociceptive effects of topical opioids. Among mice treated with the combination of a cannabinoid agonist and topical morphine, a significantly (P<.05) greater analgesic effect was demonstrated relative to topical morphine alone.¹⁸

Studies in humans have been far more limited. Phan et al¹⁹ conducted a small, nonrandomized, open-label trial of a topical cannabinoid cream in patients with facial postherpetic neuralgia. Of 8 patients treated, 5 noted a mean pain reduction of 87.8%. No comparison vehicle was used. Based on this narrow study design, it is difficult to extrapolate these positive results to a broader patient population.¹⁹

Commercial Products

Although preliminary models with topical cannabinoids have shown potential, large-scale clinical trials in humans have yet to be performed. Despite this lack of investigation, commercial formulations of topical cannabinoids are available to dermatology patients. These formulations are nonstandardized, and no safety data exists regarding their use. Topical cannabinoids on the market may contain various amounts of active ingredient and may be combined with a range of other compounds.

In dermatology offices, it is not uncommon for patients to express an intention to use topical cannabinoid products following their planned treatment or procedure. Patients also have been known to use topical cannabinoid products prior to dermatologic procedures, sometimes in place of an approved topical anesthetic, without consulting the physician performing the procedure. With interventions that lead to active areas of wound healing, the application of such products may increase the risk for contamination and infection. Therefore, patients should be counseled that the use of commercial topical cannabinoids could jeopardize the success of their planned procedure, put them at risk for infection, and possibly lead to systemic absorption and/or changes in wound-healing capacities.

Conclusion

Based on the results from recent animal models, cannabinoids may have a role in future treatment algorithms for several inflammatory conditions. However, current efficacy and safety data are almost entirely limited to preliminary animal studies in rodents. In addition, the formulation of topical cannabinoid products is nonstandardized and poorly regulated. As such, the present evidence does not support the use of topical cannabinoids in dermatology practices. Dermatologists should ask patients about the use of any cannabinoid products as part of a treatment program, especially given the unsubstantiated claims often made by unscrupulous advertisers. This issue highlights the need for further research and regulation.

Facial acne vulgaris is a common skin disease among teenagers and adolescents that may negatively affect self-esteem, perceived facial attractiveness, and social participation.¹ Treatments for acne often are multimodal and require the utmost adherence. For these reasons, acne treatments have been challenging to clinicians and patients alike, as patient compliance in maintaining the use of prescribed topical and oral medications remains essential to attain improvement in quality of life (QOL).

Salicylic acid is a popular medicament for acne treatment that frequently is used as monotherapy or as an adjuvant for other acne treatments, especially in patients with oily skin.² Salicylic acid has a keratolytic effect, causing corneocyte discohesion in clogged pores or congested follicles,² and it is effective in treating both inflammatory and noninflammatory acne.^3,4

Light therapy, particularly with visible light, has been demonstrated to improve acne outcomes.⁵ Pneumatic broadband light (PBBL) is a therapeutic light treatment in the broadband range (400–1200 nm) that is combined with vacuum suction, which creates a mechanical lysis of thin-walled pustules and dislodges pore impaction. Additionally, the blue light portion of the PBBL spectrum targets endogenous porphyrins in Propionibacterium acnes, resulting in bacterial destruction.^6-8

The purpose of this study was to compare the efficacy, tolerability, and safety of salicylic acid 30% peel versus PBBL in the treatment of mild to moderately severe facial acne vulgaris.

METHODS

Study Design

This single-blind, randomized, split-face pilot study was approved by the institutional review board of the University of Pennsylvania (Philadelphia, Pennsylvania). All patients provided informed consent before entering the study. The single-blind evaluation was performed by one dermatologist (C.T.) who examined the participants on every visit prior to PBBL treatment.

Before the study started, participants were randomized for which side of the face was to be treated with PBBL using a number assigned to each participant. Participants received both treatments—salicylic acid 30% peel on one side of the face and PBBL treatment on the other side of the face—once weekly for a total of 6 treatments. They were then asked to return for 2 follow-up evaluations at weeks 3 and 6 following the last treatment session and were instructed not to use any topical or oral acne medications during these follow-up periods.

Inclusion and Exclusion Criteria

Patients aged 18 years and older of any race and sex with noninflammatory papules, some inflammatory papules, and no more than 1 nodule (considered as mild to moderately severe facial acne) were included in the study. Participants had not been on any topical acne medications for at least 1 month and/or oral retinoids for at least 1 year prior to the study period. All women completed urine pregnancy tests prior to the study and were advised to utilize birth control during the study period.

Study Treatments

Salicylic Acid 30% Peel

The participant’s face was cleansed thoroughly before application of salicylic acid 30% (1.5 g/2.5 mL) to half of the face and left on for 5 minutes before being carefully rinsed off by spraying with spring water. Prior to initiating PBBL therapy, the peeled side of the participant’s face was covered with a towel.

Pneumatic Broadband Light

On the other side of the face, PBBL was performed to deliver broadband light within the spectrum range of 400 to 1200 nm at a setting approximately equivalent to a fluence of 4 to 6 J/cm² and a vacuum setting approximately equivalent to a negative pressure of 3 lb/in². The power setting was increased on each subsequent visit depending on each participant’s tolerability.

Participants were required to apply a moisturizer and sunscreen to the face and avoid excessive sun exposure between study visits.

Efficacy Evaluation

A comparison of the efficacy of the treatments was determined by clinical evaluation and examining the results of the outcome measurements with the modified Global Acne Grading Score (mGAGS) and Acne QOL Scale during each treatment visit. Facial photographs were taken at each visit.

Modified Global Acne Grading Score

The mGAGS is a modification of the Global Acne Grading Scale (GAGS) that has been used to evaluate acne severity in many studies.^9-11 The GAGS considers 6 locations on the face with a grading factor for each location. The local score is obtained by multiplying the factor rated by location with the factor of clinical assessment: local score = factor rated by location × factor rated by clinical assessment. The total score is the sum of the individual local scores (Table 1).

Although the original GAGS incorporated the type and location of the lesions in its calculation, we felt that the number of lesions also was important to add to our grading score. Therefore, we modified the GAGS by adding a factor rated by the number of lesions to improve the accuracy of the test. Accordingly, the local mGAGS scores were calculated by multiplying the location factor by the lesion type and number of lesions factors: local score = location factor × lesion type factor × number of lesions factor.

Acne QOL Questionnaire

Acne QOL was assessed during each visit to demonstrate if the treatment results affected participants’ socialization due to appearance.¹² Participants were asked to complete the questionnaire, which consisted of 9 questions with 4 rating answers (0=not affected; 1=mildly affected; 2=moderately affected; 3=markedly affected). A total score of 9 or higher (high score) indicated that acne had a substantial negative impact on the participant, while a total score below 9 (low score) meant acne scarcely impacted social aspects and daily activities of the patient.

Safety Evaluation

The safety of the treatments was evaluated by clinical inspection and by comparing the results of the Wong-Baker FACES Pain Rating Scale (WBPRS)¹³ after treatment. The WBPRS is used worldwide among researchers to assess pain, particularly in children.^14,15 It is composed of 6 faces expressing pain with word descriptions with a corresponding number range reflecting pain severity from 0 to 5 (0=no hurt; 1=hurts little bit; 2=hurts little more; 3=hurts even more; 4=hurts whole lot; 5=hurts worst).¹³

Statistical Analysis

All variables were presented as the median (range). A Wilcoxon signed rank test was used to compare clinical responses between the salicylic acid 30% peel and PBBL therapies. SPSS software version 12.0 was used for all statistical analysis. A 2-tailed P value of ≤.05 was considered statistically significant.

RESULTS

Study Population

Twelve participants (2 males, 10 females) aged 17 to 36 years (median age, 22 years; mean age [SD], 23.33 [1.65] years) with both comedonal and inflammatory acne were enrolled into this study for 6 split-face treatments of salicylic acid 30% peel and PBBL at 1-week intervals for 6 weeks, with 2 subsequent follow-up sessions at weeks 3 and 6 posttreatment. Of the 12 participants, 11 were white and 1 was Asian American, with Fitzpatrick skin types II to IV. Nine participants (75%) completed the study. One participant dropped out of the study after the fourth treatment due to a scheduling conflict, and the other 2 participants did not return for follow-up. No participants withdrew from the study because of adverse therapeutic events.

Efficacy Evaluation

Comparisons between the salicylic acid 30% peel and PBBL procedures for mGAGS at each visit are shown in Table 2. There was no significant difference in treatment efficacy between the salicylic acid 30% peel and PBBL therapies during the study’s treatment and follow-up events; however, both procedures contributed to a major improvement in acne symptoms by the third treatment session and through to the last follow-up session (P≤.05). Clinical photographs at baseline, at last treatment visit (week 6), and at last follow-up (week 12) are shown in Figures 1 and 2.

The results of the acne QOL questionnaire are shown in Table 2. Lower scores reflect a higher QOL. Median QOL scores at each visit ranged from 0.5 to 4.5. There was no significant difference found between the peel agent or PBBL based on the baseline QOL and subsequent visit assessments; however, the differences between the 2 treatments were significant at weeks 3 (P=.05) and 5 (P=.03) of treatment as well as at the last follow-up visit (P=.05).

According to the QOL scores, by the third treatment session participants were more satisfied with their improved acne condition from the PBBL procedure than the salicylic acid 30% peel as demonstrated by a positive range of the QOL assessments between PBBL and salicylic acid 30% peel (as shown in the difference in QOL in Table 2: week 3, 0–6; week 4, 0–3; week 5, 0–7). On the other hand, participants saw more improvement from the salicylic acid 30% peel than from PBBL by the last follow-up evaluation, as the differences in QOL scores between the 2 treatments resulted in a negative range (−5–0).

Safety

Pain assessment by the WBPRS at every visit showed a low pain rating associated with both salicylic acid 30% peel (range, 0–0.5) and PBBL (range, 1.0–1.5) treatments. The median pain score of the salicylic acid 30% peel appeared higher compared to the PBBL treatment, yet a significant difference between both treatments was seen only at weeks 1, 3, and 6 of treatment (P≤.05).

There were no unexpected therapeutic reactions reported in our study, and no participants withdrew from the study due to adverse events. Most participants experienced only mild adverse reactions, including redness, stinging, and a burning sensation on the salicylic acid 30% peel side, which were transient and disappeared in minutes; only redness occurred on the PBBL-treated side.

Comment

Facial acne treatment is challenging, as prolonged and/or severe acne contributes to scarring, declining self-confidence, and undesirable financial consequences. Even though salicylic acid peel is a commonly used acne treatment choice, the PBBL methodology was approved by the US Food and Drug Administration⁶ and has become an alternative procedure for acne treatment.

The pharmacological effects of salicylic acid are related to its corneocyte desquamation and exfoliative actions, thereby reducing corneocyte cohesion and unclogging follicular pores.¹⁶ Salicylic acid has been demonstrated to ameliorate inflammatory acne by its effects on the arachidonic acid cascade.^2,4,17 In our study, salicylic acid 30% peel met participants’ satisfaction in acne improvement similar to a study showing a 50% improvement in acne scores after just 2 treatments.¹⁸ Our data support and corroborate that salicylic acid 30% peel renders an improvement in acne sequelae reported in several other studies.^2,17,18

Pneumatic broadband light has been known to treat acne by the mechanism of pneumatic suction combined with photodynamic therapy using broadband-pulsed light (400–1200 nm).^6-8 By applying the pneumatic device, a vacuum is created on the skin to remove sebum contents from follicles, whereas broadband light is emitted simultaneously to destroy bacteria and decrease the inflammatory process.⁷ During the vacuum process, the skin is stretched to reduce pain and avoid competitive chromophores (eg, hemoglobin), while the broadband light is administered.⁷ Broadband light encompasses 2 main light spectrums: blue light (415 nm) activates coproporphyrin III, which induces reactive free radicals and singlet oxygen species and has been reported to be the cause of bacterial cell death,¹⁹ and red light (633 nm), which renders an increase of fibroblast growth factors to work against the inflammatory processes.²⁰ There are numerous studies showing a reduction of acne lesions after photopneumatic therapy with minimal side effects.^6-8

In our study, we compared the efficacy of salicylic acid 30% peel with PBBL in the treatment of acne. Both treatments showed significant reduction of mGAGS compared to baseline starting from week 3 and lasting until week 12. Remarkably, although there were some participants who reported acne recurrence after completing all treatments at week 6, which could have happened when the treatments were ended, the final acne score at week 12 was still significantly lower than baseline. It is clear that the participants continued their acne improvement up to the 6-week follow-up period without any topical or oral medication. We do not propose that either salicylic acid peel or PBBL treatment is a solitary option but speculate that the combination of both treatments may initiate a faster resolution in the disappearance of acne.

Although there was no statistically significant difference in efficacy between salicylic acid 30% peel and PBBL procedures at each visit, QOL assessments related to treatment satisfaction did yield significant differences between baseline and the end of treatment. We noticed that participants had more positive attitudes toward the PBBL side at week 3 and week 5 but only mild satisfaction at week 4, as the differences in QOL scores between both treatments showed positive ranging values. This finding is most likely related to the immediate reduction of acne pustules by the PBBL vacuum lysis of these lesions. The differences in the QOL scores between both treatments at week 12 (the last follow-up evaluation) provided opposite findings, which meant patients had nearly even improvement in both PBBL method and salicylic acid 30% peel. Therefore, according to QOL data, acne disappeared quickly with the application of PBBL therapy but reappeared on the PBBL-treated side by the follow-up evaluations, though the acne score between both sides showed no statistically significant difference.

We reason that the PBBL therapy works better than salicylic acid 30% peel because the pneumatic system may help to unclog the pores through mechanical debridement via suctioning versus desquamation from salicylic acid 30% peel. Nonetheless, salicylic acid 30% peel sustained improvement when compared to PBBL through the follow-up periods. Both salicylic acid 30% peel and PBBL treatments are well tolerated and may initiate a faster resolution in the improvement of acne when incorporated with a medical program.

Because of the recurrence of acne after treatments were stopped, additional medical therapies are advised to be used along with this study’s clinical treatments to help mitigate the acne symptoms. These treatments should be considered in patients concerned about antibiotic resistance or those who cannot take oral antibiotics or retinoids. Salicylic acid peel is more accessible and affordable than PBBL, whereas PBBL is slightly more tolerable and less irritating than salicylic acid peel. Nevertheless, the cost of investment in PBBL is quite high—as much as $70,000—and does not include disposable, single-use tips, which cost $30 each. The machine is easy to set up, weighs about 40 lb, and requires little space to store. The average cost per visit of PBBL treatment in office is $150.00 and $75.00 for salicylic acid peel (unpublished data, Hospital of the University of Pennsylvania, 2010). Most patients may select salicylic acid peel over PBBL due to the cost and convenience of the treatment. Neither procedure should be considered as a solitary treatment option but rather as adjunctive procedures combined with oral and/or topical acne medications. After this study’s treatments were stopped and without other medications to maintain treatment effectiveness, the lesions reappeared, trending back toward baseline.

Conclusion

Both salicylic acid 30% peel and PBBL procedures are effective, safe, and well tolerated in treating acne. Although there was no significant difference in the efficacy between both treatments in this study, the small sample size and short follow-up intervals warrant further studies to support the observed outstanding outcomes and should be considered in combination with other medical treatment options. These procedures may be beneficial in holding the patient compliant until their medical therapies have an opportunity to work.

Acknowledgment

The authors would like to thank Joyce Okawa, RN (Philadelphia, Pennsylvania), for her assistance in the submission to the institutional review board of the University of Pennsylvania.

Facial acne vulgaris is a common skin disease among teenagers and adolescents that may negatively affect self-esteem, perceived facial attractiveness, and social participation.¹ Treatments for acne often are multimodal and require the utmost adherence. For these reasons, acne treatments have been challenging to clinicians and patients alike, as patient compliance in maintaining the use of prescribed topical and oral medications remains essential to attain improvement in quality of life (QOL).

Salicylic acid is a popular medicament for acne treatment that frequently is used as monotherapy or as an adjuvant for other acne treatments, especially in patients with oily skin.² Salicylic acid has a keratolytic effect, causing corneocyte discohesion in clogged pores or congested follicles,² and it is effective in treating both inflammatory and noninflammatory acne.^3,4

Light therapy, particularly with visible light, has been demonstrated to improve acne outcomes.⁵ Pneumatic broadband light (PBBL) is a therapeutic light treatment in the broadband range (400–1200 nm) that is combined with vacuum suction, which creates a mechanical lysis of thin-walled pustules and dislodges pore impaction. Additionally, the blue light portion of the PBBL spectrum targets endogenous porphyrins in Propionibacterium acnes, resulting in bacterial destruction.^6-8

The purpose of this study was to compare the efficacy, tolerability, and safety of salicylic acid 30% peel versus PBBL in the treatment of mild to moderately severe facial acne vulgaris.

METHODS

Study Design

This single-blind, randomized, split-face pilot study was approved by the institutional review board of the University of Pennsylvania (Philadelphia, Pennsylvania). All patients provided informed consent before entering the study. The single-blind evaluation was performed by one dermatologist (C.T.) who examined the participants on every visit prior to PBBL treatment.

Before the study started, participants were randomized for which side of the face was to be treated with PBBL using a number assigned to each participant. Participants received both treatments—salicylic acid 30% peel on one side of the face and PBBL treatment on the other side of the face—once weekly for a total of 6 treatments. They were then asked to return for 2 follow-up evaluations at weeks 3 and 6 following the last treatment session and were instructed not to use any topical or oral acne medications during these follow-up periods.

Inclusion and Exclusion Criteria

Patients aged 18 years and older of any race and sex with noninflammatory papules, some inflammatory papules, and no more than 1 nodule (considered as mild to moderately severe facial acne) were included in the study. Participants had not been on any topical acne medications for at least 1 month and/or oral retinoids for at least 1 year prior to the study period. All women completed urine pregnancy tests prior to the study and were advised to utilize birth control during the study period.

Study Treatments

Salicylic Acid 30% Peel

The participant’s face was cleansed thoroughly before application of salicylic acid 30% (1.5 g/2.5 mL) to half of the face and left on for 5 minutes before being carefully rinsed off by spraying with spring water. Prior to initiating PBBL therapy, the peeled side of the participant’s face was covered with a towel.

Pneumatic Broadband Light

On the other side of the face, PBBL was performed to deliver broadband light within the spectrum range of 400 to 1200 nm at a setting approximately equivalent to a fluence of 4 to 6 J/cm² and a vacuum setting approximately equivalent to a negative pressure of 3 lb/in². The power setting was increased on each subsequent visit depending on each participant’s tolerability.

Participants were required to apply a moisturizer and sunscreen to the face and avoid excessive sun exposure between study visits.

Efficacy Evaluation

A comparison of the efficacy of the treatments was determined by clinical evaluation and examining the results of the outcome measurements with the modified Global Acne Grading Score (mGAGS) and Acne QOL Scale during each treatment visit. Facial photographs were taken at each visit.

Modified Global Acne Grading Score

The mGAGS is a modification of the Global Acne Grading Scale (GAGS) that has been used to evaluate acne severity in many studies.^9-11 The GAGS considers 6 locations on the face with a grading factor for each location. The local score is obtained by multiplying the factor rated by location with the factor of clinical assessment: local score = factor rated by location × factor rated by clinical assessment. The total score is the sum of the individual local scores (Table 1).

Although the original GAGS incorporated the type and location of the lesions in its calculation, we felt that the number of lesions also was important to add to our grading score. Therefore, we modified the GAGS by adding a factor rated by the number of lesions to improve the accuracy of the test. Accordingly, the local mGAGS scores were calculated by multiplying the location factor by the lesion type and number of lesions factors: local score = location factor × lesion type factor × number of lesions factor.

Acne QOL Questionnaire

Acne QOL was assessed during each visit to demonstrate if the treatment results affected participants’ socialization due to appearance.¹² Participants were asked to complete the questionnaire, which consisted of 9 questions with 4 rating answers (0=not affected; 1=mildly affected; 2=moderately affected; 3=markedly affected). A total score of 9 or higher (high score) indicated that acne had a substantial negative impact on the participant, while a total score below 9 (low score) meant acne scarcely impacted social aspects and daily activities of the patient.

Safety Evaluation

The safety of the treatments was evaluated by clinical inspection and by comparing the results of the Wong-Baker FACES Pain Rating Scale (WBPRS)¹³ after treatment. The WBPRS is used worldwide among researchers to assess pain, particularly in children.^14,15 It is composed of 6 faces expressing pain with word descriptions with a corresponding number range reflecting pain severity from 0 to 5 (0=no hurt; 1=hurts little bit; 2=hurts little more; 3=hurts even more; 4=hurts whole lot; 5=hurts worst).¹³

Statistical Analysis

All variables were presented as the median (range). A Wilcoxon signed rank test was used to compare clinical responses between the salicylic acid 30% peel and PBBL therapies. SPSS software version 12.0 was used for all statistical analysis. A 2-tailed P value of ≤.05 was considered statistically significant.

RESULTS

Study Population

Twelve participants (2 males, 10 females) aged 17 to 36 years (median age, 22 years; mean age [SD], 23.33 [1.65] years) with both comedonal and inflammatory acne were enrolled into this study for 6 split-face treatments of salicylic acid 30% peel and PBBL at 1-week intervals for 6 weeks, with 2 subsequent follow-up sessions at weeks 3 and 6 posttreatment. Of the 12 participants, 11 were white and 1 was Asian American, with Fitzpatrick skin types II to IV. Nine participants (75%) completed the study. One participant dropped out of the study after the fourth treatment due to a scheduling conflict, and the other 2 participants did not return for follow-up. No participants withdrew from the study because of adverse therapeutic events.

Efficacy Evaluation

Comparisons between the salicylic acid 30% peel and PBBL procedures for mGAGS at each visit are shown in Table 2. There was no significant difference in treatment efficacy between the salicylic acid 30% peel and PBBL therapies during the study’s treatment and follow-up events; however, both procedures contributed to a major improvement in acne symptoms by the third treatment session and through to the last follow-up session (P≤.05). Clinical photographs at baseline, at last treatment visit (week 6), and at last follow-up (week 12) are shown in Figures 1 and 2.

The results of the acne QOL questionnaire are shown in Table 2. Lower scores reflect a higher QOL. Median QOL scores at each visit ranged from 0.5 to 4.5. There was no significant difference found between the peel agent or PBBL based on the baseline QOL and subsequent visit assessments; however, the differences between the 2 treatments were significant at weeks 3 (P=.05) and 5 (P=.03) of treatment as well as at the last follow-up visit (P=.05).

According to the QOL scores, by the third treatment session participants were more satisfied with their improved acne condition from the PBBL procedure than the salicylic acid 30% peel as demonstrated by a positive range of the QOL assessments between PBBL and salicylic acid 30% peel (as shown in the difference in QOL in Table 2: week 3, 0–6; week 4, 0–3; week 5, 0–7). On the other hand, participants saw more improvement from the salicylic acid 30% peel than from PBBL by the last follow-up evaluation, as the differences in QOL scores between the 2 treatments resulted in a negative range (−5–0).

Safety

Pain assessment by the WBPRS at every visit showed a low pain rating associated with both salicylic acid 30% peel (range, 0–0.5) and PBBL (range, 1.0–1.5) treatments. The median pain score of the salicylic acid 30% peel appeared higher compared to the PBBL treatment, yet a significant difference between both treatments was seen only at weeks 1, 3, and 6 of treatment (P≤.05).

There were no unexpected therapeutic reactions reported in our study, and no participants withdrew from the study due to adverse events. Most participants experienced only mild adverse reactions, including redness, stinging, and a burning sensation on the salicylic acid 30% peel side, which were transient and disappeared in minutes; only redness occurred on the PBBL-treated side.

Comment

Facial acne treatment is challenging, as prolonged and/or severe acne contributes to scarring, declining self-confidence, and undesirable financial consequences. Even though salicylic acid peel is a commonly used acne treatment choice, the PBBL methodology was approved by the US Food and Drug Administration⁶ and has become an alternative procedure for acne treatment.

The pharmacological effects of salicylic acid are related to its corneocyte desquamation and exfoliative actions, thereby reducing corneocyte cohesion and unclogging follicular pores.¹⁶ Salicylic acid has been demonstrated to ameliorate inflammatory acne by its effects on the arachidonic acid cascade.^2,4,17 In our study, salicylic acid 30% peel met participants’ satisfaction in acne improvement similar to a study showing a 50% improvement in acne scores after just 2 treatments.¹⁸ Our data support and corroborate that salicylic acid 30% peel renders an improvement in acne sequelae reported in several other studies.^2,17,18

Pneumatic broadband light has been known to treat acne by the mechanism of pneumatic suction combined with photodynamic therapy using broadband-pulsed light (400–1200 nm).^6-8 By applying the pneumatic device, a vacuum is created on the skin to remove sebum contents from follicles, whereas broadband light is emitted simultaneously to destroy bacteria and decrease the inflammatory process.⁷ During the vacuum process, the skin is stretched to reduce pain and avoid competitive chromophores (eg, hemoglobin), while the broadband light is administered.⁷ Broadband light encompasses 2 main light spectrums: blue light (415 nm) activates coproporphyrin III, which induces reactive free radicals and singlet oxygen species and has been reported to be the cause of bacterial cell death,¹⁹ and red light (633 nm), which renders an increase of fibroblast growth factors to work against the inflammatory processes.²⁰ There are numerous studies showing a reduction of acne lesions after photopneumatic therapy with minimal side effects.^6-8

In our study, we compared the efficacy of salicylic acid 30% peel with PBBL in the treatment of acne. Both treatments showed significant reduction of mGAGS compared to baseline starting from week 3 and lasting until week 12. Remarkably, although there were some participants who reported acne recurrence after completing all treatments at week 6, which could have happened when the treatments were ended, the final acne score at week 12 was still significantly lower than baseline. It is clear that the participants continued their acne improvement up to the 6-week follow-up period without any topical or oral medication. We do not propose that either salicylic acid peel or PBBL treatment is a solitary option but speculate that the combination of both treatments may initiate a faster resolution in the disappearance of acne.

Although there was no statistically significant difference in efficacy between salicylic acid 30% peel and PBBL procedures at each visit, QOL assessments related to treatment satisfaction did yield significant differences between baseline and the end of treatment. We noticed that participants had more positive attitudes toward the PBBL side at week 3 and week 5 but only mild satisfaction at week 4, as the differences in QOL scores between both treatments showed positive ranging values. This finding is most likely related to the immediate reduction of acne pustules by the PBBL vacuum lysis of these lesions. The differences in the QOL scores between both treatments at week 12 (the last follow-up evaluation) provided opposite findings, which meant patients had nearly even improvement in both PBBL method and salicylic acid 30% peel. Therefore, according to QOL data, acne disappeared quickly with the application of PBBL therapy but reappeared on the PBBL-treated side by the follow-up evaluations, though the acne score between both sides showed no statistically significant difference.

We reason that the PBBL therapy works better than salicylic acid 30% peel because the pneumatic system may help to unclog the pores through mechanical debridement via suctioning versus desquamation from salicylic acid 30% peel. Nonetheless, salicylic acid 30% peel sustained improvement when compared to PBBL through the follow-up periods. Both salicylic acid 30% peel and PBBL treatments are well tolerated and may initiate a faster resolution in the improvement of acne when incorporated with a medical program.

Because of the recurrence of acne after treatments were stopped, additional medical therapies are advised to be used along with this study’s clinical treatments to help mitigate the acne symptoms. These treatments should be considered in patients concerned about antibiotic resistance or those who cannot take oral antibiotics or retinoids. Salicylic acid peel is more accessible and affordable than PBBL, whereas PBBL is slightly more tolerable and less irritating than salicylic acid peel. Nevertheless, the cost of investment in PBBL is quite high—as much as $70,000—and does not include disposable, single-use tips, which cost $30 each. The machine is easy to set up, weighs about 40 lb, and requires little space to store. The average cost per visit of PBBL treatment in office is $150.00 and $75.00 for salicylic acid peel (unpublished data, Hospital of the University of Pennsylvania, 2010). Most patients may select salicylic acid peel over PBBL due to the cost and convenience of the treatment. Neither procedure should be considered as a solitary treatment option but rather as adjunctive procedures combined with oral and/or topical acne medications. After this study’s treatments were stopped and without other medications to maintain treatment effectiveness, the lesions reappeared, trending back toward baseline.

Conclusion

Both salicylic acid 30% peel and PBBL procedures are effective, safe, and well tolerated in treating acne. Although there was no significant difference in the efficacy between both treatments in this study, the small sample size and short follow-up intervals warrant further studies to support the observed outstanding outcomes and should be considered in combination with other medical treatment options. These procedures may be beneficial in holding the patient compliant until their medical therapies have an opportunity to work.

Acknowledgment

The authors would like to thank Joyce Okawa, RN (Philadelphia, Pennsylvania), for her assistance in the submission to the institutional review board of the University of Pennsylvania.

Facial acne vulgaris is a common skin disease among teenagers and adolescents that may negatively affect self-esteem, perceived facial attractiveness, and social participation.¹ Treatments for acne often are multimodal and require the utmost adherence. For these reasons, acne treatments have been challenging to clinicians and patients alike, as patient compliance in maintaining the use of prescribed topical and oral medications remains essential to attain improvement in quality of life (QOL).

Salicylic acid is a popular medicament for acne treatment that frequently is used as monotherapy or as an adjuvant for other acne treatments, especially in patients with oily skin.² Salicylic acid has a keratolytic effect, causing corneocyte discohesion in clogged pores or congested follicles,² and it is effective in treating both inflammatory and noninflammatory acne.^3,4

Light therapy, particularly with visible light, has been demonstrated to improve acne outcomes.⁵ Pneumatic broadband light (PBBL) is a therapeutic light treatment in the broadband range (400–1200 nm) that is combined with vacuum suction, which creates a mechanical lysis of thin-walled pustules and dislodges pore impaction. Additionally, the blue light portion of the PBBL spectrum targets endogenous porphyrins in Propionibacterium acnes, resulting in bacterial destruction.^6-8

The purpose of this study was to compare the efficacy, tolerability, and safety of salicylic acid 30% peel versus PBBL in the treatment of mild to moderately severe facial acne vulgaris.

METHODS

Study Design

This single-blind, randomized, split-face pilot study was approved by the institutional review board of the University of Pennsylvania (Philadelphia, Pennsylvania). All patients provided informed consent before entering the study. The single-blind evaluation was performed by one dermatologist (C.T.) who examined the participants on every visit prior to PBBL treatment.

Before the study started, participants were randomized for which side of the face was to be treated with PBBL using a number assigned to each participant. Participants received both treatments—salicylic acid 30% peel on one side of the face and PBBL treatment on the other side of the face—once weekly for a total of 6 treatments. They were then asked to return for 2 follow-up evaluations at weeks 3 and 6 following the last treatment session and were instructed not to use any topical or oral acne medications during these follow-up periods.

Inclusion and Exclusion Criteria

Patients aged 18 years and older of any race and sex with noninflammatory papules, some inflammatory papules, and no more than 1 nodule (considered as mild to moderately severe facial acne) were included in the study. Participants had not been on any topical acne medications for at least 1 month and/or oral retinoids for at least 1 year prior to the study period. All women completed urine pregnancy tests prior to the study and were advised to utilize birth control during the study period.

Study Treatments

Salicylic Acid 30% Peel

The participant’s face was cleansed thoroughly before application of salicylic acid 30% (1.5 g/2.5 mL) to half of the face and left on for 5 minutes before being carefully rinsed off by spraying with spring water. Prior to initiating PBBL therapy, the peeled side of the participant’s face was covered with a towel.

Pneumatic Broadband Light

On the other side of the face, PBBL was performed to deliver broadband light within the spectrum range of 400 to 1200 nm at a setting approximately equivalent to a fluence of 4 to 6 J/cm² and a vacuum setting approximately equivalent to a negative pressure of 3 lb/in². The power setting was increased on each subsequent visit depending on each participant’s tolerability.

Participants were required to apply a moisturizer and sunscreen to the face and avoid excessive sun exposure between study visits.

Efficacy Evaluation

A comparison of the efficacy of the treatments was determined by clinical evaluation and examining the results of the outcome measurements with the modified Global Acne Grading Score (mGAGS) and Acne QOL Scale during each treatment visit. Facial photographs were taken at each visit.

Modified Global Acne Grading Score

The mGAGS is a modification of the Global Acne Grading Scale (GAGS) that has been used to evaluate acne severity in many studies.^9-11 The GAGS considers 6 locations on the face with a grading factor for each location. The local score is obtained by multiplying the factor rated by location with the factor of clinical assessment: local score = factor rated by location × factor rated by clinical assessment. The total score is the sum of the individual local scores (Table 1).

Although the original GAGS incorporated the type and location of the lesions in its calculation, we felt that the number of lesions also was important to add to our grading score. Therefore, we modified the GAGS by adding a factor rated by the number of lesions to improve the accuracy of the test. Accordingly, the local mGAGS scores were calculated by multiplying the location factor by the lesion type and number of lesions factors: local score = location factor × lesion type factor × number of lesions factor.

Acne QOL Questionnaire

Acne QOL was assessed during each visit to demonstrate if the treatment results affected participants’ socialization due to appearance.¹² Participants were asked to complete the questionnaire, which consisted of 9 questions with 4 rating answers (0=not affected; 1=mildly affected; 2=moderately affected; 3=markedly affected). A total score of 9 or higher (high score) indicated that acne had a substantial negative impact on the participant, while a total score below 9 (low score) meant acne scarcely impacted social aspects and daily activities of the patient.

Safety Evaluation

The safety of the treatments was evaluated by clinical inspection and by comparing the results of the Wong-Baker FACES Pain Rating Scale (WBPRS)¹³ after treatment. The WBPRS is used worldwide among researchers to assess pain, particularly in children.^14,15 It is composed of 6 faces expressing pain with word descriptions with a corresponding number range reflecting pain severity from 0 to 5 (0=no hurt; 1=hurts little bit; 2=hurts little more; 3=hurts even more; 4=hurts whole lot; 5=hurts worst).¹³

Statistical Analysis

All variables were presented as the median (range). A Wilcoxon signed rank test was used to compare clinical responses between the salicylic acid 30% peel and PBBL therapies. SPSS software version 12.0 was used for all statistical analysis. A 2-tailed P value of ≤.05 was considered statistically significant.

RESULTS

Study Population

Twelve participants (2 males, 10 females) aged 17 to 36 years (median age, 22 years; mean age [SD], 23.33 [1.65] years) with both comedonal and inflammatory acne were enrolled into this study for 6 split-face treatments of salicylic acid 30% peel and PBBL at 1-week intervals for 6 weeks, with 2 subsequent follow-up sessions at weeks 3 and 6 posttreatment. Of the 12 participants, 11 were white and 1 was Asian American, with Fitzpatrick skin types II to IV. Nine participants (75%) completed the study. One participant dropped out of the study after the fourth treatment due to a scheduling conflict, and the other 2 participants did not return for follow-up. No participants withdrew from the study because of adverse therapeutic events.

Efficacy Evaluation

Comparisons between the salicylic acid 30% peel and PBBL procedures for mGAGS at each visit are shown in Table 2. There was no significant difference in treatment efficacy between the salicylic acid 30% peel and PBBL therapies during the study’s treatment and follow-up events; however, both procedures contributed to a major improvement in acne symptoms by the third treatment session and through to the last follow-up session (P≤.05). Clinical photographs at baseline, at last treatment visit (week 6), and at last follow-up (week 12) are shown in Figures 1 and 2.

The results of the acne QOL questionnaire are shown in Table 2. Lower scores reflect a higher QOL. Median QOL scores at each visit ranged from 0.5 to 4.5. There was no significant difference found between the peel agent or PBBL based on the baseline QOL and subsequent visit assessments; however, the differences between the 2 treatments were significant at weeks 3 (P=.05) and 5 (P=.03) of treatment as well as at the last follow-up visit (P=.05).

According to the QOL scores, by the third treatment session participants were more satisfied with their improved acne condition from the PBBL procedure than the salicylic acid 30% peel as demonstrated by a positive range of the QOL assessments between PBBL and salicylic acid 30% peel (as shown in the difference in QOL in Table 2: week 3, 0–6; week 4, 0–3; week 5, 0–7). On the other hand, participants saw more improvement from the salicylic acid 30% peel than from PBBL by the last follow-up evaluation, as the differences in QOL scores between the 2 treatments resulted in a negative range (−5–0).

Safety

Pain assessment by the WBPRS at every visit showed a low pain rating associated with both salicylic acid 30% peel (range, 0–0.5) and PBBL (range, 1.0–1.5) treatments. The median pain score of the salicylic acid 30% peel appeared higher compared to the PBBL treatment, yet a significant difference between both treatments was seen only at weeks 1, 3, and 6 of treatment (P≤.05).

There were no unexpected therapeutic reactions reported in our study, and no participants withdrew from the study due to adverse events. Most participants experienced only mild adverse reactions, including redness, stinging, and a burning sensation on the salicylic acid 30% peel side, which were transient and disappeared in minutes; only redness occurred on the PBBL-treated side.

Comment

Facial acne treatment is challenging, as prolonged and/or severe acne contributes to scarring, declining self-confidence, and undesirable financial consequences. Even though salicylic acid peel is a commonly used acne treatment choice, the PBBL methodology was approved by the US Food and Drug Administration⁶ and has become an alternative procedure for acne treatment.

The pharmacological effects of salicylic acid are related to its corneocyte desquamation and exfoliative actions, thereby reducing corneocyte cohesion and unclogging follicular pores.¹⁶ Salicylic acid has been demonstrated to ameliorate inflammatory acne by its effects on the arachidonic acid cascade.^2,4,17 In our study, salicylic acid 30% peel met participants’ satisfaction in acne improvement similar to a study showing a 50% improvement in acne scores after just 2 treatments.¹⁸ Our data support and corroborate that salicylic acid 30% peel renders an improvement in acne sequelae reported in several other studies.^2,17,18

Pneumatic broadband light has been known to treat acne by the mechanism of pneumatic suction combined with photodynamic therapy using broadband-pulsed light (400–1200 nm).^6-8 By applying the pneumatic device, a vacuum is created on the skin to remove sebum contents from follicles, whereas broadband light is emitted simultaneously to destroy bacteria and decrease the inflammatory process.⁷ During the vacuum process, the skin is stretched to reduce pain and avoid competitive chromophores (eg, hemoglobin), while the broadband light is administered.⁷ Broadband light encompasses 2 main light spectrums: blue light (415 nm) activates coproporphyrin III, which induces reactive free radicals and singlet oxygen species and has been reported to be the cause of bacterial cell death,¹⁹ and red light (633 nm), which renders an increase of fibroblast growth factors to work against the inflammatory processes.²⁰ There are numerous studies showing a reduction of acne lesions after photopneumatic therapy with minimal side effects.^6-8

In our study, we compared the efficacy of salicylic acid 30% peel with PBBL in the treatment of acne. Both treatments showed significant reduction of mGAGS compared to baseline starting from week 3 and lasting until week 12. Remarkably, although there were some participants who reported acne recurrence after completing all treatments at week 6, which could have happened when the treatments were ended, the final acne score at week 12 was still significantly lower than baseline. It is clear that the participants continued their acne improvement up to the 6-week follow-up period without any topical or oral medication. We do not propose that either salicylic acid peel or PBBL treatment is a solitary option but speculate that the combination of both treatments may initiate a faster resolution in the disappearance of acne.

Although there was no statistically significant difference in efficacy between salicylic acid 30% peel and PBBL procedures at each visit, QOL assessments related to treatment satisfaction did yield significant differences between baseline and the end of treatment. We noticed that participants had more positive attitudes toward the PBBL side at week 3 and week 5 but only mild satisfaction at week 4, as the differences in QOL scores between both treatments showed positive ranging values. This finding is most likely related to the immediate reduction of acne pustules by the PBBL vacuum lysis of these lesions. The differences in the QOL scores between both treatments at week 12 (the last follow-up evaluation) provided opposite findings, which meant patients had nearly even improvement in both PBBL method and salicylic acid 30% peel. Therefore, according to QOL data, acne disappeared quickly with the application of PBBL therapy but reappeared on the PBBL-treated side by the follow-up evaluations, though the acne score between both sides showed no statistically significant difference.

We reason that the PBBL therapy works better than salicylic acid 30% peel because the pneumatic system may help to unclog the pores through mechanical debridement via suctioning versus desquamation from salicylic acid 30% peel. Nonetheless, salicylic acid 30% peel sustained improvement when compared to PBBL through the follow-up periods. Both salicylic acid 30% peel and PBBL treatments are well tolerated and may initiate a faster resolution in the improvement of acne when incorporated with a medical program.

Because of the recurrence of acne after treatments were stopped, additional medical therapies are advised to be used along with this study’s clinical treatments to help mitigate the acne symptoms. These treatments should be considered in patients concerned about antibiotic resistance or those who cannot take oral antibiotics or retinoids. Salicylic acid peel is more accessible and affordable than PBBL, whereas PBBL is slightly more tolerable and less irritating than salicylic acid peel. Nevertheless, the cost of investment in PBBL is quite high—as much as $70,000—and does not include disposable, single-use tips, which cost $30 each. The machine is easy to set up, weighs about 40 lb, and requires little space to store. The average cost per visit of PBBL treatment in office is $150.00 and $75.00 for salicylic acid peel (unpublished data, Hospital of the University of Pennsylvania, 2010). Most patients may select salicylic acid peel over PBBL due to the cost and convenience of the treatment. Neither procedure should be considered as a solitary treatment option but rather as adjunctive procedures combined with oral and/or topical acne medications. After this study’s treatments were stopped and without other medications to maintain treatment effectiveness, the lesions reappeared, trending back toward baseline.

Conclusion

Both salicylic acid 30% peel and PBBL procedures are effective, safe, and well tolerated in treating acne. Although there was no significant difference in the efficacy between both treatments in this study, the small sample size and short follow-up intervals warrant further studies to support the observed outstanding outcomes and should be considered in combination with other medical treatment options. These procedures may be beneficial in holding the patient compliant until their medical therapies have an opportunity to work.

Acknowledgment

The authors would like to thank Joyce Okawa, RN (Philadelphia, Pennsylvania), for her assistance in the submission to the institutional review board of the University of Pennsylvania.

Almost half of Crohn disease (CD) patients experience a dermatologic manifestation of the disease. A rare entity, metastatic CD (MCD) presents a diagnostic challenge without a high index of suspicion. Its etiology is not well defined; however, it appears to be an autoimmune response to gut antigens. Herein, we review the etiology/epidemiology, diagnostic criteria, and treatment for this uncommon condition.

Epidemiology and Clinical Characteristics of MCD

Metastatic CD was first described by Parks et al1 in 1965 and refers to a diverse collection of macroscopic dermatologic manifestations in tissue not contiguous with the gastrointestinal (GI) tract. To be classified as MCD, the tissue must demonstrate characteristic histopathologic findings, which invariably include noncaseating granulomas.

Crohn disease may affect any part of the GI tract from the mouth to anus, with a multitude of associated cutaneous manifestations having been described. The terminal ileum is the most commonly affected portion of the GI tract in CD, but the large intestine also may be involved in 55% to 80% of cases.² The incidence of non-MCD-associated anal lesions seems to correlate with intestinal involvement in that as few as 25% of patients with ileal-localized CD have anal lesions compared to nearly 80% of patients with large intestinal involvement.³

It has been estimated that 18% to 44% of patients with CD have some form of cutaneous manifestation,⁴ with MCD being a rare subcategory. As few as 100 cases have been described from 1965 to the present.⁵ The presence of MCD does not correlate well with severity of intestinal CD, and although a majority of MCD cases present after at least 6 months of GI symptoms,⁶ there are instances in which MCD presents without prior or existing evidence of intestinal CD.⁷

With regard to MCD, the term metastatic is sometimes supplanted in the literature by cutaneous to avoid any implication of cancer; however, due to a myriad of dermatologic manifestations, both terms can cause confusion. The categorization of the various types of cutaneous findings in CD is well summarized in a review by Palamaras et al8 with the following classifications: (1) granulomatous by direct extension (oral or perianal), (2) MCD lesions (genital and nongenital), (3) immune-related lesions, and (4) lesions from nutritional deficiencies. Of the cutaneous manifestations relating to CD, MCD is the least common cutaneous categorical manifestation and is further divided into subcategories of genital and nongenital lesions.⁸

The nongenital distribution of MCD is the more common variety in adults and particularly seems to affect the legs and plantar surfaces (38%), the trunk and abdomen (24%), and the face (15%).^5,9 These nongenital MCD manifestations are most commonly described as nodules, ulcerations, or erythematous to purple plaques, and less commonly described as abscesses, pustules, or papules.

The sequence of cutaneous symptoms of MCD relative to intestinal disease depends to some degree on patient age. In adults diagnosed with MCD, it has been noted that a GI flare is expected 2 months to 4 years after diagnosis; however, in children the subsequent GI flare has been noted to vary more widely from 9 months to 14 years following presentation of MCD.⁸ Furthermore, roughly 50% of children diagnosed with MCD present concomitantly with their first symptoms of a GI flare, whereas 70% of adults with MCD had been previously diagnosed with intestinal CD.⁸ In one review of 80 reported cases of MCD, 20% (16/80) had no symptoms of intestinal disease at the time of MCD diagnosis, and the majority of the asymptomatic cases were in children; interestingly, the majority of these same children were diagnosed with CD months to years later.⁹

Both the location and characteristics of cutaneous findings in MCD correlate with age.⁹ Metastatic CD has been identified in all age groups; however, lymphedema is more common in children/young adults, while nodules, ulceration, and fistulating disease are more often seen in adults.¹⁰ Affected children and adolescents with MCD range from 5 to 17 years of age, with a mean age at disease onset of 11.1 years and equal incidence in males and females.⁸ Adults with MCD range from 18 to 78 years of age, with a mean age at presentation of 38.4 years.^8,11

Concerning anatomic location of disease, adults with MCD most commonly have nodules with or without plaques on the arms and legs and less commonly in the genital area.⁸ In contrast, children with MCD are more prone to genital lesions, with up to 85% of cases including some degree of genital erythematous or nonerythematous swelling with or without induration.⁸ Genitourinary complications of CD as a broad category, however, are estimated to occur in only 5% to 20% of intestinal CD cases in both children and adults.¹²

There have been conflicting reports regarding gender predilection in MCD. Based on a review by Samitz et al¹³ of 200 cases of CD over an 18-year period, 22% of patients with CD were found to have cutaneous manifestations--presumably not MCD but rather perianal, perineal, vulvar fistulae, fissures, or abscesses--with a male to female preponderance of almost 2 to 1. A more recent review of the literature by Palamaras et al⁸ in 2008 reported that contiguous non-MCD affects adult females and children more often than adult males, with 63% adult cases being female. This review seems to be more congruent with other reports in the literature implicating that females are twice as commonly affected by MCD than males.^9,14

Pathophysiology

The etiology of MCD has not been well defined. One proposed mechanism of the distal tissue involvement of MCD is through passage of antigens to the skin with subsequent granulomatous response at the level of the dermis.¹⁰ Another proposed mechanism suggests antibody sensitization to gut antigens, possibly bacterial antigens, that then coincidentally cross-react with analogous skin antigens.^8,14 Burgdorf¹¹ supported this notion in a 1981 report in which it was suggested that the granulomatous reaction was related to deposition of immune complexes in the skin. Slater et al¹⁵ and Tatnall et al¹⁶ offered a variation of Burgdorf's notion, suggesting that it was sensitized T cells to circulating antigens that were the initiators of granuloma formation in the periphery.

An examination of MCD tissue in 1990 by Shum and Guenther¹⁷ under electron microscopy and immunofluorescence provided evidence against prior studies that purported to have identified immune complexes as the causative agents of MCD. In this study, the authors found no evidence of immune complexes in the dermis of MCD lesions. In addition, an attempt to react serum antibodies of a patient with MCD, which were postulated to have IgG, IgM, and IgA antibodies to specific gut antigens, yielded no response when reacted with the tongue, ileum, and colon tissue from a rat. As a culminant finding, the authors also noted MCD dermis tissue with granulomas without vasculitis, suggesting a T-cell mediated type IV hypersensitivity response with a secondary vasculitis from T-cell origin lymphokines and T-cell mediated monocyte activation.¹⁷

Research implicating other immunologic entities involved in the pathophysiology of CD such as β-2 integrin,¹⁸ CD14⁺ monocytes,¹⁹ and the role of the DNA repair gene MLH1 (mutL homolog 1)²⁰ have been considered but without a clearly definitive role in the manifestations of MCD.

The utility of metronidazole in the treatment of MCD has been suggested as evidence that certain bacteria in the gut may either serve as the causative antigen or may induce its formation²¹; however, the causative antigen has yet to be identified, and whether it travels distally to the skin or merely resembles a similar antigen normally present in the dermis has not yet been determined. Some research has used in situ polymerase chain reaction techniques to attempt to detect similar microbial pathogens in both the vasculature of active bowel lesions and in the skin, but to date, bacterial RNA noted to be present in the gut vasculature adjacent to CD lesions has not been detected in skin lesions.²²

Diagnosis

Physical Findings

Overall, it is estimated that roughly 56% of all MCD cases affect the external genitalia.²³ The classic appearance of MCD includes well-demarcated ulcerations in the areas of intertriginous skin folds with or without diffuse edema and tenderness to palpation.²³ Although MCD has been historically noted as having a predilection for moist skin folds, there are numerous case reports of MCD all over the body, including the face,^7,24-29 retroauricular areas,³⁰ arms and legs,^16,17,31-34 lower abdomen,^3,5 under the breasts,¹ perineum,³⁵ external genitalia,^1,9,36-40 and even the lungs⁴¹ and bladder.⁴²

As a dermatologic disease, MCD has been referred to as yet another great imitator, both on the macroscopic and microscopic levels.⁸ As such, more common causes of genital edema should be considered first and investigated based on the patient's history, physical examination, skin biopsy, lymphangiogram, ultrasound, and cystogram.⁴³ Ultrasonography and color Doppler sonography have been shown to be helpful in patients with genital involvement. This modality can evaluate not only the presence of normal testes but also intratesticular and scrotal wall fluid, especially when the physical examination reveals swelling that makes testicle palpation more difficult.⁶ Clinically, the correct diagnosis of MCD often is made through suspicion of inflammatory bowel disease based on classic symptoms and/or physical findings including abdominal pain, weight loss, bloody stool, diarrhea, perianal skin tags, and anal fissures or fistulas. Any of these GI findings should prompt an intestinal biopsy to rule out any histologic evidence of CD.

Metastatic CD affecting the vulva often presents with vulvar pain and pruritus and may clinically mimic a more benign disease such as balanitis plasmacellularis, also referred to as Zoon vulvitis.²³ Similar to MCD on any given body surface, there is dramatic variation in the macroscopic presentation of vulvar MCD, with physical examination findings ranging from bilateral diffuse, edematous, deeply macerated, red, ulcerated lesions over the vulva with lymphadenopathy to findings of bilateral vulvar pain with yellow drainage from the labia majora.²³ There have been cases of vulvar MCD that include exquisite vulvar pain but without structural abnormalities including normal uterus, cervix, adnexa, rectovaginal septum, and rectum. In these more nebulous cases of vulvar MCD, the diagnosis often is discovered incidentally when nonspecific diagnostic imaging suggests underlying CD.²³

Beyond the case-by-case variations on physical examination, the great difficulty in diagnosis, particularly in children, occurs in the absence of any GI symptoms and therefore no logical consideration of underlying CD. Consequently, there have been cases of children presenting with irritation of the vulva who were eventually diagnosed with MCD only after erroneous treatment of contact dermatitis, candidiasis, and even consideration of sexual abuse.³⁷ Because it is so rare and obscure among practicing clinicians, the diagnosis of MCD often is considered only after irritation or swelling of the external genitalia has not responded to standard therapies. If and when the diagnosis of MCD is considered in children, it has been suggested to screen patients for anorectal stricture, as case studies have found the condition to be relatively common in this subpopulation.⁴⁴

In the less common case of adults with genitourinary symptoms that suggest possible MCD, the differential diagnosis for penile or vaginal ulcers should include contact and irritant dermatitis, chronic infectious lesions (eg, hidradenitis suppurativa, actinomycosis, tuberculosis),⁴⁵ sexually transmitted ulcerative diseases (eg, chancroid, lymphogranuloma venereum, herpes genitalia, granuloma inguinale),⁴⁶ drug reactions, and even extramammary Paget disease.⁴⁷

Histologic Findings

Because MCD has so much macroscopic variation and can present anywhere on the surface of the body, formal diagnosis relies on microscopy. As an added measure of difficulty in diagnosis, one random biopsy of a suspicious segment of tissue may not contain the expected histologic findings; therefore, clinical suspicion may warrant a second biopsy.¹⁰ There have been reported cases of an adult patient without history of CD presenting with a lesion that resembled a more common pathology, such as a genital wart, and the correct diagnosis of MCD with pseudocondylomatous morphology was made only after intestinal manifestations prompted the clinician to consider such an unusual diagnosis.⁴⁸

From a histopathologic perspective, MCD is characterized by discrete, noncaseating, sarcoidlike granulomas with abundant multinucleated giant cells (Langhans giant cells) in the superficial dermis (papillary), deep dermis (reticular), and adipose tissue (Figure).^8,17 In the presence of concomitant intestinal disease, the granulomas of both the intestinal and dermal tissues should share the same microscopic characteristics.⁸ In addition, copious neutrophils and granulomas surrounding the microvasculature have been described,³⁴ as well as general lymphocyte and plasma cell infiltrate.⁴⁵ Some histologic samples have included collagen degeneration termed necrobiosis in the middle dermal layer as another variable finding in MCD.^14,34

On microscopy, it has been reported that use of Verhoeff-van Gieson staining may be helpful to highlight the presence of neutrophil obstruction within the dermal vasculature, particularly the arterial lumen, as well as to aid in highlighting swelling of the endothelium with fragmentation of the internal elastic lamina.¹⁷ Although not part of the routine diagnosis, electron microscopy of MCD tissue samples have confirmed hypertrophy of the endothelial cells composing the capillaries with resulting extravasation of fibrin, red blood cells, lymphocytes, and epithelioid histiocytes.¹⁷ Observation of tissue under direct immunofluorescence has been less helpful, as it has shown only nonspecific fibrinogen deposition within the dermis and dermal vessels.¹⁷

In an article on treatment of MCD, Escher et al⁴³ reinforced that the macroscopic findings of MCD are diverse, and the microscopic findings characteristic of MCD also can be mimicked by other etiologies such as sarcoidosis, tuberculosis, fungal infections, lymphogranuloma venereum, leishmaniasis, and connective tissue disorders.⁴³ As such, the workup to rule out infectious, anatomic, and autoimmune etiologies should be diverse. Often, the workup for MCD will include special stains such as Ziehl-Neelsen stain to rule out Mycobacterium tuberculosis and acid-fast bacilli and Fite stain to consider atypical mycobacteria. Other tests such as tissue culture, chest radiograph, tuberculin skin test (Mantoux test), IFN-γ release assay, or polarized light microscopy may rule out infectious etiologies.^9,49 Serologic testing might include VDRL test, Treponema pallidum hemagglutination assay, hepatitis B, hepatitis C, and human immunodeficiency virus.⁵

Crohn disease is characterized histologically by sarcoidlike noncaseating granulomas, and as such, it is important to differentiate MCD from sarcoidosis prior to histologic analysis. Sarcoidosis also can be considered much less likely with a normal chest radiograph and in the absence of increased serum calcium and angiotensin-converting enzyme levels.⁷ The differentiation of sarcoidosis from MCD on the microscopic scale is subtle but is sometimes facilitated in the presence of an ulcerated epidermis or lymphocytic/eosinophilic infiltrate and edema within the dermis, all suggestive of MCD.¹⁴

Metastatic CD also should be differentiated from erythema nodosum and pyoderma gangrenosum, which are among the most common cutaneous findings associated with CD.¹⁴ Pyoderma gangrenosum can be distinguished histologically by identifying copious neutrophilic infiltrate with pseudoepitheliomatous hyperplasia.⁵⁰

Treatment

Because MCD is relatively rare, there are no known randomized trials suggesting a particular medical or surgical treatment. In a review of perineal MCD from 2007, the 40-year-old recommendation by Moutain³ opting for surgical debridement versus medical management still resonates, particularly for perineal disease, as an effective measure in all but the mildest of presentations.⁵¹ However, recent case reports also suggest that the tumor necrosis factor α (TNF-α) inhibitors such as infliximab and adalimumab should be considered prior to surgery even with severe perineal MCD.⁵¹ Moreover, even if medical management with TNF-α inhibitors or some combination of immunosuppressants and antibiotics does not eradicate the disease, it often helps reduce the size of the ulcers prior to surgery.⁵² With a limited understanding of MCD, one might think that removal of the affected bowel would eliminate cutaneous disease, but it has been shown that this strategy is not effective.^53,54

The composition and location of the particular lesion affects the trajectory of treatment. For example, MCD manifesting as local ulcers and plaques has been described as responding well to topical and intralesional steroids.^10,55,56 In the case of penile swelling and/or phimosis, circumcision has been helpful to improve the patient's ability to void as well as to attain and maintain erection.¹⁰ In the case of scrotal swelling secondary to MCD, early treatment (ie, within 4 to 6 months) with oral steroids and/or metronidazole is likely beneficial to prevent refractory edematous organization of the tissue.⁵⁷

As a general rule, an effective treatment will include a combination of an immunosuppressant, antibiotic therapy, and sometimes surgery. The most commonly used immunosuppressant agents include topical or intralesional steroids, infliximab,^43,58 cyclosporine A,^59,60 dapsone, minocycline, thalidomide, methotrexate, mycophenolate mofetil, sulfasalazine, azathioprine, tacrolimus, and 6-mercaptopurine.⁴ Steroids have been the conventional treatment of extraintestinal manifestations of CD⁶¹; however, perineal CD has been poorly controlled with systemic steroids.⁶² If steroids are found not to be effective, sometimes agents such as dapsone or thalidomide are considered. One case report noted stabilization of MCD penile ulcers with oral thalidomide 300 mg once daily, oral minocycline 100 mg once daily, and topical tacrolimus 0.3% with benzocaine twice daily with continuation of prednisolone and methotrexate as parts of previously unsuccessful regimen.⁵²

Metronidazole is perhaps the most commonly used antibiotic, having been a component of many successful regimens.^4,63 For example, a 27-year-old patient with MCD presenting as a nonhealing ulcerative lesion in the subcoronal area of the penis and scrotum was treated successfully with a 6-month course of mesalamine, prednisone, and metronidazole.⁴⁵ Another case report of vulvar MCD reported initial success with intravenous methylprednisolone, ciprofloxacin, and metronidazole.²³ The primary limitation of metronidazole is that subsequent tapering of the dose seems to result in recurrence of disease.⁶⁴ Consequently, patients must remain on the antibiotic for an indeterminate course, with dosages ranging from 5 mg/kg daily in adolescents⁶⁵ to 1000 to 1500 mg daily in adults.⁶⁶

Of the various immunosuppressants available, infliximab has been listed in numerous reports as a successful agent in both the induction and maintenance of extraintestinal manifestations of CD including MCD.^67-71 Infliximab has been reported to be effective in the treatment of penile and scrotal edema secondary to MCD that did not respond to other immunosuppressants including oral prednisolone, azathioprine, and cyclosporine.⁴³ Infliximab may be a good option to help heal draining fistulas, particularly in combination with an antibiotic such as metronidazole and ciprofloxacin, which helps to prevent abscess formation during healing.⁷² The response to infliximab has been dramatic, with resolution of cutaneous lesions after just 6 weeks in some cases.⁷³ The dosing regimen of infliximab has been suggested at 5 mg/kg administered at 0, 2, and 6 weeks, with subsequent maintenance infusions every 10 weeks,⁷⁰ or at 0, 4, and 12 weeks, with subsequent infusions every 8 weeks.⁴³

Adalimumab may be considered as an alternative to infliximab and is potentially less allergenic as a fully humanized monoclonal antibody to TNF-α, which also has been used successfully to both induce and maintain remission of moderate to severe CD.^42,74,75 Proposed dosing of adalimumab includes a loading dose of 160 mg subcutaneously on day 1, followed by an 80-mg dose 2 weeks later and a 40-mg maintenance dose every other week indefinitely.⁴⁸ Of note, adalimumab has been noted in the literature to have many potential side effects, including one particular case in which severe headaches were attributed to its use.⁵⁹ As a consequence of the headaches, the patient was switched from adalimumab to cyclosporine and responded well with no subsequent flare-ups on follow-up.

In summary, treatment of MCD depends on cutaneous location, severity, physician experience with certain antibiotics or immunosuppressants, availability of medication, and patient disposition. It seems reasonable to attempt medical management with one or more medical regimens before committing to surgical intervention. Furthermore, even with debridement, curettage, skin graft, or other surgical strategy, the patient is likely to require some period of immunosuppression to provide long-lasting remission.

Conclusion

Patients with inflammatory bowel disease often develop dermatologic sequelae, with MCD being a rare but serious process. Patients may present with a wide array of physical concerns and symptoms, many resembling other disease processes. As such, education and a high index of suspicion are needed for proper diagnosis and treatment.

Almost half of Crohn disease (CD) patients experience a dermatologic manifestation of the disease. A rare entity, metastatic CD (MCD) presents a diagnostic challenge without a high index of suspicion. Its etiology is not well defined; however, it appears to be an autoimmune response to gut antigens. Herein, we review the etiology/epidemiology, diagnostic criteria, and treatment for this uncommon condition.

Epidemiology and Clinical Characteristics of MCD

Metastatic CD was first described by Parks et al1 in 1965 and refers to a diverse collection of macroscopic dermatologic manifestations in tissue not contiguous with the gastrointestinal (GI) tract. To be classified as MCD, the tissue must demonstrate characteristic histopathologic findings, which invariably include noncaseating granulomas.

Crohn disease may affect any part of the GI tract from the mouth to anus, with a multitude of associated cutaneous manifestations having been described. The terminal ileum is the most commonly affected portion of the GI tract in CD, but the large intestine also may be involved in 55% to 80% of cases.² The incidence of non-MCD-associated anal lesions seems to correlate with intestinal involvement in that as few as 25% of patients with ileal-localized CD have anal lesions compared to nearly 80% of patients with large intestinal involvement.³

It has been estimated that 18% to 44% of patients with CD have some form of cutaneous manifestation,⁴ with MCD being a rare subcategory. As few as 100 cases have been described from 1965 to the present.⁵ The presence of MCD does not correlate well with severity of intestinal CD, and although a majority of MCD cases present after at least 6 months of GI symptoms,⁶ there are instances in which MCD presents without prior or existing evidence of intestinal CD.⁷

With regard to MCD, the term metastatic is sometimes supplanted in the literature by cutaneous to avoid any implication of cancer; however, due to a myriad of dermatologic manifestations, both terms can cause confusion. The categorization of the various types of cutaneous findings in CD is well summarized in a review by Palamaras et al8 with the following classifications: (1) granulomatous by direct extension (oral or perianal), (2) MCD lesions (genital and nongenital), (3) immune-related lesions, and (4) lesions from nutritional deficiencies. Of the cutaneous manifestations relating to CD, MCD is the least common cutaneous categorical manifestation and is further divided into subcategories of genital and nongenital lesions.⁸

The nongenital distribution of MCD is the more common variety in adults and particularly seems to affect the legs and plantar surfaces (38%), the trunk and abdomen (24%), and the face (15%).^5,9 These nongenital MCD manifestations are most commonly described as nodules, ulcerations, or erythematous to purple plaques, and less commonly described as abscesses, pustules, or papules.

The sequence of cutaneous symptoms of MCD relative to intestinal disease depends to some degree on patient age. In adults diagnosed with MCD, it has been noted that a GI flare is expected 2 months to 4 years after diagnosis; however, in children the subsequent GI flare has been noted to vary more widely from 9 months to 14 years following presentation of MCD.⁸ Furthermore, roughly 50% of children diagnosed with MCD present concomitantly with their first symptoms of a GI flare, whereas 70% of adults with MCD had been previously diagnosed with intestinal CD.⁸ In one review of 80 reported cases of MCD, 20% (16/80) had no symptoms of intestinal disease at the time of MCD diagnosis, and the majority of the asymptomatic cases were in children; interestingly, the majority of these same children were diagnosed with CD months to years later.⁹

Both the location and characteristics of cutaneous findings in MCD correlate with age.⁹ Metastatic CD has been identified in all age groups; however, lymphedema is more common in children/young adults, while nodules, ulceration, and fistulating disease are more often seen in adults.¹⁰ Affected children and adolescents with MCD range from 5 to 17 years of age, with a mean age at disease onset of 11.1 years and equal incidence in males and females.⁸ Adults with MCD range from 18 to 78 years of age, with a mean age at presentation of 38.4 years.^8,11

Concerning anatomic location of disease, adults with MCD most commonly have nodules with or without plaques on the arms and legs and less commonly in the genital area.⁸ In contrast, children with MCD are more prone to genital lesions, with up to 85% of cases including some degree of genital erythematous or nonerythematous swelling with or without induration.⁸ Genitourinary complications of CD as a broad category, however, are estimated to occur in only 5% to 20% of intestinal CD cases in both children and adults.¹²

There have been conflicting reports regarding gender predilection in MCD. Based on a review by Samitz et al¹³ of 200 cases of CD over an 18-year period, 22% of patients with CD were found to have cutaneous manifestations--presumably not MCD but rather perianal, perineal, vulvar fistulae, fissures, or abscesses--with a male to female preponderance of almost 2 to 1. A more recent review of the literature by Palamaras et al⁸ in 2008 reported that contiguous non-MCD affects adult females and children more often than adult males, with 63% adult cases being female. This review seems to be more congruent with other reports in the literature implicating that females are twice as commonly affected by MCD than males.^9,14

Pathophysiology

The etiology of MCD has not been well defined. One proposed mechanism of the distal tissue involvement of MCD is through passage of antigens to the skin with subsequent granulomatous response at the level of the dermis.¹⁰ Another proposed mechanism suggests antibody sensitization to gut antigens, possibly bacterial antigens, that then coincidentally cross-react with analogous skin antigens.^8,14 Burgdorf¹¹ supported this notion in a 1981 report in which it was suggested that the granulomatous reaction was related to deposition of immune complexes in the skin. Slater et al¹⁵ and Tatnall et al¹⁶ offered a variation of Burgdorf's notion, suggesting that it was sensitized T cells to circulating antigens that were the initiators of granuloma formation in the periphery.

An examination of MCD tissue in 1990 by Shum and Guenther¹⁷ under electron microscopy and immunofluorescence provided evidence against prior studies that purported to have identified immune complexes as the causative agents of MCD. In this study, the authors found no evidence of immune complexes in the dermis of MCD lesions. In addition, an attempt to react serum antibodies of a patient with MCD, which were postulated to have IgG, IgM, and IgA antibodies to specific gut antigens, yielded no response when reacted with the tongue, ileum, and colon tissue from a rat. As a culminant finding, the authors also noted MCD dermis tissue with granulomas without vasculitis, suggesting a T-cell mediated type IV hypersensitivity response with a secondary vasculitis from T-cell origin lymphokines and T-cell mediated monocyte activation.¹⁷

Research implicating other immunologic entities involved in the pathophysiology of CD such as β-2 integrin,¹⁸ CD14⁺ monocytes,¹⁹ and the role of the DNA repair gene MLH1 (mutL homolog 1)²⁰ have been considered but without a clearly definitive role in the manifestations of MCD.

The utility of metronidazole in the treatment of MCD has been suggested as evidence that certain bacteria in the gut may either serve as the causative antigen or may induce its formation²¹; however, the causative antigen has yet to be identified, and whether it travels distally to the skin or merely resembles a similar antigen normally present in the dermis has not yet been determined. Some research has used in situ polymerase chain reaction techniques to attempt to detect similar microbial pathogens in both the vasculature of active bowel lesions and in the skin, but to date, bacterial RNA noted to be present in the gut vasculature adjacent to CD lesions has not been detected in skin lesions.²²

Diagnosis

Physical Findings

Overall, it is estimated that roughly 56% of all MCD cases affect the external genitalia.²³ The classic appearance of MCD includes well-demarcated ulcerations in the areas of intertriginous skin folds with or without diffuse edema and tenderness to palpation.²³ Although MCD has been historically noted as having a predilection for moist skin folds, there are numerous case reports of MCD all over the body, including the face,^7,24-29 retroauricular areas,³⁰ arms and legs,^16,17,31-34 lower abdomen,^3,5 under the breasts,¹ perineum,³⁵ external genitalia,^1,9,36-40 and even the lungs⁴¹ and bladder.⁴²

As a dermatologic disease, MCD has been referred to as yet another great imitator, both on the macroscopic and microscopic levels.⁸ As such, more common causes of genital edema should be considered first and investigated based on the patient's history, physical examination, skin biopsy, lymphangiogram, ultrasound, and cystogram.⁴³ Ultrasonography and color Doppler sonography have been shown to be helpful in patients with genital involvement. This modality can evaluate not only the presence of normal testes but also intratesticular and scrotal wall fluid, especially when the physical examination reveals swelling that makes testicle palpation more difficult.⁶ Clinically, the correct diagnosis of MCD often is made through suspicion of inflammatory bowel disease based on classic symptoms and/or physical findings including abdominal pain, weight loss, bloody stool, diarrhea, perianal skin tags, and anal fissures or fistulas. Any of these GI findings should prompt an intestinal biopsy to rule out any histologic evidence of CD.

Metastatic CD affecting the vulva often presents with vulvar pain and pruritus and may clinically mimic a more benign disease such as balanitis plasmacellularis, also referred to as Zoon vulvitis.²³ Similar to MCD on any given body surface, there is dramatic variation in the macroscopic presentation of vulvar MCD, with physical examination findings ranging from bilateral diffuse, edematous, deeply macerated, red, ulcerated lesions over the vulva with lymphadenopathy to findings of bilateral vulvar pain with yellow drainage from the labia majora.²³ There have been cases of vulvar MCD that include exquisite vulvar pain but without structural abnormalities including normal uterus, cervix, adnexa, rectovaginal septum, and rectum. In these more nebulous cases of vulvar MCD, the diagnosis often is discovered incidentally when nonspecific diagnostic imaging suggests underlying CD.²³

Beyond the case-by-case variations on physical examination, the great difficulty in diagnosis, particularly in children, occurs in the absence of any GI symptoms and therefore no logical consideration of underlying CD. Consequently, there have been cases of children presenting with irritation of the vulva who were eventually diagnosed with MCD only after erroneous treatment of contact dermatitis, candidiasis, and even consideration of sexual abuse.³⁷ Because it is so rare and obscure among practicing clinicians, the diagnosis of MCD often is considered only after irritation or swelling of the external genitalia has not responded to standard therapies. If and when the diagnosis of MCD is considered in children, it has been suggested to screen patients for anorectal stricture, as case studies have found the condition to be relatively common in this subpopulation.⁴⁴

In the less common case of adults with genitourinary symptoms that suggest possible MCD, the differential diagnosis for penile or vaginal ulcers should include contact and irritant dermatitis, chronic infectious lesions (eg, hidradenitis suppurativa, actinomycosis, tuberculosis),⁴⁵ sexually transmitted ulcerative diseases (eg, chancroid, lymphogranuloma venereum, herpes genitalia, granuloma inguinale),⁴⁶ drug reactions, and even extramammary Paget disease.⁴⁷

Histologic Findings

Because MCD has so much macroscopic variation and can present anywhere on the surface of the body, formal diagnosis relies on microscopy. As an added measure of difficulty in diagnosis, one random biopsy of a suspicious segment of tissue may not contain the expected histologic findings; therefore, clinical suspicion may warrant a second biopsy.¹⁰ There have been reported cases of an adult patient without history of CD presenting with a lesion that resembled a more common pathology, such as a genital wart, and the correct diagnosis of MCD with pseudocondylomatous morphology was made only after intestinal manifestations prompted the clinician to consider such an unusual diagnosis.⁴⁸

From a histopathologic perspective, MCD is characterized by discrete, noncaseating, sarcoidlike granulomas with abundant multinucleated giant cells (Langhans giant cells) in the superficial dermis (papillary), deep dermis (reticular), and adipose tissue (Figure).^8,17 In the presence of concomitant intestinal disease, the granulomas of both the intestinal and dermal tissues should share the same microscopic characteristics.⁸ In addition, copious neutrophils and granulomas surrounding the microvasculature have been described,³⁴ as well as general lymphocyte and plasma cell infiltrate.⁴⁵ Some histologic samples have included collagen degeneration termed necrobiosis in the middle dermal layer as another variable finding in MCD.^14,34

On microscopy, it has been reported that use of Verhoeff-van Gieson staining may be helpful to highlight the presence of neutrophil obstruction within the dermal vasculature, particularly the arterial lumen, as well as to aid in highlighting swelling of the endothelium with fragmentation of the internal elastic lamina.¹⁷ Although not part of the routine diagnosis, electron microscopy of MCD tissue samples have confirmed hypertrophy of the endothelial cells composing the capillaries with resulting extravasation of fibrin, red blood cells, lymphocytes, and epithelioid histiocytes.¹⁷ Observation of tissue under direct immunofluorescence has been less helpful, as it has shown only nonspecific fibrinogen deposition within the dermis and dermal vessels.¹⁷

In an article on treatment of MCD, Escher et al⁴³ reinforced that the macroscopic findings of MCD are diverse, and the microscopic findings characteristic of MCD also can be mimicked by other etiologies such as sarcoidosis, tuberculosis, fungal infections, lymphogranuloma venereum, leishmaniasis, and connective tissue disorders.⁴³ As such, the workup to rule out infectious, anatomic, and autoimmune etiologies should be diverse. Often, the workup for MCD will include special stains such as Ziehl-Neelsen stain to rule out Mycobacterium tuberculosis and acid-fast bacilli and Fite stain to consider atypical mycobacteria. Other tests such as tissue culture, chest radiograph, tuberculin skin test (Mantoux test), IFN-γ release assay, or polarized light microscopy may rule out infectious etiologies.^9,49 Serologic testing might include VDRL test, Treponema pallidum hemagglutination assay, hepatitis B, hepatitis C, and human immunodeficiency virus.⁵

Crohn disease is characterized histologically by sarcoidlike noncaseating granulomas, and as such, it is important to differentiate MCD from sarcoidosis prior to histologic analysis. Sarcoidosis also can be considered much less likely with a normal chest radiograph and in the absence of increased serum calcium and angiotensin-converting enzyme levels.⁷ The differentiation of sarcoidosis from MCD on the microscopic scale is subtle but is sometimes facilitated in the presence of an ulcerated epidermis or lymphocytic/eosinophilic infiltrate and edema within the dermis, all suggestive of MCD.¹⁴

Metastatic CD also should be differentiated from erythema nodosum and pyoderma gangrenosum, which are among the most common cutaneous findings associated with CD.¹⁴ Pyoderma gangrenosum can be distinguished histologically by identifying copious neutrophilic infiltrate with pseudoepitheliomatous hyperplasia.⁵⁰

Treatment

Because MCD is relatively rare, there are no known randomized trials suggesting a particular medical or surgical treatment. In a review of perineal MCD from 2007, the 40-year-old recommendation by Moutain³ opting for surgical debridement versus medical management still resonates, particularly for perineal disease, as an effective measure in all but the mildest of presentations.⁵¹ However, recent case reports also suggest that the tumor necrosis factor α (TNF-α) inhibitors such as infliximab and adalimumab should be considered prior to surgery even with severe perineal MCD.⁵¹ Moreover, even if medical management with TNF-α inhibitors or some combination of immunosuppressants and antibiotics does not eradicate the disease, it often helps reduce the size of the ulcers prior to surgery.⁵² With a limited understanding of MCD, one might think that removal of the affected bowel would eliminate cutaneous disease, but it has been shown that this strategy is not effective.^53,54

The composition and location of the particular lesion affects the trajectory of treatment. For example, MCD manifesting as local ulcers and plaques has been described as responding well to topical and intralesional steroids.^10,55,56 In the case of penile swelling and/or phimosis, circumcision has been helpful to improve the patient's ability to void as well as to attain and maintain erection.¹⁰ In the case of scrotal swelling secondary to MCD, early treatment (ie, within 4 to 6 months) with oral steroids and/or metronidazole is likely beneficial to prevent refractory edematous organization of the tissue.⁵⁷

As a general rule, an effective treatment will include a combination of an immunosuppressant, antibiotic therapy, and sometimes surgery. The most commonly used immunosuppressant agents include topical or intralesional steroids, infliximab,^43,58 cyclosporine A,^59,60 dapsone, minocycline, thalidomide, methotrexate, mycophenolate mofetil, sulfasalazine, azathioprine, tacrolimus, and 6-mercaptopurine.⁴ Steroids have been the conventional treatment of extraintestinal manifestations of CD⁶¹; however, perineal CD has been poorly controlled with systemic steroids.⁶² If steroids are found not to be effective, sometimes agents such as dapsone or thalidomide are considered. One case report noted stabilization of MCD penile ulcers with oral thalidomide 300 mg once daily, oral minocycline 100 mg once daily, and topical tacrolimus 0.3% with benzocaine twice daily with continuation of prednisolone and methotrexate as parts of previously unsuccessful regimen.⁵²

Metronidazole is perhaps the most commonly used antibiotic, having been a component of many successful regimens.^4,63 For example, a 27-year-old patient with MCD presenting as a nonhealing ulcerative lesion in the subcoronal area of the penis and scrotum was treated successfully with a 6-month course of mesalamine, prednisone, and metronidazole.⁴⁵ Another case report of vulvar MCD reported initial success with intravenous methylprednisolone, ciprofloxacin, and metronidazole.²³ The primary limitation of metronidazole is that subsequent tapering of the dose seems to result in recurrence of disease.⁶⁴ Consequently, patients must remain on the antibiotic for an indeterminate course, with dosages ranging from 5 mg/kg daily in adolescents⁶⁵ to 1000 to 1500 mg daily in adults.⁶⁶

Of the various immunosuppressants available, infliximab has been listed in numerous reports as a successful agent in both the induction and maintenance of extraintestinal manifestations of CD including MCD.^67-71 Infliximab has been reported to be effective in the treatment of penile and scrotal edema secondary to MCD that did not respond to other immunosuppressants including oral prednisolone, azathioprine, and cyclosporine.⁴³ Infliximab may be a good option to help heal draining fistulas, particularly in combination with an antibiotic such as metronidazole and ciprofloxacin, which helps to prevent abscess formation during healing.⁷² The response to infliximab has been dramatic, with resolution of cutaneous lesions after just 6 weeks in some cases.⁷³ The dosing regimen of infliximab has been suggested at 5 mg/kg administered at 0, 2, and 6 weeks, with subsequent maintenance infusions every 10 weeks,⁷⁰ or at 0, 4, and 12 weeks, with subsequent infusions every 8 weeks.⁴³

Adalimumab may be considered as an alternative to infliximab and is potentially less allergenic as a fully humanized monoclonal antibody to TNF-α, which also has been used successfully to both induce and maintain remission of moderate to severe CD.^42,74,75 Proposed dosing of adalimumab includes a loading dose of 160 mg subcutaneously on day 1, followed by an 80-mg dose 2 weeks later and a 40-mg maintenance dose every other week indefinitely.⁴⁸ Of note, adalimumab has been noted in the literature to have many potential side effects, including one particular case in which severe headaches were attributed to its use.⁵⁹ As a consequence of the headaches, the patient was switched from adalimumab to cyclosporine and responded well with no subsequent flare-ups on follow-up.

In summary, treatment of MCD depends on cutaneous location, severity, physician experience with certain antibiotics or immunosuppressants, availability of medication, and patient disposition. It seems reasonable to attempt medical management with one or more medical regimens before committing to surgical intervention. Furthermore, even with debridement, curettage, skin graft, or other surgical strategy, the patient is likely to require some period of immunosuppression to provide long-lasting remission.

Conclusion

Patients with inflammatory bowel disease often develop dermatologic sequelae, with MCD being a rare but serious process. Patients may present with a wide array of physical concerns and symptoms, many resembling other disease processes. As such, education and a high index of suspicion are needed for proper diagnosis and treatment.

Almost half of Crohn disease (CD) patients experience a dermatologic manifestation of the disease. A rare entity, metastatic CD (MCD) presents a diagnostic challenge without a high index of suspicion. Its etiology is not well defined; however, it appears to be an autoimmune response to gut antigens. Herein, we review the etiology/epidemiology, diagnostic criteria, and treatment for this uncommon condition.

Epidemiology and Clinical Characteristics of MCD

Metastatic CD was first described by Parks et al1 in 1965 and refers to a diverse collection of macroscopic dermatologic manifestations in tissue not contiguous with the gastrointestinal (GI) tract. To be classified as MCD, the tissue must demonstrate characteristic histopathologic findings, which invariably include noncaseating granulomas.

Crohn disease may affect any part of the GI tract from the mouth to anus, with a multitude of associated cutaneous manifestations having been described. The terminal ileum is the most commonly affected portion of the GI tract in CD, but the large intestine also may be involved in 55% to 80% of cases.² The incidence of non-MCD-associated anal lesions seems to correlate with intestinal involvement in that as few as 25% of patients with ileal-localized CD have anal lesions compared to nearly 80% of patients with large intestinal involvement.³

It has been estimated that 18% to 44% of patients with CD have some form of cutaneous manifestation,⁴ with MCD being a rare subcategory. As few as 100 cases have been described from 1965 to the present.⁵ The presence of MCD does not correlate well with severity of intestinal CD, and although a majority of MCD cases present after at least 6 months of GI symptoms,⁶ there are instances in which MCD presents without prior or existing evidence of intestinal CD.⁷

With regard to MCD, the term metastatic is sometimes supplanted in the literature by cutaneous to avoid any implication of cancer; however, due to a myriad of dermatologic manifestations, both terms can cause confusion. The categorization of the various types of cutaneous findings in CD is well summarized in a review by Palamaras et al8 with the following classifications: (1) granulomatous by direct extension (oral or perianal), (2) MCD lesions (genital and nongenital), (3) immune-related lesions, and (4) lesions from nutritional deficiencies. Of the cutaneous manifestations relating to CD, MCD is the least common cutaneous categorical manifestation and is further divided into subcategories of genital and nongenital lesions.⁸

The nongenital distribution of MCD is the more common variety in adults and particularly seems to affect the legs and plantar surfaces (38%), the trunk and abdomen (24%), and the face (15%).^5,9 These nongenital MCD manifestations are most commonly described as nodules, ulcerations, or erythematous to purple plaques, and less commonly described as abscesses, pustules, or papules.

The sequence of cutaneous symptoms of MCD relative to intestinal disease depends to some degree on patient age. In adults diagnosed with MCD, it has been noted that a GI flare is expected 2 months to 4 years after diagnosis; however, in children the subsequent GI flare has been noted to vary more widely from 9 months to 14 years following presentation of MCD.⁸ Furthermore, roughly 50% of children diagnosed with MCD present concomitantly with their first symptoms of a GI flare, whereas 70% of adults with MCD had been previously diagnosed with intestinal CD.⁸ In one review of 80 reported cases of MCD, 20% (16/80) had no symptoms of intestinal disease at the time of MCD diagnosis, and the majority of the asymptomatic cases were in children; interestingly, the majority of these same children were diagnosed with CD months to years later.⁹

Both the location and characteristics of cutaneous findings in MCD correlate with age.⁹ Metastatic CD has been identified in all age groups; however, lymphedema is more common in children/young adults, while nodules, ulceration, and fistulating disease are more often seen in adults.¹⁰ Affected children and adolescents with MCD range from 5 to 17 years of age, with a mean age at disease onset of 11.1 years and equal incidence in males and females.⁸ Adults with MCD range from 18 to 78 years of age, with a mean age at presentation of 38.4 years.^8,11

Concerning anatomic location of disease, adults with MCD most commonly have nodules with or without plaques on the arms and legs and less commonly in the genital area.⁸ In contrast, children with MCD are more prone to genital lesions, with up to 85% of cases including some degree of genital erythematous or nonerythematous swelling with or without induration.⁸ Genitourinary complications of CD as a broad category, however, are estimated to occur in only 5% to 20% of intestinal CD cases in both children and adults.¹²

There have been conflicting reports regarding gender predilection in MCD. Based on a review by Samitz et al¹³ of 200 cases of CD over an 18-year period, 22% of patients with CD were found to have cutaneous manifestations--presumably not MCD but rather perianal, perineal, vulvar fistulae, fissures, or abscesses--with a male to female preponderance of almost 2 to 1. A more recent review of the literature by Palamaras et al⁸ in 2008 reported that contiguous non-MCD affects adult females and children more often than adult males, with 63% adult cases being female. This review seems to be more congruent with other reports in the literature implicating that females are twice as commonly affected by MCD than males.^9,14

Pathophysiology

The etiology of MCD has not been well defined. One proposed mechanism of the distal tissue involvement of MCD is through passage of antigens to the skin with subsequent granulomatous response at the level of the dermis.¹⁰ Another proposed mechanism suggests antibody sensitization to gut antigens, possibly bacterial antigens, that then coincidentally cross-react with analogous skin antigens.^8,14 Burgdorf¹¹ supported this notion in a 1981 report in which it was suggested that the granulomatous reaction was related to deposition of immune complexes in the skin. Slater et al¹⁵ and Tatnall et al¹⁶ offered a variation of Burgdorf's notion, suggesting that it was sensitized T cells to circulating antigens that were the initiators of granuloma formation in the periphery.

An examination of MCD tissue in 1990 by Shum and Guenther¹⁷ under electron microscopy and immunofluorescence provided evidence against prior studies that purported to have identified immune complexes as the causative agents of MCD. In this study, the authors found no evidence of immune complexes in the dermis of MCD lesions. In addition, an attempt to react serum antibodies of a patient with MCD, which were postulated to have IgG, IgM, and IgA antibodies to specific gut antigens, yielded no response when reacted with the tongue, ileum, and colon tissue from a rat. As a culminant finding, the authors also noted MCD dermis tissue with granulomas without vasculitis, suggesting a T-cell mediated type IV hypersensitivity response with a secondary vasculitis from T-cell origin lymphokines and T-cell mediated monocyte activation.¹⁷

Research implicating other immunologic entities involved in the pathophysiology of CD such as β-2 integrin,¹⁸ CD14⁺ monocytes,¹⁹ and the role of the DNA repair gene MLH1 (mutL homolog 1)²⁰ have been considered but without a clearly definitive role in the manifestations of MCD.

The utility of metronidazole in the treatment of MCD has been suggested as evidence that certain bacteria in the gut may either serve as the causative antigen or may induce its formation²¹; however, the causative antigen has yet to be identified, and whether it travels distally to the skin or merely resembles a similar antigen normally present in the dermis has not yet been determined. Some research has used in situ polymerase chain reaction techniques to attempt to detect similar microbial pathogens in both the vasculature of active bowel lesions and in the skin, but to date, bacterial RNA noted to be present in the gut vasculature adjacent to CD lesions has not been detected in skin lesions.²²

Diagnosis

Physical Findings

Overall, it is estimated that roughly 56% of all MCD cases affect the external genitalia.²³ The classic appearance of MCD includes well-demarcated ulcerations in the areas of intertriginous skin folds with or without diffuse edema and tenderness to palpation.²³ Although MCD has been historically noted as having a predilection for moist skin folds, there are numerous case reports of MCD all over the body, including the face,^7,24-29 retroauricular areas,³⁰ arms and legs,^16,17,31-34 lower abdomen,^3,5 under the breasts,¹ perineum,³⁵ external genitalia,^1,9,36-40 and even the lungs⁴¹ and bladder.⁴²

As a dermatologic disease, MCD has been referred to as yet another great imitator, both on the macroscopic and microscopic levels.⁸ As such, more common causes of genital edema should be considered first and investigated based on the patient's history, physical examination, skin biopsy, lymphangiogram, ultrasound, and cystogram.⁴³ Ultrasonography and color Doppler sonography have been shown to be helpful in patients with genital involvement. This modality can evaluate not only the presence of normal testes but also intratesticular and scrotal wall fluid, especially when the physical examination reveals swelling that makes testicle palpation more difficult.⁶ Clinically, the correct diagnosis of MCD often is made through suspicion of inflammatory bowel disease based on classic symptoms and/or physical findings including abdominal pain, weight loss, bloody stool, diarrhea, perianal skin tags, and anal fissures or fistulas. Any of these GI findings should prompt an intestinal biopsy to rule out any histologic evidence of CD.

Metastatic CD affecting the vulva often presents with vulvar pain and pruritus and may clinically mimic a more benign disease such as balanitis plasmacellularis, also referred to as Zoon vulvitis.²³ Similar to MCD on any given body surface, there is dramatic variation in the macroscopic presentation of vulvar MCD, with physical examination findings ranging from bilateral diffuse, edematous, deeply macerated, red, ulcerated lesions over the vulva with lymphadenopathy to findings of bilateral vulvar pain with yellow drainage from the labia majora.²³ There have been cases of vulvar MCD that include exquisite vulvar pain but without structural abnormalities including normal uterus, cervix, adnexa, rectovaginal septum, and rectum. In these more nebulous cases of vulvar MCD, the diagnosis often is discovered incidentally when nonspecific diagnostic imaging suggests underlying CD.²³

Beyond the case-by-case variations on physical examination, the great difficulty in diagnosis, particularly in children, occurs in the absence of any GI symptoms and therefore no logical consideration of underlying CD. Consequently, there have been cases of children presenting with irritation of the vulva who were eventually diagnosed with MCD only after erroneous treatment of contact dermatitis, candidiasis, and even consideration of sexual abuse.³⁷ Because it is so rare and obscure among practicing clinicians, the diagnosis of MCD often is considered only after irritation or swelling of the external genitalia has not responded to standard therapies. If and when the diagnosis of MCD is considered in children, it has been suggested to screen patients for anorectal stricture, as case studies have found the condition to be relatively common in this subpopulation.⁴⁴

In the less common case of adults with genitourinary symptoms that suggest possible MCD, the differential diagnosis for penile or vaginal ulcers should include contact and irritant dermatitis, chronic infectious lesions (eg, hidradenitis suppurativa, actinomycosis, tuberculosis),⁴⁵ sexually transmitted ulcerative diseases (eg, chancroid, lymphogranuloma venereum, herpes genitalia, granuloma inguinale),⁴⁶ drug reactions, and even extramammary Paget disease.⁴⁷

Histologic Findings

Because MCD has so much macroscopic variation and can present anywhere on the surface of the body, formal diagnosis relies on microscopy. As an added measure of difficulty in diagnosis, one random biopsy of a suspicious segment of tissue may not contain the expected histologic findings; therefore, clinical suspicion may warrant a second biopsy.¹⁰ There have been reported cases of an adult patient without history of CD presenting with a lesion that resembled a more common pathology, such as a genital wart, and the correct diagnosis of MCD with pseudocondylomatous morphology was made only after intestinal manifestations prompted the clinician to consider such an unusual diagnosis.⁴⁸

From a histopathologic perspective, MCD is characterized by discrete, noncaseating, sarcoidlike granulomas with abundant multinucleated giant cells (Langhans giant cells) in the superficial dermis (papillary), deep dermis (reticular), and adipose tissue (Figure).^8,17 In the presence of concomitant intestinal disease, the granulomas of both the intestinal and dermal tissues should share the same microscopic characteristics.⁸ In addition, copious neutrophils and granulomas surrounding the microvasculature have been described,³⁴ as well as general lymphocyte and plasma cell infiltrate.⁴⁵ Some histologic samples have included collagen degeneration termed necrobiosis in the middle dermal layer as another variable finding in MCD.^14,34

On microscopy, it has been reported that use of Verhoeff-van Gieson staining may be helpful to highlight the presence of neutrophil obstruction within the dermal vasculature, particularly the arterial lumen, as well as to aid in highlighting swelling of the endothelium with fragmentation of the internal elastic lamina.¹⁷ Although not part of the routine diagnosis, electron microscopy of MCD tissue samples have confirmed hypertrophy of the endothelial cells composing the capillaries with resulting extravasation of fibrin, red blood cells, lymphocytes, and epithelioid histiocytes.¹⁷ Observation of tissue under direct immunofluorescence has been less helpful, as it has shown only nonspecific fibrinogen deposition within the dermis and dermal vessels.¹⁷

In an article on treatment of MCD, Escher et al⁴³ reinforced that the macroscopic findings of MCD are diverse, and the microscopic findings characteristic of MCD also can be mimicked by other etiologies such as sarcoidosis, tuberculosis, fungal infections, lymphogranuloma venereum, leishmaniasis, and connective tissue disorders.⁴³ As such, the workup to rule out infectious, anatomic, and autoimmune etiologies should be diverse. Often, the workup for MCD will include special stains such as Ziehl-Neelsen stain to rule out Mycobacterium tuberculosis and acid-fast bacilli and Fite stain to consider atypical mycobacteria. Other tests such as tissue culture, chest radiograph, tuberculin skin test (Mantoux test), IFN-γ release assay, or polarized light microscopy may rule out infectious etiologies.^9,49 Serologic testing might include VDRL test, Treponema pallidum hemagglutination assay, hepatitis B, hepatitis C, and human immunodeficiency virus.⁵

Crohn disease is characterized histologically by sarcoidlike noncaseating granulomas, and as such, it is important to differentiate MCD from sarcoidosis prior to histologic analysis. Sarcoidosis also can be considered much less likely with a normal chest radiograph and in the absence of increased serum calcium and angiotensin-converting enzyme levels.⁷ The differentiation of sarcoidosis from MCD on the microscopic scale is subtle but is sometimes facilitated in the presence of an ulcerated epidermis or lymphocytic/eosinophilic infiltrate and edema within the dermis, all suggestive of MCD.¹⁴

Metastatic CD also should be differentiated from erythema nodosum and pyoderma gangrenosum, which are among the most common cutaneous findings associated with CD.¹⁴ Pyoderma gangrenosum can be distinguished histologically by identifying copious neutrophilic infiltrate with pseudoepitheliomatous hyperplasia.⁵⁰

Treatment

Because MCD is relatively rare, there are no known randomized trials suggesting a particular medical or surgical treatment. In a review of perineal MCD from 2007, the 40-year-old recommendation by Moutain³ opting for surgical debridement versus medical management still resonates, particularly for perineal disease, as an effective measure in all but the mildest of presentations.⁵¹ However, recent case reports also suggest that the tumor necrosis factor α (TNF-α) inhibitors such as infliximab and adalimumab should be considered prior to surgery even with severe perineal MCD.⁵¹ Moreover, even if medical management with TNF-α inhibitors or some combination of immunosuppressants and antibiotics does not eradicate the disease, it often helps reduce the size of the ulcers prior to surgery.⁵² With a limited understanding of MCD, one might think that removal of the affected bowel would eliminate cutaneous disease, but it has been shown that this strategy is not effective.^53,54

The composition and location of the particular lesion affects the trajectory of treatment. For example, MCD manifesting as local ulcers and plaques has been described as responding well to topical and intralesional steroids.^10,55,56 In the case of penile swelling and/or phimosis, circumcision has been helpful to improve the patient's ability to void as well as to attain and maintain erection.¹⁰ In the case of scrotal swelling secondary to MCD, early treatment (ie, within 4 to 6 months) with oral steroids and/or metronidazole is likely beneficial to prevent refractory edematous organization of the tissue.⁵⁷

As a general rule, an effective treatment will include a combination of an immunosuppressant, antibiotic therapy, and sometimes surgery. The most commonly used immunosuppressant agents include topical or intralesional steroids, infliximab,^43,58 cyclosporine A,^59,60 dapsone, minocycline, thalidomide, methotrexate, mycophenolate mofetil, sulfasalazine, azathioprine, tacrolimus, and 6-mercaptopurine.⁴ Steroids have been the conventional treatment of extraintestinal manifestations of CD⁶¹; however, perineal CD has been poorly controlled with systemic steroids.⁶² If steroids are found not to be effective, sometimes agents such as dapsone or thalidomide are considered. One case report noted stabilization of MCD penile ulcers with oral thalidomide 300 mg once daily, oral minocycline 100 mg once daily, and topical tacrolimus 0.3% with benzocaine twice daily with continuation of prednisolone and methotrexate as parts of previously unsuccessful regimen.⁵²

Metronidazole is perhaps the most commonly used antibiotic, having been a component of many successful regimens.^4,63 For example, a 27-year-old patient with MCD presenting as a nonhealing ulcerative lesion in the subcoronal area of the penis and scrotum was treated successfully with a 6-month course of mesalamine, prednisone, and metronidazole.⁴⁵ Another case report of vulvar MCD reported initial success with intravenous methylprednisolone, ciprofloxacin, and metronidazole.²³ The primary limitation of metronidazole is that subsequent tapering of the dose seems to result in recurrence of disease.⁶⁴ Consequently, patients must remain on the antibiotic for an indeterminate course, with dosages ranging from 5 mg/kg daily in adolescents⁶⁵ to 1000 to 1500 mg daily in adults.⁶⁶

Of the various immunosuppressants available, infliximab has been listed in numerous reports as a successful agent in both the induction and maintenance of extraintestinal manifestations of CD including MCD.^67-71 Infliximab has been reported to be effective in the treatment of penile and scrotal edema secondary to MCD that did not respond to other immunosuppressants including oral prednisolone, azathioprine, and cyclosporine.⁴³ Infliximab may be a good option to help heal draining fistulas, particularly in combination with an antibiotic such as metronidazole and ciprofloxacin, which helps to prevent abscess formation during healing.⁷² The response to infliximab has been dramatic, with resolution of cutaneous lesions after just 6 weeks in some cases.⁷³ The dosing regimen of infliximab has been suggested at 5 mg/kg administered at 0, 2, and 6 weeks, with subsequent maintenance infusions every 10 weeks,⁷⁰ or at 0, 4, and 12 weeks, with subsequent infusions every 8 weeks.⁴³

Adalimumab may be considered as an alternative to infliximab and is potentially less allergenic as a fully humanized monoclonal antibody to TNF-α, which also has been used successfully to both induce and maintain remission of moderate to severe CD.^42,74,75 Proposed dosing of adalimumab includes a loading dose of 160 mg subcutaneously on day 1, followed by an 80-mg dose 2 weeks later and a 40-mg maintenance dose every other week indefinitely.⁴⁸ Of note, adalimumab has been noted in the literature to have many potential side effects, including one particular case in which severe headaches were attributed to its use.⁵⁹ As a consequence of the headaches, the patient was switched from adalimumab to cyclosporine and responded well with no subsequent flare-ups on follow-up.

In summary, treatment of MCD depends on cutaneous location, severity, physician experience with certain antibiotics or immunosuppressants, availability of medication, and patient disposition. It seems reasonable to attempt medical management with one or more medical regimens before committing to surgical intervention. Furthermore, even with debridement, curettage, skin graft, or other surgical strategy, the patient is likely to require some period of immunosuppression to provide long-lasting remission.

Conclusion

Patients with inflammatory bowel disease often develop dermatologic sequelae, with MCD being a rare but serious process. Patients may present with a wide array of physical concerns and symptoms, many resembling other disease processes. As such, education and a high index of suspicion are needed for proper diagnosis and treatment.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.

Chronic urticaria (CU) is clinically defined as the daily or almost daily presence of wheals on the skin for at least 6 weeks.¹ Chronic urticaria severely affects patients’ quality of life and can cause emotional disability and distress.² In clinical practice, CU is one of the most common and challenging conditions for general practitioners, dermatologists, and allergists. It can be provoked by a wide variety of different causes or may be the clinical presentation of certain systemic diseases^3,4; thus, CU often requires a detailed and time-consuming diagnostic procedure that includes screening for allergies, autoimmune diseases, parasites, malignancies, infections, and metabolic disorders.^5,6 In many patients (up to 50% in some case series), the cause or pathogenic mechanism cannot be identified, and the disease is then classified as chronic idiopathic urticaria (CIU).⁷

It has previously been shown that contact sensitization could have some relation with CIU,⁸ which was further explored in this study. This study sought to evaluate if contact allergy may play a role in disease development in CIU patients in Saudi Arabia and if patch testing should be routinely performed for CIU patients to determine if any allergens can be avoided.

Methods

This prospective study was conducted at the King Khalid University Hospital Allergy Clinic (Riyadh, Saudi Arabia) in patients aged 18 to 60 years who had CU for more than 6 weeks. It was a clinic-based study conducted over a period of 2 years (March 2010 to February 2012). The study protocol was approved by the local ethics committee at King Khalid University Hospital. Valid written consent was obtained from each patient.

Patients were excluded if they had CU caused by physical factors (eg, hot or cold temperature, water, physical contact) or drug reactions that were possible causative factors or if they had taken oral prednisolone or other oral immunosuppressive drugs (eg, azathioprine, cyclosporine) in the last month. However, patients taking antihistamines were not excluded because it was impossible for the patients to discontinue their urticaria treatment. Other exclusion criteria included CU associated with any systemic disease, thyroid disease, diabetes mellitus, autoimmune disorder, or atopic dermatitis. Pregnant and lactating women were not included in this study.

All new adult CU patients (ie, disease duration >6 weeks) were worked up using the routine diagnostic tests that are typically performed for any new CU patient, including complete blood cell count with differential, erythrocyte sedimentation rate, liver function tests, urine analysis, and hepatitis B and C screenings. Further diagnostic tests also were carried out when appropriate according to the patient’s history and physical examination, including levels of urea, electrolytes, thyrotropin, thyroid antibodies (antithyroglobulin and antimicrosomal), and antinuclear antibodies, as well as a Helicobacter pylori test.

All of the patients enrolled in the study were evaluated by skin prick testing to establish the link between CU and its cause. Patch testing was performed in patients who were negative on skin prick testing.

Skin Prick Testing
All patients were advised to temporarily discontinue the use of antihistamines and corticosteroids 5 to 6 days prior to testing. To assess the presence of allergen-specific IgE antibodies, skin prick testing is preferred because it is more sensitive and specific, is simple to use, is inexpensive, and is not associated with any complications.⁹

Patch Testing
Patch tests were carried out using a ready-to-use epicutaneous patch test system for the diagnosis of allergic contact dermatitis (ACD).¹⁰ A European standard series was used with the addition of 4 allergens of local relevance: black seed oil, local perfume mix, henna, and myrrh (a topical herbal medicine used to promote healing). Patients with a negative skin prick test who had a positive patch test were enrolled in an allergen-avoidance program to avoid the offending allergen for 8 weeks.

Assessment of Improvement
Assessment of urticaria severity using the Chronic Urticaria Severity Score (CUSS), a simple semiquantitative assessment of disease activity, was calculated as the sum of the number of wheals and the degree of itch severity graded from 0 (none) to 3 (severe), according to the guidelines established by the Dermatology Section of the European Academy of Allergology and Clinical Immunology, the Global Allergy and Asthma European Network, the European Dermatology Forum, and the World Allergy Organization.¹¹ The avoidance group of patients was assessed at baseline and after 1 month to evaluate changes in their CUSS after allergen avoidance for 8 weeks.

Statistical Analysis
All of the statistical analyses were carried out using SPSS software version 16. Results were presented as the median with the range or the mean (SD). Descriptive statistics were used to describe the demographic data. The comparability of demographic and baseline characteristics among CIU patients was assessed using the Student t test, and P<.05 was considered statistically significant.

Results

During the study period, a total of 120 CU patients were seen at the clinic. Ninety-three patients with CU met our selection criteria (77.5%) and were enrolled in the study. The mean age (SD) of the patients was 34.7 (12.4) years. Women comprised 68.8% (64/93) of the study population (Table 1).

The duration of urticaria ranged from 0.6 to 20 years, with a median duration of 4 years. Approximately half of the patients (50/93) experienced severe symptoms of urticaria, but only 26.9% (25/93) had graded their urticaria as very severe.

Negative results from the skin prick test were reported in 62.4% (58/93) of patients and were subsequently patch tested. These patients also had no other etiologic factors (eg, infection; thyroid, autoimmune, or metabolic disease). Patients who had positive skin prick test results (35/93 [37.6%]) were not considered to be cases of CIU, according to diagnostic recommendations.¹² Of the 58 CIU patients who were patch tested, 31 (53.4%) had positive results and 27 (46.5%) had negative results to both skin prick and patch tests (Figure).

Univariate analysis revealed significant associations between age, gender, and duration of urticaria and patch test positivity (χ² test, P<.05). Twenty of 31 (64.5%) patch test–positive patients were aged 30 to 45 years. Positive patch test results were observed in 31 of 43 female patients (72.1%; P<.001). Of the patch test–positive patients, disease duration was greater than 5 years in 16 of 31 patients (51.6%).

Of the 31 patients with positive patch tests, there were 20 positive reactions to nickel, 6 to formaldehyde, 4 to phenylenediamine, 3 to cobalt, and 3 to a fragrance mix (Table 2). Some patients showed patch test reactivity to more than 1 allergen concomitantly. Overall, these 31 patients had positive reactions to 16 allergens. None of the patients showed actual signs of contact dermatitis (Table 2).

Of the 31 patch test–positive patients, 10 were enrolled but only 8 (25.8%) agreed to take appropriate avoidance measures for the sensitizing substances; 5 (62.5%) showed excellent improvement in their baseline symptoms at a 1-month follow-up visit.

Comment

Chronic idiopathic urticaria is the diagnosis given when urticarial vasculitis, physical urticaria, and all other possible etiologic factors have been excluded in patients with CU. Our study was designed to assess patch test reactivity in patients with CU without any identifiable systemic etiologic factor after detailed laboratory testing and negative skin prick tests.

Chronic idiopathic urticaria can be an extremely disabling and difficult-to-treat condition. Because the cause is unknown, the management of CIU often is frustrating. The efficacy of performing patch tests in CIU has not yet been proven, as there are conflicting results regarding the role of contact sensitization in CIU. Prior studies in this field have shown that contact allergy can play a role in the etiopathogenesis of CU; these findings have stimulated new approaches for investigation of CIU.^8,12 There were no details of how a common allergen such as nickel was avoided, which caused remission in the majority of patch test–positive patients.

Patch testing is commonly performed to diagnose ACD, and if contact allergens are found via patch testing, patients can often be cured of their dermatitis by avoiding these agents. However, patch testing is not routinely performed in the evaluation of patients with CIU. It is a relatively inexpensive and safe procedure to determine a causal link between sensitization to a specific agent and ACD. In patch test clinics, agents often are tested in standard and screening series. Sensitization that is not suspected from the patient’s history and/or clinical examination can be detected in this manner. Requirements for the inclusion of a chemical in a standard series have been formulated by Bruze et al.¹³ In addition, ready-to-use materials relevant to the specific leisure activities and working conditions also can be selected for patch testing.

A study conducted in Saudi Arabia showed that the European standard series is suitable for patch testing patients in this community¹⁴; however, 3 allergens of local relevance were added in our study: black seed oil, local perfume mix, and henna. Moreover, in our study we added a local allergen known as myrrh, which is a topical herbal medicine used to promote healing that has been reported to cause ACD in some cases.¹⁵ We sought to determine if contact allergens can be identified with patch testing in patients with CU and if avoiding these contact allergens would resolve the CU.

Urticaria was once considered an IgE-mediated hypersensitivity reaction, but recent studies have demonstrated the existence of different subgroupsof urticaria, some with an autoimmune mechanism.^1-4,11 In CU, skin prick tests are recommended for etiologic workup, while patch testing generally is not recommended.¹⁶

It has been observed in clinical practice that a substantial number of patients with CU are positive to patch tests, even without a clear clinical history or signs of contact dermatitis.¹⁷ In 2007, Guerra et al¹⁷ reported that of 121 patients with CU, 50 (41.3%) tested positive for contact allergens. In all of the patch test–positive patients, avoidance measures led to complete remission within 10 days to 1 month. Therefore, this result suggested that testing for contact sensitization could be helpful in the management of CU. Patients with nickel sensitivity were subsequently allowed to ingest small amounts of nickel-containing foods after 8 weeks of a completely nickel-free diet, and remission persisted.¹⁷

Contact dermatitis affects approximately 20% of the general population¹⁸; however, there has been little investigation (limited to nickel) into the relationship between contact allergens and CU,^19,20 and the underlying mechanisms of the disease are unknown. It has been hypothesized that small amounts of the substances are absorbed through the skin or the digestive tract into the bloodstream over the long-term and are delivered to antigen-presenting cells in the skin, which provide the necessary signals for mast cell activation. Nonetheless, the reasons for a selectively cutaneous localization of the reaction remain largely unclear.

Management of CU is debated among physicians, and several diagnostic flowcharts have been proposed.^1,2 In general, patch tests for contact dermatitis are not recommended as a fundamental part of the diagnostic procedure, but Guerra et al¹⁷ suggested that contact allergy often plays a role in CU.

There have been inadequate reports of CU found to be caused by common contact sensitizers.^21-24 Interestingly, no signs of contact allergy were demonstrated in CU patients before urticarial attack.

Our findings supported our patient selection criteria and also confirmed that contact sensitization may be one of the many possible mechanisms involved in the etiology of CU. Urticaria may have a delayed-type hypersensitivity reaction element, and patients with CU without an obvious causal factor can have positive patch test results.

The role of contact sensitization in CU has not yet been established, as another study showed no relationship between avoidance of contact allergens and the course of CIU.²⁵ In that study, patients with severe CIU who previously had been patch tested were retrospectively studied. Three groups were studied: CIU patients with positive patch tests; CIU patients with negative patch tests; and a control group, which included patients with CIU who had not been patch tested. The groups were followed monthly to assess changes in CUSS after allergen avoidance. Forty-three patients with severe CIU were patch tested. Nickel sulfate testing was positive in 4 cases (9.3%); potassium dichromate testing was positive in 2 cases (4.7%); and cobalt, balsam of Peru, paraphenylenediamine, fragrance mix, and epoxy resin testing were positive in 1 case (2.3%) each. The mean (SD) baseline CUSS score (5.4 [0.5]) significantly improved after 1 month of allergen avoidance (3.2 [1.1]; P<.001); however, similar improvement in CUSS was observed in 34 patients with CIU with negative patch test results (5.3 [0.5] to 3.2 [1.3]; P<.001) and in 49 patients with CIU in the control group after 1 month (5.2 [0.4] to 3.4 [1.3]; P<.001).²⁵

The main findings of our study were that 53.4% of patients with CIU had positive patch test results and that avoidance of the sensitizing substance was effective in 5 of 8 patients who completed an avoidance program. Almost all of the patients showed notable remission of symptoms after limiting their exposure to the offending allergens. This study clearly showed that a cause or pathogenesis for CIU could be identified, thus showing that CIU occurs less frequently than is usually assumed.

Our study had limitations. The first is our lack of a controlled challenge test, which is important to confirm an allergen as a cause of CIU.²⁶ Nonetheless, avoidance of the revealed contact allergen was associated with comparable improvement of CIU severity after 1 month in 5 of 8 patients, though such measures were not tested in all 31 of 58 CIU patients who had positive patch test results.

Conclusion

We propose that patch tests should be performed while investigating CU because they give effective diagnostic and therapeutic results in a substantial number of patients. Urticaria, or at least a subgroup of the disease, may have a delayed-type reaction element, which may explain the disease etiology for many CIU patients. Patients with CU without a detectable underlying etiologic factor can have positive patch test results.