Roselyn Kellen, BA

Perioral dermatitis is an acneform eruption presenting with erythematous papules, vesicles, and rarely pustules clustered around the orifices of the face. ¹ Lesions may be found near the eyes, mouth, and nose but typically spare the vermilion border of the lips. ² Nguyen and Eichenfield ³ preferred the term periorificial dermatitis (POD), which has since been adopted by others. ⁴ Patients may report pruritus, but there generally are no systemic symptoms unless patients have comorbid conditions such as atopic dermatitis. ⁵ Although this condition has been well examined in the literature on adults, data in the pediatric population are far more limited, consisting of case series and retrospective chart reviews. In 1979, Wilkinson et al ⁶ published a study of more than 200 patients with perioral dermatitis, but only 15 patients younger than 12 years were included.

Etiology

Although the exact pathogenesis of POD is unknown, a common denominator among many patients is prior exposure to topical corticosteroids.^3,7-9 Periorificial dermatitis also has been linked to the use of systemic corticosteroids in pediatric patients.¹⁰ The exact relationship between steroid use and dermatitis is unknown; it may be related to a change in the flora of hair follicles and in particular an association with fusiform bacteria–rich conditions.¹¹ Aside from steroid exposure, POD has been associated with the use of physical sunscreen in pediatric patients with dry skin,¹² rosin in chewing gum,¹³ and inhaled corticosteroids in those with asthma.¹⁴ In one case, a 15-year-old adolescent girl developed POD and swelling of the lips after 2 years of playing a flute made of cocus wood.^15,16

Epidemiology

In the largest chart review to date in the US pediatric population, Goel et al¹⁷ examined the clinical course of POD in 222 patients aged 3 months to 18 years at the Dermatology Clinic at the University of North Carolina Chapel Hill between June 2002 and March 2014. Consistent with prior studies, females seemed to be slightly more affected than males (55.4% vs 44.6%).¹⁷ Similarly, the patient population for a study conducted by Nguyen and Eichenfield³ consisted of more females (58% [46/79]) than males (42% [33/79]). Weston and Morelli⁹ conducted a retrospective chart review of steroid rosacea in 106 patients younger than 13 years, which included 29 patients younger than 3 years; the study included 46 males and 60 females.

Comorbidities and Family History

Goel et al¹⁷ (N=222) reported the following comorbidities associated with pediatric POD: atopic dermatitis (29.3%), asthma (14.9%), and allergies (9.9%). Steroid exposure was noted in 58.1% of patients.¹⁷ Similarly, Nguyen and Eichenfield³ (N=79) found that the most common comorbidities were atopic dermatitis (14%), keratosis pilaris (14%), viral infections (14%), acne (10%), and seborrheic dermatitis (10%). Family history of atopy was noted in 55% of patients and family history of rosacea was noted in 3%. In a case series of 11 pediatric patients, 3 (27%) had keratosis pilaris, 7 (64%) had a family history of atopy, and 2 (18%) had a family history of rosacea.⁸ Weston and Morelli⁹ found a much higher incidence of familial rosacea (20%) in 106 children with steroid rosacea. It is hard to interpret the role of genetic tendency in rosacea, as different populations have different background prevalence of rosacea and atopic dermatitis (ie, rosacea is immensely more common in white individuals).

Clinical Presentation

Periorificial dermatitis generally presents with small, pink- to flesh-colored papules in a perioral, periocular, and perinasal distribution. Although many patients are white, a particularly prominent variant has been noted in black children with papules that may be hyperpigmented.¹⁸ In a 2006 chart review in 79 pediatric POD patients aged 6 months to 18 years, Nguyen and Eichenfield³ reported that 92% (73/79) of patients presented for a facial rash with an average duration ranging from 2 weeks to 4 years. Interestingly, although Tempark and Shwayder¹ did not report burning associated with pediatric POD, Nguyen and Eichenfield³ found that 19% of patients reported pruritus and 4% reported burning or tenderness. Seventy-two percent of patients had been exposed to steroids for treatment of their dermatitis. Seventy percent had perioral involvement, 43% had perinasal involvement, 25% had periocular involvement, and 1% had a perivulvar rash; 64% of patients only had perioral, perinasal, and periocular involvement. In others, lesions also were found on the cheeks, chin, neck, and forehead. Perioral lesions were more likely to be found in patients younger than 5 years compared to those who were at least 5 years of age. Eighty-six percent of patients had erythema with or without scaling, 66% had papules, and 11% had pustules. Fewer than 3% had lichenification, telangiectases, or changes in pigmentation.³

Boeck et al¹⁹ described 7 pediatric patients with perioral dermatitis. Six (86%) patients had perioral lesions, and 6 (86%) had previously been treated with moderate- to high-potency topical corticosteroids. Skin prick tests were negative in 6 (86%) patients.¹⁹ In one case report, a 6-year-old boy did not present with the classic acneform lesions but rather sharply demarcated eczematous patches around the eyes, nose, and mouth. The rash began to fade after 2 weeks of using metronidazole gel 1%, and after 4 months he was only left with mild hyperpigmentation.⁴

Periorificial dermatitis was once thought to be a juvenile form of rosacea.⁵ In 1972, Savin et al⁸ described 11 pediatric patients with “rosacea-like” facial flushing, papules, pustules, and scaling over the cheeks, forehead, and chin. In some patients, the eyelids also were involved. At least 8 patients had been using potent topical corticosteroids and had noticed exacerbation of their skin lesions after stopping therapy.⁸

Variants of POD

Several other variants of POD have been described in pediatric patients including childhood granulomatous periorificial dermatitis (CGPD)(also known as facial Afro-Caribbean [childhood] eruption) and lupus miliaris disseminatus faciei. Childhood granulomatous periorificial dermatitis presents in prepubertal children as dome-shaped, red to yellow-brown, monomorphous papules around the eyes, nose, and mouth; there are no systemic findings.^20,21 It occurs equally in males and females and is more commonly seen in dark-skinned patients. Childhood granulomatous periorificial dermatitis usually resolves within a few months to years but may be associated with blepharitis or conjunctivitis.²⁰ Urbatsch et al²⁰ analyzed extrafacial lesions in 8 patients (aged 2–12 years) with CGPD. Lesions were found on the trunk (38% [3/8]), neck (25% [2/8]), ears (25% [2/8]), extremities (50% [4/8]), labia majora (38% [3/8]), and abdomen (13% [1/8]). In addition, 2 (25% [2/8]) patients had blepharitis.²⁰

Lupus miliaris disseminatus faciei, which occurs in adolescents and adults, commonly involves the eyelids and central areas of the face such as the nose and upper lips. Patients typically present with erythematous or flesh-colored papules.¹

Diagnosis

Diagnosis of POD is made clinically based on the observation of papules (and sometimes pustules) around the orifices of the face, sparing the vermilion border, together with a lack of comedones.¹⁷ Laboratory tests are not useful.⁵ Biopsies rarely are performed, and the results mimic those of rosacea, demonstrating a perifollicular lymphohistiocytic infiltrate, epithelioid cells, and occasionally giant cells.^5,22,23 Early papular lesions can show mild acanthosis, epidermal edema, and parakeratosis.²³ Biopsies in patients with CGPD reveal noncaseating perifollicular granulomas.²⁰

Treatment and Clinical Outcome

Although topical corticosteroids can improve facial lesions in pediatric POD, the eruption often rebounds when therapy is discontinued.¹ One therapy frequently used in adults is oral tetracyclines; however, these agents must not be used in patients younger than 9 years due to potential dental staining.⁴ The standards are either topical metronidazole twice daily with clearance in 3 to 8 weeks or oral erythromycin.⁷

In the review conducted by Goel et al,¹⁷ treatment included azithromycin (44.6%), topical metronidazole (42.3%), sodium sulfacetamide lotion (35.6%), oral antibiotic monotherapy (15.3%), topical agent monotherapy (44.6%), and combined oral and topical agent therapy (40.1%). Of those patients who presented for a follow-up visit (59%), 72% of cases resolved and 10.7% showed some improvement. For those patients who returned for follow-up, the average duration until symptom resolution was approximately 4 months. The most common side effects were pigmentation changes (1.8%), worsening of symptoms (1.8%), gastrointestinal upset (0.9%), irritant dermatitis (0.9%), and xerosis (0.5%).¹⁷

Changes were made to the treatment plans for 16 patients, most often due to inadequate treatment response.¹⁷ Five patients treated with sodium sulfacetamide lotion also were started on oral azithromycin. Four patients treated with oral antibiotics were given a topical agent (metronidazole or sodium sulfacetamide lotion). Other modifications included replacing sodium sulfacetamide lotion with topical metronidazole and an oral antibiotic (azithromycin or doxycycline, n=3), adjusting the doses of oral or topical medications (n=2), adding tacrolimus (n=1), and replacing topical metronidazole with sodium sulfacetamide lotion (n=1). Of the patients who underwent a change in treatment plan, 5 experienced symptom recurrence, 4 had mild improvement, and 1 patient had no improvement. Six patients were lost to follow-up.¹⁷

In the study conducted by Nguyen and Eichenfield,³ follow-up visits occurred approximately 3 months after the first visit. Fifty-two percent of patients used metronidazole alone or with another medication; for most of these patients, the POD cleared an average of 7 weeks after starting treatment, ranging from 1 to 24 weeks. The use of topical calcineurin inhibitors, sulfacetamide, hydrocortisone, or antifungal therapies was associated with persistence of the rash at the follow-up visit. In contrast, the use of metronidazole and/or oral erythromycin was associated with resolution of the rash at the follow-up visit. The investigators recommended the following regimen: topical metronidazole for 1 to 2 months and, if necessary, the addition of oral erythromycin.³

In the case series by Boeck et al,¹⁹ all patients were started on metronidazole gel 1% applied once daily for the first week, and then twice daily until the lesions resolved. All patients showed improvement after 4 to 6 weeks, and eventually the disease cleared between 3 and 6 months. All patients were still symptom free during a 2-year observation period.¹⁹

Manders and Lucky⁷ described 14 patients with POD (aged 9 months to 6.5 years). Eight patients used only metronidazole gel 0.75%, while 5 used the gel in combination with topical corticosteroids (21% [3/14]), oral erythromycin (7% [1/14]), or topical erythromycin (7% [1/14]); 1 patient remained on hydrocortisone 1% and cleared. Patients responded well within 1 to 8 weeks and were symptom free for up to 16 months. Mid- to high-potency steroids were discontinued in all patients.⁷

In some pediatric patients with CGPD, recovery occurs faster with the use of oral macrolides or tetracyclines, either alone or in combination with topical antibiotics or sulfur-based lotions.²⁰ Extrafacial lesions associated with CGPD do not appear to negatively impact treatment response or duration of disease. In the review conducted by Urbatsch et al,²⁰ 7 of 8 (88%) CGPD patients with extrafacial lesions were treated with oral agents including erythromycin, hydroxychloroquine, cyclosporine, minocycline, and azithromycin. Most of these patients also were using topical agents such as triamcinolone acetonide, desonide, metronidazole, and erythromycin. The time to resolution ranged from several weeks to 6 months.²⁰

Weston and Morelli⁹ described a treatment regimen for steroid rosacea. The study included data on 106 children (60 females, 46 males) who had been exposed to mostly class 7 low-potency agents. All patients were advised to immediately stop topical steroid therapy without gradual withdrawal and to begin oral erythromycin stearate 30 mg/kg daily in 2 doses per day for 4 weeks. Patients who were unable to tolerate erythromycin were advised to use topical clindamycin phosphate twice daily for 4 weeks (n=6). Eighty-six percent of patients showed resolution within 4 weeks, and 100% showed clearance by 8 weeks. Twenty-two percent of patients had clearance within 3 weeks. There was no difference in the duration until resolution for those who had used oral or topical antibiotics.⁹ A different study suggested that low-potency topical steroids can be used to control inflammation when weaning patients off of strong steroids.⁵

Differential Diagnosis

The differential diagnosis should include acne vulgaris, allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, impetigo, dermatophyte infection, rosacea, and angiofibromas.⁴

Acne vulgaris commonly is found in older adolescents, and unlike POD, it will present with open or closed comedones.² In patients aged 1 to 7 years, acne is a reason to consider endocrine evaluation. Allergic contact dermatitis is extremely pruritic, and the lesions often are papulovesicular with active weeping or crusting. Patients with irritant contact dermatitis often report burning and pain, and papules and pustules typically are absent. A thorough history can help rule out allergic or irritant contact dermatitis. Seborrheic dermatitis presents with erythema and scaling of the scalp, eyebrows, and nasolabial folds; it tends to spare the perioral regions and also lacks papules.² The lesions of impetigo typically have a yellow-brown exudate, which forms a honey-colored crust.²⁴ Tinea faciei, unlike the other tinea infections, can have an extremely variable presentation. Lesions usually begin as scaly macules that develop raised borders with central hypopigmentation, but papules, vesicles, and crusts can be seen.²⁵ Potassium hydroxide preparation can help diagnose a fungal infection. Rosacea presents with flushing of the central face regions, sometimes accompanied by papules, pustules, and telangiectases.² Although rare, physicians must rule out angiofibromas. Typically found in patients older than 5 years, angiofibromas are pink or flesh-colored papules often found on the nasolabial folds, cheeks, and chin.² Many angiofibromas can be associated with tuberous sclerosis.

Conclusion

Diagnosis of POD is clinical and rests upon the finding of erythematous papules on the face near the eyes, mouth, and nose. Extrafacial lesions also have been described, particularly in pediatric patients with CGPD. Many patients will report a history of atopic dermatitis and asthma. Therapy for POD includes both topical and systemic agents. For those with mild disease, topical metronidazole commonly is used. For patients requiring oral antibiotics, tetracyclines or macrolides can be prescribed based on the age of the patient. Many pediatric patients who begin with both oral and topical agents can later be maintained on topical therapy, sometimes with a low-dose oral antibiotic. Periorificial dermatitis has an excellent prognosis and most pediatric patients show marked improvement within weeks to months.

Perioral dermatitis is an acneform eruption presenting with erythematous papules, vesicles, and rarely pustules clustered around the orifices of the face. ¹ Lesions may be found near the eyes, mouth, and nose but typically spare the vermilion border of the lips. ² Nguyen and Eichenfield ³ preferred the term periorificial dermatitis (POD), which has since been adopted by others. ⁴ Patients may report pruritus, but there generally are no systemic symptoms unless patients have comorbid conditions such as atopic dermatitis. ⁵ Although this condition has been well examined in the literature on adults, data in the pediatric population are far more limited, consisting of case series and retrospective chart reviews. In 1979, Wilkinson et al ⁶ published a study of more than 200 patients with perioral dermatitis, but only 15 patients younger than 12 years were included.

Etiology

Although the exact pathogenesis of POD is unknown, a common denominator among many patients is prior exposure to topical corticosteroids.^3,7-9 Periorificial dermatitis also has been linked to the use of systemic corticosteroids in pediatric patients.¹⁰ The exact relationship between steroid use and dermatitis is unknown; it may be related to a change in the flora of hair follicles and in particular an association with fusiform bacteria–rich conditions.¹¹ Aside from steroid exposure, POD has been associated with the use of physical sunscreen in pediatric patients with dry skin,¹² rosin in chewing gum,¹³ and inhaled corticosteroids in those with asthma.¹⁴ In one case, a 15-year-old adolescent girl developed POD and swelling of the lips after 2 years of playing a flute made of cocus wood.^15,16

Epidemiology

In the largest chart review to date in the US pediatric population, Goel et al¹⁷ examined the clinical course of POD in 222 patients aged 3 months to 18 years at the Dermatology Clinic at the University of North Carolina Chapel Hill between June 2002 and March 2014. Consistent with prior studies, females seemed to be slightly more affected than males (55.4% vs 44.6%).¹⁷ Similarly, the patient population for a study conducted by Nguyen and Eichenfield³ consisted of more females (58% [46/79]) than males (42% [33/79]). Weston and Morelli⁹ conducted a retrospective chart review of steroid rosacea in 106 patients younger than 13 years, which included 29 patients younger than 3 years; the study included 46 males and 60 females.

Comorbidities and Family History

Goel et al¹⁷ (N=222) reported the following comorbidities associated with pediatric POD: atopic dermatitis (29.3%), asthma (14.9%), and allergies (9.9%). Steroid exposure was noted in 58.1% of patients.¹⁷ Similarly, Nguyen and Eichenfield³ (N=79) found that the most common comorbidities were atopic dermatitis (14%), keratosis pilaris (14%), viral infections (14%), acne (10%), and seborrheic dermatitis (10%). Family history of atopy was noted in 55% of patients and family history of rosacea was noted in 3%. In a case series of 11 pediatric patients, 3 (27%) had keratosis pilaris, 7 (64%) had a family history of atopy, and 2 (18%) had a family history of rosacea.⁸ Weston and Morelli⁹ found a much higher incidence of familial rosacea (20%) in 106 children with steroid rosacea. It is hard to interpret the role of genetic tendency in rosacea, as different populations have different background prevalence of rosacea and atopic dermatitis (ie, rosacea is immensely more common in white individuals).

Clinical Presentation

Periorificial dermatitis generally presents with small, pink- to flesh-colored papules in a perioral, periocular, and perinasal distribution. Although many patients are white, a particularly prominent variant has been noted in black children with papules that may be hyperpigmented.¹⁸ In a 2006 chart review in 79 pediatric POD patients aged 6 months to 18 years, Nguyen and Eichenfield³ reported that 92% (73/79) of patients presented for a facial rash with an average duration ranging from 2 weeks to 4 years. Interestingly, although Tempark and Shwayder¹ did not report burning associated with pediatric POD, Nguyen and Eichenfield³ found that 19% of patients reported pruritus and 4% reported burning or tenderness. Seventy-two percent of patients had been exposed to steroids for treatment of their dermatitis. Seventy percent had perioral involvement, 43% had perinasal involvement, 25% had periocular involvement, and 1% had a perivulvar rash; 64% of patients only had perioral, perinasal, and periocular involvement. In others, lesions also were found on the cheeks, chin, neck, and forehead. Perioral lesions were more likely to be found in patients younger than 5 years compared to those who were at least 5 years of age. Eighty-six percent of patients had erythema with or without scaling, 66% had papules, and 11% had pustules. Fewer than 3% had lichenification, telangiectases, or changes in pigmentation.³

Boeck et al¹⁹ described 7 pediatric patients with perioral dermatitis. Six (86%) patients had perioral lesions, and 6 (86%) had previously been treated with moderate- to high-potency topical corticosteroids. Skin prick tests were negative in 6 (86%) patients.¹⁹ In one case report, a 6-year-old boy did not present with the classic acneform lesions but rather sharply demarcated eczematous patches around the eyes, nose, and mouth. The rash began to fade after 2 weeks of using metronidazole gel 1%, and after 4 months he was only left with mild hyperpigmentation.⁴

Periorificial dermatitis was once thought to be a juvenile form of rosacea.⁵ In 1972, Savin et al⁸ described 11 pediatric patients with “rosacea-like” facial flushing, papules, pustules, and scaling over the cheeks, forehead, and chin. In some patients, the eyelids also were involved. At least 8 patients had been using potent topical corticosteroids and had noticed exacerbation of their skin lesions after stopping therapy.⁸

Variants of POD

Several other variants of POD have been described in pediatric patients including childhood granulomatous periorificial dermatitis (CGPD)(also known as facial Afro-Caribbean [childhood] eruption) and lupus miliaris disseminatus faciei. Childhood granulomatous periorificial dermatitis presents in prepubertal children as dome-shaped, red to yellow-brown, monomorphous papules around the eyes, nose, and mouth; there are no systemic findings.^20,21 It occurs equally in males and females and is more commonly seen in dark-skinned patients. Childhood granulomatous periorificial dermatitis usually resolves within a few months to years but may be associated with blepharitis or conjunctivitis.²⁰ Urbatsch et al²⁰ analyzed extrafacial lesions in 8 patients (aged 2–12 years) with CGPD. Lesions were found on the trunk (38% [3/8]), neck (25% [2/8]), ears (25% [2/8]), extremities (50% [4/8]), labia majora (38% [3/8]), and abdomen (13% [1/8]). In addition, 2 (25% [2/8]) patients had blepharitis.²⁰

Lupus miliaris disseminatus faciei, which occurs in adolescents and adults, commonly involves the eyelids and central areas of the face such as the nose and upper lips. Patients typically present with erythematous or flesh-colored papules.¹

Diagnosis

Diagnosis of POD is made clinically based on the observation of papules (and sometimes pustules) around the orifices of the face, sparing the vermilion border, together with a lack of comedones.¹⁷ Laboratory tests are not useful.⁵ Biopsies rarely are performed, and the results mimic those of rosacea, demonstrating a perifollicular lymphohistiocytic infiltrate, epithelioid cells, and occasionally giant cells.^5,22,23 Early papular lesions can show mild acanthosis, epidermal edema, and parakeratosis.²³ Biopsies in patients with CGPD reveal noncaseating perifollicular granulomas.²⁰

Treatment and Clinical Outcome

Although topical corticosteroids can improve facial lesions in pediatric POD, the eruption often rebounds when therapy is discontinued.¹ One therapy frequently used in adults is oral tetracyclines; however, these agents must not be used in patients younger than 9 years due to potential dental staining.⁴ The standards are either topical metronidazole twice daily with clearance in 3 to 8 weeks or oral erythromycin.⁷

In the review conducted by Goel et al,¹⁷ treatment included azithromycin (44.6%), topical metronidazole (42.3%), sodium sulfacetamide lotion (35.6%), oral antibiotic monotherapy (15.3%), topical agent monotherapy (44.6%), and combined oral and topical agent therapy (40.1%). Of those patients who presented for a follow-up visit (59%), 72% of cases resolved and 10.7% showed some improvement. For those patients who returned for follow-up, the average duration until symptom resolution was approximately 4 months. The most common side effects were pigmentation changes (1.8%), worsening of symptoms (1.8%), gastrointestinal upset (0.9%), irritant dermatitis (0.9%), and xerosis (0.5%).¹⁷

Changes were made to the treatment plans for 16 patients, most often due to inadequate treatment response.¹⁷ Five patients treated with sodium sulfacetamide lotion also were started on oral azithromycin. Four patients treated with oral antibiotics were given a topical agent (metronidazole or sodium sulfacetamide lotion). Other modifications included replacing sodium sulfacetamide lotion with topical metronidazole and an oral antibiotic (azithromycin or doxycycline, n=3), adjusting the doses of oral or topical medications (n=2), adding tacrolimus (n=1), and replacing topical metronidazole with sodium sulfacetamide lotion (n=1). Of the patients who underwent a change in treatment plan, 5 experienced symptom recurrence, 4 had mild improvement, and 1 patient had no improvement. Six patients were lost to follow-up.¹⁷

In the study conducted by Nguyen and Eichenfield,³ follow-up visits occurred approximately 3 months after the first visit. Fifty-two percent of patients used metronidazole alone or with another medication; for most of these patients, the POD cleared an average of 7 weeks after starting treatment, ranging from 1 to 24 weeks. The use of topical calcineurin inhibitors, sulfacetamide, hydrocortisone, or antifungal therapies was associated with persistence of the rash at the follow-up visit. In contrast, the use of metronidazole and/or oral erythromycin was associated with resolution of the rash at the follow-up visit. The investigators recommended the following regimen: topical metronidazole for 1 to 2 months and, if necessary, the addition of oral erythromycin.³

In the case series by Boeck et al,¹⁹ all patients were started on metronidazole gel 1% applied once daily for the first week, and then twice daily until the lesions resolved. All patients showed improvement after 4 to 6 weeks, and eventually the disease cleared between 3 and 6 months. All patients were still symptom free during a 2-year observation period.¹⁹

Manders and Lucky⁷ described 14 patients with POD (aged 9 months to 6.5 years). Eight patients used only metronidazole gel 0.75%, while 5 used the gel in combination with topical corticosteroids (21% [3/14]), oral erythromycin (7% [1/14]), or topical erythromycin (7% [1/14]); 1 patient remained on hydrocortisone 1% and cleared. Patients responded well within 1 to 8 weeks and were symptom free for up to 16 months. Mid- to high-potency steroids were discontinued in all patients.⁷

In some pediatric patients with CGPD, recovery occurs faster with the use of oral macrolides or tetracyclines, either alone or in combination with topical antibiotics or sulfur-based lotions.²⁰ Extrafacial lesions associated with CGPD do not appear to negatively impact treatment response or duration of disease. In the review conducted by Urbatsch et al,²⁰ 7 of 8 (88%) CGPD patients with extrafacial lesions were treated with oral agents including erythromycin, hydroxychloroquine, cyclosporine, minocycline, and azithromycin. Most of these patients also were using topical agents such as triamcinolone acetonide, desonide, metronidazole, and erythromycin. The time to resolution ranged from several weeks to 6 months.²⁰

Weston and Morelli⁹ described a treatment regimen for steroid rosacea. The study included data on 106 children (60 females, 46 males) who had been exposed to mostly class 7 low-potency agents. All patients were advised to immediately stop topical steroid therapy without gradual withdrawal and to begin oral erythromycin stearate 30 mg/kg daily in 2 doses per day for 4 weeks. Patients who were unable to tolerate erythromycin were advised to use topical clindamycin phosphate twice daily for 4 weeks (n=6). Eighty-six percent of patients showed resolution within 4 weeks, and 100% showed clearance by 8 weeks. Twenty-two percent of patients had clearance within 3 weeks. There was no difference in the duration until resolution for those who had used oral or topical antibiotics.⁹ A different study suggested that low-potency topical steroids can be used to control inflammation when weaning patients off of strong steroids.⁵

Differential Diagnosis

The differential diagnosis should include acne vulgaris, allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, impetigo, dermatophyte infection, rosacea, and angiofibromas.⁴

Acne vulgaris commonly is found in older adolescents, and unlike POD, it will present with open or closed comedones.² In patients aged 1 to 7 years, acne is a reason to consider endocrine evaluation. Allergic contact dermatitis is extremely pruritic, and the lesions often are papulovesicular with active weeping or crusting. Patients with irritant contact dermatitis often report burning and pain, and papules and pustules typically are absent. A thorough history can help rule out allergic or irritant contact dermatitis. Seborrheic dermatitis presents with erythema and scaling of the scalp, eyebrows, and nasolabial folds; it tends to spare the perioral regions and also lacks papules.² The lesions of impetigo typically have a yellow-brown exudate, which forms a honey-colored crust.²⁴ Tinea faciei, unlike the other tinea infections, can have an extremely variable presentation. Lesions usually begin as scaly macules that develop raised borders with central hypopigmentation, but papules, vesicles, and crusts can be seen.²⁵ Potassium hydroxide preparation can help diagnose a fungal infection. Rosacea presents with flushing of the central face regions, sometimes accompanied by papules, pustules, and telangiectases.² Although rare, physicians must rule out angiofibromas. Typically found in patients older than 5 years, angiofibromas are pink or flesh-colored papules often found on the nasolabial folds, cheeks, and chin.² Many angiofibromas can be associated with tuberous sclerosis.

Conclusion

Diagnosis of POD is clinical and rests upon the finding of erythematous papules on the face near the eyes, mouth, and nose. Extrafacial lesions also have been described, particularly in pediatric patients with CGPD. Many patients will report a history of atopic dermatitis and asthma. Therapy for POD includes both topical and systemic agents. For those with mild disease, topical metronidazole commonly is used. For patients requiring oral antibiotics, tetracyclines or macrolides can be prescribed based on the age of the patient. Many pediatric patients who begin with both oral and topical agents can later be maintained on topical therapy, sometimes with a low-dose oral antibiotic. Periorificial dermatitis has an excellent prognosis and most pediatric patients show marked improvement within weeks to months.

Perioral dermatitis is an acneform eruption presenting with erythematous papules, vesicles, and rarely pustules clustered around the orifices of the face. ¹ Lesions may be found near the eyes, mouth, and nose but typically spare the vermilion border of the lips. ² Nguyen and Eichenfield ³ preferred the term periorificial dermatitis (POD), which has since been adopted by others. ⁴ Patients may report pruritus, but there generally are no systemic symptoms unless patients have comorbid conditions such as atopic dermatitis. ⁵ Although this condition has been well examined in the literature on adults, data in the pediatric population are far more limited, consisting of case series and retrospective chart reviews. In 1979, Wilkinson et al ⁶ published a study of more than 200 patients with perioral dermatitis, but only 15 patients younger than 12 years were included.

Etiology

Although the exact pathogenesis of POD is unknown, a common denominator among many patients is prior exposure to topical corticosteroids.^3,7-9 Periorificial dermatitis also has been linked to the use of systemic corticosteroids in pediatric patients.¹⁰ The exact relationship between steroid use and dermatitis is unknown; it may be related to a change in the flora of hair follicles and in particular an association with fusiform bacteria–rich conditions.¹¹ Aside from steroid exposure, POD has been associated with the use of physical sunscreen in pediatric patients with dry skin,¹² rosin in chewing gum,¹³ and inhaled corticosteroids in those with asthma.¹⁴ In one case, a 15-year-old adolescent girl developed POD and swelling of the lips after 2 years of playing a flute made of cocus wood.^15,16

Epidemiology

In the largest chart review to date in the US pediatric population, Goel et al¹⁷ examined the clinical course of POD in 222 patients aged 3 months to 18 years at the Dermatology Clinic at the University of North Carolina Chapel Hill between June 2002 and March 2014. Consistent with prior studies, females seemed to be slightly more affected than males (55.4% vs 44.6%).¹⁷ Similarly, the patient population for a study conducted by Nguyen and Eichenfield³ consisted of more females (58% [46/79]) than males (42% [33/79]). Weston and Morelli⁹ conducted a retrospective chart review of steroid rosacea in 106 patients younger than 13 years, which included 29 patients younger than 3 years; the study included 46 males and 60 females.

Comorbidities and Family History

Goel et al¹⁷ (N=222) reported the following comorbidities associated with pediatric POD: atopic dermatitis (29.3%), asthma (14.9%), and allergies (9.9%). Steroid exposure was noted in 58.1% of patients.¹⁷ Similarly, Nguyen and Eichenfield³ (N=79) found that the most common comorbidities were atopic dermatitis (14%), keratosis pilaris (14%), viral infections (14%), acne (10%), and seborrheic dermatitis (10%). Family history of atopy was noted in 55% of patients and family history of rosacea was noted in 3%. In a case series of 11 pediatric patients, 3 (27%) had keratosis pilaris, 7 (64%) had a family history of atopy, and 2 (18%) had a family history of rosacea.⁸ Weston and Morelli⁹ found a much higher incidence of familial rosacea (20%) in 106 children with steroid rosacea. It is hard to interpret the role of genetic tendency in rosacea, as different populations have different background prevalence of rosacea and atopic dermatitis (ie, rosacea is immensely more common in white individuals).

Clinical Presentation

Periorificial dermatitis generally presents with small, pink- to flesh-colored papules in a perioral, periocular, and perinasal distribution. Although many patients are white, a particularly prominent variant has been noted in black children with papules that may be hyperpigmented.¹⁸ In a 2006 chart review in 79 pediatric POD patients aged 6 months to 18 years, Nguyen and Eichenfield³ reported that 92% (73/79) of patients presented for a facial rash with an average duration ranging from 2 weeks to 4 years. Interestingly, although Tempark and Shwayder¹ did not report burning associated with pediatric POD, Nguyen and Eichenfield³ found that 19% of patients reported pruritus and 4% reported burning or tenderness. Seventy-two percent of patients had been exposed to steroids for treatment of their dermatitis. Seventy percent had perioral involvement, 43% had perinasal involvement, 25% had periocular involvement, and 1% had a perivulvar rash; 64% of patients only had perioral, perinasal, and periocular involvement. In others, lesions also were found on the cheeks, chin, neck, and forehead. Perioral lesions were more likely to be found in patients younger than 5 years compared to those who were at least 5 years of age. Eighty-six percent of patients had erythema with or without scaling, 66% had papules, and 11% had pustules. Fewer than 3% had lichenification, telangiectases, or changes in pigmentation.³

Boeck et al¹⁹ described 7 pediatric patients with perioral dermatitis. Six (86%) patients had perioral lesions, and 6 (86%) had previously been treated with moderate- to high-potency topical corticosteroids. Skin prick tests were negative in 6 (86%) patients.¹⁹ In one case report, a 6-year-old boy did not present with the classic acneform lesions but rather sharply demarcated eczematous patches around the eyes, nose, and mouth. The rash began to fade after 2 weeks of using metronidazole gel 1%, and after 4 months he was only left with mild hyperpigmentation.⁴

Periorificial dermatitis was once thought to be a juvenile form of rosacea.⁵ In 1972, Savin et al⁸ described 11 pediatric patients with “rosacea-like” facial flushing, papules, pustules, and scaling over the cheeks, forehead, and chin. In some patients, the eyelids also were involved. At least 8 patients had been using potent topical corticosteroids and had noticed exacerbation of their skin lesions after stopping therapy.⁸

Variants of POD

Several other variants of POD have been described in pediatric patients including childhood granulomatous periorificial dermatitis (CGPD)(also known as facial Afro-Caribbean [childhood] eruption) and lupus miliaris disseminatus faciei. Childhood granulomatous periorificial dermatitis presents in prepubertal children as dome-shaped, red to yellow-brown, monomorphous papules around the eyes, nose, and mouth; there are no systemic findings.^20,21 It occurs equally in males and females and is more commonly seen in dark-skinned patients. Childhood granulomatous periorificial dermatitis usually resolves within a few months to years but may be associated with blepharitis or conjunctivitis.²⁰ Urbatsch et al²⁰ analyzed extrafacial lesions in 8 patients (aged 2–12 years) with CGPD. Lesions were found on the trunk (38% [3/8]), neck (25% [2/8]), ears (25% [2/8]), extremities (50% [4/8]), labia majora (38% [3/8]), and abdomen (13% [1/8]). In addition, 2 (25% [2/8]) patients had blepharitis.²⁰

Lupus miliaris disseminatus faciei, which occurs in adolescents and adults, commonly involves the eyelids and central areas of the face such as the nose and upper lips. Patients typically present with erythematous or flesh-colored papules.¹

Diagnosis

Diagnosis of POD is made clinically based on the observation of papules (and sometimes pustules) around the orifices of the face, sparing the vermilion border, together with a lack of comedones.¹⁷ Laboratory tests are not useful.⁵ Biopsies rarely are performed, and the results mimic those of rosacea, demonstrating a perifollicular lymphohistiocytic infiltrate, epithelioid cells, and occasionally giant cells.^5,22,23 Early papular lesions can show mild acanthosis, epidermal edema, and parakeratosis.²³ Biopsies in patients with CGPD reveal noncaseating perifollicular granulomas.²⁰

Treatment and Clinical Outcome

Although topical corticosteroids can improve facial lesions in pediatric POD, the eruption often rebounds when therapy is discontinued.¹ One therapy frequently used in adults is oral tetracyclines; however, these agents must not be used in patients younger than 9 years due to potential dental staining.⁴ The standards are either topical metronidazole twice daily with clearance in 3 to 8 weeks or oral erythromycin.⁷

In the review conducted by Goel et al,¹⁷ treatment included azithromycin (44.6%), topical metronidazole (42.3%), sodium sulfacetamide lotion (35.6%), oral antibiotic monotherapy (15.3%), topical agent monotherapy (44.6%), and combined oral and topical agent therapy (40.1%). Of those patients who presented for a follow-up visit (59%), 72% of cases resolved and 10.7% showed some improvement. For those patients who returned for follow-up, the average duration until symptom resolution was approximately 4 months. The most common side effects were pigmentation changes (1.8%), worsening of symptoms (1.8%), gastrointestinal upset (0.9%), irritant dermatitis (0.9%), and xerosis (0.5%).¹⁷

Changes were made to the treatment plans for 16 patients, most often due to inadequate treatment response.¹⁷ Five patients treated with sodium sulfacetamide lotion also were started on oral azithromycin. Four patients treated with oral antibiotics were given a topical agent (metronidazole or sodium sulfacetamide lotion). Other modifications included replacing sodium sulfacetamide lotion with topical metronidazole and an oral antibiotic (azithromycin or doxycycline, n=3), adjusting the doses of oral or topical medications (n=2), adding tacrolimus (n=1), and replacing topical metronidazole with sodium sulfacetamide lotion (n=1). Of the patients who underwent a change in treatment plan, 5 experienced symptom recurrence, 4 had mild improvement, and 1 patient had no improvement. Six patients were lost to follow-up.¹⁷

In the study conducted by Nguyen and Eichenfield,³ follow-up visits occurred approximately 3 months after the first visit. Fifty-two percent of patients used metronidazole alone or with another medication; for most of these patients, the POD cleared an average of 7 weeks after starting treatment, ranging from 1 to 24 weeks. The use of topical calcineurin inhibitors, sulfacetamide, hydrocortisone, or antifungal therapies was associated with persistence of the rash at the follow-up visit. In contrast, the use of metronidazole and/or oral erythromycin was associated with resolution of the rash at the follow-up visit. The investigators recommended the following regimen: topical metronidazole for 1 to 2 months and, if necessary, the addition of oral erythromycin.³

In the case series by Boeck et al,¹⁹ all patients were started on metronidazole gel 1% applied once daily for the first week, and then twice daily until the lesions resolved. All patients showed improvement after 4 to 6 weeks, and eventually the disease cleared between 3 and 6 months. All patients were still symptom free during a 2-year observation period.¹⁹

Manders and Lucky⁷ described 14 patients with POD (aged 9 months to 6.5 years). Eight patients used only metronidazole gel 0.75%, while 5 used the gel in combination with topical corticosteroids (21% [3/14]), oral erythromycin (7% [1/14]), or topical erythromycin (7% [1/14]); 1 patient remained on hydrocortisone 1% and cleared. Patients responded well within 1 to 8 weeks and were symptom free for up to 16 months. Mid- to high-potency steroids were discontinued in all patients.⁷

In some pediatric patients with CGPD, recovery occurs faster with the use of oral macrolides or tetracyclines, either alone or in combination with topical antibiotics or sulfur-based lotions.²⁰ Extrafacial lesions associated with CGPD do not appear to negatively impact treatment response or duration of disease. In the review conducted by Urbatsch et al,²⁰ 7 of 8 (88%) CGPD patients with extrafacial lesions were treated with oral agents including erythromycin, hydroxychloroquine, cyclosporine, minocycline, and azithromycin. Most of these patients also were using topical agents such as triamcinolone acetonide, desonide, metronidazole, and erythromycin. The time to resolution ranged from several weeks to 6 months.²⁰

Weston and Morelli⁹ described a treatment regimen for steroid rosacea. The study included data on 106 children (60 females, 46 males) who had been exposed to mostly class 7 low-potency agents. All patients were advised to immediately stop topical steroid therapy without gradual withdrawal and to begin oral erythromycin stearate 30 mg/kg daily in 2 doses per day for 4 weeks. Patients who were unable to tolerate erythromycin were advised to use topical clindamycin phosphate twice daily for 4 weeks (n=6). Eighty-six percent of patients showed resolution within 4 weeks, and 100% showed clearance by 8 weeks. Twenty-two percent of patients had clearance within 3 weeks. There was no difference in the duration until resolution for those who had used oral or topical antibiotics.⁹ A different study suggested that low-potency topical steroids can be used to control inflammation when weaning patients off of strong steroids.⁵

Differential Diagnosis

The differential diagnosis should include acne vulgaris, allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, impetigo, dermatophyte infection, rosacea, and angiofibromas.⁴

Acne vulgaris commonly is found in older adolescents, and unlike POD, it will present with open or closed comedones.² In patients aged 1 to 7 years, acne is a reason to consider endocrine evaluation. Allergic contact dermatitis is extremely pruritic, and the lesions often are papulovesicular with active weeping or crusting. Patients with irritant contact dermatitis often report burning and pain, and papules and pustules typically are absent. A thorough history can help rule out allergic or irritant contact dermatitis. Seborrheic dermatitis presents with erythema and scaling of the scalp, eyebrows, and nasolabial folds; it tends to spare the perioral regions and also lacks papules.² The lesions of impetigo typically have a yellow-brown exudate, which forms a honey-colored crust.²⁴ Tinea faciei, unlike the other tinea infections, can have an extremely variable presentation. Lesions usually begin as scaly macules that develop raised borders with central hypopigmentation, but papules, vesicles, and crusts can be seen.²⁵ Potassium hydroxide preparation can help diagnose a fungal infection. Rosacea presents with flushing of the central face regions, sometimes accompanied by papules, pustules, and telangiectases.² Although rare, physicians must rule out angiofibromas. Typically found in patients older than 5 years, angiofibromas are pink or flesh-colored papules often found on the nasolabial folds, cheeks, and chin.² Many angiofibromas can be associated with tuberous sclerosis.

Conclusion

Diagnosis of POD is clinical and rests upon the finding of erythematous papules on the face near the eyes, mouth, and nose. Extrafacial lesions also have been described, particularly in pediatric patients with CGPD. Many patients will report a history of atopic dermatitis and asthma. Therapy for POD includes both topical and systemic agents. For those with mild disease, topical metronidazole commonly is used. For patients requiring oral antibiotics, tetracyclines or macrolides can be prescribed based on the age of the patient. Many pediatric patients who begin with both oral and topical agents can later be maintained on topical therapy, sometimes with a low-dose oral antibiotic. Periorificial dermatitis has an excellent prognosis and most pediatric patients show marked improvement within weeks to months.

According to the US Food and Drug Administration (FDA), a biosimilar is “highly similar to an FDA-approved biological product, . . . and has no clinically meaningful differences in terms of safety and effectiveness.”¹ The Biologics Price Competition and Innovation (BPCI) Act of 2009 created an expedited pathway for the approval of products shown to be biosimilar to FDA-licensed reference products.² In 2013, the European Medicines Agency approved the first biosimilar modeled on infliximab (Remsima [formerly known as CT-P13], Celltrion Healthcare Co, Ltd) for the same indications as its reference product.³ In 2016, the FDA approved Inflectra (Hospira, a Pfizer Company), an infliximab biosimilar; Erelzi (Sandoz, a Novartis Division), an etanercept biosimilar; and Amjevita (Amgen Inc), an adalimumab biosimilar, all for numerous clinical indications including plaque psoriasis and psoriatic arthritis.^4-6

There has been a substantial amount of distrust surrounding the biosimilars; however, as the patents for the biologic agents expire, new biosimilars will undoubtedly flood the market. In this article, we provide information that will help dermatologists understand the need for and use of these agents.

Biosimilars Versus Generic Drugs

Small-molecule generics can be made in a process that is relatively inexpensive, reproducible, and able to yield identical products with each lot.⁷ In contrast, biosimilars are large complex proteins made in living cells. They differ from their reference product because of changes that occur during manufacturing (eg, purification system, posttranslational modifications).^7-9 Glycosylation is particularly sensitive to manufacturing and can affect the immunogenicity of the product.⁹ The impact of manufacturing can be substantial; for example, during phase 3 trials for efalizumab, a change in the manufacturing facility affected pharmacokinetic properties to such a degree that the FDA required a repeat of the trials.¹⁰

FDA Guidelines on Biosimilarity

The FDA outlines the following approach to demonstrate biosimilarity.² The first step is structural characterization to evaluate the primary, secondary, tertiary, and quaternary structures and posttranslational modifications. The next step utilizes in vivo and/or in vitro functional assays to compare the biosimilar and reference product. The third step is a focus on toxicity and immunogenicity. The fourth step involves clinical studies to study pharmacokinetic and pharmacodynamic data, immunogenicity, safety, and efficacy. After the biosimilar has been approved, there must be a system in place to monitor postmarketing safety. If a biosimilar is tested in one patient population (eg, patients with plaque psoriasis), a request can be made to approve the drug for all the conditions that the reference product was approved for, such as plaque psoriasis, rheumatoid arthritis, and inflammatory bowel disease, even though clinical trials were not performed in all of these patient populations.² The BPCI Act leaves it up to the FDA to determine how much and what type of data (eg, in vitro, in vivo, clinical) are required.¹¹

Extrapolation and Interchangeability

Once a biosimilar has been approved, 2 questions must be answered: First, can its use be extrapolated to all indications for the reference product? The infliximab biosimilar approved by the European Medicines Agency and the FDA had only been studied in patients with ankylosing spondylitis¹² and rheumatoid arthritis,¹³ yet it was granted all the indications for infliximab, including severe plaque psoriasis.¹⁴ As of now, the various regulatory agencies differ on their policies regarding extrapolation. Extrapolation is not automatically bestowed on a biosimilar in the United States but can be requested by the manufacturer.²

Second, can the biosimilar be seamlessly switched with its reference product at the pharmacy level? The BPCI Act allows for the substitution of biosimilars that are deemed interchangeable without notifying the provider, yet individual states ultimately can pass laws regarding this issue.^15,16 An interchangeable agent would “produce the same clinical result as the reference product,” and “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product.”¹⁵ Generic drugs are allowed to be substituted without notifying the patient or prescriber¹⁶; however, biosimilars that are not deemed interchangeable would require permission from the prescriber before substitution.¹¹

Biosimilars for Psoriasis

In April 2016, an infliximab biosimilar (Inflectra) became the second biosimilar approved by the FDA.⁴ Inflectra was studied in clinical trials for patients with ankylosing spondylitis¹⁷ and rheumatoid arthritis,¹⁸ and in both trials the biosimilar was found to have similar efficacy and safety profiles to that of the reference product. In August 2016, an etanercept biosimilar (Erelzi) was approved,⁵ and in September 2016, an adalimumab biosimilar (Amjevita) was approved.⁶

The Table summarizes clinical trials (both completed and ongoing) evaluating biosimilars in adults with plaque psoriasis; thus far, there are 2464 participants enrolled across 5 different studies of adalimumab biosimilars (registered at www.clinicaltrials.gov with the identifiers NCT01970488, NCT02016105, NCT02489227, NCT02714322, NCT02581345) and 531 participants in an etanercept biosimilar study (NCT01891864).

A phase 3 double-blind study compared adalimumab to an adalimumab biosimilar (ABP 501) in 350 adults with plaque psoriasis (NCT01970488). Participants received an initial loading dose of adalimumab (n=175) or ABP 501 (n=175) 80 mg subcutaneously on week 1/day 1, followed by 40 mg at week 2 every 2 weeks thereafter. At week 16, participants with psoriasis area and severity index (PASI) 50 or greater remained in the study for up to 52 weeks; those who were receiving adalimumab were re-randomized to receive either ABP 501 or adalimumab. Participants receiving ABP 501 continued to receive the biosimilar. The mean PASI improvement at weeks 16, 32, and 50 was 86.6, 87.6, and 87.2, respectively, in the ABP 501/ABP 501 group (A/A) compared to 88.0, 88.2, and 88.1, respectively, in the adalimumab/adalimumab group (B/B).¹⁹ Autoantibodies developed in 68.4% of participants in the A/A group compared to 74.7% in the B/B group. The incidence of treatment-emergent adverse events (TEAEs) was 86.2% in the A/A group and 78.5% in the B/B group. The most common TEAEs were nasopharyngitis, headache, and upper respiratory tract infection. The incidence of serious TEAEs was 4.6% in the A/A group compared to 5.1% in the B/B group. Overall, the efficacy, safety, and immunogenicity of the adalimumab biosimilar was comparable to the reference product.¹⁹

A second phase 3 trial (ADACCESS) evaluated the adalimumab biosimilar GP2017 (NCT02016105). Participants received an initial dose of 80 mg subcutaneously of either GP2017 or adalimumab at week 0, followed by 40 mg every other week starting at week 1 and ending at week 51. The study has been completed but results are not yet available.

The third trial is evaluating the adalimumab biosimilar CHS-1420 (NCT02489227). Participants in the experimental arm receive two 40-mg doses of CHS-1420 at week 0/day 0, and then 1 dose every 2 weeks from week 1 for 23 weeks. At week 24, participants continue with an open-label study. Participants in the adalimumab group receive two 40-mg doses at week 0/day 0, and then 1 dose every 2 weeks from week 1 to week 15. At week 16, participants will be re-randomized (1:1) to continue adalimumab or start CHS-1420 at one 40-mg dose every 2 weeks during weeks 17 to 23. At week 24, participants will switch to CHS-1420 open label until the end of the study. Study results are not yet available; the study is ongoing but not recruiting.

The fourth ongoing trial is evaluating the adalimumab biosimilar MYL-1401A (NCT02714322). Participants receive an initial dose of 80 mg subcutaneously of either MYL-1401A or adalimumab (2:1), followed by 40 mg every other week starting 1 week after the initial dose. After the 52-week treatment period, there is an 8-week safety follow-up period. Study results are not yet available; the study is ongoing but not recruiting.

A fifth adalimumab biosimilar, M923, also is currently being tested in clinical trials (NCT02581345). Participants receive either M923, adalimumab, or alternate between the 2 agents. Although the study is still ongoing, data released from the manufacturer state that the proportion of participants who achieved PASI 75 after 16 weeks of treatment was equivalent in the 2 treatment groups. The proportion of participants who achieved PASI 90, as well as the type, frequency, and severity of adverse events, also were comparable.²⁰

The EGALITY trial, completed in March 2015, compared the etanercept biosimilar GP2015 to etanercept over a 52-week period (NCT01891864). Participants received either GP2015 or etanercept 50 mg twice weekly for the first 12 weeks. Participants with at least PASI 50 were then re-randomized into 4 groups: the first 2 groups stayed with their current treatments while the other 2 groups alternated treatments every 6 weeks until week 30. Participants then stayed on their last treatment from week 30 to week 52. The adjusted PASI 75 response rate at week 12 was 73.4% in the group receiving GP2015 and 75.7% in the group receiving etanercept.²¹ The percentage change in PASI score at all time points was found to be comparable from baseline until week 52. Importantly, the incidence of TEAEs up to week 52 was comparable and no new safety issues were reported. Additionally, switching participants from etanercept to the biosimilar during the subsequent treatment periods did not cause an increase in formation of antidrug antibodies.²¹

There are 2 upcoming studies involving biosimilars that are not yet recruiting patients. The first (NCT02925338) will analyze the characteristics of patients treated with Inflectra as well as their response to treatment. The second (NCT02762955) will be comparing the efficacy and safety of an adalimumab biosimilar (BCD-057, BIOCAD) to adalimumab.

Economic Advantages of Biosimilars

The annual economic burden of psoriasis in the United States is substantial, with estimates between $35.2 billion²² and $112 billion.²³ Biosimilars can be 25% to 30% cheaper than their reference products^9,11,24 and have the potential to save the US health care system billions of dollars.²⁵ Furthermore, the developers of biosimilars could offer patient assistance programs.¹¹ That being said, drug developers can extend patents for their branded drugs; for instance, 2 patents for Enbrel (Amgen Inc) could protect the drug until 2029.^26,27

Although cost is an important factor in deciding which medications to prescribe for patients, it should never take precedence over safety and efficacy. Manufacturers can develop new drugs with greater efficacy, fewer side effects, or more convenient dosing schedules,^26,27 or they could offer co-payment assistance programs.^26,28 Physicians also must consider how the biosimilars will be integrated into drug formularies. Would patients be required to use a biosimilar before a branded drug?^11,29 Will patients already taking a branded drug be grandfathered in?¹¹ Would they have to pay a premium to continue taking their drug? And finally, could changes in formularies and employer-payer relationships destabilize patient regimens?³⁰

Conclusion

Preliminary results suggest that biosimilars can have similar safety, efficacy, and immunogenicity data compared to their reference products.^19,21 Biosimilars have the potential to greatly reduce the cost burden associated with psoriasis. However, how similar is “highly similar”? Although cost is an important consideration in selecting drug therapies, the reason for using a biosimilar should never be based on cost alone.

According to the US Food and Drug Administration (FDA), a biosimilar is “highly similar to an FDA-approved biological product, . . . and has no clinically meaningful differences in terms of safety and effectiveness.”¹ The Biologics Price Competition and Innovation (BPCI) Act of 2009 created an expedited pathway for the approval of products shown to be biosimilar to FDA-licensed reference products.² In 2013, the European Medicines Agency approved the first biosimilar modeled on infliximab (Remsima [formerly known as CT-P13], Celltrion Healthcare Co, Ltd) for the same indications as its reference product.³ In 2016, the FDA approved Inflectra (Hospira, a Pfizer Company), an infliximab biosimilar; Erelzi (Sandoz, a Novartis Division), an etanercept biosimilar; and Amjevita (Amgen Inc), an adalimumab biosimilar, all for numerous clinical indications including plaque psoriasis and psoriatic arthritis.^4-6

There has been a substantial amount of distrust surrounding the biosimilars; however, as the patents for the biologic agents expire, new biosimilars will undoubtedly flood the market. In this article, we provide information that will help dermatologists understand the need for and use of these agents.

Biosimilars Versus Generic Drugs

Small-molecule generics can be made in a process that is relatively inexpensive, reproducible, and able to yield identical products with each lot.⁷ In contrast, biosimilars are large complex proteins made in living cells. They differ from their reference product because of changes that occur during manufacturing (eg, purification system, posttranslational modifications).^7-9 Glycosylation is particularly sensitive to manufacturing and can affect the immunogenicity of the product.⁹ The impact of manufacturing can be substantial; for example, during phase 3 trials for efalizumab, a change in the manufacturing facility affected pharmacokinetic properties to such a degree that the FDA required a repeat of the trials.¹⁰

FDA Guidelines on Biosimilarity

The FDA outlines the following approach to demonstrate biosimilarity.² The first step is structural characterization to evaluate the primary, secondary, tertiary, and quaternary structures and posttranslational modifications. The next step utilizes in vivo and/or in vitro functional assays to compare the biosimilar and reference product. The third step is a focus on toxicity and immunogenicity. The fourth step involves clinical studies to study pharmacokinetic and pharmacodynamic data, immunogenicity, safety, and efficacy. After the biosimilar has been approved, there must be a system in place to monitor postmarketing safety. If a biosimilar is tested in one patient population (eg, patients with plaque psoriasis), a request can be made to approve the drug for all the conditions that the reference product was approved for, such as plaque psoriasis, rheumatoid arthritis, and inflammatory bowel disease, even though clinical trials were not performed in all of these patient populations.² The BPCI Act leaves it up to the FDA to determine how much and what type of data (eg, in vitro, in vivo, clinical) are required.¹¹

Extrapolation and Interchangeability

Once a biosimilar has been approved, 2 questions must be answered: First, can its use be extrapolated to all indications for the reference product? The infliximab biosimilar approved by the European Medicines Agency and the FDA had only been studied in patients with ankylosing spondylitis¹² and rheumatoid arthritis,¹³ yet it was granted all the indications for infliximab, including severe plaque psoriasis.¹⁴ As of now, the various regulatory agencies differ on their policies regarding extrapolation. Extrapolation is not automatically bestowed on a biosimilar in the United States but can be requested by the manufacturer.²

Second, can the biosimilar be seamlessly switched with its reference product at the pharmacy level? The BPCI Act allows for the substitution of biosimilars that are deemed interchangeable without notifying the provider, yet individual states ultimately can pass laws regarding this issue.^15,16 An interchangeable agent would “produce the same clinical result as the reference product,” and “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product.”¹⁵ Generic drugs are allowed to be substituted without notifying the patient or prescriber¹⁶; however, biosimilars that are not deemed interchangeable would require permission from the prescriber before substitution.¹¹

Biosimilars for Psoriasis

In April 2016, an infliximab biosimilar (Inflectra) became the second biosimilar approved by the FDA.⁴ Inflectra was studied in clinical trials for patients with ankylosing spondylitis¹⁷ and rheumatoid arthritis,¹⁸ and in both trials the biosimilar was found to have similar efficacy and safety profiles to that of the reference product. In August 2016, an etanercept biosimilar (Erelzi) was approved,⁵ and in September 2016, an adalimumab biosimilar (Amjevita) was approved.⁶

The Table summarizes clinical trials (both completed and ongoing) evaluating biosimilars in adults with plaque psoriasis; thus far, there are 2464 participants enrolled across 5 different studies of adalimumab biosimilars (registered at www.clinicaltrials.gov with the identifiers NCT01970488, NCT02016105, NCT02489227, NCT02714322, NCT02581345) and 531 participants in an etanercept biosimilar study (NCT01891864).

A phase 3 double-blind study compared adalimumab to an adalimumab biosimilar (ABP 501) in 350 adults with plaque psoriasis (NCT01970488). Participants received an initial loading dose of adalimumab (n=175) or ABP 501 (n=175) 80 mg subcutaneously on week 1/day 1, followed by 40 mg at week 2 every 2 weeks thereafter. At week 16, participants with psoriasis area and severity index (PASI) 50 or greater remained in the study for up to 52 weeks; those who were receiving adalimumab were re-randomized to receive either ABP 501 or adalimumab. Participants receiving ABP 501 continued to receive the biosimilar. The mean PASI improvement at weeks 16, 32, and 50 was 86.6, 87.6, and 87.2, respectively, in the ABP 501/ABP 501 group (A/A) compared to 88.0, 88.2, and 88.1, respectively, in the adalimumab/adalimumab group (B/B).¹⁹ Autoantibodies developed in 68.4% of participants in the A/A group compared to 74.7% in the B/B group. The incidence of treatment-emergent adverse events (TEAEs) was 86.2% in the A/A group and 78.5% in the B/B group. The most common TEAEs were nasopharyngitis, headache, and upper respiratory tract infection. The incidence of serious TEAEs was 4.6% in the A/A group compared to 5.1% in the B/B group. Overall, the efficacy, safety, and immunogenicity of the adalimumab biosimilar was comparable to the reference product.¹⁹

A second phase 3 trial (ADACCESS) evaluated the adalimumab biosimilar GP2017 (NCT02016105). Participants received an initial dose of 80 mg subcutaneously of either GP2017 or adalimumab at week 0, followed by 40 mg every other week starting at week 1 and ending at week 51. The study has been completed but results are not yet available.

The third trial is evaluating the adalimumab biosimilar CHS-1420 (NCT02489227). Participants in the experimental arm receive two 40-mg doses of CHS-1420 at week 0/day 0, and then 1 dose every 2 weeks from week 1 for 23 weeks. At week 24, participants continue with an open-label study. Participants in the adalimumab group receive two 40-mg doses at week 0/day 0, and then 1 dose every 2 weeks from week 1 to week 15. At week 16, participants will be re-randomized (1:1) to continue adalimumab or start CHS-1420 at one 40-mg dose every 2 weeks during weeks 17 to 23. At week 24, participants will switch to CHS-1420 open label until the end of the study. Study results are not yet available; the study is ongoing but not recruiting.

The fourth ongoing trial is evaluating the adalimumab biosimilar MYL-1401A (NCT02714322). Participants receive an initial dose of 80 mg subcutaneously of either MYL-1401A or adalimumab (2:1), followed by 40 mg every other week starting 1 week after the initial dose. After the 52-week treatment period, there is an 8-week safety follow-up period. Study results are not yet available; the study is ongoing but not recruiting.

A fifth adalimumab biosimilar, M923, also is currently being tested in clinical trials (NCT02581345). Participants receive either M923, adalimumab, or alternate between the 2 agents. Although the study is still ongoing, data released from the manufacturer state that the proportion of participants who achieved PASI 75 after 16 weeks of treatment was equivalent in the 2 treatment groups. The proportion of participants who achieved PASI 90, as well as the type, frequency, and severity of adverse events, also were comparable.²⁰

The EGALITY trial, completed in March 2015, compared the etanercept biosimilar GP2015 to etanercept over a 52-week period (NCT01891864). Participants received either GP2015 or etanercept 50 mg twice weekly for the first 12 weeks. Participants with at least PASI 50 were then re-randomized into 4 groups: the first 2 groups stayed with their current treatments while the other 2 groups alternated treatments every 6 weeks until week 30. Participants then stayed on their last treatment from week 30 to week 52. The adjusted PASI 75 response rate at week 12 was 73.4% in the group receiving GP2015 and 75.7% in the group receiving etanercept.²¹ The percentage change in PASI score at all time points was found to be comparable from baseline until week 52. Importantly, the incidence of TEAEs up to week 52 was comparable and no new safety issues were reported. Additionally, switching participants from etanercept to the biosimilar during the subsequent treatment periods did not cause an increase in formation of antidrug antibodies.²¹

There are 2 upcoming studies involving biosimilars that are not yet recruiting patients. The first (NCT02925338) will analyze the characteristics of patients treated with Inflectra as well as their response to treatment. The second (NCT02762955) will be comparing the efficacy and safety of an adalimumab biosimilar (BCD-057, BIOCAD) to adalimumab.

Economic Advantages of Biosimilars

The annual economic burden of psoriasis in the United States is substantial, with estimates between $35.2 billion²² and $112 billion.²³ Biosimilars can be 25% to 30% cheaper than their reference products^9,11,24 and have the potential to save the US health care system billions of dollars.²⁵ Furthermore, the developers of biosimilars could offer patient assistance programs.¹¹ That being said, drug developers can extend patents for their branded drugs; for instance, 2 patents for Enbrel (Amgen Inc) could protect the drug until 2029.^26,27

Although cost is an important factor in deciding which medications to prescribe for patients, it should never take precedence over safety and efficacy. Manufacturers can develop new drugs with greater efficacy, fewer side effects, or more convenient dosing schedules,^26,27 or they could offer co-payment assistance programs.^26,28 Physicians also must consider how the biosimilars will be integrated into drug formularies. Would patients be required to use a biosimilar before a branded drug?^11,29 Will patients already taking a branded drug be grandfathered in?¹¹ Would they have to pay a premium to continue taking their drug? And finally, could changes in formularies and employer-payer relationships destabilize patient regimens?³⁰

Conclusion

Preliminary results suggest that biosimilars can have similar safety, efficacy, and immunogenicity data compared to their reference products.^19,21 Biosimilars have the potential to greatly reduce the cost burden associated with psoriasis. However, how similar is “highly similar”? Although cost is an important consideration in selecting drug therapies, the reason for using a biosimilar should never be based on cost alone.

According to the US Food and Drug Administration (FDA), a biosimilar is “highly similar to an FDA-approved biological product, . . . and has no clinically meaningful differences in terms of safety and effectiveness.”¹ The Biologics Price Competition and Innovation (BPCI) Act of 2009 created an expedited pathway for the approval of products shown to be biosimilar to FDA-licensed reference products.² In 2013, the European Medicines Agency approved the first biosimilar modeled on infliximab (Remsima [formerly known as CT-P13], Celltrion Healthcare Co, Ltd) for the same indications as its reference product.³ In 2016, the FDA approved Inflectra (Hospira, a Pfizer Company), an infliximab biosimilar; Erelzi (Sandoz, a Novartis Division), an etanercept biosimilar; and Amjevita (Amgen Inc), an adalimumab biosimilar, all for numerous clinical indications including plaque psoriasis and psoriatic arthritis.^4-6

There has been a substantial amount of distrust surrounding the biosimilars; however, as the patents for the biologic agents expire, new biosimilars will undoubtedly flood the market. In this article, we provide information that will help dermatologists understand the need for and use of these agents.

Biosimilars Versus Generic Drugs

Small-molecule generics can be made in a process that is relatively inexpensive, reproducible, and able to yield identical products with each lot.⁷ In contrast, biosimilars are large complex proteins made in living cells. They differ from their reference product because of changes that occur during manufacturing (eg, purification system, posttranslational modifications).^7-9 Glycosylation is particularly sensitive to manufacturing and can affect the immunogenicity of the product.⁹ The impact of manufacturing can be substantial; for example, during phase 3 trials for efalizumab, a change in the manufacturing facility affected pharmacokinetic properties to such a degree that the FDA required a repeat of the trials.¹⁰

FDA Guidelines on Biosimilarity

The FDA outlines the following approach to demonstrate biosimilarity.² The first step is structural characterization to evaluate the primary, secondary, tertiary, and quaternary structures and posttranslational modifications. The next step utilizes in vivo and/or in vitro functional assays to compare the biosimilar and reference product. The third step is a focus on toxicity and immunogenicity. The fourth step involves clinical studies to study pharmacokinetic and pharmacodynamic data, immunogenicity, safety, and efficacy. After the biosimilar has been approved, there must be a system in place to monitor postmarketing safety. If a biosimilar is tested in one patient population (eg, patients with plaque psoriasis), a request can be made to approve the drug for all the conditions that the reference product was approved for, such as plaque psoriasis, rheumatoid arthritis, and inflammatory bowel disease, even though clinical trials were not performed in all of these patient populations.² The BPCI Act leaves it up to the FDA to determine how much and what type of data (eg, in vitro, in vivo, clinical) are required.¹¹

Extrapolation and Interchangeability

Once a biosimilar has been approved, 2 questions must be answered: First, can its use be extrapolated to all indications for the reference product? The infliximab biosimilar approved by the European Medicines Agency and the FDA had only been studied in patients with ankylosing spondylitis¹² and rheumatoid arthritis,¹³ yet it was granted all the indications for infliximab, including severe plaque psoriasis.¹⁴ As of now, the various regulatory agencies differ on their policies regarding extrapolation. Extrapolation is not automatically bestowed on a biosimilar in the United States but can be requested by the manufacturer.²

Second, can the biosimilar be seamlessly switched with its reference product at the pharmacy level? The BPCI Act allows for the substitution of biosimilars that are deemed interchangeable without notifying the provider, yet individual states ultimately can pass laws regarding this issue.^15,16 An interchangeable agent would “produce the same clinical result as the reference product,” and “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product.”¹⁵ Generic drugs are allowed to be substituted without notifying the patient or prescriber¹⁶; however, biosimilars that are not deemed interchangeable would require permission from the prescriber before substitution.¹¹

Biosimilars for Psoriasis

In April 2016, an infliximab biosimilar (Inflectra) became the second biosimilar approved by the FDA.⁴ Inflectra was studied in clinical trials for patients with ankylosing spondylitis¹⁷ and rheumatoid arthritis,¹⁸ and in both trials the biosimilar was found to have similar efficacy and safety profiles to that of the reference product. In August 2016, an etanercept biosimilar (Erelzi) was approved,⁵ and in September 2016, an adalimumab biosimilar (Amjevita) was approved.⁶

The Table summarizes clinical trials (both completed and ongoing) evaluating biosimilars in adults with plaque psoriasis; thus far, there are 2464 participants enrolled across 5 different studies of adalimumab biosimilars (registered at www.clinicaltrials.gov with the identifiers NCT01970488, NCT02016105, NCT02489227, NCT02714322, NCT02581345) and 531 participants in an etanercept biosimilar study (NCT01891864).

A phase 3 double-blind study compared adalimumab to an adalimumab biosimilar (ABP 501) in 350 adults with plaque psoriasis (NCT01970488). Participants received an initial loading dose of adalimumab (n=175) or ABP 501 (n=175) 80 mg subcutaneously on week 1/day 1, followed by 40 mg at week 2 every 2 weeks thereafter. At week 16, participants with psoriasis area and severity index (PASI) 50 or greater remained in the study for up to 52 weeks; those who were receiving adalimumab were re-randomized to receive either ABP 501 or adalimumab. Participants receiving ABP 501 continued to receive the biosimilar. The mean PASI improvement at weeks 16, 32, and 50 was 86.6, 87.6, and 87.2, respectively, in the ABP 501/ABP 501 group (A/A) compared to 88.0, 88.2, and 88.1, respectively, in the adalimumab/adalimumab group (B/B).¹⁹ Autoantibodies developed in 68.4% of participants in the A/A group compared to 74.7% in the B/B group. The incidence of treatment-emergent adverse events (TEAEs) was 86.2% in the A/A group and 78.5% in the B/B group. The most common TEAEs were nasopharyngitis, headache, and upper respiratory tract infection. The incidence of serious TEAEs was 4.6% in the A/A group compared to 5.1% in the B/B group. Overall, the efficacy, safety, and immunogenicity of the adalimumab biosimilar was comparable to the reference product.¹⁹

A second phase 3 trial (ADACCESS) evaluated the adalimumab biosimilar GP2017 (NCT02016105). Participants received an initial dose of 80 mg subcutaneously of either GP2017 or adalimumab at week 0, followed by 40 mg every other week starting at week 1 and ending at week 51. The study has been completed but results are not yet available.

The third trial is evaluating the adalimumab biosimilar CHS-1420 (NCT02489227). Participants in the experimental arm receive two 40-mg doses of CHS-1420 at week 0/day 0, and then 1 dose every 2 weeks from week 1 for 23 weeks. At week 24, participants continue with an open-label study. Participants in the adalimumab group receive two 40-mg doses at week 0/day 0, and then 1 dose every 2 weeks from week 1 to week 15. At week 16, participants will be re-randomized (1:1) to continue adalimumab or start CHS-1420 at one 40-mg dose every 2 weeks during weeks 17 to 23. At week 24, participants will switch to CHS-1420 open label until the end of the study. Study results are not yet available; the study is ongoing but not recruiting.

The fourth ongoing trial is evaluating the adalimumab biosimilar MYL-1401A (NCT02714322). Participants receive an initial dose of 80 mg subcutaneously of either MYL-1401A or adalimumab (2:1), followed by 40 mg every other week starting 1 week after the initial dose. After the 52-week treatment period, there is an 8-week safety follow-up period. Study results are not yet available; the study is ongoing but not recruiting.

A fifth adalimumab biosimilar, M923, also is currently being tested in clinical trials (NCT02581345). Participants receive either M923, adalimumab, or alternate between the 2 agents. Although the study is still ongoing, data released from the manufacturer state that the proportion of participants who achieved PASI 75 after 16 weeks of treatment was equivalent in the 2 treatment groups. The proportion of participants who achieved PASI 90, as well as the type, frequency, and severity of adverse events, also were comparable.²⁰

The EGALITY trial, completed in March 2015, compared the etanercept biosimilar GP2015 to etanercept over a 52-week period (NCT01891864). Participants received either GP2015 or etanercept 50 mg twice weekly for the first 12 weeks. Participants with at least PASI 50 were then re-randomized into 4 groups: the first 2 groups stayed with their current treatments while the other 2 groups alternated treatments every 6 weeks until week 30. Participants then stayed on their last treatment from week 30 to week 52. The adjusted PASI 75 response rate at week 12 was 73.4% in the group receiving GP2015 and 75.7% in the group receiving etanercept.²¹ The percentage change in PASI score at all time points was found to be comparable from baseline until week 52. Importantly, the incidence of TEAEs up to week 52 was comparable and no new safety issues were reported. Additionally, switching participants from etanercept to the biosimilar during the subsequent treatment periods did not cause an increase in formation of antidrug antibodies.²¹

There are 2 upcoming studies involving biosimilars that are not yet recruiting patients. The first (NCT02925338) will analyze the characteristics of patients treated with Inflectra as well as their response to treatment. The second (NCT02762955) will be comparing the efficacy and safety of an adalimumab biosimilar (BCD-057, BIOCAD) to adalimumab.

Economic Advantages of Biosimilars

The annual economic burden of psoriasis in the United States is substantial, with estimates between $35.2 billion²² and $112 billion.²³ Biosimilars can be 25% to 30% cheaper than their reference products^9,11,24 and have the potential to save the US health care system billions of dollars.²⁵ Furthermore, the developers of biosimilars could offer patient assistance programs.¹¹ That being said, drug developers can extend patents for their branded drugs; for instance, 2 patents for Enbrel (Amgen Inc) could protect the drug until 2029.^26,27

Although cost is an important factor in deciding which medications to prescribe for patients, it should never take precedence over safety and efficacy. Manufacturers can develop new drugs with greater efficacy, fewer side effects, or more convenient dosing schedules,^26,27 or they could offer co-payment assistance programs.^26,28 Physicians also must consider how the biosimilars will be integrated into drug formularies. Would patients be required to use a biosimilar before a branded drug?^11,29 Will patients already taking a branded drug be grandfathered in?¹¹ Would they have to pay a premium to continue taking their drug? And finally, could changes in formularies and employer-payer relationships destabilize patient regimens?³⁰

Conclusion

Preliminary results suggest that biosimilars can have similar safety, efficacy, and immunogenicity data compared to their reference products.^19,21 Biosimilars have the potential to greatly reduce the cost burden associated with psoriasis. However, how similar is “highly similar”? Although cost is an important consideration in selecting drug therapies, the reason for using a biosimilar should never be based on cost alone.

Rosacea is a chronic skin disease characterized by flushing, erythema, telangiectasia, papules, and pustules in the central face region.¹ It most often affects middle-aged women (age range, 30–50 years).² Rosacea is rare in the pediatric population, especially before puberty.³ There are 3 subtypes of pediatric rosacea: vascular, papulopustular, and ocular. Phymatous/rhinophymatous rosacea is only seen in the adult population.³ Recommendations for the management of pediatric rosacea heavily rely on data from retrospective chart reviews and case series.

Etiology of Pediatric Rosacea

Rosacea is thought to be a consequence of vasomotor instability in both adults and children. A family history of rosacea is sometimes reported in patients with pediatric rosacea.⁴ Patients often are sensitive to heat, sunlight, topical corticosteroids, spicy foods, hot liquids, and certain soaps and cleansers.^1,3,4 In a review of the literature by Vemuri et al,⁵ the various reported triggers of rosacea include harsh climates that damage the blood vessels and dermal connective tissue, defects in the endothelium and dermal matrix, perivascular inflammation, orally ingested chemicals, changes in the flora of the hair follicles, excessive antimicrobial peptides, and the presence of free radicals. Overall, it is unclear which of these factors are triggers of pediatric rosacea.

The molecular basis of rosacea has been elucidated. It is well known that rosacea patients have higher levels of cathelicidins in the facial skin. Furthermore, they appear to have different processed forms of cathelicidin peptides compared to adults without rosacea, possibly due to changes in posttranslational processing.⁶ One such peptide, cathelicidin LL-37, also has been implicated in atopic dermatitis⁷ and psoriasis.⁸ Its role in rosacea appears to be multifaceted. Cathelicidin LL-37 helps to attract neutrophils, monocytes, and T lymphocytes, and also has antimicrobial properties; therefore, it plays a role in both the innate and adaptive immune systems.⁹ Cathelicidin LL-37 also has been implicated in inducing angiogenesis¹⁰ and suppressing dermal fibroblasts.¹¹

Muto et al¹² found that there is an increased number of mast cells in the dermis of patients with rosacea. Mast cells contribute to vasodilation, angiogenesis, and the recruitment of other inflammatory cells.¹² Importantly, human mast cells are a source of cathelicidins including cathelicidin LL-37; these proteins play a vital role in the antimicrobial capabilities of mast cells.¹³

Clinical Presentation and Comorbidities

Vascular rosacea presents with characteristic flushing and erythema, which lasts more than a few minutes as compared to physiologic erythema,¹ and sometimes telangiectasia is seen.³ The cheeks, chin, and nasolabial folds are most commonly involved.² In papulopustular rosacea, papules and pustules are seen overlying the erythema.^1,3 Open and closed comedones also have been documented in case reports but are not commonly seen.² Pediatric rosacea often begins with flushing of the face and then progresses to the development of papules and pustules.⁴

Ocular rosacea can occur with or without cutaneous findings. In a retrospective study of 20 pediatric patients (aged 1–15 years), 11 (55%) patients had both ocular and cutaneous rosacea, 3 (15%) only had ocular symptoms, and 6 (30%) only had cutaneous symptoms. The most common form of rosacea in this study was papulopustular rosacea.¹⁴ Ocular symptoms often are bilateral¹⁵ and can include blepharitis, conjunctival injection, recurrent chalazion, conjunctivitis,² and less commonly corneal ulceration and scarring.¹⁶ Patients also may report photophobia or a foreign body sensation.¹⁷ Importantly, ocular symptoms often precede the cutaneous symptoms and can delay the diagnosis of rosacea,^14,16,18 as these symptoms often are misdiagnosed as viral or bacterial infections.¹⁵ Fortunately, ocular disease responds well to treatment if diagnosed early.

Weston and Morelli¹⁹ conducted a retrospective study of 106 children (46 males; 60 females) 13 years and younger with steroid rosacea; 29 children were younger than 3 years. A family history of rosacea was present in 20% of participants, and prior use of class 7 steroids was reported in 54%, whereas only 3% had used class 1 topical steroids. Ninety-eight participants had perinasal involvement, 94 had perioral involvement, and 44 had periorbital involvement of the lower eyelids.¹⁹

Rosacea fulminans (also known as pyoderma faciale) is a rare acute-onset eruption typically found in young women in their 20s and 30s.²⁰ Rosacea fulminans is characterized by papules, pustules, nodules, cysts, draining sinuses, communicating sinus tracts, and less commonly comedones.^20,21 The skin can appear erythematous, cyanotic, or dull red.²¹ Most of the lesions are found on the face, particularly on the forehead, cheeks, nose, and chin,²¹ but lesions on the chest and back have been documented in adult patients.²⁰ In an examination of prior case series, most patients were otherwise healthy. There are case reports documenting rosacea fulminans in teenagers,²⁰ but the youngest patient recorded was an otherwise healthy 3-year-old girl who developed a sudden onset of erythematous papules, pustules, cysts, and purulent discharging sinuses on the cheeks that spread to the chin, perioral, and paranasal areas.²¹

Differential Diagnosis

Rosacea is rare in children, so other papulopustular disorders must be ruled out, including acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, systemic lupus erythematosus, steroid-induced rosacea, ataxia telangiectasia, and demodicosis.

Acne vulgaris commonly presents in older adolescents and teenagers with open and closed comedones, inflammatory papules, and pustules.² Intense facial flushing and telangiectasia usually is not seen.

In perioral dermatitis, skin lesions often are clustered around the mouth, nose, and eyes. Typically there are no telangiectases or ocular complications.³ Facial flushing and telangiectases are uncommon, except in steroid-induced perioral dermatitis.²

The cutaneous findings of sarcoidosis include red-brown papules on the face and lips, and patients also may have ocular involvement such as uveitis and iritis.³ However, there are typically other systemic findings such as pulmonary symptoms, weight loss, fatigue, lethargy, fever, and erythema nodosum.^2,3 Chest radiograph findings (eg, bilateral hilar lym-phadenopathy), ophthalmologic examination, and laboratory data (eg, elevated alkaline phosphate and/or elevated angiotensin-converting enzyme) can help confirm or rule out the diagnosis of sarcoidosis.^2,3

Unlike systemic lupus erythematosus, patients with rosacea will have involvement of sun-protected areas of the skin. Patients with systemic lupus erythematosus typically report arthralgia and severe photosensitivity and will have elevated antinuclear antibody titers. Skin biopsies and immunofluorescence can help confirm the diagnosis.³ Importantly, some patients with rosacea will have a positive lupus band test.^22,23

Steroid-induced rosacea typically occurs 2 weeks after discontinuing therapy with topical fluorinated glucocorticosteroids.²⁴ Children present with monomorphic papules, pustules, and telangiectases⁴ on the eyelids and lateral face as opposed to the central face regions.²⁴

Ataxia telangiectasia can present with telangiectases, skin atrophy, café au lait spots, and premature graying.²⁵ A 15-year-old adolescent girl with ataxia telangiectasia presented with granulomatous acne rosacea that improved after 4 weeks of treatment with isotretinoin 0.5 mg/kg daily. The lesions cleared almost completely after 5 months.²⁵

Demodicosis is a disorder of the pilosebaceous units caused by the human Demodex mite.²⁶ It typically involves the periorificial regions in adults and the elderly population. Patients can present with fine, white-yellow, scaly changes of the sebaceous hair follicles, with minimal erythema and inflammation. Papules and pustules also can be present.²⁶

Diagnosis and Histopathology

Because rosacea is rare in children, it is important to thoroughly evaluate other possible diagnoses. The diagnosis of pediatric rosacea is clinical and biopsies are rarely performed. Laboratory tests such as cultures generally are not useful.

Marks and Harcourt-Webster²⁷ reviewed the biopsies of 108 adult patients with rosacea. The biopsies of patients with predominantly erythema and telangiectasia showed evidence of vascular dilatation with a perivascular infiltrate composed predominantly of lymphocytes and 39 specimens that were compared to controls showed more solar elastosis. Biopsies of papular rosacea contained inflammatory infiltrates in the upper and mid dermis composed primarily of lymphocytes and histiocytes. In some patients, neutrophils, plasma cells, and giant cells also were observed. Hair follicle abnormalities were present in 20% of the biopsies, with 19% showing evidence of the Demodex mite. Vascular dilatation also was common. Overall, common findings included lymphohistiocytic infiltrates around the blood vessels of the upper dermis, dilated vessels, edema, elastosis, and disorganization of connective tissue in the upper dermis.

Helm et al²⁸ reviewed histopathologic patterns from 53 patients with granulomatous rosacea. Findings included a mixed lymphohistiocytic infiltrate (predominantly lymphocytic in 40% of patients and predominantly histiocytic with occasional giant cells in 34% of patients), epithelioid granulomas (11% of patients), and epithelioid granulomas with caseation necrosis (11% of patients).

The histopathology of rosacea fulminans is characterized by dense perivascular and periadnexal infiltrates composed of granulocytes, eosinophils, and epithelioid granulomas, as well as panniculitis.²⁰

Treatment and Clinical Outcomes

Certain lifestyle recommendations are integral components of disease management, including avoidance of triggers such as extreme temperatures, hot drinks, spicy food, and topical agents that could be irritating (especially topical corticosteroids).²⁹ Patients should be advised to use daily sunscreen containing physical blockers such as titanium dioxide or zinc oxide. Teenagers should avoid the use of cosmetics and makeup, especially products containing sodium lauryl sulfate, menthol, and camphor. Daily use of emollients can help some patients.²⁹

There are both topical and systemic therapies available for pediatric rosacea; however, most of the data are based on the use of these treatments in the adult population. Patients with mild to moderate disease often can be managed using topical agents. Metronidazole (0.75% cream, 1% gel, or 0.75% lotion) has been studied extensively in adult patients, and when used once daily for 12 weeks, it has been able to control moderate to severe disease.^30,31 In one study conducted in adult patients, topical metronidazole was able to maintain remission in adults who had previously been treated with a combination of oral tetracycline and metronidazole gel.³¹ Sodium sulfacetamide 10%–sulfur 5% (cleanser or lotion) has been successful in adult patients and often is used in combination with other therapies such as topical metronidazole.^32-34 Azelaic acid cream 20%,³⁵ benzoyl peroxide (wash or gel),²⁹ topical clindamycin,³⁶ topical erythromycin,^29,37 tacrolimus ointment 0.1%,³⁸ and tretinoin cream also have been studied in adults.^3,39 Several of these topical agents can cause irritation on application (eg, metronidazole, sulfur-based agents, azelaic acid, benzoyl peroxide, erythromycin, tretinoin).³

The use of systemic treatments in pediatric patients is heavily based on case reports and case series.^2,14,16,40 Therapies have included tetracycline (500 mg twice daily tapered to 250 mg daily),²⁹ minocycline (50–100 mg twice daily), doxycycline (50–100 mg twice daily or 4 times daily), erythromycin (30–50 mg/kg daily), clarithromycin (15 mg/kg twice daily for 4 weeks and then daily for 4 weeks), and azithromycin (5–10 mg/kg daily).³ Tetracycline antibiotics should not be used in children 8 years or younger.

In a case series by Drolet and Paller,² an 11-year-old girl was treated with tetracycline 500 mg (later tapered to 250 mg daily) and metronidazole gel 0.75%, both used twice daily. Previously, she had not responded to topical steroids, tretinoin cream 0.05%, benzoyl peroxide 5%, or systemic prednisone. After 6 weeks of treatment, the pustules and chalazion had resolved and she had only minimal erythema of the skin and conjunctiva. Sixteen months after the start of treatment, a regimen of tetracycline 250 mg daily and metronidazole gel resulted in disease clearance on the face.²

A 9-year-old girl with concurrent systemic lupus erythematosus was treated with tetracycline 250 mg and topical erythromycin 2%, both used twice daily.² After 4 weeks her face was clear. Four months later she developed new telangiectases and topical erythromycin was replaced with topical metronidazole. Eventually the dose of tetracycline was reduced to 250 mg daily.²

An 11-year-old boy with likely granulomatous rosacea was treated with erythromycin 250 mg 4 times daily, alclometasone dipropionate cream 0.05% twice daily, and topical clindamycin twice daily.² Marked improvement was noticed after 3 weeks of treatment. Metronidazole gel 0.75% was added and 3 months later the patient’s face was clear, without evidence of scarring. The dose of erythromycin was later reduced to 500 mg daily, and eventually the patient experienced clearance with the use of metronidazole gel daily.²

In another case series, 4 female patients (age range, 4–12 years) were treated with systemic erythromycin 20 mg/kg daily (ocular involvement only) or doxycycline 2.2 mg/kg daily used in two 12-year-old patients with ocular and cutaneous involvement for at least 12 months. All 4 patients showed considerable improvement within 1 month and remained free of disease throughout a mean follow-up period of 25.5 months.⁴⁰

As evidenced by these case reports, there is a wide array of treatments that have been used for pediatric rosacea. Although there are no formal evidence-based guidelines, there are certain considerations that must be taken into account when choosing treatment plans. Doxycycline and minocycline are known to cause less gastrointestinal upset than tetracycline with similar efficacy.⁴¹ Importantly, the tetracyclines are contraindicated in children younger than 9 years, as they can cause teeth staining and possibly affect skeletal growth.^3,4 When used in older children (age range, 9–12 years), patients must be advised not to take their medication with calcium or antacids.³ Clarithromycin and azithromycin tend to have fewer gastrointestinal side effects than erythromycin. Erythromycin and other macrolides can be used in children of all ages and in patients who are allergic to tetracyclines.³

Children with mild ocular symptoms often can control their disease with bacitracin and topical ocular antibiotics such as erythromycin.^2,15 For patients who require systemic antibiotics, various tetracyclines and macrolides have been used with success.^2,14-16,40

Adults with rosacea fulminans can require treatment with isotretinoin, oral antibiotics, and topical or even systemic corticosteroids.⁴² The 3-year-old girl with rosacea fulminans initially was treated with oral erythromycin (250 mg 4 times daily), oral prednisolone (0.5 mg/kg daily tapered over 2 weeks), fluocinolone acetonide cream 0.025%, and warm compresses with only moderate improvement.²¹ She was then started on oral isotretinoin (0.75 mg/kg daily) and within 4 weeks marked improvement was noted. After 8 weeks, the lesions had disappeared completely with only a few pitted scars remaining. Isotretinoin was continued for 24 weeks. One year after completion of treatment, she was still disease free.²¹

Weston and Morelli¹⁹ recommended the following treatment regimen for children with steroid rosacea: abrupt cessation of topical steroid use (as opposed to gradual withdrawal) and initiation of oral erythromycin stearate (30 mg/kg daily) in 2 daily doses for 4 weeks. Children who were unable to tolerate erythromycin (n=6) were told to use topical clindamycin phosphate twice daily for 4 weeks. Within 3 weeks 22% of patients had resolution, while 86% had resolution within 4 weeks. All of the patients cleared within 8 weeks. Importantly, there was no significant difference in duration of time until clearance between children who used the oral antibiotic or topical antibiotic.¹⁹

Conclusion

We know that the skin of rosacea patients contains higher levels of cathelicidins, which have been implicated in amplifying and contributing to the inflammatory response in several ways. Mast cells, which are a source of cathelicidins, also are increased in the skin of these patients. Children can present with vascular rosacea (characterized by flushing, erythema, and/or telangiectasia), papulopustular rosacea, or ocular rosacea. Common ocular symptoms include blepharitis, conjunctivitis, and recurrent chalazion. It is important to refer pediatric rosacea patients with ocular symptoms to an ophthalmologist to prevent ocular sequelae.

Rosacea is a clinical diagnosis but biopsy can be performed to rule out other diagnoses. Treatment consists of lifestyle modifications such as avoiding known triggers and the use of topical and/or oral agents. Common topical therapies include metronidazole and erythromycin. Systemic antibiotics include tetracycline, doxycycline, minocycline, azithromycin, and erythromycin. Some children are able to taper systemic agents and maintain disease control with topical therapy, while others may need to continue a low-dose antibiotic. Although flares can be controlled within weeks to months, rosacea is a chronic disorder and childhood rosacea tends to persist into adulthood.

Rosacea is a chronic skin disease characterized by flushing, erythema, telangiectasia, papules, and pustules in the central face region.¹ It most often affects middle-aged women (age range, 30–50 years).² Rosacea is rare in the pediatric population, especially before puberty.³ There are 3 subtypes of pediatric rosacea: vascular, papulopustular, and ocular. Phymatous/rhinophymatous rosacea is only seen in the adult population.³ Recommendations for the management of pediatric rosacea heavily rely on data from retrospective chart reviews and case series.

Etiology of Pediatric Rosacea

Rosacea is thought to be a consequence of vasomotor instability in both adults and children. A family history of rosacea is sometimes reported in patients with pediatric rosacea.⁴ Patients often are sensitive to heat, sunlight, topical corticosteroids, spicy foods, hot liquids, and certain soaps and cleansers.^1,3,4 In a review of the literature by Vemuri et al,⁵ the various reported triggers of rosacea include harsh climates that damage the blood vessels and dermal connective tissue, defects in the endothelium and dermal matrix, perivascular inflammation, orally ingested chemicals, changes in the flora of the hair follicles, excessive antimicrobial peptides, and the presence of free radicals. Overall, it is unclear which of these factors are triggers of pediatric rosacea.

The molecular basis of rosacea has been elucidated. It is well known that rosacea patients have higher levels of cathelicidins in the facial skin. Furthermore, they appear to have different processed forms of cathelicidin peptides compared to adults without rosacea, possibly due to changes in posttranslational processing.⁶ One such peptide, cathelicidin LL-37, also has been implicated in atopic dermatitis⁷ and psoriasis.⁸ Its role in rosacea appears to be multifaceted. Cathelicidin LL-37 helps to attract neutrophils, monocytes, and T lymphocytes, and also has antimicrobial properties; therefore, it plays a role in both the innate and adaptive immune systems.⁹ Cathelicidin LL-37 also has been implicated in inducing angiogenesis¹⁰ and suppressing dermal fibroblasts.¹¹

Muto et al¹² found that there is an increased number of mast cells in the dermis of patients with rosacea. Mast cells contribute to vasodilation, angiogenesis, and the recruitment of other inflammatory cells.¹² Importantly, human mast cells are a source of cathelicidins including cathelicidin LL-37; these proteins play a vital role in the antimicrobial capabilities of mast cells.¹³

Clinical Presentation and Comorbidities

Vascular rosacea presents with characteristic flushing and erythema, which lasts more than a few minutes as compared to physiologic erythema,¹ and sometimes telangiectasia is seen.³ The cheeks, chin, and nasolabial folds are most commonly involved.² In papulopustular rosacea, papules and pustules are seen overlying the erythema.^1,3 Open and closed comedones also have been documented in case reports but are not commonly seen.² Pediatric rosacea often begins with flushing of the face and then progresses to the development of papules and pustules.⁴

Ocular rosacea can occur with or without cutaneous findings. In a retrospective study of 20 pediatric patients (aged 1–15 years), 11 (55%) patients had both ocular and cutaneous rosacea, 3 (15%) only had ocular symptoms, and 6 (30%) only had cutaneous symptoms. The most common form of rosacea in this study was papulopustular rosacea.¹⁴ Ocular symptoms often are bilateral¹⁵ and can include blepharitis, conjunctival injection, recurrent chalazion, conjunctivitis,² and less commonly corneal ulceration and scarring.¹⁶ Patients also may report photophobia or a foreign body sensation.¹⁷ Importantly, ocular symptoms often precede the cutaneous symptoms and can delay the diagnosis of rosacea,^14,16,18 as these symptoms often are misdiagnosed as viral or bacterial infections.¹⁵ Fortunately, ocular disease responds well to treatment if diagnosed early.

Weston and Morelli¹⁹ conducted a retrospective study of 106 children (46 males; 60 females) 13 years and younger with steroid rosacea; 29 children were younger than 3 years. A family history of rosacea was present in 20% of participants, and prior use of class 7 steroids was reported in 54%, whereas only 3% had used class 1 topical steroids. Ninety-eight participants had perinasal involvement, 94 had perioral involvement, and 44 had periorbital involvement of the lower eyelids.¹⁹

Rosacea fulminans (also known as pyoderma faciale) is a rare acute-onset eruption typically found in young women in their 20s and 30s.²⁰ Rosacea fulminans is characterized by papules, pustules, nodules, cysts, draining sinuses, communicating sinus tracts, and less commonly comedones.^20,21 The skin can appear erythematous, cyanotic, or dull red.²¹ Most of the lesions are found on the face, particularly on the forehead, cheeks, nose, and chin,²¹ but lesions on the chest and back have been documented in adult patients.²⁰ In an examination of prior case series, most patients were otherwise healthy. There are case reports documenting rosacea fulminans in teenagers,²⁰ but the youngest patient recorded was an otherwise healthy 3-year-old girl who developed a sudden onset of erythematous papules, pustules, cysts, and purulent discharging sinuses on the cheeks that spread to the chin, perioral, and paranasal areas.²¹

Differential Diagnosis

Rosacea is rare in children, so other papulopustular disorders must be ruled out, including acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, systemic lupus erythematosus, steroid-induced rosacea, ataxia telangiectasia, and demodicosis.

Acne vulgaris commonly presents in older adolescents and teenagers with open and closed comedones, inflammatory papules, and pustules.² Intense facial flushing and telangiectasia usually is not seen.

In perioral dermatitis, skin lesions often are clustered around the mouth, nose, and eyes. Typically there are no telangiectases or ocular complications.³ Facial flushing and telangiectases are uncommon, except in steroid-induced perioral dermatitis.²

The cutaneous findings of sarcoidosis include red-brown papules on the face and lips, and patients also may have ocular involvement such as uveitis and iritis.³ However, there are typically other systemic findings such as pulmonary symptoms, weight loss, fatigue, lethargy, fever, and erythema nodosum.^2,3 Chest radiograph findings (eg, bilateral hilar lym-phadenopathy), ophthalmologic examination, and laboratory data (eg, elevated alkaline phosphate and/or elevated angiotensin-converting enzyme) can help confirm or rule out the diagnosis of sarcoidosis.^2,3

Unlike systemic lupus erythematosus, patients with rosacea will have involvement of sun-protected areas of the skin. Patients with systemic lupus erythematosus typically report arthralgia and severe photosensitivity and will have elevated antinuclear antibody titers. Skin biopsies and immunofluorescence can help confirm the diagnosis.³ Importantly, some patients with rosacea will have a positive lupus band test.^22,23

Steroid-induced rosacea typically occurs 2 weeks after discontinuing therapy with topical fluorinated glucocorticosteroids.²⁴ Children present with monomorphic papules, pustules, and telangiectases⁴ on the eyelids and lateral face as opposed to the central face regions.²⁴

Ataxia telangiectasia can present with telangiectases, skin atrophy, café au lait spots, and premature graying.²⁵ A 15-year-old adolescent girl with ataxia telangiectasia presented with granulomatous acne rosacea that improved after 4 weeks of treatment with isotretinoin 0.5 mg/kg daily. The lesions cleared almost completely after 5 months.²⁵

Demodicosis is a disorder of the pilosebaceous units caused by the human Demodex mite.²⁶ It typically involves the periorificial regions in adults and the elderly population. Patients can present with fine, white-yellow, scaly changes of the sebaceous hair follicles, with minimal erythema and inflammation. Papules and pustules also can be present.²⁶

Diagnosis and Histopathology

Because rosacea is rare in children, it is important to thoroughly evaluate other possible diagnoses. The diagnosis of pediatric rosacea is clinical and biopsies are rarely performed. Laboratory tests such as cultures generally are not useful.

Marks and Harcourt-Webster²⁷ reviewed the biopsies of 108 adult patients with rosacea. The biopsies of patients with predominantly erythema and telangiectasia showed evidence of vascular dilatation with a perivascular infiltrate composed predominantly of lymphocytes and 39 specimens that were compared to controls showed more solar elastosis. Biopsies of papular rosacea contained inflammatory infiltrates in the upper and mid dermis composed primarily of lymphocytes and histiocytes. In some patients, neutrophils, plasma cells, and giant cells also were observed. Hair follicle abnormalities were present in 20% of the biopsies, with 19% showing evidence of the Demodex mite. Vascular dilatation also was common. Overall, common findings included lymphohistiocytic infiltrates around the blood vessels of the upper dermis, dilated vessels, edema, elastosis, and disorganization of connective tissue in the upper dermis.

Helm et al²⁸ reviewed histopathologic patterns from 53 patients with granulomatous rosacea. Findings included a mixed lymphohistiocytic infiltrate (predominantly lymphocytic in 40% of patients and predominantly histiocytic with occasional giant cells in 34% of patients), epithelioid granulomas (11% of patients), and epithelioid granulomas with caseation necrosis (11% of patients).

The histopathology of rosacea fulminans is characterized by dense perivascular and periadnexal infiltrates composed of granulocytes, eosinophils, and epithelioid granulomas, as well as panniculitis.²⁰

Treatment and Clinical Outcomes

Certain lifestyle recommendations are integral components of disease management, including avoidance of triggers such as extreme temperatures, hot drinks, spicy food, and topical agents that could be irritating (especially topical corticosteroids).²⁹ Patients should be advised to use daily sunscreen containing physical blockers such as titanium dioxide or zinc oxide. Teenagers should avoid the use of cosmetics and makeup, especially products containing sodium lauryl sulfate, menthol, and camphor. Daily use of emollients can help some patients.²⁹

There are both topical and systemic therapies available for pediatric rosacea; however, most of the data are based on the use of these treatments in the adult population. Patients with mild to moderate disease often can be managed using topical agents. Metronidazole (0.75% cream, 1% gel, or 0.75% lotion) has been studied extensively in adult patients, and when used once daily for 12 weeks, it has been able to control moderate to severe disease.^30,31 In one study conducted in adult patients, topical metronidazole was able to maintain remission in adults who had previously been treated with a combination of oral tetracycline and metronidazole gel.³¹ Sodium sulfacetamide 10%–sulfur 5% (cleanser or lotion) has been successful in adult patients and often is used in combination with other therapies such as topical metronidazole.^32-34 Azelaic acid cream 20%,³⁵ benzoyl peroxide (wash or gel),²⁹ topical clindamycin,³⁶ topical erythromycin,^29,37 tacrolimus ointment 0.1%,³⁸ and tretinoin cream also have been studied in adults.^3,39 Several of these topical agents can cause irritation on application (eg, metronidazole, sulfur-based agents, azelaic acid, benzoyl peroxide, erythromycin, tretinoin).³

The use of systemic treatments in pediatric patients is heavily based on case reports and case series.^2,14,16,40 Therapies have included tetracycline (500 mg twice daily tapered to 250 mg daily),²⁹ minocycline (50–100 mg twice daily), doxycycline (50–100 mg twice daily or 4 times daily), erythromycin (30–50 mg/kg daily), clarithromycin (15 mg/kg twice daily for 4 weeks and then daily for 4 weeks), and azithromycin (5–10 mg/kg daily).³ Tetracycline antibiotics should not be used in children 8 years or younger.

In a case series by Drolet and Paller,² an 11-year-old girl was treated with tetracycline 500 mg (later tapered to 250 mg daily) and metronidazole gel 0.75%, both used twice daily. Previously, she had not responded to topical steroids, tretinoin cream 0.05%, benzoyl peroxide 5%, or systemic prednisone. After 6 weeks of treatment, the pustules and chalazion had resolved and she had only minimal erythema of the skin and conjunctiva. Sixteen months after the start of treatment, a regimen of tetracycline 250 mg daily and metronidazole gel resulted in disease clearance on the face.²

A 9-year-old girl with concurrent systemic lupus erythematosus was treated with tetracycline 250 mg and topical erythromycin 2%, both used twice daily.² After 4 weeks her face was clear. Four months later she developed new telangiectases and topical erythromycin was replaced with topical metronidazole. Eventually the dose of tetracycline was reduced to 250 mg daily.²

An 11-year-old boy with likely granulomatous rosacea was treated with erythromycin 250 mg 4 times daily, alclometasone dipropionate cream 0.05% twice daily, and topical clindamycin twice daily.² Marked improvement was noticed after 3 weeks of treatment. Metronidazole gel 0.75% was added and 3 months later the patient’s face was clear, without evidence of scarring. The dose of erythromycin was later reduced to 500 mg daily, and eventually the patient experienced clearance with the use of metronidazole gel daily.²

In another case series, 4 female patients (age range, 4–12 years) were treated with systemic erythromycin 20 mg/kg daily (ocular involvement only) or doxycycline 2.2 mg/kg daily used in two 12-year-old patients with ocular and cutaneous involvement for at least 12 months. All 4 patients showed considerable improvement within 1 month and remained free of disease throughout a mean follow-up period of 25.5 months.⁴⁰

As evidenced by these case reports, there is a wide array of treatments that have been used for pediatric rosacea. Although there are no formal evidence-based guidelines, there are certain considerations that must be taken into account when choosing treatment plans. Doxycycline and minocycline are known to cause less gastrointestinal upset than tetracycline with similar efficacy.⁴¹ Importantly, the tetracyclines are contraindicated in children younger than 9 years, as they can cause teeth staining and possibly affect skeletal growth.^3,4 When used in older children (age range, 9–12 years), patients must be advised not to take their medication with calcium or antacids.³ Clarithromycin and azithromycin tend to have fewer gastrointestinal side effects than erythromycin. Erythromycin and other macrolides can be used in children of all ages and in patients who are allergic to tetracyclines.³

Children with mild ocular symptoms often can control their disease with bacitracin and topical ocular antibiotics such as erythromycin.^2,15 For patients who require systemic antibiotics, various tetracyclines and macrolides have been used with success.^2,14-16,40

Adults with rosacea fulminans can require treatment with isotretinoin, oral antibiotics, and topical or even systemic corticosteroids.⁴² The 3-year-old girl with rosacea fulminans initially was treated with oral erythromycin (250 mg 4 times daily), oral prednisolone (0.5 mg/kg daily tapered over 2 weeks), fluocinolone acetonide cream 0.025%, and warm compresses with only moderate improvement.²¹ She was then started on oral isotretinoin (0.75 mg/kg daily) and within 4 weeks marked improvement was noted. After 8 weeks, the lesions had disappeared completely with only a few pitted scars remaining. Isotretinoin was continued for 24 weeks. One year after completion of treatment, she was still disease free.²¹

Weston and Morelli¹⁹ recommended the following treatment regimen for children with steroid rosacea: abrupt cessation of topical steroid use (as opposed to gradual withdrawal) and initiation of oral erythromycin stearate (30 mg/kg daily) in 2 daily doses for 4 weeks. Children who were unable to tolerate erythromycin (n=6) were told to use topical clindamycin phosphate twice daily for 4 weeks. Within 3 weeks 22% of patients had resolution, while 86% had resolution within 4 weeks. All of the patients cleared within 8 weeks. Importantly, there was no significant difference in duration of time until clearance between children who used the oral antibiotic or topical antibiotic.¹⁹

Conclusion

We know that the skin of rosacea patients contains higher levels of cathelicidins, which have been implicated in amplifying and contributing to the inflammatory response in several ways. Mast cells, which are a source of cathelicidins, also are increased in the skin of these patients. Children can present with vascular rosacea (characterized by flushing, erythema, and/or telangiectasia), papulopustular rosacea, or ocular rosacea. Common ocular symptoms include blepharitis, conjunctivitis, and recurrent chalazion. It is important to refer pediatric rosacea patients with ocular symptoms to an ophthalmologist to prevent ocular sequelae.

Rosacea is a clinical diagnosis but biopsy can be performed to rule out other diagnoses. Treatment consists of lifestyle modifications such as avoiding known triggers and the use of topical and/or oral agents. Common topical therapies include metronidazole and erythromycin. Systemic antibiotics include tetracycline, doxycycline, minocycline, azithromycin, and erythromycin. Some children are able to taper systemic agents and maintain disease control with topical therapy, while others may need to continue a low-dose antibiotic. Although flares can be controlled within weeks to months, rosacea is a chronic disorder and childhood rosacea tends to persist into adulthood.

Rosacea is a chronic skin disease characterized by flushing, erythema, telangiectasia, papules, and pustules in the central face region.¹ It most often affects middle-aged women (age range, 30–50 years).² Rosacea is rare in the pediatric population, especially before puberty.³ There are 3 subtypes of pediatric rosacea: vascular, papulopustular, and ocular. Phymatous/rhinophymatous rosacea is only seen in the adult population.³ Recommendations for the management of pediatric rosacea heavily rely on data from retrospective chart reviews and case series.

Etiology of Pediatric Rosacea

Rosacea is thought to be a consequence of vasomotor instability in both adults and children. A family history of rosacea is sometimes reported in patients with pediatric rosacea.⁴ Patients often are sensitive to heat, sunlight, topical corticosteroids, spicy foods, hot liquids, and certain soaps and cleansers.^1,3,4 In a review of the literature by Vemuri et al,⁵ the various reported triggers of rosacea include harsh climates that damage the blood vessels and dermal connective tissue, defects in the endothelium and dermal matrix, perivascular inflammation, orally ingested chemicals, changes in the flora of the hair follicles, excessive antimicrobial peptides, and the presence of free radicals. Overall, it is unclear which of these factors are triggers of pediatric rosacea.

The molecular basis of rosacea has been elucidated. It is well known that rosacea patients have higher levels of cathelicidins in the facial skin. Furthermore, they appear to have different processed forms of cathelicidin peptides compared to adults without rosacea, possibly due to changes in posttranslational processing.⁶ One such peptide, cathelicidin LL-37, also has been implicated in atopic dermatitis⁷ and psoriasis.⁸ Its role in rosacea appears to be multifaceted. Cathelicidin LL-37 helps to attract neutrophils, monocytes, and T lymphocytes, and also has antimicrobial properties; therefore, it plays a role in both the innate and adaptive immune systems.⁹ Cathelicidin LL-37 also has been implicated in inducing angiogenesis¹⁰ and suppressing dermal fibroblasts.¹¹

Muto et al¹² found that there is an increased number of mast cells in the dermis of patients with rosacea. Mast cells contribute to vasodilation, angiogenesis, and the recruitment of other inflammatory cells.¹² Importantly, human mast cells are a source of cathelicidins including cathelicidin LL-37; these proteins play a vital role in the antimicrobial capabilities of mast cells.¹³

Clinical Presentation and Comorbidities

Vascular rosacea presents with characteristic flushing and erythema, which lasts more than a few minutes as compared to physiologic erythema,¹ and sometimes telangiectasia is seen.³ The cheeks, chin, and nasolabial folds are most commonly involved.² In papulopustular rosacea, papules and pustules are seen overlying the erythema.^1,3 Open and closed comedones also have been documented in case reports but are not commonly seen.² Pediatric rosacea often begins with flushing of the face and then progresses to the development of papules and pustules.⁴

Ocular rosacea can occur with or without cutaneous findings. In a retrospective study of 20 pediatric patients (aged 1–15 years), 11 (55%) patients had both ocular and cutaneous rosacea, 3 (15%) only had ocular symptoms, and 6 (30%) only had cutaneous symptoms. The most common form of rosacea in this study was papulopustular rosacea.¹⁴ Ocular symptoms often are bilateral¹⁵ and can include blepharitis, conjunctival injection, recurrent chalazion, conjunctivitis,² and less commonly corneal ulceration and scarring.¹⁶ Patients also may report photophobia or a foreign body sensation.¹⁷ Importantly, ocular symptoms often precede the cutaneous symptoms and can delay the diagnosis of rosacea,^14,16,18 as these symptoms often are misdiagnosed as viral or bacterial infections.¹⁵ Fortunately, ocular disease responds well to treatment if diagnosed early.

Weston and Morelli¹⁹ conducted a retrospective study of 106 children (46 males; 60 females) 13 years and younger with steroid rosacea; 29 children were younger than 3 years. A family history of rosacea was present in 20% of participants, and prior use of class 7 steroids was reported in 54%, whereas only 3% had used class 1 topical steroids. Ninety-eight participants had perinasal involvement, 94 had perioral involvement, and 44 had periorbital involvement of the lower eyelids.¹⁹

Rosacea fulminans (also known as pyoderma faciale) is a rare acute-onset eruption typically found in young women in their 20s and 30s.²⁰ Rosacea fulminans is characterized by papules, pustules, nodules, cysts, draining sinuses, communicating sinus tracts, and less commonly comedones.^20,21 The skin can appear erythematous, cyanotic, or dull red.²¹ Most of the lesions are found on the face, particularly on the forehead, cheeks, nose, and chin,²¹ but lesions on the chest and back have been documented in adult patients.²⁰ In an examination of prior case series, most patients were otherwise healthy. There are case reports documenting rosacea fulminans in teenagers,²⁰ but the youngest patient recorded was an otherwise healthy 3-year-old girl who developed a sudden onset of erythematous papules, pustules, cysts, and purulent discharging sinuses on the cheeks that spread to the chin, perioral, and paranasal areas.²¹

Differential Diagnosis

Rosacea is rare in children, so other papulopustular disorders must be ruled out, including acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, systemic lupus erythematosus, steroid-induced rosacea, ataxia telangiectasia, and demodicosis.

Acne vulgaris commonly presents in older adolescents and teenagers with open and closed comedones, inflammatory papules, and pustules.² Intense facial flushing and telangiectasia usually is not seen.

In perioral dermatitis, skin lesions often are clustered around the mouth, nose, and eyes. Typically there are no telangiectases or ocular complications.³ Facial flushing and telangiectases are uncommon, except in steroid-induced perioral dermatitis.²

The cutaneous findings of sarcoidosis include red-brown papules on the face and lips, and patients also may have ocular involvement such as uveitis and iritis.³ However, there are typically other systemic findings such as pulmonary symptoms, weight loss, fatigue, lethargy, fever, and erythema nodosum.^2,3 Chest radiograph findings (eg, bilateral hilar lym-phadenopathy), ophthalmologic examination, and laboratory data (eg, elevated alkaline phosphate and/or elevated angiotensin-converting enzyme) can help confirm or rule out the diagnosis of sarcoidosis.^2,3

Unlike systemic lupus erythematosus, patients with rosacea will have involvement of sun-protected areas of the skin. Patients with systemic lupus erythematosus typically report arthralgia and severe photosensitivity and will have elevated antinuclear antibody titers. Skin biopsies and immunofluorescence can help confirm the diagnosis.³ Importantly, some patients with rosacea will have a positive lupus band test.^22,23

Steroid-induced rosacea typically occurs 2 weeks after discontinuing therapy with topical fluorinated glucocorticosteroids.²⁴ Children present with monomorphic papules, pustules, and telangiectases⁴ on the eyelids and lateral face as opposed to the central face regions.²⁴

Ataxia telangiectasia can present with telangiectases, skin atrophy, café au lait spots, and premature graying.²⁵ A 15-year-old adolescent girl with ataxia telangiectasia presented with granulomatous acne rosacea that improved after 4 weeks of treatment with isotretinoin 0.5 mg/kg daily. The lesions cleared almost completely after 5 months.²⁵

Demodicosis is a disorder of the pilosebaceous units caused by the human Demodex mite.²⁶ It typically involves the periorificial regions in adults and the elderly population. Patients can present with fine, white-yellow, scaly changes of the sebaceous hair follicles, with minimal erythema and inflammation. Papules and pustules also can be present.²⁶

Diagnosis and Histopathology

Because rosacea is rare in children, it is important to thoroughly evaluate other possible diagnoses. The diagnosis of pediatric rosacea is clinical and biopsies are rarely performed. Laboratory tests such as cultures generally are not useful.

Marks and Harcourt-Webster²⁷ reviewed the biopsies of 108 adult patients with rosacea. The biopsies of patients with predominantly erythema and telangiectasia showed evidence of vascular dilatation with a perivascular infiltrate composed predominantly of lymphocytes and 39 specimens that were compared to controls showed more solar elastosis. Biopsies of papular rosacea contained inflammatory infiltrates in the upper and mid dermis composed primarily of lymphocytes and histiocytes. In some patients, neutrophils, plasma cells, and giant cells also were observed. Hair follicle abnormalities were present in 20% of the biopsies, with 19% showing evidence of the Demodex mite. Vascular dilatation also was common. Overall, common findings included lymphohistiocytic infiltrates around the blood vessels of the upper dermis, dilated vessels, edema, elastosis, and disorganization of connective tissue in the upper dermis.

Helm et al²⁸ reviewed histopathologic patterns from 53 patients with granulomatous rosacea. Findings included a mixed lymphohistiocytic infiltrate (predominantly lymphocytic in 40% of patients and predominantly histiocytic with occasional giant cells in 34% of patients), epithelioid granulomas (11% of patients), and epithelioid granulomas with caseation necrosis (11% of patients).

The histopathology of rosacea fulminans is characterized by dense perivascular and periadnexal infiltrates composed of granulocytes, eosinophils, and epithelioid granulomas, as well as panniculitis.²⁰

Treatment and Clinical Outcomes

Certain lifestyle recommendations are integral components of disease management, including avoidance of triggers such as extreme temperatures, hot drinks, spicy food, and topical agents that could be irritating (especially topical corticosteroids).²⁹ Patients should be advised to use daily sunscreen containing physical blockers such as titanium dioxide or zinc oxide. Teenagers should avoid the use of cosmetics and makeup, especially products containing sodium lauryl sulfate, menthol, and camphor. Daily use of emollients can help some patients.²⁹

There are both topical and systemic therapies available for pediatric rosacea; however, most of the data are based on the use of these treatments in the adult population. Patients with mild to moderate disease often can be managed using topical agents. Metronidazole (0.75% cream, 1% gel, or 0.75% lotion) has been studied extensively in adult patients, and when used once daily for 12 weeks, it has been able to control moderate to severe disease.^30,31 In one study conducted in adult patients, topical metronidazole was able to maintain remission in adults who had previously been treated with a combination of oral tetracycline and metronidazole gel.³¹ Sodium sulfacetamide 10%–sulfur 5% (cleanser or lotion) has been successful in adult patients and often is used in combination with other therapies such as topical metronidazole.^32-34 Azelaic acid cream 20%,³⁵ benzoyl peroxide (wash or gel),²⁹ topical clindamycin,³⁶ topical erythromycin,^29,37 tacrolimus ointment 0.1%,³⁸ and tretinoin cream also have been studied in adults.^3,39 Several of these topical agents can cause irritation on application (eg, metronidazole, sulfur-based agents, azelaic acid, benzoyl peroxide, erythromycin, tretinoin).³

The use of systemic treatments in pediatric patients is heavily based on case reports and case series.^2,14,16,40 Therapies have included tetracycline (500 mg twice daily tapered to 250 mg daily),²⁹ minocycline (50–100 mg twice daily), doxycycline (50–100 mg twice daily or 4 times daily), erythromycin (30–50 mg/kg daily), clarithromycin (15 mg/kg twice daily for 4 weeks and then daily for 4 weeks), and azithromycin (5–10 mg/kg daily).³ Tetracycline antibiotics should not be used in children 8 years or younger.

In a case series by Drolet and Paller,² an 11-year-old girl was treated with tetracycline 500 mg (later tapered to 250 mg daily) and metronidazole gel 0.75%, both used twice daily. Previously, she had not responded to topical steroids, tretinoin cream 0.05%, benzoyl peroxide 5%, or systemic prednisone. After 6 weeks of treatment, the pustules and chalazion had resolved and she had only minimal erythema of the skin and conjunctiva. Sixteen months after the start of treatment, a regimen of tetracycline 250 mg daily and metronidazole gel resulted in disease clearance on the face.²

A 9-year-old girl with concurrent systemic lupus erythematosus was treated with tetracycline 250 mg and topical erythromycin 2%, both used twice daily.² After 4 weeks her face was clear. Four months later she developed new telangiectases and topical erythromycin was replaced with topical metronidazole. Eventually the dose of tetracycline was reduced to 250 mg daily.²

An 11-year-old boy with likely granulomatous rosacea was treated with erythromycin 250 mg 4 times daily, alclometasone dipropionate cream 0.05% twice daily, and topical clindamycin twice daily.² Marked improvement was noticed after 3 weeks of treatment. Metronidazole gel 0.75% was added and 3 months later the patient’s face was clear, without evidence of scarring. The dose of erythromycin was later reduced to 500 mg daily, and eventually the patient experienced clearance with the use of metronidazole gel daily.²

In another case series, 4 female patients (age range, 4–12 years) were treated with systemic erythromycin 20 mg/kg daily (ocular involvement only) or doxycycline 2.2 mg/kg daily used in two 12-year-old patients with ocular and cutaneous involvement for at least 12 months. All 4 patients showed considerable improvement within 1 month and remained free of disease throughout a mean follow-up period of 25.5 months.⁴⁰

As evidenced by these case reports, there is a wide array of treatments that have been used for pediatric rosacea. Although there are no formal evidence-based guidelines, there are certain considerations that must be taken into account when choosing treatment plans. Doxycycline and minocycline are known to cause less gastrointestinal upset than tetracycline with similar efficacy.⁴¹ Importantly, the tetracyclines are contraindicated in children younger than 9 years, as they can cause teeth staining and possibly affect skeletal growth.^3,4 When used in older children (age range, 9–12 years), patients must be advised not to take their medication with calcium or antacids.³ Clarithromycin and azithromycin tend to have fewer gastrointestinal side effects than erythromycin. Erythromycin and other macrolides can be used in children of all ages and in patients who are allergic to tetracyclines.³

Children with mild ocular symptoms often can control their disease with bacitracin and topical ocular antibiotics such as erythromycin.^2,15 For patients who require systemic antibiotics, various tetracyclines and macrolides have been used with success.^2,14-16,40

Adults with rosacea fulminans can require treatment with isotretinoin, oral antibiotics, and topical or even systemic corticosteroids.⁴² The 3-year-old girl with rosacea fulminans initially was treated with oral erythromycin (250 mg 4 times daily), oral prednisolone (0.5 mg/kg daily tapered over 2 weeks), fluocinolone acetonide cream 0.025%, and warm compresses with only moderate improvement.²¹ She was then started on oral isotretinoin (0.75 mg/kg daily) and within 4 weeks marked improvement was noted. After 8 weeks, the lesions had disappeared completely with only a few pitted scars remaining. Isotretinoin was continued for 24 weeks. One year after completion of treatment, she was still disease free.²¹

Weston and Morelli¹⁹ recommended the following treatment regimen for children with steroid rosacea: abrupt cessation of topical steroid use (as opposed to gradual withdrawal) and initiation of oral erythromycin stearate (30 mg/kg daily) in 2 daily doses for 4 weeks. Children who were unable to tolerate erythromycin (n=6) were told to use topical clindamycin phosphate twice daily for 4 weeks. Within 3 weeks 22% of patients had resolution, while 86% had resolution within 4 weeks. All of the patients cleared within 8 weeks. Importantly, there was no significant difference in duration of time until clearance between children who used the oral antibiotic or topical antibiotic.¹⁹

Conclusion

We know that the skin of rosacea patients contains higher levels of cathelicidins, which have been implicated in amplifying and contributing to the inflammatory response in several ways. Mast cells, which are a source of cathelicidins, also are increased in the skin of these patients. Children can present with vascular rosacea (characterized by flushing, erythema, and/or telangiectasia), papulopustular rosacea, or ocular rosacea. Common ocular symptoms include blepharitis, conjunctivitis, and recurrent chalazion. It is important to refer pediatric rosacea patients with ocular symptoms to an ophthalmologist to prevent ocular sequelae.

Rosacea is a clinical diagnosis but biopsy can be performed to rule out other diagnoses. Treatment consists of lifestyle modifications such as avoiding known triggers and the use of topical and/or oral agents. Common topical therapies include metronidazole and erythromycin. Systemic antibiotics include tetracycline, doxycycline, minocycline, azithromycin, and erythromycin. Some children are able to taper systemic agents and maintain disease control with topical therapy, while others may need to continue a low-dose antibiotic. Although flares can be controlled within weeks to months, rosacea is a chronic disorder and childhood rosacea tends to persist into adulthood.