Angular Cheilitis (Perleche, Angular Stomatitis, Cheilosis)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Angular cheilitis, also known as perlèche, is diagnosed clinically by the presence of inflammation, maceration and fissuring of the oral commissures. Affected patients may complain of a burning sensation or tenderness at the corners of the mouth. The discomfort associated with this eruption may limit range of motion of the mouth and impair eating.

Characteristic findings on physical examination

Both oral commissures are typically affected. Early lesions are small, grey-white thickened areas bordered by mild mucosal erythema. More established lesions exhibit a blue-white hue and are associated with scaling, erythematous patches on surrounding skin (Figure 1, Figure 2). Maceration, fissuring and crusting of the oral commissures are common late findings. Physical examination may also reveal evidence of lip licking, drooling, or an anatomical predisposition to the condition, such as dental malocclusion or poorly-fitting dentures, which result in overlap of the upper and lower lips.

Angular cheilitis (perleche) is characterized by maceration, erythema and fissuring at the oral commissures. Skin adjacent to the angles of the mouth may exhibit scale and erythema.
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Skin adjacent to the angles of the mouth may exhibit scale and erythema.

Expected results of diagnostic studies

Lesional fungal and bacterial cultures, along with KOH and gram stain, may be helpful in directing therapy, as angular cheilitis has been associated with infectious organisms including Candida albicans, Staphylococcus and Streptococcus spp, and, less frequently, gram negative rods. Skin biopsy is not necessary or helpful for this diagnosis.

Diagnosis confirmation

Although angular cheilitis is encountered relatively frequently (especially among the aging population), it is important to consider that it can be a presenting sign of nutritional deficiency of iron, riboflavin (B2), folate (B9), cobalamin (B12), or zinc. Angular cheilitis may also be seen in anemia of chronic disease and in the Plummer-Vinson syndrome, which manifests with the triad of dysphagia, esophageal webs and iron deficiency anemia. In addition, hypervitaminosis A or oral retinoid use can result in angular cheilitis.

A careful dietary and medication history and review of symptoms should be obtained. If indicated, laboratory testing should be performed to evaluate the complete blood cell count, reticulocyte count, appropriate vitamin levels, and serum zinc level

The differential diagnosis of angular cheilitis also includes physical trauma, chemical injury, and allergic contact dermatitis (classically to toothpaste or metals used in dental or orthodontic appliances). Individuals with impaired immunity, including those with HIV, primary immunodeficiency or diabetes mellitus (DM), are at increased risk for angular cheilitis. Laboratory screening to rule out undiagnosed underlying systemic disorders and patch testing to rule out allergic contact dermatitis should be considered on an individual patient basis.

Who is at Risk for Developing this Disease?

Angular cheilitis can occur at any age. Risk factors for development of this condition include lip licking, drooling, hyposalivation (such as occurs in Sjögren’s syndrome and terminal malignancy), malocclusion, Down syndrome, orthodontic treatment, denture use, anatomical volume loss in the aging face resulting in lip overlap, nutritional deficiency, hypervitaminosis A, atopic dermatitis, HIV, primary immunodeficiency syndromes, conditions requiring pharmaceutical immunosuppression, and diabetes mellitus.

Isolated case reports describe angular cheilitis in association with pancreatic glucagonoma and occurring as an adverse event after laser hair removal with long-pulsed alexandrite laser. Additionally, angular cheilitis can occur acutely in the post-operative period after tonsillectomy.

Large cross-sectional studies in the United States and Sweden have measured the overall prevalence of angular cheilitis in the adult population to be 0.71- 3.76% respectively. However, a higher prevalence of 11% has been observed in sequential patients receiving orthodontic treatment, and a prevalence of 28% was reported in elderly denture wearers based on a cross-sectional study of elderly patients (mean subject age 83 years).

What is the Cause of the Disease?

Etiology

Pathophysiology

The etiology of angular cheilitis is multifactorial and may involve interplay of physical conditions promoting a moist environment at the oral commissures and infectious agents. Although C albicans can exist harmoniously in the oral cavity, it is thought to contribute to the pathophysiology of angular cheilitis. A higher incidence of C albicans in affected individuals versus unaffected control patients and observed improvement of the condition with anti-candidal treatment supports this supposition. Other pathogens implicated in angular cheilitis include methicillin-sensitive S aureus, Streptococcus spp and gram negative bacteria.

Systemic Implications and Complications

Awareness that angular cheilitis may be associated with nutritional deficiency (B2, B12, folate, iron, zinc), vitamin overdose (hypervitaminosis A), anemia of chronic disease, or undiagnosed immunosuppressing systemic disorders (HIV, DM, primary immunodeficiency) will enable the physician to perform appropriate testing to diagnose any associated systemic disorders as directed by patient history. Recurrent angular cheilitis in a patient without dentures should prompt suspicion for HIV or DM. In addition, patients with severe or chronic angular cheilitis should be monitored for weight loss or secondary nutritional deficiencies, which may develop as a consequence of decreased food intake due to pain from the condition.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Medical Treatment	Surgical Treatment	Physical Modalities
Identify and treat any nutritional deficiencies	Injection of fillers to restore anatomy/repair sulcus at oral commissure	Behavioral modification (limit lip licking, thumb sucking, and/or aggressive dental floss use)
Topical anti-candidal agent (clotrimazole, miconazole, ketoconazole, nystatin)+ barrier paste (zinc oxide)+ topical corticosteroid (low to mid-potency)	Reconstructive dental or orofacial repair
Topical antibiotic (mupirocin, erythromycin, clindamycin) if bacterial culture positive or high index of suspicion for bacterial overgrowth
Frequent barrier paste (zinc oxide) or emollient (petrolatum, lip balm) application for barrier protection alone
Topical corticosteroids alone (low to mid-potency)
Intralesional corticosteroids

Optimal Therapeutic Approach for this Disease

Treatment of angular cheilitis should be customized to address the suspected cause/causes of this multifactorial condition in the individual patient. For each case, it is helpful to determine if the condition is likely due to mechanical factors alone or due to a combination of local factors and yeast and/or bacterial overgrowth.

Perform a careful dietary history and review of symptoms. If concerned about the possibility of nutritional deficiency, check complete blood count (CBC), reticulocyte count, iron, B2, B9, B12 and zinc levels. Angular cheilitis that is secondary to nutritional deficiency will improve with appropriate nutritional supplementation.

Although limited randomized control trial data exists for the treatment of angular cheilitis, the available evidence suggests an important role for antifungal medications. In one small study of Candida culture-positive angular cheilitis (n=8), treatment with topical nystatin resulted in statistically significant shortened time to healing when compared to placebo ointment application in a split-lip treatment study design. Another study that randomized 52 patients with red palate, angular cheilitis, or both conditions to treatment with nystatin, amphotericin B or placebo oral lozenges found that use of either nystatin or amphotericin B lozenges resulted in a statistically significant cure rate of angular cheilitis at 1 month when compared to placebo lozenge use.

Anecdotal evidence supports empiric treatment of angular cheilitis with a topical anti-candidal agent (clotrimazole, miconazole, ketoconazole, nystatin) and barrier paste (zinc oxide) layered with low-to-mid potency topical corticosteroid as needed to control inflammation. Clotrimazole and miconazole may be advantageous over the other anti-candidal choices as they demonstrate both anti-candidal and anti-staphylococcal activity. If the patient is also affected by thrush, the oral cavity should be simultaneously treated with nystatin solution or systemic fluconazole.

If honey-colored crusts are present or the patient has active atopic dermatitis, consider bacterial culture at the first visit and empiric treatment with antibiotic ointment (mupirocin, clindamycin, erythromycin).

Obtain fungal and bacterial cultures to identify contributing infections if poor response to empiric therapy (topical anti-candidal agent, zinc oxide and corticosteroid) after 2-3 weeks.

If physical and behavioral factors (thumb sucking, lip licking, aggressive dental floss use) are suspected as the etiology, consider frequent emollient or barrier paste application and behavioral modification as initial therapy.

Refer any patients with malocclusion or ill-fitting dentures to a dental specialist. With time, ill-fitting dentures can promote bone remodeling which will eventually exacerbate overlapping of lips and create a more favorable environment for angular cheilitis. In some cases, reconstructive oral surgery can be performed to correct anatomical abnormalities which promote angular cheilitis.

If depressions at the oral commissures are likely promoting angular cheilitis, injection of dermal filler (such as hyaluronic acid) can be considered as a minimally invasive method to achieve improvement in the local anatomy.

Topical corticosteroids or intralesional corticosteroid injections may be used as single agent therapy, but if an element of yeast or bacterial overgrowth is present, may not result in significant improvement.

Obtain history about dental hygiene practices, history of dental procedures and/or orthodontic work, and dental appliances. Determine how any changes in these factors may relate to timing of onset of angular cheilitis. If angular cheilitis symptoms do not respond to empiric therapy (topical anti-candidal agent, barrier paste and a low-to-mid corticosteroid) or historical timing suggests allergic contact dermatitis, consider patch testing to toothpastes, as well as chemicals and metals used in orthodontics and dental appliances.

If recurrent angular cheilitis occurs in an individual without dentures, inquire about risk factors and consider HIV testing and blood sugar screening to rule out HIV and DM as underlying predisposing conditions.

Patient Management

Although the various treatment options for angular cheilitis have not been rigorously studied in large randomized placebo controlled trials, the proposed treatments (topical anti-candidal agents, zinc oxide barrier paste, low-to-mid potency topical corticosteroids, antibiotic ointments, and emollients) are supported by anecdotal evidence and offer minimal risk to the patient.

Given the multifactorial nature of this eruption, patients should have a follow-up visit in 2-3 weeks after initiation of therapy to determine if their treatment regimen should be adjusted. Given that chronic local factors often contribute to the development of angular cheilitis, it is likely that the condition will recur. In one study of 48 patients who were successful treated with antimicrobial therapy and followed for 5 years, 80% experienced recurrence of symptoms on one or more occasion. Neither the type of microbe (ie, Candida vs bacterial species) cultured at diagnosis nor the presence of associated denture stomatitis was predicative of number of flares of angular cheilitis.

No maintenance or preventative regimens have been well studied to date. A double blind, randomized control trial of patients aged 60 or greater living in residential homes demonstrated reduction of angular cheilitis with chewing of placebo gum and chlorhexidine acetate containing gum twice daily for 15 minutes. While the study did not analyze its results with intention-to-treat methodology, the reduction of angular cheilitis and microbial colonization in the chlorhexidine gum group was significantly greater than that of the control gum (xylitol) and no gum control groups. Future studies may indicate that chlorhexidine containing mouthwashes or gums are effective for prevention of angular cheilitis in specific populations.

In patients with dentures or anatomical changes predisposing them to recurrent episodes of angular cheilitis, optimization of dental hygiene (including denture fit and cleaning) and frequent application of barrier paste or emollient (zinc oxide, petrolatum, lip balm) seem to be reasonable but unproven prevention strategies. In patients with significant impairment from recurrent angular cheilitis flares in the context of anatomical distortion, injection of filler material or oral surgery to restore anatomy should be considered.

Physicians should monitor patients who are chronically affected by angular cheilitis for weight loss and nutritional deficiencies that may develop from decreased food intake secondary to pain from the condition.

Unusual Clinical Scenarios to Consider in Patient Management

Recurrent angular cheilitis in patients without dentures who lack obvious predisposing behaviors or anatomical changes should prompt testing to rule out HIV, DM and other immunodeficiency syndromes.

What is the Evidence?

Axell, T. “A prevalence study of oral mucosal lesions in an adult Swedish population”. Odontol Revy Suppl. vol. 36. 1976. pp. 1-103. (This cross-sectional study helps to define the prevalence of angular cheilitis and other oral lesions in adults.)

Cross, D, Eide, ML, Kotinas, A. “The clinical features of angular cheilitis occurring during orthodontic treatment: a multi-centre observational study”. J Orthod. vol. 37. 2010. pp. 80-6. (This multicenter European study reports the incidence of angular cheilitis in patients undergoing orthodontic treatment.)

Dorocka-Bobkowska, B, Zozulinska-Ziolkiewicz, D, Wierusz-Wysocka, B, Hedzelek, W, Szumala-Kakol, A, Budtz-Jorgensen, E. “Candida-associated denture stomatitis in type 2 diabetes mellitus”. Diabetes Res Clin Pract. vol. 90. 2010. pp. 81-6. (This cohort study of patients with type 2 diabetes mellitus examines the relationship of denture stomatitis, angular cheilitis and glossitis with glucose control in diabetes. As compared to the control group, patients with diabetes mellitus demonstrated a significantly higher incidence of angular cheilitis. In addition, oral complaints coincided with elevated hemoglobin A1c levels.)

Ohman, SC, Jontell, M. “Treatment of angular cheilitis. The significance of microbial analysis, antimicrobial treatment, and interfering factors”. Acta Odontol Scand. vol. 46. 1988. pp. 267-72. (This prospective, open trial monitored patients diagnosed with C albicans and/or S aureus associated angular cheilitis after treatment with nystatin and/or fusidic acid as guided by culture. After 42 days of antimicrobial treatment, 96% of treated patients demonstrated no signs of infection. In addition, 8 patients with C albicans associated angular cheilitis were treated in a double-blind study. Angular cheilitis lesions treated with nystatin healed within 28 days, whereas angular cheilitis persisted past 1 month with placebo treatment.)

Ohman, SC, Jontell, M, Dahlen, G. “Recurrence of angular cheilitis”. Scand J Dent Res. vol. 96. 1988. pp. 360-5. (This prospective, observational study reports the incidence of recurrence of angular cheilitis following successful antimicrobial treatment in 48 patients over a 5-year period. During the 5-year observation period, 80% of patients experienced one of more repeat episodes of angular cheilitis. Primary infection with C albicans or S aureus was not correlated to the number of recurrent episodes.)

Peltola, P, Vehkalahti, MM, Wuolijoki-Saaristo, K. “Oral health and treatment needs of the long-term hospitalised elderly”. Gerodontology. vol. 21. 2004. pp. 93-9. (This cross-sectional study of the long-term hospitalized elderly reports that angular cheilitis occurred in 28% of denture wearers in this population.)

Sharon, V, Fazel, N. “Oral candidiasis and angular cheilitis”. Dermatol Ther. vol. 23. 2010. pp. 230-42. (This review discusses risk factors and manifestations of the spectrum of Candida associated oral lesions and their treatment.)

Shulman, JD, Beach, MM, Rivera-Hidalgo, F. “The prevalence of oral mucosal lesions in U.S. adults: data from the Third National Health and Nutrition Examination Survey, 1988-1994”. J Am Dent Assoc. vol. 135. 2004. pp. 1279-86. (This large cross-sectional study of the U.S. population reports the overall prevalence of angular cheilitis and other oral lesions in U.S. adults.)

Simons, D, Brailsford, SR, Kidd, EA, Beighton, D. “The effect of medicated chewing gums on oral health in frail older people: a 1-year clinical trial”. J Am Geriatr Soc. vol. 50. 2002. pp. 1348-53. (This randomized, placebo-controlled double-blind trial investigates the efficacy of chewing chlorhexidine medicated gum versus control gum versus no gum in the institutionalized population over age 60 years. Although intention-to-treat analysis was not done in this 1-year study, a significant reduction of angular cheilitis is observed in the -chlorhexidine gum treated population when compared to both the control gum- and no gum- treated groups.)

Yesudian, PD, Memon, A. “Nickel-induced angular cheilitis due to orthodontic braces”. Contact Dermatitis. vol. 48. 2003. pp. 287-8. (This single case report describes the diagnosis of allergic contact dermatitis due to nickel sulfate contained in orthodontic metal in a 12-year-old boy with treatment-resistant angular cheilitis. Removal of braces after identification of the allergen by patch testing resulted in rapid resolution of the angular cheilitis. This article supports patch testing to relevant chemicals and metals in patients with treatment resistant angular cheilitis beginning at the time that new orthodonture or dental work is installed.)

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