Management of Papulopustular Rosacea and Perioral Dermatitis with Emphasis on Iatrogenic Causation or Exacerbation of Inflammatory Facial Dermatoses Use of Doxycycline-modified Release 40mg Capsule Once Daily in Combination with Properly Selected Skin Care as an Effective Therapeutic Approach

James Q. Del Rosso, DO, FAOCD

Dermatology Residency Program Director, Valley Hospital Medical Center, Las Vegas, Nevada; Clinical Professor (Dermatology), Touro University College of Osteopathic Medicine, Henderson, Nevada; and Private Practice, Dermatology and Cutaneous Surgery, Las Vegas Skin & Cancer Clinics, Las Vegas, Nevada and Henderson, Nevada

Disclosure: Dr. Del Rosso serves as a consultant, researcher, and/or speaker for Allergan, Coria/Valeant, Galderma, Graceway, Intendis/Bayer, LeoPharma, Medicis, Onset Dermatologics, Ortho Dermatology, Pharmaderm, Promius, Ranbaxy, TriaBeauty, Unilever, and Warner-Chilcott.

A variety of inflammatory facial dermatoses, such as papulopustular rosacea and perioral dermatitis, are often idiopathic. However, prolonged continuous and/or repeated intermittent topical corticosteroid use can exacerbate these disorders or, in some cases, induce them. This article discusses corticosteroid-induced rosacea-like dermatitis and primary perioral dermatitis with regard to clinical presentations, including in both adults and children, and management considerations. The rationale for use of an anti-inflammatory dose of doxycycline that is subantimicrobial, doxycycline modified-release 40mg capsule once daily, along with properly selected skin care, is discussed. Case illustrations are also included.
(J Clin Aesthet Dermatol. 2011;4(8):20–30.)

The category basket referred to as “common inflammatory facial dermatoses” comprises a diverse group of disorders that includes acne vulgaris (AV), papulopustular rosacea (PPR), erythematotelangiectatic rosacea (ETR), perioral dermatitis, seborrheic dermatitis (SD), and atopic dermatitis (AD). Despite some overlapping visible features, these disorders are distinct in terms of clinical presentation and in their apparent pathogenic mechanisms, although there may be some overlap of specific pathogenic pathways among some of these disorders. In the case of eczematous dermatoses and seborrheic dermatitis, topical corticosteroid (TC) therapy is an effective short-term approach to achieve rapid improvement, followed quickly by adjustment of its use and discontinuation of application to avoid predictable adverse reactions associated with prolonged use.[1] Nonsteroidal therapies also help to control flares and sustain remission.[2] In the case of PPR, ETR, AV, and perioral dermatitis, published treatment recommendations do not include use of a TC.[3–9] In fact, it is strongly suggested that these agents are best avoided for prolonged and frequently repeated facial use. Despite initial visible improvement, prolonged use of TCs to the face, including intermittent repeated courses of application, results in adverse outcomes that are predictable and often difficult to manage.[4,8,10] These adverse outcomes are well established in the literature and typically include exacerbation of several features of the underlying dermatosis, rebound flaring after discontinuation of TC use (“red skin syndromes” and “corticosteroid addiction and withdrawal”), and emergence of rosacea-like dermatitis induced by prolonged or repeated episodes of TC application.[4,8,10–13] The latter scenario often presents with symptomatic facial erythema and a more intensified appearance of edematous inflammation and suffusion.[4,8,10–13]

For many of the common inflammatory facial dermatoses, such as AV, SD, AD, and PPR, there are multiple studies supporting management recommendations, a reasonable body of scientific data on pathogenesis, and some therapies that are approved by the United States Food and Drug Administration (FDA) for these primary indications based on large-scale studies. However, for clinical presentations that are “rosaceaform” in nature, such as corticosteroid-induced rosacea-like dermatitis (CIRD) and perioral dermatitis both with and without a history of TC use, management is more dependent on “after-the-fact” case report collections, literature reviews, and anecdotal experience.[5,7–11] In such cases, there is a conspicuous absence of prospective clinical trials as well as an absence of large-scale pivotal studies, as no topical or oral agents are FDA approved for these diagnoses as specific indications.[5,7,9–11]

Some cases of CIRD are clinically consistent with PPR or ETR that has been complicated by prolonged TC use. If this historical scenario is confirmed, then the primary diagnosis is the initial PPR or ETR that was erroneously treated with a TC, and the CIRD in such cases represents the secondary overlap of adverse effects caused by repeated TC use. Figure 1 depicts an adult patient with a 10-year history of PPR who developed CIRD secondary to chronic intermittent use of betamethasone dipropionate 0.05%-clotrimazole 1% cream twice daily for three months followed by repeated courses of mometasone furoate 0.1% cream daily for six months.

In other cases, CIRD is diagnosed without the ability to fully ascertain the primary diagnosis, although some have reported that the most common initial diagnoses in patients with CIRD that prompted facial TC use from the outset are AD, SD, and sometimes “dry skin” or rosacea.[8,10,12,13] Perioral dermatitis and its variant presentations (e.g., periocular dermatitis, perinasal dermatitis) may present as a clinical subset of CIRD or may be idiopathic.[8,9,11] Figure 2 illustrates a woman with perioral dermatitis who developed the perioral subtype of CIRD induced by repeated courses of fluocinonide 0.05% cream twice daily over seven months. Note the brisk inflammatory nature of the individual perioral papules and the more confluent infranasal foci that were present bilaterally. Idiopathic perioral dermatitis has been described in adults and children without a history of TC exposure on facial skin and is not uncommon. Figure 3 shows a woman with a two-month history of idiopathic perioral dermatitis that was not responsive to treatment with metronidazole 0.75% cream once daily for six weeks. Note the characteristic light pink hue of individual small papules and regions of confluence, along with perivermillion sparing, as opposed to the more briskly inflamed and more swollen-appearing papules of CIRD, which present more commonly with a red hue rather than “pink erythema.” When encountering a patient with perioral dermatitis, it is important to recognize that topical exposure of facial skin to a corticosteroid may occur not only during intentional application of TC-containing products, but also unintentionally and insidiously during use of an inhaled corticosteroid for allergic airway disease (e.g., asthma, allergic rhinitis). As many patients who develop CIRD have been reported to be atopic, this history is not unlikely and requires an index of suspicion and directed questioning by the clinician to elicit this potential cause of CIRD, including a presentation of perioral dermatitis associated with corticosteroid exposure.[10,12,13–15]

A variety of therapeutic approaches have been suggested in the literature for patients with rosaceaform facial eruptions and/or perioral dermatitis associated with TC use and for perioral dermatitis not associated with TC exposure. As there is a dearth of prospective scientific evidence to support a consensus approach to these distinct clinical disorders, much of what dermatologists do to manage these disorders is based on “recycled dogma” derived from lectures or articles, or in many cases, spoken to the clinician from within their own mind. Either way, we do our best to manage these disorders based on our best understanding from the information and experiences that we have, and from this we subliminally develop strong belief systems on how to best manage such cases. This is simply human nature; however, each of us needs to maintain an open mind as additional information or new perspectives may sometimes provide opportunities to modify how we manage specific disorders and improve therapeutic outcomes with greater consistency.

In this article, the author suggests a simplified and practical management approach to both facial CIRD and idiopathic perioral dermatitis based on his assessment of the best evidence from current publications and clinical experience. A common theme of the management approach for these disorders is the concept of first “priming the skin,” a concept initially presented by the author at the 2010 Fall Clinical Dermatology Conference in Las Vegas, Nevada. Case studies will be used to illustrate important points felt to be worthy of emphasis. Although it is recognized that cutaneous side effects associated with prolonged TC use can occur at sites other than the face, this article specifically discusses facial involvement, which is the anatomic site most commonly affected by CIRD.

Corticosteroid-induced Rosacea-like Dermatitis (CIRD)
The untoward effects of prolonged and repeated TC use on facial skin have been thoroughly documented in the literature and the clinical presentations of these effects have been well described in both adults and children.[8,10,12–21] In many cases, the diagnosis of CIRD is made without knowledge of the initial diagnosis that led to facial application of the TC in the first place. In other cases, the TC is used erroneously to treat PPR or ETR leading to emergence of TC-exacerbated rosacea, which most simulates severe PPR. However, the papular and erythematous components of the eruption tend to be more diffuse rather than predominantly centrofacial. The designation CIRD will be used to describe both circumstances, although in some cases the patient had PPR or ETR initially. Prolonged TC use can also exacerbate or induce perioral dermatitis, which if associated with TC use is one of the subtypes of CIRD. Importantly, CIRD is categorized as an adverse drug reaction pattern, and is not felt to be a clinical subtype or variant of rosacea.[4,10,22,23]

TC potency and development of CIRD. It is generally accepted that the risk for development of CIRD correlates with TC potency, although CIRD may occur in association with prolonged use of TCs of any potency ranking, including hydrocortisone 1%.[10,12,13,20] CIRD may also occur after prolonged application of both halogenated and nonhalogenated TCs.

Duration of TC application associated with CIRD. CIRD has been noted to occur over a broad range of treatment durations, and CIRD may develop after a minimum of two months of TC application. However, in many cases, six months or more of facial application of a TC has been noted prior to the development of clinically evident CIRD.[10] In another report, the duration of TC use associated with CIRD ranged from 3 to 480 months, with most cases occurring over 1 to 2 years of TC use.[24]

Clinical presentation of CIRD. Three subtypes of CIRD have been described based on anatomic location—perioral, centrofacial, and diffuse.10 The perioral subtype is the most common presentation of CIRD involving the face, has been noted in both adults and children, and represents a common subset of perioral dermatitis.[8,10] Children commonly present with perioral dermatitis, with or without perinasal and/or periocular involvement.[10,23] However, perinasal involvement, often misdiagnosed as SD, may be the only anatomic site affected initially in many children. Figure 4 depicts an 11-year-old girl with CIRD presenting as perinasal dermatitis, a clinical variant of perioral dermatitis    that occurs without perioral or periocular involvement. This eruption developed after repeated courses of application of mometasone furoate 0.1% cream over a duration of 10 months. CIRD is reported to occur more commonly in female patients (72%), often with a history of atopy (67%).[24]
CIRD is reported to occur more commonly in female patients (72%), often with a history of atopy (67%).[24]

It has been suggested that patients with PPR or ETR are more susceptible to CIRD.[4] Patients with CIRD often complain of sensitive or painful skin that is symptomatic, as typified by complaints of burning, stinging, pruritus, or dryness.[8,10] The primary lesions of CIRD are small flesh-colored, pink or red (most common) papules, pustules, and/or papulovesicles (pseudovesicles) that often exhibit a perilesional flare of erythema.10 Areas of confluence are also commonly noted. Perivermillion sparing is common overall, but is not always a complete finding. The eventual sequelae of resolved papules is erythema, which is persistent and edematous, with a propensity to become more diffuse.[10,12,13] Telangiectasias and deeper follicular papules and nodules progressively increase with prolonged duration and/or continued episodes of TC use.

The perioral dermatitis subset of CIRD is the most common presentation in both adults and children (Figure 2).[8,10,21,23] In some cases, perinasal (Figure 4) and/or periocular involvement (Figure 5) is also observed. The centrofacial subtype of CIRD involves the inner cheeks, lower eyelids, nose, and medial forehead including the glabellar region, with usual absence of perioral involvement.[10] In the diffuse subtype, the entire face is involved with extension onto the neck a common finding (Figure 1).[10,12,13]

Differential diagnosis of CIRD. Facial skin disorders that are to be considered in the differential diagnosis of CIRD include idiopathic PPR or ETR, corticosteroid-induced acneiform eruptions, chronic cutaneous lupus erythematosus (LE), systemic LE, sarcoidosis (simulant of CIRD with granulomatous changes), polymorphous light eruption, tinea faciei (especially tinea incognito secondary to TC use), lupus miliaris, and dermatomyositis. Most can be differentiated by clinical characteristics, history, physical examination, and laboratory testing, including histological findings when the need for a skin biopsy is clinically applicable.8,10 Diagnosis of CIRD is based on clinical suspicion, history, and physical examination.[8,10,12,13] There are no confirmatory laboratory tests that definitively support the diagnosis of CIRD, and histological findings are not specifically diagnostic.[4,8,10,12,13]

Clinical course of CIRD. The development and progression of CIRD is consistent among affected patients.[10,12,13,24] CIRD typically begins with either self-treatment with OTC hydrocortisone or a prescription TC for a variety of possible underlying disorders. After initial clearance, the underlying disorder flares within a few weeks, which leads to restarting of the TC. The repeated cycles of flaring and restarting of TC therapy continues to lead to more frequent flaring with repeated episodes of TC application. Eventually, the efficacy of TC application diminishes, sometimes leading to physicians increasing the potency of the TC or prescribing systemic corticosteroid therapy.[24] As the eruption progresses, symptoms of burning, stinging, and itching increase in regularity and severity.[10,24] Over time, the visible presentation of CIRD progresses, usually associated with increased intensity of inflammation and erythema. The clinical subtype correlates primarily with the facial locations where repeated intentional or insidious TC application occurs.

Pathogenic mechanisms of CIRD. Several cutaneous abnormalities occur as a result of TC exposure based on studies completed in both human and animal models.[25–28] Alterations in epidermal structure and the permeability barrier of the epidermis have been associated with TC use, including decreased density and maturation of lamellar body formation, downregulation of epidermal lipid synthesis-related enzymes, decreased epidermal cellular layers, and reduced size of keratinocytes. Other epidermal and dermal changes include thinning of the stratum corneum with loss of “basket-weave” appearance, diminution of the granular layer, increased transepidermal water loss (TEWL), delayed response and recovery of permeability barrier, decreased dermal collagen and mucopolysaccharide synthesis, thinning of upper dermal elastin fibers, and reduced epidermal lipids including ceramides.[26–28] In patients with CIRD and an underlying AD history, additional innate stratum corneum abnormalities associated with AD and atopic skin are present, including a decrease in specific ceramide subfractions and other lipids, and in some cases fillagrin gene mutations leading to a decrease in natural moisturizing factor.[29–31] In addition, increased facial TEWL has been noted as an inherent characteristic of perioral dermatitis, ETR, and PPR, with atopic diathesis suggested as a possible risk factor for development of perioral dermatitis.[32] Signs and symptoms characteristic of facial skin sensitivity inherent to untreated PPR have been documented, including dryness (65–69%), scaling (51–57%), edema (32–38%), pruritus (49–52%), burning (33–36%), stinging (29–34%), and pain/discomfort (17–21%). Male and female patients with rosacea find several skin care and personal use products to be irritating based on large-scale surveys.[6,33–35]

Chronic TC application leads to several functional and biological changes within the skin, which alter cutaneous response. Reduction in collagen and elastin synthesis leads to degradation of dermal matrix with reduced structural support for superficial vasculature leading to cutaneous vasodilation, which is visible clinically as telangiectasias and diffuse erythema.[4,10,12,13,26–28] TC-induced alterations in the normal homeostatic balance of chemical mediators, which modify cutaneous blood flow, appears to be a major factor in the pathogenesis of CIRD.[10,12,13] The predominant force in creating symptomatic exacerbations of CIRD that follow discontinuation of TC application appears to be release of accumulated cutaneous endothelial nitric oxide stores leading to exaggerated dilatation of cutaneous vessels.[10,12,13,24] Endothelial nitric oxide (eNO), also referred to as endothelium-derived relaxing factor, is an endogenous vasodilator that is markedly inhibited by glucocorticosteroids, including with TC application.[24] During TC application, vasoconstriction occurs, and release of eNO is inhibited. As a result, eNO accumulates and is stored. Upon discontinuation of TC use, there is a surge of eNO release, which results in vascular “hyperdilation.” As a result, rebound flaring with suffusion occurs characterized by brisk erythema, edema, and symptoms of discomfort—stinging, burning, and pruritus.[10,24] The repeated offset and onset of nonphysiological storage and release of eNO creates what has been described as a “trampoline effect” or “neon sign” effect, ultimately resulting in persistent vasodilatation as a sequelae of repeated episodes of vasoconstriction-vasoldilatation.[12]

Perioral Dermatitis Not Associated With Topical Corticosteroid Use (Idiopathic Perioral Dermatitis)
As noted above, perioral dermatitis may be a subset of CIRD or can occur in the absence of previous TC use.[8–10] This disorder is estimated to affect female patients in 90 percent of cases, usually between the ages of 20 to 45 years, although male patients may be affected.[8,9] Occurrence in children has been noted without an apparent gender predominance, with a variety of designations and variants described, such as Gianotti-type perioral dermatitis, rosacea-like eruption of childhood, granulomatous periorificial dermatitis of childhood, or facial Afro-Caribbean childhood eruption (FACE).[21,23,36] Some reports in children and adults include both the perioral subset of CIRD and cases of idiopathic perioral dermatitis. The granulomatous form of perioral dermatitis (periorificial granulomatous dermatitis) is more commonly seen in African-American children and may be associated with TC use, with both perioral (Figure 6a) and periocular involvement (Figure 6b) noted in some cases.[8] Perioral dermatitis is not classified as a subtype of rosacea despite clinical similarities to PPR and response to many of the same therapeutic agents.[4,22]

Many potential etiologies of idiopathic perioral dermatitis have been suggested, including fluorinated toothpaste, overuse of “heavy” cosmetic creams and moisturizers (e.g., petrolatum or paraffin-based products), emotional stress, and microbiological factors. However, all of these suggested etiologies are speculative, and none of these factors have been shown to be definitively causative.[8]

Clinical presentation. Idiopathic perioral dermatitis typically presents as small, discrete, pink-to-red papules, papulovesicles, and less commonly pustules involving the perioral region. The lesions tend to form a complete or partial circumoral ring of involvement, with a characteristic rim of perivermillion sparing (Figure 3
).[8,9] Individual papules sometimes exhibit a microvesicular appearance, although the lesions are solid. The primary lesions of idiopathic perioral dermatitis most commonly exhibit a characteristic pink color, with areas of confluence commonly noted, and fine scaling sometimes present (Figure 7). Perinasal and/or periocular involvement is sometimes present. Figure 8a-8c
depict a nine-year-old girl with idiopathic nongranulomatous perioral dermatitis involving multiple facial sites. In children, especially preteens, perinasal involvement is often the only affected location, at least initially, and is frequently misdiagnosed as SD and erroneously treated with a TC. Figure 9 depicts an 11-year-old boy with idiopathic perioral dermatitis presenting only with perinasal involvement. In some children, idiopathic nongranulomatous perioral dermatitis often presents as noninflamed micropapular lesions, which, in some areas, may simulate lesions of molluscum contagiosum.

Patients with untreated perioral dermatitis have been shown to exhibit higher levels of centrofacial TEWL than patients with ETR and PPR, and an atopic history has been suggested as a potential predisposing factor.[32] The increased TEWL, reflective of an impaired permeability barrier, accounts at least partially for the tendency of the facial skin of patients with perioral dermatitis to be easily irritated by several contactants, such as skin care products and topical medications.[6,33,35]

Management of Corticosteroid-Induced Rosacea-like Dermatitis and Idiopathic Perioral Dermatitis
Although there are important distinctions between CIRD, including the perioral subset, and idiopathic perioral dermatitis, certain common characteristics suggest that a unified management plan is likely to be efficacious. However, the time course of response may be more prolonged in CIRD.[10,12] Importantly, depending on the duration and severity of CIRD, rebound flaring once TC use is discontinued may result in the need for continued support and encouragement and a longer course of therapy.[8] In CIRD, to reduce the intensity of rebound, some authors suggest tapering the frequency of TC use or “step down” to a lower potency TC. However, there is no support for this approach other than anecdotal suggestion.[10] Some authors, including the author of this article, do not suggest this “tapering” approach and recommend abrupt discontinuation of  all TC application to the face and “working through” rebound flares—the so called “cold turkey” approach.[8,12,13,24]

Medical therapy options. Several therapies, including oral antibiotics (e.g., tetracyclines), topical antibiotics (e.g., erythromycin, clindamycin), topical metronidazole, topical azelaic acid, topical sulfacetamide-sulfur, and topical calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), have been used with some success to treat perioral dermatitis, including the perioral CIRD subset, although cutaneous irritation may be problematic in some patients treated with topical agents.[4,5,8–11,36] For CIRD, some authors have recommended the use of tacrolimus as the preferred topical agent; however, exacerbations may occur, and the body of data supporting this approach is limited.

Topical therapy considerations. Overall, the author agrees with the suggested “null therapy” approach to the topical management of idiopathic perioral dermatitis.[8] In addition, the author suggests this same approach in the management of CIRD. Essentially, it is strongly recommended to limit as much as possible what is applied to the skin, including both skin care products and topical medications, especially over the first few weeks of treatment.[8] Avoidance of soaps, astringents, abrasives, and patient-selected skin care products is an important component of this approach, as the epidermal permeability barrier is perturbed in both CIRD and in idiopathic perioral dermatitis, and facial skin is exquisitely sensitive.

Oral therapy considerations. Despite the absence of well-controlled clinical trials, among the available therapeutic agents used to treat perioral dermatitis, the tetracyclines appear to be consistently efficacious.[8,9] Additionally, as eNO appears to be an important mediator in the pathogenesis of at least the vascular component of CIRD, the ability of tetracyclines to inhibit NO production, along with several other direct anti-inflammatory properties, supports their role in the treatment of CIRD.[37–40] As there is no definitive evidence that a bacterium is causative in the etiology of either CIRD or PPR, the author has used the same subantimicrobial dosing that is FDA-approved for PPR—doxycycline-modified release (MR) 40mg, one capsule daily—to treat both CIRD and idiopathic perioral dermatitis with consistent success anecdotally. This dosing regimen has been shown to exhibit anti-inflammatory activity without producing antibiotic selection pressure or emergence of antibiotic-resistant bacterial strains, including with chronic administration over nine months or greater.[41–43]

Although a comprehensive understanding of the pathophysiology of these disorders is not currently known, certain features may be taken into account when considering treatment options. In both CIRD and idiopathic perioral dermatitis, addressing repair of the altered permeability barrier of the stratum corneum and reduction of increased TEWL is significant in order to reduce associated skin sensitivity, erythema, and propensity for secondary inflammation.[5–7,32,44,45] The ability of tetracyclines to inhibit many pathways of inflammation (e.g., reduction in activity of reactive oxygen species, downregulated expression of some matrix metalloproteinases, decreased serine protease activity, decreased eNO production) also seems to correlate with therapeutic benefit in CIRD and idiopathic perioral dermatitis, as has been noted with PPR in both clinical and basic science studies.[4–7,37–41,43] In CIRD, inhibition of the altered vascular response produced by episodes of eNO production, storage, and release appears to be a relevant component of the mode of action of tetracyclines, as discussed above.[10,12,13,24]

Conceptual and rational approach to management. The major components of the management approach used by the author in both CIRD and idiopathic perioral dermatitis are 1) “priming the skin” with management of skin care for the outset, 2) consideration of the need for and selection of topical therapy after skin priming, and 3) use of doxycycline-MR 40mg once daily from the outset. Although a controlled study has not yet been initiated, the author has regularly used this approach for the past two years with consistent success in the vast majority of cases, with experience in more than 50 adult and pediatric patients to date with perioral dermatitis, CIRD, and PPR over the past 18 months.

Priming the skin. Due to innate permeability barrier impairment of the stratum corneum and facial skin sensitivity associated with both CIRD and idiopathic perioral dermatitis, taking control of fundamental skin care is a “rate-limiting step” in achieving a favorable therapeutic outcome. As it is difficult to fully know the magnitude of permeability barrier impairment in patients at baseline, or be fully informed of their actual skin care practices despite what they tell us, dermatologist-directed skin care is recommended to “reset” the permeability barrier from the start of treatment, an approach the author refers to as “priming the skin.” That is, you as the clinician direct the status of their epidermal permeability barrier from the start as an integral part of the overall management of their facial problem. The patient is instructed to disband other cleansers and moisturizers, astringents, facial scrubs, and any procedures, such as exfoliation procedures (e.g., facials, superficial peels) or microdermabrasion, during treatment of their current disorder. Photoprotection with use of a dermatologist-selected sunblock and avoidance of ultraviolet light exposure as much as possible is recommended.

How is priming of the skin carried out by the patient? Priming the skin is done by incorporating a gentle nonmedicated cleanser and moisturizer without initial use of topical medication for the first 3 to 5 days. In idiopathic perioral dermatitis, the addition of topical medication is often not needed, as oral therapy alone is almost always sufficient. In CIRD, after initially priming the skin with gentle skin care, use of a topical agent can then be initiated with less potential for cutaneous irritation. Priming the skin allows for this by first improving the functional integrity of the epidermal permeability barrier by incorporating proper skin care from the outset of management and by removing any patient-directed improper skin care approaches that augment damage to the stratum corneum and potentiate skin sensitivity. Also in CIRD, all TC agents are discontinued abruptly so initial rebound flares are anticipated. The author has observed overall that the frequency of rebound flares appears to be less, and the flares that do occur seem blunted in intensity with the initial “priming” approach. However, marked rebound may still occur and facial sensitivity to even gentle skin care products may be present in some cases, especially with intensely inflamed CIRD.

Selection of topical therapy. There is no single topical medication definitively shown to be most effective in either idiopathic perioral dermatitis or CIRD. Topical options discussed in the literature include metronidazole, azelaic acid, clindamycin (aqueous-based formulation), sulfacetamide 10% lotion, sulfacetamide 10%-sulfur 5% formulations, and calcineurin inhibitors.[9–1,36] The author most currently uses only controlled skin care alone in combination with oral therapy from the outset for idiopathic perioral dermatitis and has tried this approach in some cases of CIRD with success, including the perioral subtype and in cases of PPR complicated by CIRD. In most cases of CIRD, the author initiates priming of the skin and oral therapy from the outset. After five days of this regimen, proper skin care is continued along with oral therapy, and in many cases a topical agent is added. The author has the most experience with adding either topical sulfacetamide 10% lotion, azelaic acid 15% gel, or metronidazole 1% gel.  However, there are no well-controlled studies to differentiate the therapeutic impact or relative benefits among these topical therapies in CIRD or perioral dermatitis. Available data are primarily anecdotal and based on small studies and case report series.[9–11,36]

Selection of  oral therapy. Oral tetracycline agents, including tetracycline, doxycycline, and minocycline, exhibit anti-inflammatory properties that appear to contribute to their efficacy in disorders such as PPR and perioral dermatitis.[5,9,11] The author has elected to use doxycycline-MR 40mg once daily for treatment of CIRD and idiopathic perioral dermatitis as anti-inflammatory activity is preserved with absence of antibiotic selection pressure.[37,39,41–43] In addition, doxycycline-MR 40mg once daily has been shown to be as effective in reducing inflammatory lesions in PPR as doxycycline 100mg daily, with a markedly lower risk of gastrointestinal side effects.[46]  None of the subjects treated with doxycycline-MR 40mg once daily in this study experienced abdominal pain, nausea, vomiting, or diarrhea. Additionally, none of the female subjects (n=185) actively treated for PPR in the two phase III pivotal trials with doxycycline-MR 40mg once daily developed vaginal yeast infections.[43] This latter factor is important as the majority of patients with CIRD and perioral dermatitis are females.8,10,12,13,24

Illustrative Case Studies
The following cases illustrate clinical presentations of CIRD and idiopathic perioral dermatitis with focus on a simplified management approach selected to address underlying pathophysiological abnormalities occurring in these disorders.

Case 1. A 22-year-old healthy, white, female college student presented with a three-month history of erythematous papules with occasional pruritus on the chin and inner cheek region bilaterally. She related no history of TC use and has no history of any skin disorders other than mild acne in her early teen years. She did admit to picking at her facial lesions and recently had used a facial scrub along with an OTC benzoyl peroxide (BP) product. Examination revealed erythematous papules on the inner cheeks and chin with some light red diffuse erythema and diffuse scaling. Excoriated papules were also noted (Figure 10a
). The diffuse erythema and scaling was felt to be caused by cutaneous irritation from the facial scrub and/or the BP product. A diagnosis of idiopathic perioral dermatitis was made. A diagnosis of acne vulgaris was also considered, but was excluded clinically based on the “overall gestalt,” which took into account the absence of comedones and other acne lesion types on the face and trunk, the monomorphic nature of the primary lesions, and the distribution pattern of the eruption. Irritant dermatitis secondary to inappropriate skin care and OTC treatment was also noted. The patient was treated with a ceramide-based gentle cleanser, a ceramide-based physiological lipid moisturizer cream, and doxycycline-MR 40mg capsule  once daily. One month later, there was definite improvement with marked reduction in inflammatory lesions, absence of pruritus, and absence of scaling and background erythema (Figure 10b
) The patient was very pleased with the results, and treatment was continued for four more weeks. No adverse reactions were reported or observed.

Case 2. A 50-year-old Caucasian male insurance agent presented with a two-month history of pink erythematous pinpoint papules and papulopustules noted within a background of confluent pink erythema involving the lateral third of the left upper and lower eyelid and the left lateral canthus (Figure 11a). The right periocular region was minimally affected. A mild stinging sensation was noted intermittently. No other areas of involvement were present. The patient had not used any TCs or other prescription or OTC topical medications on the face, and there was no history of use of any prescription or OTC ophthalmic products. The patient did not wear goggles of any type or contact lenses, and there was no history of this type of periocular or facial eruption occurring in the past. Previous medical history was unremarkable except for hyperlipemia treated for the last six years with atorvastatin 20mg daily and allergic rhinitis treated with cetirizine 10mg daily. A diagnosis of idiopathic periocular dermatitis (variant of perioral dermatitis) was made. The patient was treated with a gentle cleanser and moisturizer and doxycycline-MR capsule 40mg once daily. One month later, the eruption was completely clear and no further therapy was needed (Figure 11b). No adverse reactions were reported or observed.

Case 3. A 42-year-old white female office manager presented with a 10-year history of PPR that was treated intermittently in the past with “an oral antibiotic” and sulfacetamide 10% lotion twice daily with some success. Approximately nine months ago, her facial eruption flared extensively on the cheeks, forehead, and chin. She saw a new physician who initially prescribed betamethasone dipropionate 0.05%-clotrimazole 1% cream twice daily for three months. During this time, the eruption cleared, but would recur within 7 to 10 days of stopping treatment. Her medication was then changed to mometasone furoate 0.1% cream daily used in repeated courses for six months to control flares. However, the patient noted that the flares became more frequent, the eruption more extensive, and her skin became more sensitive with symptoms of burning and itching over this six-month time period. Ultimately, the eruption became unresponsive to the TC treatment she was repeatedly using.

On examination, multiple discrete papules and pustules were noted diffusely on the cheeks, jawline, anterior-lateral neck, and central forehead with surrounding erythema (Figure 12a and Figure 13a). The patient was treated with a ceramide-based gentle cleanser, a prescription ceramide-based topical emulsion, and doxycycline-MR 40mg capsule once daily. After two months, marked improvement was noted with a decreased number of inflammatory lesions, reduction in erythema, and clearance of symptoms (Figure 12b and Figure 13b). The patient stated she was very pleased with her response to therapy. Treatment was continued and no adverse reactions were reported or observed.

CIRD involving facial skin and idiopathic perioral dermatitis are two common inflammatory facial dermatoses that have not been well studied prospectively with regard to treatment. Although there are differences in the time course of response, and CIRD is associated with a propensity for rebound flaring, both entities are responsive to a simple regimen involving “priming the skin” with appropriate skin care and use of doxycycline-MR 40mg capsule once daily. This oral therapy approach provides anti-inflammatory effects without antibiotic activity, thus avoiding the emergence of antibiotic-resistant bacterial strains.[39–43] In addition, doxycycline-MR 40mg capsule once daily is associated with a markedly lower risk of gastro-intestinal side effects as compared to an immediate-release formulation of doxycycline 100mg once daily based on a comparative study.[46] Anecdotal experience supports this therapeutic approach for CIRD and idiopathic perioral dermatitis, which was conceptualized based on an understanding of apparent pathogenic factors and clinical experience in managing such cases.

1.    Warner MR, Camisa C. Topical corticosteroids. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 2nd ed. Philadelphia: Saunders-Elsevier; 2007:606–613.
2.    Del Rosso JQ. Adult seborrheic dermatitis: a status report on practical topical management. J Clin Aesthet Dermatol. 2011;4(5):32–38.
3.    Gollnick H, Cunliffe W, Berson D, et al. Management of acne: report from a global alliance to improve outcomes in acne. J Am Acad Dermatol. 2003;49(1):S1–S37.
4.    Crawford GH, Pelle MT, James WD. Rosacea I: etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004;51:327–341.
5.    Pelle MT, Crawford GH, James WD. Rosacea II: therapy. J Am Acad Dermatol. 2004;51:499–512.
6.    Del Rosso JQ, Baum EW. Comprehensive medical management of rosacea: an interim study report and literature review. J Clin Aesthet Dermatol. 2008;1:20–25.
7.    Del Rosso JQ, Baldwin H, Webster G. Rosacea medical management guidelines. J Drugs Dermatol. 2008;7:1–3.
8.    Lipozencic J, Ljubojevic S. Perioral dermatitis. Clinics Dermatol. 2011;29:157–161.
9.    Kanelleas A, Berth-Jones J. Perioral dermatitis. In: Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Diseases: Comprehensive Therapeutic Strategies. 3rd ed. Philadelphia: Saunders-Elsevier; 2010:547–548.
10.    Chen AYY, Zirwas MJ. Steroid-induced rosacea-like dermatitis: case report and review of the literature. Cutis. 2009;83:198–204.
11.    Gupta A. Perioral dermatitis. In: Williams H, Bigby M, Diepgen T, Herxheimer A, Nadir L, Rzany B, eds. Evidence-Based Dermatology. 2nd ed. Malden, Massachusetts: Blackwell Publishing; 2008:111–116.
12.    Rappaport MJ, Lebwohl M. Corticosteroid addiction and withdrawal in the atopic: the red burning skin syndrome. Clinics Dermatol. 2003;21:201–214.
13.    Rappaport MJ, Rappaport V. The red skin syndromes: corticosteroid addiction and withdrawal. Expert Rev Dermatol. 2006;1(4):547–561.
14.    Dubus JC, Marguet C, Deschildre A, et al. Local side effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age, and device. Allergy. 2001;56:944–948.
15.    Egan CA, Rallis TM, Meadows KP, et al. Rosacea induced by beclomethasone dipropionate nasal spray. Int J Dermatol. 1999;38:133–134.
16.    Bhat YJ, Manzoor S, Qayoom S. Steroid-induced rosacea: a clinical study of 200 patients. Indian J Dermatol. 2011;56(1):30–32.
17.    Weber G. Rosacea-like dermatitis: contraindication or intolerance reaction to strong steroids. Br J Dermatol. 1972;86:253–259.
18.    Leyden JJ, Thew M, Kligman AM. Steroid rosacea. Arch Dermatol. 1974;110:619–622.
19.    Sneddon I. Adverse effect of topical fluorinated corticosteroids in rosacea. Br Med J. 1969;1:671–673.
20.    Guin JD. Complications of topical hydrocortisone. J Am Acad Dermatol. 1981;4:417–422.
21.    Savin JA, Alexander S, Marks R. A rosacea-like eruption of children. Br J Dermatol. 1972;87:425–429.
22.    Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: a report of the National Rosacea Society Expert Committee on classification and staging of rosacea. J Am Acad Dermatol. 2002;46:584–587.
23.    Manders SM, Lucky AW. Perioral dermatitis in childhood. J Am Acad Dermatol. 1992;27:688–692.
24.    Rappaport MJ, Rappaport V. Eyelid dermatitis to red face syndrome. J Am Acad Dermatol. 1999;41:435–442.
25.    Hong SP, Oh Y, Jung M, et al. Topical calcitriol repairs epidermal permeability and antimicrobial barriers induced by cortico-steroids. Br J Dermatol. 2010;162:1251–1260.
26.    Kao JS, Fluhr JW, Man MQ, et al. Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid syunthesis accounts for functional abnormalities. J Invest Dermatol. 2003;120:456–464.
27.    Del Rosso J, Friedlander SF. Corticosteroids: options in the era of steroid-sparing therapy. J Am Acad Dermatol. 2005;53:850–858.
28.    Sheu HM, Tai CL, Kuo KW, et al. Modulation of epidermal terminal differentiation in patients after long term cortico-steroids. J Dermatol. 1991;18:454–464.
29.    Proksch E, Elias PM. Epidermal barrier in atopic dermatitis. In: Bieber T, Leung DYM, eds. Atopic Dermatitis. New York: Marcel Dekker; 2002:123–143.
30.    Di Nardo A, Wetz PW. Atopic dermatitis. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. 1st ed. New York: Marcel Dekker; 2002:165–178.
31.    McLean I. Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum. J Invest Dermatol. 2008;128:2117–2119.
32.    Dirschka T, Tronnier H, Folster-Holst R. Epithelial barrier function and atopic diathesis in rosacea and perioral dermatitis. Br J Dermatol. 2004;150:1136–1141.
33.    Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results of two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003;48:836–845.
34.    Elewski BE, Fleischer AB, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea. Arch Dermatol. 2003;139:1444–1450.
35.    Torok HM. Rosacea skin care. Cutis. 2000;66(4 Suppl):14–16.
36.    Jansen T, Melnick BC, Schadendorf D. Steroid-induced perioroficial dermatitis in children—clinical features and response to azelaic acid. Pediatr Dermatol. 2010;27:137–142.
37.    Del Rosso JQ. Update on rosacea pathogenesis and correlation with medical therapeutic agents. Cutis. 2006;78:97–100.
38.    Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258–265.
39.    Golub LM, Lee HM, Ryan ME, et al. Tetracyclines inhibit connective tissue breakdown by multiple nonantimicrobial mecahanisms. Adv Derm Res. 1998;12:12–26.
40.    Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007;25:122–135.
41.    Del Rosso JQ. Anti-inflammatory dose doxycycline in the treatment of rosacea. J Drugs Dermatol. 2009;8:664–668.
42.    Preshaw PM, Novak MJ, Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease. J Periodontol. 2008;79:440–452.
43.    Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40 mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56:791–802.
44.    Subramanyan K. Role of mild cleansing in the management of patient skin. Dermatol Ther. 2004;17(suppl 1):26–34.
45.    Del Rosso JQ. The use of moisturizers as an integral component of topical therapy for rosacea: clinical results based on the assessment of skin characteristics study. Cutis. 2009;84:72–76.
46.    Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:1–4