Diagnosis and Management of Oral Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease

Abstract

Inflammatory bowel diseases (IBD) represent a group of chronic inflammatory disorders of the gastrointestinal tract that lead to impaired quality of life and substantial health care costs. Up to 50% of pediatric IBD cases present with manifestations in the oral cavity. These may develop in nearly every oral tissue, including the soft tissues, tongue, lips, teeth, and lymph nodes. The goal of this review is to offer a systematic approach to diagnose and manage commonly encountered oral manifestations of pediatric IBD. This knowledge is critical for enhancing the comprehensive care and quality of life of children with these debilitating diseases.

INTRODUCTION

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), represent a group of chronic, immune-mediated diseases of the gastrointestinal tract that lead to impaired quality of life and substantial public health care costs [1]. Most North American studies estimate IBD prevalence to be between 400-600 cases per 100,000 individuals [2]. This equates to roughly 1.6 million individuals living with IBD in the United States. Of these, an estimated 70,000 patients are children less than 18 years of age [3].

The oral cavity is known to display a variety of signs and symptoms of IBD. In the pediatric IBD population, 48%-80% of patients present with oral extraintestinal manifestations (EIMs), which may or may not precede gastrointestinal symptoms [4, 5]. This variation in reported oral EIM prevalence may be due to inconsistent EIM presentation, the difficulty of examining the pediatric oral cavity, and under-recognition by medical providers. This article aims to provide a practical approach to diagnosing and managing oral EIMs in established pediatric IBD patients.

DIAGNOSIS OF ORAL EIMs IN PEDIATRIC IBD

Oral cavity examination

The recognition of oral EIMs relies on performing a thorough oral cavity examination. Although there are no specific guidelines, we recommend performing an oral exam on all pediatric IBD patients at the time of diagnosis. Subsequent examinations should be performed annually, and with the development of any new oral symptoms. A systematic approach will ensure all key structures are examined. These include 1) the lip mucosa, buccal mucosa, gingiva; 2) the palatal mucosa and oropharynx; 3) the tongue dorsum, tongue ventrum, and floor of the mouth; and 4) the teeth. A video demonstrating a concise oral examination created by the National Institute of Dental and Craniofacial Research is accessible at https://www.nidcr.nih.gov/research/clinical-director/oral-exam [6]. A healthy oral examination is shown in Fig. 1.

Figure 1. Normal oral cavity examination.

(A) Lips; (B) Gingiva; (C) Buccal mucosa; (D) Palatal mucosa and oropharynx; and (E) Tongue.

The lips, buccal mucosa, and gingiva are the most common sites for oral EIMs in pediatric IBD, with cobblestoning, erythema, and ulceration representing the most common clinical features [7, 8]. The descriptions below classify EIMs based on their location and include common etiologies. Examples of these lesions are shown in Fig. 2. The specific image panel is indicated in parentheses.

Figure 2. Common oral lesions in pediatric IBD.

(A) Lip erythema with perioral edema. (B) Cheilitis (arrowheads) and angular cheilitis (arrows). (C) Erythema multiforme secondary to infliximab. (D) Glossitis with fissuring (arrowheads), erythema, and edema. (E) Lichenoid mucositis of the tongue with ulceration (arrowheads) secondary to adalimumab. (F) Severe candidiasis with pseudomembranes (*) and white papules (arrowheads). (G) Erythema (*) and multiple aphthous ulcers of the soft palate mucosa (arrowheads). (H) Aphthous ulcer of the ventral tongue (arrowhead). (I) Deep, linear mucosal ulceration. (J) Erythema of the hard palate mucosa (*). (K) Cobblestoned buccal mucosa (arrowheads). (L) Lichenoid ulcer (arrowhead) with surrounding erythema and white reticular pattern (arrows) secondary to adalimumab. (M) Gingival erythema (arrowheads) with severe maxillary inflammation and edema (*). (N) Erythema of the non-keratinized alveolar and vestibular mucosa (arrowheads). (O) Gingival hyperplasia (arrowheads) secondary to cyclosporine. (P) Orofacial Crohn’s with angular cheilitis (arrows), cheilitis (*), and mucogingivitis (arrowheads). (Q) Pyostomatitis vegetans with multiple coalescing ulcers (arrowheads). (R) Methotrexate-induced tongue ulceration (arrowhead).

Lips

EIMs of the lips may present as mucosal cobblestoning, erythema (A), fissures, cheilitis (B), pustules, and ulcerations. Angular cheilitis (B) presents as erythema and/or crusting of the corners of the mouth. This may be associated with active IBD, infection (Candida and/or Staphylococcus aureus), nutritional deficiencies (vitamin B complex, folic acid, iron, and zinc), or pooling of saliva at the corners of the mouth [4, 7, 8]. Hemorrhagic ulcers with crusting may be secondary to severe drug reactions such as erythema multiforme (C) or Stevens-Johnson Syndrome [9, 10].

Tongue and Oropharynx

Tongue atrophy, glossitis (D), and ulcers (E) may be directly associated with underlying IBD. Nutritional deficiencies (i.e. iron, folic acid, vitamin B complex, and zinc) can cause changes of the tongue, including pallor, glossitis, and dysgeusia (taste alterations). The tongue is also a common site for oral candidiasis (F), which may be associated with nutritional deficiency and medications (e.g. corticosteroids and antibiotics) [10]. Lichenoid mucositis of the tongue is characterized by a white reticular pattern, erythema, and/or ulceration (E). This can occur secondary to several IBD medications, including tumor necrosis factor inhibitors (anti-TNFs), thiopurines, and sulfasalazine. EIMs of the oropharynx may present as edema, erythema, and aphthous ulceration (G) [7, 11].

Buccal and Palatal Mucosa

EIMs of the buccal and palatal mucosa include aphthous ulcers (H), deep linear ulcerations (I), fistulae of the vestibular mucosa, erythema (J), edema, mucosal cobblestoning (K), and mucosal tags. Aphthous ulcers (H) present as well-defined round ulcers and may develop secondary to active IBD, nutritional deficiency (anemia, iron, folic acid, and vitamin B complex), or medications (e.g. methotrexate and azathioprine) [10, 12]. Lichenoid ulcerations, as described above for the tongue, can also occur on the buccal mucosa (L). These can be distinguished from aphthous ulcers based on their irregular appearance, surrounding erythema, and white reticulations.

Gingiva

IBD patients may develop mucogingival erythema (M-N), edema (M), and pustules. IBD-associated gingivitis presents as focal erythema and hyperplasia of the gums, with ulceration involving the gingiva around the tooth and the muco-alveolar mucosa. IBD-associated gingivitis is often not responsive to measures used to treat classical (non-IBD) gingivitis, such as improved oral hygiene, dental plaque biofilm removal, and/or periodontal therapy. Isolated gingival hyperplasia may be secondary to medications such as cyclosporine (O) [13]. Scurvy and gingival bleeding are seen in patients with nutritional deficiencies of vitamin C and K, respectively [14].

Salivary glands

The floor of the mouth may reveal an inflamed appearance of the sublingual and/or submandibular duct opening. EIMs of the parotid gland ducts may reveal edema, occlusion, and pus discharge/abscess [15]. Patients may also complain of dry mouth (xerostomia) which can be secondary to dehydration, medications, or anxiety [16, 17].

MANAGEMENT OF ORAL EIMs IN PEDIATRIC IBD

In this section, we provide a practical approach to managing the oral lesions described above. There is a paucity of clinical studies in this field to support robust guidelines, and such work is clearly needed. We offer our group’s perspective on key questions below as a general framework for managing oral lesions in established pediatric IBD patients. In our practice, early referral to an oral medicine specialist is typically made, allowing for confirmation of the diagnosis and timely multi-disciplinary management.

Is the oral lesion a direct manifestation of active underlying IBD?

A key question to consider in IBD patients with oral lesions is whether the observed EIMs are being driven by active IBD. Orofacial CD, oral aphthous ulcerations, and pyostomatitis vegetans are examples of this type of EIM.

Orofacial Crohn’s disease (oral CD)

Oral CD (P) is observed in 5 to 15% of pediatric patients with CD [18, 19]. These patients present with lip swelling, oral pain, sensitivity to spicy/acidic foods, and difficulty eating and speaking. Clinical features include cheilitis, mucosal cobblestoning, mucogingivitis, deep linear ulcers, mucosal tags, fissures, and stomatitis. When these features are confined to the oral cavity, with no intestinal involvement, it is often referred to as orofacial granulomatosis (OFG) [20, 21]. To confirm the diagnosis of oral CD (or OFG), a 3-4 mm punch biopsy should be performed of the cobblestoned mucosa, cheilitis, linear ulcers, or mucogingivitis. Histopathology reveals the same features seen in CD-associated gastrointestinal inflammation.

Oral CD typically correlates with active intestinal disease. As such, lesions often resolve by optimizing control of the patient’s underlying IBD. In some cases, however, oral manifestations may not improve despite gastrointestinal disease remission. In these cases, topical therapy is indicated. For focal oral ulcers or erythema that can be easily accessed, we recommend a moderate or high-potency topical corticosteroid such as fluocinonide 0.05% and/or clobetasol 0.05% gel. For best efficacy, we instruct patients to apply the gel using cotton gauze to the affected lesion for 10 minutes, 3-4 times per day, until resolution of symptoms. For diffuse or difficult to access lesions, we recommend an oral solution such as dexamethasone (0.1 mg/ml), swish (5 ml for 5 minutes) and spit, 3-4 times per day until resolution of symptoms.

For patients with large, painful oral ulcers who are unable to eat or drink, we recommend systemic corticosteroids such as oral prednisone (1 mg/kg) for 14 days. For pain control, a 2% lidocaine solution may be used. Patients are instructed to swish (5 ml for 1-2 minutes) and spit, as needed for pain. This is especially beneficial when used immediately before meals, as it allows patients to tolerate food and drink with minimal discomfort, thereby improving nutrition.

Oral CD-associated cheilitis (B) can be a challenging entity to treat when it does not resolve by controlling intestinal disease. For these recalcitrant cases, lesions may require a low-potency topical steroid such as desonide (0.05% cream, applied to the affected lesion three times per day). The prescribing provider should recognize that the long-term use of topical corticosteroids on the lip can iatrogenically cause irreversible lip atrophy, which may result in a chronic burning sensation and discomfort.

Oral aphthous ulcerations (OAU)

The term aphthous ulceration is used for well-defined ulcers with a surrounding erythematous halo, with a known underlying etiology (H). Although more common in CD, OAU may be associated with UC as well. Biopsy of these lesions is typically not indicated, as histopathology is nonspecific and does not reveal classical features seen in IBD. The frequency and severity of OAU often correlate with underlying gastrointestinal disease, so it is first necessary to ensure adequate inflammation control by optimizing IBD therapy. In patients with persistent oral ulcers despite gastrointestinal disease control, other etiologies may be considered. These include food intolerances (gluten, nuts), allergies, concomitant celiac disease, medications (e.g. NSAIDs, COX-2 inhibitors), and vitamin deficiencies (e.g. vitamin B6, B12, iron, folic acid, zinc).

Management of aphthous ulcers that do not improve with control of gastrointestinal disease and have no associated secondary causes involves topical corticosteroid therapy as described above for oral CD. For lesions refractory to topical corticosteroids, intralesional (triamcinolone acetonide) or systemic therapy (prednisone, colchicine, pentoxifylline, mycophenolate mofetil, cyclosporine, and thalidomide) may be considered, depending on how debilitating the lesions are for a given patient [12, 22].

Pyostomatitis vegetans (PV)

PV is a rare condition that can be seen in children with ulcerative colitis (~70%), Crohn’s disease (~10-15%), or liver disease [23, 24]. Patients may report multiple painful oral lesions, inability to eat or drink, and difficulty swallowing. PV presents as multiple white or yellow pustules and ulcers that may coalesce to form fissures (Q). There is controversy as to whether these lesions belong to an oral form of pyoderma gangrenosum or a neutrophilic dermatosis [25]. Peripheral blood eosinophilia is often found in patients with PV [25, 26]. Diagnosis is confirmed by a 3-4 mm punch biopsy of the PV lesions, which may reveal eosinophilic microabscesses and negative direct immunofluorescence (IF) for IgA, IgM, IgG, and C3.

PV often indicates active intestinal disease and typically resolves with improvement of the patient’s underlying inflammation. Should local treatment be required, we recommend topical corticosteroids such as dexamethasone 0.1 mg/ml solution, swish (5 ml for 5 minutes) and spit, three times per day, until resolution of symptoms. For lesions that do not respond to dexamethasone, we recommend a compounded tacrolimus solution (0.1%, swish 5 ml for 5 minutes and spit, three times a day). Oral lidocaine (2% solution) can be used for local analgesia.

Is the oral lesion due to a patient’s IBD medications?

The oral mucosa can be adversely affected by a wide variety of IBD medications [10, 19]. Reported oral adverse events secondary to IBD therapeutics include non-specific erythema and ulcers, lichenoid reactions (E, L), or more severe reactions such as erythema multiforme (EM) (C) and Stevens-Johnson syndrome (SJS). For mild-to-moderate drug reactions, it is important to highlight that drug cessation or changing IBD therapy is reserved for patients who do not respond symptomatically to the approaches described below. The mere presence of medication-induced oral lesions, if symptoms are controlled and diet is well tolerated, does not necessitate drug cessation.

IBD medications associated with non-specific erythema and ulcers include methotrexate and thiopurines [9, 27–29]. Methotrexate-associated oral ulcers (R) can occur as an adverse event or secondary to folic acid deficiency [30]. This type of reaction should be considered in patients on methotrexate who exhibit persistent oral ulceration despite adequate control of their underlying intestinal disease. Treatment with topical therapy (as described above) and correction of folic acid deficiency are first-line considerations. If lesions are severe or continue to recur, drug cessation and/or alternate therapy should be considered.

Patients with oral lichenoid reactions (E,L) may complain of pain, sensitivity, and poor oral intake. Although several IBD drugs can cause lichenoid reactions, they are most commonly reported with sulfasalazine and the anti-TNF inhibitors [10, 27, 28, 31]. A biopsy may confirm the diagnosis by demonstrating interface mucositis with or without lichenoid features (i.e. spongiosis, basal vacuolar changes, sub-epithelial clefting, and a dense lymphocytic band that may contain eosinophils) [25]. Direct IF demonstrates a non-specific linear band of fibrinogen along the basement membrane zone and is negative for IgG, IgM, and C3 [32].

We recommend treating oral lichenoid reactions topically as described for oral CD. If needed, severe symptoms often respond to systemic corticosteroids (prednisone 1 mg/kg daily for 14 days), which can be used to bridge to topical therapy. Steroid-refractory lesions may be treated with a compounded tacrolimus 0.1% ointment (apply using gauze for 10 minutes to the affected lesion, three to four times per day) or 0.1% solution (swish 5 ml for 5 minutes and spit, three to four times per day), until resolution of symptoms. If still recalcitrant, patients may require intralesional steroid therapy (triamcinolone) or other systemic therapies (hydroxychloroquine, cyclosporine, dapsone, doxycycline) [33–35].

EM and SJS (C) are severe drug reactions that typically do necessitate drug cessation. The most common IBD medications associated with these disorders are sulfasalazine and the anti-TNF inhibitors, though these reactions have been reported with other IBD therapies such as methotrexate and mesalamine as well [10, 36]. Patients present with acute onset of pain, hemorrhagic oral and lip ulcers, and inability to tolerate oral intake. For acute symptoms, systemic corticosteroid therapy (prednisone 1 mg/kg for 14 days) is indicated. This may be bridged to topical therapy (dexamethasone 0.1 mg/mL swish 5 ml for 5 minutes and spit, three to four times per day) as symptoms improve. Biopsy is indicated if there is no response to steroid therapy. This reveals an ulcer bed with lymphocytes, histiocytes, and neutrophils. IF is negative for IgA, IgG, IgM, C3, and fibrinogen [37]. Recalcitrant cases may require other systemic therapies such as colchicine, pentoxifylline, dapsone, cyclosporine, and apremilast [38, 39].

Is the oral lesion due to a nutritional deficiency?

Oral manifestations in pediatric IBD patients may occur from a long-standing or severe deficiency of specific nutrients. Deficiencies of vitamin B6, B12, folic acid, and iron may present as cheilitis or angular cheilitis (B), glossitis (D), stomatitis, and aphthous ulcers (G-H) [40, 41]. These deficiencies may also be associated with anemia and can predispose to oral candidiasis (F) [42]. Zinc deficiency has been reported in up to 15% of IBD patients [43]. Oral manifestations of zinc deficiency may include taste changes, candidiasis, aphthous ulcers, gingivitis, and dental caries [41, 44]. Although rare, IBD patients can also develop vitamin K deficiency, which can manifest as bleeding gums and early loss of teeth [41, 45]. For patients with the oral manifestations described, it is essential to screen for the corresponding vitamin deficiencies and treat them as needed.

CONCLUSION

Oral EIMs are frequent manifestations of pediatric IBD that may significantly impact our patients’ quality of life. Pediatric gastroenterologists should be able to identify these lesions and broadly consider if the patient has active intestinal disease, a medication-induced reaction, or nutritional deficiency. Early referral to an oral medicine specialist will help confirm the diagnosis and formulate a collaborative treatment plan that focuses on addressing the underlying cause of the oral lesion, as well as directed therapy if indicated.