Granulomatous rosacea and periorificial dermatitis are common skin conditions affecting the face. This article examines the historical origin, causes, clinical presentation, and management strategies for these entities.
Key points
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Granulomatous rosacea (GR) is a rare inflammatory skin condition characterized by reddish brown papules favoring the face.
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GR is thought to arise from various antigenic triggers causing granuloma formation.
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Treatment of GR is difficult and often requires a trial of various topical and systemic therapies.
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Periorificial dermatitis (PD) is a self-limiting inflammatory skin condition characterized by erythema, papules, pustules, and a distinct sparing around the vermillion border.
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Management of PD should include ending use of any triggering topical medication, especially topical steroids.
Introduction
Granulomatous rosacea (GR) and periorificial dermatitis (PD) are inflammatory skin conditions characterized by erythematous papules most commonly affecting the face ( Figs. 1 and 2 ). These entities have been the topic of controversy because they are similar in clinical presentation, yet have variable causes and prognoses. They are both benign and self-limiting but GR tends to have a chronic course compared with PD. Some clinicians consider PD and its clinical variants on the same spectrum as rosacea because these entities have the same clinical response to similar therapies. Although acknowledging this controversy, for the sake of clarity this article describes them separate clinical entities. This article attempts to explain the origin of each disease and the different perspectives in terms of nomenclature and causes, as well as summarize existing literature on each entity.
In 2002, rosacea was classified and standardized by the National Rosacea Society Expert Committee into 4 recognized subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Using this classification, epidemiologic studies show erythematotelangiectatic rosacea to be by far the most common type. GR is not one of the subtypes of rosacea, but is thought to be a variant of rosacea based on unique clinical and histologic findings of granulomas. At present, the Committee recognizes GR as a variant of rosacea and GR is diagnosed in the setting of histologically confirmed papular granulomas on the face after ruling out other entities, such as PD and sarcoidosis.
PD, which can involve the perinasal, perioral, and/or periorbital area, is an inflammatory skin eruption characterized by erythematous papules and pustules on the face. As such, PD has been erroneously referred to as perioral dermatitis even when lesions appear in locations other than the perioral area. In 1957, PD was first described by Frumess and Lewis as a cyclic dermatitis called “light-sensitive seborrheid.” In 1964 it became a distinct entity called “perioral dermatitis.” This condition is commonly found in young adult women between the ages of 16 and 45 years. However, PD has also been reported in children between the ages of 6 months and 18 years. Originally described in 1970by Gianotti and colleagues, childhood granulomatous PD (CGPD) is a distinct subtype of PD typically seen in prepubertal children of darker skin color. Since then, several cases of children with a spectrum of skin colors with similar findings have been described. In the literature, this entity has been given various names including childhood granulomatous perioral dermatitis, sarcoid-like granulomatous dermatitis, and facial Afro-Caribbean eruption (FACE). Currently, the most accepted term for this disease is CGPD, which the authors agree best describes the entity. The granulomatous variant of PD can also be seen in adults and is clinically very similar to GR without the background erythema. The cause of this variant of PD is thought to be topical steroid use.
Introduction
Granulomatous rosacea (GR) and periorificial dermatitis (PD) are inflammatory skin conditions characterized by erythematous papules most commonly affecting the face ( Figs. 1 and 2 ). These entities have been the topic of controversy because they are similar in clinical presentation, yet have variable causes and prognoses. They are both benign and self-limiting but GR tends to have a chronic course compared with PD. Some clinicians consider PD and its clinical variants on the same spectrum as rosacea because these entities have the same clinical response to similar therapies. Although acknowledging this controversy, for the sake of clarity this article describes them separate clinical entities. This article attempts to explain the origin of each disease and the different perspectives in terms of nomenclature and causes, as well as summarize existing literature on each entity.
In 2002, rosacea was classified and standardized by the National Rosacea Society Expert Committee into 4 recognized subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Using this classification, epidemiologic studies show erythematotelangiectatic rosacea to be by far the most common type. GR is not one of the subtypes of rosacea, but is thought to be a variant of rosacea based on unique clinical and histologic findings of granulomas. At present, the Committee recognizes GR as a variant of rosacea and GR is diagnosed in the setting of histologically confirmed papular granulomas on the face after ruling out other entities, such as PD and sarcoidosis.
PD, which can involve the perinasal, perioral, and/or periorbital area, is an inflammatory skin eruption characterized by erythematous papules and pustules on the face. As such, PD has been erroneously referred to as perioral dermatitis even when lesions appear in locations other than the perioral area. In 1957, PD was first described by Frumess and Lewis as a cyclic dermatitis called “light-sensitive seborrheid.” In 1964 it became a distinct entity called “perioral dermatitis.” This condition is commonly found in young adult women between the ages of 16 and 45 years. However, PD has also been reported in children between the ages of 6 months and 18 years. Originally described in 1970by Gianotti and colleagues, childhood granulomatous PD (CGPD) is a distinct subtype of PD typically seen in prepubertal children of darker skin color. Since then, several cases of children with a spectrum of skin colors with similar findings have been described. In the literature, this entity has been given various names including childhood granulomatous perioral dermatitis, sarcoid-like granulomatous dermatitis, and facial Afro-Caribbean eruption (FACE). Currently, the most accepted term for this disease is CGPD, which the authors agree best describes the entity. The granulomatous variant of PD can also be seen in adults and is clinically very similar to GR without the background erythema. The cause of this variant of PD is thought to be topical steroid use.
Granulomatous rosacea
Etiopathogenesis
GR is a rare chronic inflammatory skin disease reported primarily in middle-aged women that has been given various names in the literature. In 1896, Darier first described the concept of tuberculids, which were defined as skin findings associated with a distant focus of active tuberculoid infection. In 1917, Lewandowsky described a patient with a rosacea-like tuberculid granuloma that clinically mimicked the appearance of papular rosacea. Laymon reported similar cases and called it “micropapular tuberculid.” However, in 1949, Snapp presented 20 patients with rosacea-like tuberculids; all except one displayed a low degree of tuberculin sensitivity. He concluded, therefore, that tuberculid rosacea does not exist and posited that it is a distinct form of rosacea. Because the common features of rosacea (flushing, nontransient erythema, papules and pustules, and telangiectasia) are not necessary, or even typical, for the diagnosis of GR, it has been questioned whether the pathophysiology of GR is even related to that of rosacea. For that reason, some investigators have even suggested the term granulomatous facial dermatitis for the condition. Just as the nomenclature is controversial, the etiologic factors of both rosacea and GR are disputed. Several triggering and aggravating factors for rosacea have been described. These include systemic steroids, topical steroids, ultraviolet radiation (UVR), heat, spicy food, alcohol, and infectious organisms, including Demodex mites and GI bacteria. Mullanax and Kierland first reported cases of GR with the key pathologic finding of noncaseating epithelioid granulomas with a mixed inflammatory infiltrate. Because granulomas are thought to be a response to persistent antigen presence, researchers subsequently looked for antigens as the triggering factors. Demodex folliculorum has been at the center of this discussion ever since histologic examination of a facial papule from a patient with GR showed foreign body granulomas along with D folliculorum species within enlarged hair follicles. Most recently, in 2008, a study reviewed pathologic specimens from 24 subjects with GR and D folliculorum was identified in only 7 out of these 24 specimens. However, in those that were positive for D folliculorum , the mites were found within the granuloma suggesting their role in the pathogenesis of at least some cases. Other researchers suggest it may not simply be the presence of the D folliculorum mites but the combination of location of the mites, density of the organisms, and host susceptibility that may play a role in the pathogenesis of GR. Another recent study suggests the role of UVR in causing both sun damage and increased matrix metalloproteinase (MMP)-2 and MMP-9, contributing to tissue remodeling and, thereby, recruiting inflammatory cells that contribute to the formation of granuloma in the dermis. Also of note is the historical but unsupported association between gastrointestinal disturbances caused by Helicobacter pylori and GR. There is a study showing improvement of GR after eradicating H pylori ; however, there are no large trials supporting this data. Currently, the consensus is that GR is a histologic variant of rosacea, not a distinct clinical subtype, and may have multifactorial causes that are distinct from rosacea.
Clinical Presentation
The lesions of GR consist of monomorphic, firm, yellow, red, brown, or flesh-colored papules or nodules localized around eyes, nose, and mouth on relatively normal appearing skin. Specifically, the characteristic papules are on the lateral side of the face and on the neck below the mandible. Other signs of rosacea, such as flushing, erythema, or telangiectasia, may be seen but are not needed for diagnosis. However, if patients have overlap of GR and rosacea, they can have symptoms of burning or stinging, pruritus, facial swelling, or irritation. In a review study of 53 patients with GR, 15% had extrafacial lesions in the ears, neck, axilla, shoulder, groin, thigh, and knees. GR tends to be a chronic condition that is difficult to treat and has unpredictable responses to standard rosacea treatments. Based on case reports in the literature, the clinical course ranges from 6 months to 4 years.
The differential diagnosis of GR includes PD, CGPD, lupus miliaris disseminatus faciei (LMDF), sarcoidosis, FACE, and cutaneous tuberculosis ( Table 1 ). PD is a papulopustular facial dermatitis that typically spares the vermillion border. Clinically and histologically, PD can be similar to GR but typically has a less granulomatous histology, responds better to treatment, and has a shorter clinical course. CGPD is characterized by periorificial papules, pustules, and erythema and may be a subtype of GR. LMDF is a rare chronic skin condition characterized by papules distributed across the face symmetrically and can be differentiated by histologic findings of caseating granulomas. LMDF tends to heal by leaving permanent scars. Sarcoidosis can also cause granulomatous papules on the face but typically has other extracutaneous findings, such as granulomas, fatigue, fever, weight loss, pulmonary symptoms, and less mixed inflammation on histopathology. FACE is similar to PD but is more commonly seen in children with dark skin. Some investigators think FACE is also a variant of GR.
| Patient Characteristics | Clinical Features | Histopathology | |
|---|---|---|---|
| GR | Young adults, light skin | Periorificial, extrafacial papules | Noncaseating epithelioid cell granulomas with mixed infiltrate |
| PD | Children or young women | Periorificial erythema, papules and pustules | Perifollicular lymphocytic and perivascular infiltration |
| CGPD | Prepubertal | Periorificial, extrafacial papules | Perifollicular granulomatous infiltration on the upper half of body |
| LMDF | Adolescent or adult | Symmetric papules across central face | Perifollicular caseating granulomatous lymphohistiocytic infiltration with occasional neutrophils |
| Sarcoidosis | Any age | Noninflammatory facial papules and nodules May have systemic findings of fatigue, weight loss, joint pain, pulmonary symptoms | Naked, noncaseating granulomatous infiltration |
| FACE | Children, dark skin | Periorificial, favoring outer helix of the ear | Perifollicular granulomatous infiltration |
| Cutaneous tuberculosis | Any age | Systemic findings, weight loss, malaise, pulmonary symptoms | Caseating granuloma |
Systemic Associations
Involvement of other organ systems is not typically associated with GR. However, it is on the spectrum of rosacea. Ocular rosacea coexists in 50% of patients with cutaneous rosacea. There is a case report of a patient with GR who developed lacrimal, parotid, and submandibular gland swelling after treatment with systemic steroids. The scleritis, conjunctivitis, and parotiditis resolved after a month of minocycline therapy. In fact, if patients have other systemic complaints, the clinician should seek out other possible diagnoses in the differential such as sarcoidosis.
Evaluation and Management
When approaching patients with facial papular dermatitis, differential diagnoses of GR, PD, CGPD, sarcoidosis, LMDF, FACE, and cutaneous tuberculosis should be considered. Diagnosis of these entities can be challenging and evaluation should include a thorough clinical history, physical examination, and skin biopsy. Depending on clinical suspicion of sarcoidosis or tuberculosis, evaluation can include routine complete blood cell count with differential, chemistry panel, purified protein-derived or QuantiFERON-TB Gold test (QTF-G, Cellestis Limited, Carnegie, Victoria, Australia), baseline pulmonary radiograph, and autoimmune panel.
Currently, there is no standard of treatment of GR and limited data on therapeutic effectiveness are reported in individual cases. With limited data on treatment of GR, therapeutic efforts have been based on the use of medications that are effective for sarcoidosis and papulopustular rosacea, the 2 diseases with which it has the most in common. The tetracycline family of medications is the obvious first therapeutic choice. Use of tetracycline 250 mg daily to 500 mg 3 times a day, doxycycline 50 to 100 mg twice a day, or minocycline 50 to 100 mg twice a day has been reported in the literature. Their mechanism of action against granuloma formation is thought to be due to inhibition of protein kinase C, a signaling enzyme in the inflammatory pathway. Other therapeutic agents to consider include azelaic acid, benzoyl peroxide, topical metronidazole, topical corticosteroids, systemic corticosteroids, and oral erythromycin. There is a case report suggesting the role of H pylori in the pathogenesis of GR in which the patient’s skin lesions resolved 2 months after taking clarithromycin 250 mg twice a day, oral metronidazole 500 mg twice a day, and pantoprazole 40 mg daily for 7 days. There are 2 case reports of the use of pimecrolimus 1% cream applied to lesions twice a day with good efficacy. One patient used pimecrolimus 1% topical cream combined with sun block twice a day resulting in complete resolution of lesions after 4 months of therapy. The other patient responded well to pimecrolimus 1% cream after failing a 45-day course of topical metronidazole and oral doxycyline. There was no evidence of relapse after stopping the medication.
For recalcitrant GR, isotretinoin 0.7 mg/kg for 6 months as monotherapy showed some clinical resolution of disease without recurrence. After failing systemic doxycycline, isotretinoin, and corticosteroid, 2 patients tried oral dapsone with clinical improvement. Limited data on physical modalities as treatment options include laser and ablative laser therapy. One patient received 6 treatments at 2-week intervals of photodynamic therapy with aminolevulinic acid with improvement seen after the third treatment. Another patient underwent 6 sessions of intense pulsed dye laser at 4-week interval with satisfactory improvement.
Although unreported in the literature for specific use against GR, combination therapy with oral metronidazole and oral ivermectin has been shown to be the most effective regimen for eradication of D folliculorum . Given the role this organism is suspected to play in GR, a trial of this regimen would be reasonable in a case that does not respond to therapy with oral tetracyclines. The studied regimen for D folliculorum is metronidazole 250 mg 3 times a day for 14 days along with ivermectin 0.2 mg/kg of body weight on days 1 and 7 of the metronidazole course. For current available treatments for GR, see Table 2 .
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