Alimentary Pharmacology and Therapeutics

Review article: non-malignant oral manifestations in inflammatory bowel diseases K. H. Katsanos*, J. Torres*, G. Roda*, A. Brygo†, E. Delaporte‡ & J.-F. Colombel*

*The Henry D. Janowitz Division of Gastroenterology, The Leona M. Harry B. Helmsley Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. † Department of Stomatology, Centre Hospitalier R
egional Universitaire de Lille 2, Lille Cedex, France. ‡ Department of Dermatology, Centre Hospitalier R
egional Universitaire de Lille 2, Lille Cedex, France.

Correspondence to: Prof. J.-F. Colombel, The Leona M. and Harry B. Helmsley Inflammatory Bowel Disease Center, The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029, USA. E-mail: jean-frederic.colombel@mssm. edu

Publication data Submitted 26 January 2015 First decision 4 March 2015 Resubmitted 16 March 2015 Resubmitted 8 April 2015 Accepted 8 April 2015 EV Pub Online 28 April 2015 This uncommissioned review article was subject to full peer-review.

SUMMARY Background Patients with inflammatory bowel diseases (IBD) may present with lesions in their oral cavity. Lesions may be associated with the disease itself representing an extraintestinal manifestation, with nutritional deficiencies or with complications from therapy. Aim To review and describe the spectrum of oral nonmalignant manifestations in patients with inflammatory bowel diseases [ulcerative colitis (UC), Crohn’s disease (CD)] and to critically review all relevant data. Methods A literature search using the terms and variants of all nonmalignant oral manifestations of inflammatory bowel diseases (UC, CD) was performed in November 2014 within Pubmed, Embase and Scopus and restricted to human studies. Results Oral lesions in IBD can be divided into three categories: (i) lesions highly specific for IBD, (ii) lesions highly suspicious of IBD and (iii) nonspecific lesions. Oral lesions are more common in CD compared to UC, and more prevalent in children. In adult CD patients, the prevalence rate of oral lesions is higher in CD patients with proximal gastrointestinal tract and/or perianal involvement, and estimated to range between 20% and 50%. Oral lesions can also occur in UC, with aphthous ulcers being the most frequent type. Oral manifestations in paediatric UC may be present in up to onethird of patients and are usually nonspecific. Conclusions Oral manifestations in IBD can be a diagnostic challenge. Treatment generally involves managing the underlying intestinal disease. In cases presenting with local disabling symptoms and impaired quality of life, local and systemic medical therapy must be considered and/or oral surgery may be required. Aliment Pharmacol Ther 2015; 42: 40–60

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ª 2015 John Wiley & Sons Ltd doi:10.1111/apt.13217

Review: non-malignant oral manifestations in IBD INTRODUCTION A significant proportion of patients diagnosed with inflammatory bowel disease (IBD) may have one or more manifestations in the oral cavity and in the perioral skin area.1 The spectrum of oral lesions in patients with IBD has been reported in case reports1–15 and in large cohorts of IBD patients16–19 and varies widely.2 Oral manifestations may be associated with the disease itself, with nutritional deficiencies or with complications from therapy. They may be considered to represent an IBD-related extraintestinal manifestation or simply an extension of IBD, more specifically Crohn’s disease (CD), to the oral cavity. Oral lesions may precede IBD diagnosis, may or not be associated with active intestinal disease and may involve any part of the oral cavity, including the buccal mucosa, lips, tongue, hard and soft palate, salivary glands, gingival and teeth. They may cause significant symptoms and disability, requiring specific and intensive local and/or systemic treatment. For the clinician taking care of the IBD patient, there are two common clinical scenarios: (i) the patient referred for oral lesions associated with altered bowel habits, and (ii) the patient with established IBD complaining of new oral lesions. As the spectrum of oral lesions in IBD is wide, minimum knowledge about the type of lesions most commonly associated with IBD, their approach and management is required, so that appropriate work-up and treatment are timely undertaken. Herein, we make a comprehensive review of oral lesions associated with IBD, providing a guide for the clinicians, with supporting iconography, helpful in the management, diagnosis and treatment of these sometimes challenging manifestations. SEARCH STRATEGY A comprehensive literature search using the terms and variants of all nonmalignant oral manifestations of inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) was performed in Pubmed, Embase and Scopus. All databases were searched from their inception through November 2014. Studies in any language describing oral nonmalignant manifestations in IBD human subjects were included. Additionally, references from significant papers were hand searched for additional relevant studies (search strategy is available in Appendix S1).

Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

PREVALENCE OF ORAL MANIFESTATIONS IN IBD The prevalence of oral lesions in IBD has been reported to range from 5% to 50%.20, 21 The significant variability in the reported prevalence of oral lesions associated with IBD is most probably due to the inclusion of nonspecific IBD oral changes in many of the reports. In general, oral lesions are more common in CD as compared to UC, and more prevalent in children as compared to adults. Oral lesions in CD Oral lesions in adult CD patients have a prevalence rate ranging between 20% and 50%.21–24 The prevalence seems to be higher in patients with proximal gastrointestinal tract and/or perianal involvement.25 Aphthous ulcers, the most common type of oral lesions, occurring in 20–30% of adult patients with CD.26 The exact proportion of CD patients that have oral CD (CD involving the mouth) is difficult to define. In fact, it is difficult to determine exactly which oral manifestation are definitely related to oral CD and which are related to CD therapy or other aetiologies. It is logical to hypothesise that some of these lesions are in fact consequence of the disease or secondary reaction to medical treatment.27, 28 Oral lesions may be the primary presenting sign, preceding gastrointestinal symptoms in 5–10% of affected patients.29–31 A high incidence of upper gastrointestinal tract involvement in children with CD compared to adults has been reported,32 which may per se explain the higher prevalence of oral lesions in paediatric CD. The highest reported rate of oral manifestations in children with CD indicated a prevalence rate of almost 50%33 Although the lesions might be more severe at the time of active intestinal disease, this correlation is not universal, and up to 30% of affected paediatric patients may continue to manifest oral lesions despite intestinal disease control.34 However, in general, oral CD resolves in the majority of children treated for intestinal CD. In a prospective study35 of 24 paediatric CD patients, oral manifestations developed in 29% of patients with a mean period follow-up of 55 months. No differences were found between patients with and without oral CD with regard to medical therapy, disease location and disease activity. Furthermore, the buccal epithelium of children with CD seems to be immunologically more active when compared to adults, even in the absence of oral lesions. This has been demonstrated in one study36, where buccal epithelial cells were obtained from children and adults with

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K. H. Katsanos et al. CD, UC and controls. Paediatric CD patients when compared to the other groups were the only group exhibiting enhanced production of chemokines CXCL-8, CXCL-9 and CXCL-10. Authors hypothesised that assessment of chemokines production by buccal epithelial cells may be used in the future as a screening tool for children with IBD. Of interest, the prevalence, distribution and function of human lymphoid follicles is dependent and eventually decreasing with ageing.37, 38 The presenting oral symptoms are often nonspecific (i.e. chronic aphthous stomatitis).39 Older children as compared to younger children have a higher rate of oral involvement.40 As there is usually a low index of suspicion by the primary care physician to the possibility of IBD in a young child, paediatric and dentists play a critical role in the diagnosis of oral manifestations as an early sign of IBD.34

Oral manifestations in UC There is no focused study on the prevalence of oral lesions in adult patients with UC. Aphthous ulcers can occur in 10% of patients with UC. In an isolated report, 4.3% of UC patients had aphthous stomatitis during intestinal disease flare-ups, and thus the presence of this nonspecific manifestation may have some correlation with disease activity in UC.31 Oral manifestations in paediatric patients with UC may be present in up one-third of patients and are usually nonspecific.41 DIAGNOSIS OF ORAL LESIONS IN IBD Oral lesions in IBD can be specific or nonspecific (Table 1) and may involve any part of the oral cavity (Table 2), therefore causing different symptoms and signs. Common symptoms include pain on touch or on eating acidic or spicy foods, impaired eating, speaking,

Table 1 | Specific and nonspecific oral changes in patients with IBD Description 1. Specific oral changes or lesions Orofacial Crohn’s disease Mostly young patients with Crohn’s Granular cheilitis Mostly in Crohn’s disease Pyostomatitis vegetans In ulcerative colitis and in Crohn’s 2. Nonspecific oral changes or lesions Oral cavity changes Ulcers, cobblestoning, swelling, abscesses, tags, tongue changes, gingival changes etc. Lip changes Cheilitis, swelling, redness, scaling, fissures, ulcers Malabsorption-related oral changes or lesions Folic acid deficiency Glossitis and/or cheilitis Iron deficiency Glossitis and/or cheilitis Zinc deficiency Oral candidiasis, glossitis Vitamin A deficiency Oral white patches/keratinisation Vitamin B complex deficiency Stomatitis, glossitis, angular cheilitis, burning mouth syndrome, reduced or altered taste Vitamin C deficiency Scurvy Vitamin K deficiency Gum and/or oral cavity bleeding Medication-related oral changes or lesions Adalimumab Infections, angio-oedema, paradoxical reactions Azathioprine Sicca syndrome Budesonide Glossitis, dry mouth Certolizumab pegol Angio-oedema, Stevens–Johnson syndrome/toxic epidermal necrolyis, paradoxical reactions Cholestyramine Glossitis, altered taste, dental changes, gum bleeding Cyclosporin Gingivitis, gum hyperplasia Ciprofloxacin Angio-oedema, Stevens–Johnson syndrome/Toxic epidermal necrolyis, oral candidiasis, loss of taste Infliximab Infections, angio-oedema, paradoxical reactions Loperamide Angio-oedema, Stevens–Johnson syndrome/toxic epidermal necrolyis, dry mouth Mesalazine Stomatitis, dry mouth, altered taste Methotrexate Stomatitis, gingivitis Metronidazole Metallic taste, glossitis, stomatitis, candidiasis, dry mouth (Methyl)prednisolone Oral candidiasis Mycophenolate mofetil Sicca syndrome Sulphasalazine Angio-oedema, stomatitis, Stevens–Johnson syndrome/toxic epidermal necrolyis, altered taste Tacrolimus Sicca syndrome 42

Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD Table 2 | Clinical signs of oral involvement in IBD by oral anatomical location Oral involvement in IBD

Table 3 | Oral symptoms in patients with inflammatory bowel disease Dental symptoms

Clinical signs Oral symptoms

Orofacial Crohn disease

Oral mucosa [masticatory or lining (labial/ buccal)]

Lip(s)

Gingiva Hard palate Teeth

Tongue

Tonsils Salivary glands

One or more clinical signs of spectrum: perioral erythema, metastatic Crohn’s of skin of the face with ulcers, facial swelling, mucosal tags, deep linear ulcers, cobblestoning, lip swelling or fissuring, granulomatous cheilitis, mucogingivitis, papules, nodules, plaques or persistent swelling. Abscesses (mostly in buccal space) Aphthous lesions (minor or major) Aphthous stomatitis Circumferential ulcers Cobblestoning, cobblestone plaques Diffuse oral oedema Fissures IgA pustulosis Leukoplakia, hairy leukoplakia Linear ulcers Lumps Mucosal tags Permanent maloformartions/scarring Pseudopolyps Polypoid lesions Pyostomatitis vegetans Swelling and induration Angular cheilitis Fissuring, induration Granulomatous cheilitis Macrocheilia with or without fissuring Neoformations of the genian mucosa (papilloma, fibroma) Swelling Nonspecific gingivitis Hyperplastic granular gingivitis Palatal ulcer(s) Parodontal lesions Paraodontosis Reduction in the alveolar bony tissue Erosions Glossitis Ulcers Granulomatous tonsillitis Tonsillar granulomas Fistula Granulomatous inflammation, Minor salivary gland enlargement reduced salivation Sicca syndrome

swallowing and, of importance, psychological distress and even depression due to altered cosmetic appearance (Table 3). Oral localisation in CD is characterised by a marked male predominance, a young age at onset and a very proAliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Gingiva Lip changes Oral mucosa changes Perioral skin changes Lymphadenopathy Tongue changes

Discomfort, pain, infections, dental caries, decay, periodontal involvement Dry mouth (sicca syndrome), reduced salivation, difficulty in speaking and/or swallowing, halitosis Gingival hypertrophy, swelling, pain, bleeding Swelling, macrocheilia, redness, scaling, fissures Ulcer(s), cobblestoning, polypoid tags, buccal swelling, leukoplakia, mucosal discolouration Perioral erythema with scaling, erythema migrans, swelling, malformations, scarring Persistent submandibular lymphadenopathy Painful tongue, glossitis in top or lateral or whole tongue, hairy tongue, metallic dysgeusia

tracted course. Oral CD may precede30, 42 or may predict intestinal disease.43 According to a study, oral inflammation may precede intestinal symptoms of CD in 60% of cases.44 Lips are the most frequent site of oral CD disease followed by buccal mucosa, gingiva, vestibular and retromolar areas. Sometimes the appearance of the oral lesions is very similar to the appearance of affected bowel mucosa with oedema, apthous ulcers and polypoid papulous hyperplastic mucosa.30 Oral CD can be specific or nonspecific, based on the presence of granulomas noted on the histopathology reports. Specific CD lesions are differentiated from nonspecific aphthous ulcers because they contain granulomatous changes found on histopathological examination.22 Specific CD lesions are less common than nonspecific aphthous ulcers, and can occur either concomitantly with intestinal symptoms or before gut presentation by several years. Differential diagnosis of these CD-specific granulomatous lesions need to be made from response to foreign bodies such as dental materials, tuberculosis, fungal infections, sarcoidosis, leprosy, syphilis, orofacial granulomatosis, T-cell lymphoma and Wegener’s disease which can all produce a granulomatous reaction in the oral cavity, and also from nutritional deficiencies and side effects of drugs. Differential diagnosis of the granulomatous diseases of the oral tissues as well as of oral aphthous lesions is often challenging and requires clinical, laboratory and pathology expertise as biopsies are important for diagnosis (Table 4).25 43

K. H. Katsanos et al. Table 4 | Differential diagnosis of oral aphthous and oral granulomatous lesions in patients with inflammatory bowel disease Oral aphthous or ulcerous or oedematous lesions

Oral granulomatous lesions

Recurrent aphthous stomatitis (RAS) Autoimmune rheumatic diseases (Reiter’s syndrome, systemic lupus erythematosus, Adamantiadis-Behcet’s syndrome) Autoimmune bullous diseases, cicatricial pemphigoid, pemphigus vulgaris, epidermolysis bullosa acquisita Infections (mucobacterial, systemic fungal infections, parasites, sexually transmitted infections, herpetic gingivostomatitis, CMV, Coxsackie, oral histoplasmosis). Oral staphylococcal (S. aureus) mucositis Lymphatic oedema, lymphangioma, vascular oedema, Neutropenias Desquamative gingivitis Pre-cancerous lesions (lichen planus) Cancer (mouth T-cell lymphoma) Traumas and allergies

Orofacial granulomatosis (OFG) Melkersson–Rosenthal syndrome Cheilitis granulomatosa (Miescher cheilitis) Foreign body reaction-sarcoid-like (Polishingpaste-induced silica granuloma, delayed hypersensitivity to cobalt, oral cavity piercing) Sarcoidosis Sj€ ogren syndrome Wegener’s granulomatosis Tuberculosis Tuberculoid leprosy

In general, any patient with relapsing or persisting oral lesions should be considered for endoscopy. The indication for endoscopy is absolute in patients with concomitant bowel symptoms or/and highly specific types of oral lesions.

20–25% of the general population, also occur in up to 10% of patients with UC,47 and 20–30% of those with CD.48, 49 Older children at diagnosis have higher rates (up to 21%) compared with younger children regarding aphthous stomatitis.

Investigation and risk for IBD in children with oral pathology Children with persisting oral lesions need to be carefully evaluated and several systemic diseases have to be excluded including, Crohn’s disease, ulcerative colitis, Adamantiadis-Behcet’s syndrome, Reiter’s syndrome, neutropaenias and allergies. Personal and family history, clinical examination, dental and oral cavity examination are mandatory. Targeted biopsies must be taken. Peripheral blood examinations as well as ASCA and p-ANCA serology may be of help.24 Granulomas noted upon histology examination are the hallmark in both orofacial granulomatosis (OFG) and oral CD, and there is no ability of distinguishing those two diseases by histology. The only way to exclude CD is by clinical presentation. As mentioned previously, oral manifestations may precede gastrointestinal involvement in CD for many years. Thus, cases labelled as OFG may later progress to being diagnosed as CD. It has been reported that 10–37% of children with OFG in early childhood will be diagnosed with CD on follow-up.45 The majority of persistent aphthous ulcers in children are linked to IBD in the long-term follow-up.46 However, persistent aphthous eruptions are not specific for IBD and may be observed in several other disorders including coeliac disease, HIV/AIDS, Behcet’s disease and Reiter’s syndrome. Furthermore, the common aphthae seen in

SPECTRUM OF ORAL MANIFESTATIONS IN IBD The spectrum of oral lesions described in the medical and dental literature is wide (Figures 1–6). Some of these lesions are related to IBD, while others represent nutritional deficiencies secondary to malabsorption or adverse reactions to medical therapies. Oral lesions in patients with IBD can be divided into three categories. First, there are highly specific, pathognomonic entities, occurring almost always in association with IBD with characteristic morphology or/and

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Figure 1 | Lip fissuring and oedema in Crohn’s disease. Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD (a)

(b)

Figure 2 | Oral Crohn’s disease: macrocheileitis (a), angular stomatitis and mucosal tags (b).

Figure 3 | Oral Crohn’s disease: scaling and fissures of the labial mucosa. Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

histology. In second place, there are lesions that are highly suspicious for IBD, meaning that the probability of an underlying IBD, especially CD, is considered to be high. These two categories above may be useful in directing the physician into making the correct IBD diagnosis. Finally, the most common lesions encountered are nonspecific lesions that may occur in association with IBD, but also in its absence (Figure 7). Of note, in CD, the macroscopic and histological appearances of oral lesions often resemble the gastrointestinal tract lesions while in patients with UC oral lesions are histologically unrelated to lesions found in the colon.50

Highly specific oral lesions Highly specific oral lesions are almost pathognomonic for IBD diagnosis as they show typical morphology or/ and histology. These lesions are orofacial and granulomatous cheilitis (Figure 2a,b) in patients with CD and pyostomatitis vegetans in patients with UC and CD (Figure 6). Orofacial Crohn’s disease. The phenomenon of oral ulcers and cobblestoning appearance in the mouth of patients with CD has been nicely illustrated in a significant number of cases.51–57 Some authors are referring to them as ‘CD of the mouth’.58 The typical linear fissures and ulcerations have the same histopathological features of intestinal CD59 (Figure 3). Orofacial CD is a specific manifestation of CD (5–15% of patients) and is regarded as an acute oral form of the disease with ulcer formation.60 It is characterised by relapsing aphthous ulcers with coexisting oedema of the oral cavity and of the lips (Figure 1). It can occur simultaneously with bowel symptoms or it may precede CD diagnosis, and therefore an appropriate work-up is needed to exclude bowel involvement. Usually, the bowel disease develops within a few months of the orofacial condition, but delays of up to 9 years have also been reported.61 Orofacial CD can affect all age groups, but it has been suggested to be more common in children than adults. Persisting or untreated lesions may result in a reacting, hyperplastic, oedematous-granulomatous tissue reaction in the area of ulcers, giving to the mucosa a ‘cobblestone’ appearance (Figure 5) with a micropolypoid or papulomatous surface mimicking neoplastic infiltration62 (Figure 4a–d). Orofacial CD is clinically and histologically indistinguishable from orofacial granulomatosis (OFG), which occurs in the absence of any bowel disease. OFG encompasses two conditions: granulomatous cheilitis (or Miescher cheilitis or cheilitis granulomatosa) and 45

K. H. Katsanos et al. (a)

(c)

(b)

(d)

Figure 4 | (a–b–c–d) Pseudotumoral hyperplasia in oral Crohn’s disease (a) and the corresponding histology (b–c– d).

Melkersson–Rosenthal syndrome63–65 (Figure 8). Both are associated with mucosal oedema and induration, a chronic protracted course and noncaseating granulomas on biopsy. Melkersson–Rosenthal syndrome is characterised by the triad of relapsing oedema of the face and lips (Melkersson–Rosenthal–Miescher syndrome), permanent or intermittent facial palsy and fissured or plicated tongue. Permanent swelling may follow. Less commonly, the eyelids, forehead or one side of the scalp may be involved. Recurrent attacks may occur within days or even years after the first episode. Localisation on the upper lip leads often to a proboscis-like malformation called ‘tapirus mouth’. Other non-oral symptoms that may occur include fever, visual disturbances and regional lymphadenopathy. The aetiology of the syndrome remains unknown.66

Granulomatous cheilitis. Granulomatous cheilitis (or cheilitis granulomatosa or Miescher cheilitis) is an uncommon condition, regarded as a sub-acute involvement of the area of the mouth in CD. Changes are restricted to the lip, mostly focal granulomatous inflammation of the lower lip.67 There is a chronic inflammatory 46

infiltration with granuloma formation with giant cells and epithelioid cells. The first symptom is a sudden swelling of the lip(s) and in the majority of cases, this first episode subsides completely within hours or days.29 The chronic phase is characterised by permanent oedema and lumpy swelling of the lips.68 Several cases of granulomatous cheilitis have been described in association with CD,69, 70 including cases of granulomatous cheilitis preceeding CD71 or in combination with optic neuropathy.59 Other entities that may also present with granulomatous cheilitis include allergy, sarcoidosis, Melkersson–Rosenthal syndrome, relapsing herpes simplex, relapsing erysipelas, cancers and genetic disorders.

Pyostomatitis vegetans. Pyostomatitis vegetans (PV) is a rare condition characterised by erythematous and thickened oral mucosa with multiple pustules and superficial erosions. In the area underlying the erosions, there is hypertrophy and a network of crossing fissures leading to the characteristic morphology of ‘snail tracks’ appearance. In some cases, peripheral eosinophilia is present.72 Some authors have suggested that PV belongs to the spectrum of neutrophilic dermatoses or even represents an oral form of pyoderma gangrenosum.73 Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD (a)

Figure 6 | Pyostomatitis vegetans in Crohn’s disease.

(b)

Highly suspicious oral lesions for IBD Oral lesions like gingival hypertrophy, indurated tag-like lesions, cobblestoning, mucogingivitis, lip swelling with vertical fissures and deep linear ulcers of the buccal and/ or labial mucosa (usually in the buccal sulci with hyperplastic folds), and midline lip fissuring are highly suggestive of underlying IBD, especially CD, and therefore should trigger appropriate work-up to prompt differential diagnosis. The most common affected portions are the buccal mucosa, gingiva, lips, vestibular and retromolar areas.1, 8, 16–18, 20, 22 These lesions are described in Tables 1, 2 and 4. Nonspecific lesions in IBD The clinical signs of oral involvement in IBD by anatomical location are presented in Table 1.

Figure 5 | (a–b) Oral Crohn’s disease: cobblestoning and linear ulcers in the buccal mucosa.

Pyostomatitis vegetans is associated with IBD in 75% of cases.23, 26, 74 PV can be diagnosed either as an extraintestinal manifestation during relapsing phases of IBD75 or in rare cases, in patients with ‘silent’76 or ‘asymptomatic’ IBD.77 Other differential diagnoses include autoimmune pemphigoid diseases and sometimes infections.78 Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Recurrent aphthous stomatitis. Any patient with recurring or insisting oral ulcers should be evaluated medically for the possible presence of later development of a more serious systemic disease.79 Aphthous-like lesions may be seen in 4–5% of patients with IBD.79 They can be located anywhere in the oral cavity. Ulcerations can be characterised as ‘minor’ or ‘major’ (Sutton) type of aphthae. Minor aphthous ulcers (2–4 mm diameter) are the most common type. Major aphthous ulcers cause more severe symptoms and present with larger (>1 cm diameter) ulcers that take much longer to heal and may leave scarring. Aphthous stomatitis usually occurs in the nonkeratinised oral mucosa (i.e. the inside of the cheeks, lips, underneath the tongue), although major aphthous ulcers may also occur in other parts of the mouth on keratinised mucosal surfaces. There is a third much rarer form of RAS, 47

K. H. Katsanos et al. Spectrum of oral manifestations and lesions in inflammatory bowel disease Crohn’s disease Ulcerative colitis Highly specific

Highly suspicious

-Tag-like lesions -Cobblestoning -Mucogingivitis -Orofacial -Lip swelling & -Granulomatous vertical fissuring -Deep linear oral cheilitis ulcers (buccal sulci) -“Metastatic”

Nonspecific oral lesions

Highly specific

In IBD and non-IBD patients

-Pyostomatitis vegetans

-Malabsorption related -Medication related -Other

Figure 7 | Spectrum of specific and nonspecific oral manifestations in inflammatory bowel diseases. The index of suspicion for IBD (UC or CD) is increased with the increasing intensity of the grey colour.

Orofacial granulomatosis Granulomatous cheilitis Melkerson-Rosenthal syndrome

Other causes (i.e sarcoidosis, allergy)

Absence of bowel disease

Orofacial Crohn’s

Orofacial Crohn’s

(preceeding bowel symptoms)

(extraintestinal manifestation)

Bowel disease

characterised by numerous microscopic ulcers, which forms herpes-like lesions (‘herpetiform ulcerations’).80 The aphthae associated with CD tend to be more widespread and more severe in presentation than those seen in other conditions; they may occur with, or precede, a symptomatic exacerbation of the intestinal disease. Colonic, rather than small intestinal, CD is more often associated with oral manifestations.81 An important differential diagnosis in young patients is AdamantiadisBehcet’s disease.82 Adamantiadis-Behcet’s disease patients may have GI involvement identical or similar to that of IBD83 and co-existence of both diseases in the same patient has been reported.84 The list of differential diagnosis of recurrent aphthoid lesions and aphthous ulcers is long, and includes IBD, autoimmune rheumatic diseases (lupus and Reiter’s syndrome), infections (herpes, CMV), autoimmune bullous diseases, allergies, traumas, desquamative gingivitis, precancerous, cancerous lesions and lymphomas85 (Table 4). Differential diagnosis has to be done also from T-cell lymphoma and idiopathic benign recurrent aphthous stomatitis (RAS) not related to IBD.85–88 48

Figure 8 | The evolving spectrum of orofacial granulomatosis and orofacial Crohn’s disease.

Salivary duct and saliva in IBD. Patients with IBD may complain of dry mouth, similar to the sicca syndrome observed in transplanted patients under immunosuppressive therapy. Interleukin-6 changes in saliva of patients with IBD have been reported89 as well as several abnormal immunological findings in whole and parotid saliva.90, 91 Granulomatous inflammation of minor salivary gland ducts has been suggested as another oral manifestation of active intestinal CD.92 Salivary duct fistula together with recurrent buccal infection may also be present in CD.93 Surgical excision when needed reveals multiple sublingual cystic masses with noncaseating granulomatous inflammation involving the walls of minor salivary gland ducts. In some areas, this ductal lesion is associated with rupture and mucocele formation. This condition has to be differentiated from multiple granulomatous inflammations in the minor salivary glands, an entity known as allergic granulomatous sialadenitis.94 Linear IgA disease. Association of linear IgA bullous disease with CD95 and with UC has been reported, Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD including cases of successful treatment with infliximab96 or even with colectomy.97 Linear immunoglobulin A (IgA) dermatosis is an autoimmune subepidermal vesiculobullous disease that may be idiopathic or drug-induced. The clinical presentation is heterogeneous and appears similar to other blistering diseases, such as bullous pemphigoid and dermatitis herpetiformis. Linear IgA dermatosis needs to be differentiated from intra-epidermic IgA pustulosis which is currently encountered within the spectrum of neutrophilic dermatoses.

Buccal abcesses in IBD. Recurrent and persisting buccal space aseptic abscesses have been reported in CD. In fact, oral abscesses have unclear pathogenesis and there have been cases of Crohn’s disease patients with small abscesses covering the entire buccal mucosa excepting the tongue74 and with extensive subcutaneous aseptic, neutrophilic abscesses where bacterial and mycological samples were negative.98 Systemic corticosteroid treatment is helpful and extraoral drainage is important.99 Tongue involvement in IBD. Rare cases of non-neoplastic tongue involvement in IBD have been described including a case of oral ulcers on the vestibular sulci leading to oral CD diagnosis and alterations of taste perception presenting as metallic dysgeusia in CD.100 Alterations of taste (metallic dysgeusia) may be related with disease activity,101 nutritional habits102 or with therapy with metronidazole. Dental and gingival manifestations in IBD. Dentists can play a critical role in the early diagnosis of dental and gingival manifestations in IBD patients, and they can help in preventing complications. A considerable number of dental infections and dental alterations are related to malabsorption103 and to disease activity of IBD.104 Panoramic radiographs reveal more infectious foci in the teeth of patients with active CD than in patients with inactive disease and several studies demonstrated an association of periodontal disease with CD.105 Gingival involvement in CD is infrequent. Patients with high suspicion of oral CD are those having persistent gingival lesions manifesting as pustular ulcerations, erythema, swelling and cobblestoning. Gingival biopsy may be helpful for early diagnosis of an underlying CD.106 Tonsils and IBD. Tonsillar granulomas not associated with chronic tonsillitis or recurrent tonsillar infection of unknown origin must raise the clinician’s suspicion for an underlying systemic disease including IBD.107, 108 Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Mandibula involvement. Rare cases of mandibular osteomyelitis,109 abacterial osteomyelitis of the jaw so-called ‘osteomyelitis sicca’110, 111 and ‘SAPHO’ syndrome (synovitis, acne, pustulosis, hyperostosis and ostitis) have been also reported in UC and CD.112 Oral lesions secondary to nutritional deficiencies. Nutritional deficiencies may cause oral lesions, the most common being angular cheilitis associated with iron deficiency. Many other lesions may require adequate work-up and supplementation.18, 20 Malnutrition in patients with CD usually develops over a long period of time. A combination of factors contributes to malnutrition in IBD. A relationship between disease activity and a reduced supply of nutrients is often observed because inflammatory mediators, including pro-inflammatory cytokines induce anorexia and cachexia. Nutritional deficiencies include deficiencies in iron, folic acid, vitamin B12, potassium, calcium, magnesium, vitamin A, vitamin C, vitamin D, zinc and selenium. A complete nutritional assessment is therefore an important aspect of the treatment of IBD patients with oral lesions.22, 113 Therapy-related oral lesions. All the medications used to treat the various aspects of IBD may cause oral lesions or symptoms (Table 1). Management should be directed to the severity of the lesion and sometimes discontinuation of medication is necessary. Of note, cases of infection or osteonecrosis of the jaw during infliximab114 or adalimumab therapy have been reported.115 Oral paradoxical reactions to biologicals include oral lichenoid reaction to infliximab116, 117 and new onset of oral lichen planus during certolizumab pegol use.118 PATHOGENESIS OF ORAL MANIFESTATIONS IN IBD The pathogenesis of the oral manifestations of IBD is still unclear. Biopsies of apparently normal buccal mucosa taken from patients with CD showed an increased number of lymphocytes around vessels in the subepithelial tissue and a significant correlation between the activity of the disease and the number of plasma cells containing IgM.119–121 The rate of granuloma detection in oral CD has been reported30 to be as high (67–77%) as that observed in intestinal lesions (45–71%) but does not always parallel intestinal disease activity.104 Interestingly, normal buccal mucosa from patients with CD, incubated with its own serum has shown a positive reaction that was not observed in buccal mucosa from normal controls or patients with ulcerative colitis (UC). It has been suggested that oral lesions in CD 49

K. H. Katsanos et al. might represent a local immunological reaction of oral mucosa after direct contact with oral antigens.120 Because suppressor/regulatory T cells are thought to be one mechanism for the promotion of oral tolerance, authors attempted to induce tolerance with keyhole limpet haemocyanin in normal controls and patients with either Crohn’s disease or ulcerative colitis. Results suggested that oral antigen administration does not result in tolerance in CD and UC patients, and might actually result in active immunity. Authors suggested that this may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD and in a subsequent study, they supported that there is a genetic defect in oral tolerance induction in CD.122 Few studies have attempted to understand the mechanisms underlying inflammation in oral lesions. Recurrent aphthous ulcers (RAU) in CD have been associated with decreased heat shock protein 27 (HSP27) expression compared to controls.121 Inconclusive studies have looked at the presence of Mycobacterium paratuberculosis DNA in oral CD tissue.123 It has also been questioned whether braces can provoke oral lesions in CD.124 Alterations in the pattern of cytokine production by T-cell subclasses leading to loss of tolerance to oral antigens have been documented.125 A study was conducted to assess the association between HLA B27 and the IBD extraintestinal symptoms. HLA B27 was significantly more common in the patients with sacroiliitis, spondylitis, enthesitis, peripheral arthritis, erythema nodosum, uveitis and oral ulcers126, and in another study, the DRB1*0103 allele was increased in UC patients with mouth ulcers.127 Regarding genetic predisposition to oral disease, only weak positive indications are evident. In such a study while none of the patients with orofacial granulomatosis carried any of the NOD2 variations, whereas four of the 12 patients with coexisting Crohn’s disease had a NOD2 variant (Arg702Trp).128 However, all studies, do not support the role of CARD15 in oral symptoms and periodontal lesions in patients with CD129 and unlike in Crohn’s disease, the 3020insC mutation of the NOD2/ CARD15 gene does not seem to influence the pathophysiology of periodontitis.130 Finally, in a report describing the similarities and differences in the complicated course of Crohn’s disease in identical twins, it was demonstrated that while the development of Crohn’s disease may be genetically influenced, the site of gastrointestinal involvement including oral Crohn’s is affected by other than genetic factors.131 By contrast, anti-Saccharomyces cerevisiae antibodies (ASCA) status described patients with CD who had a 50

specific phenotype, showed an association with markers of disease severity and oral CD involvement132, and it has been hypothesised that in ASCA-positive cases, a systemic immune response against Saccharomyces cerevisiae suggests the end of the oral tolerance against the yeast’s antigens.133 A study showed increased frequency of oral manifestations among IBD patients, indicating aberrations in the oral microbiota.134 Based on these observations, authors analysed the composition of salivary microbiota of IBD patients and showed that Bacteroidetes was significantly increased with a concurrent decrease in Proteobacteria in the salivary microbiota of IBD patients. The dominant genera, Streptococcus, Prevotella, Neisseria, Haemophilus, Veillonella and Gemella, were found to largely contribute to dysbiosis (dysbacteriosis) observed in the salivary microbiota of IBD patients. In addition, analysis of immunological biomarkers in the saliva of IBD patients showed elevated levels of many inflammatory cytokines and immunoglobulin A, and a lower lysozyme level. A strong correlation was shown between lysozyme and IL-1b levels and the relative abundance of Streptococcus, Prevotella, Haemophilus and Veillonella. Authors concluded that dysbiosis of salivary microbiota is associated with inflammatory responses in IBD patients, suggesting that it is possibly linked to dysbiosis of their gut microbiota. As parotid IgA secretion is reduced with increasing activity of bowel disease, the suggestion has been made that local immunological mechanisms may be responsible for the development of the oral lesions. It has been suggested that in these patients, biological mediators are released by sensitised lymphocytes when E. coli antigens and related Klebsiella antigens from the mouth enter the oral tissues, with consequent development of inflammatory lesions.135, 136 In patients with CD, salivary IgA antibody responses to Saccharomyces cerevisiae, Candida albicans and Streptococcus mutans have been demonstrated. Production of salivary IgA was found reduced in active CD.137 By contrast, another study showed that salivary flow rate, total protein, buffering capacity, amylase, and IgA and IgG concentrations did not differ with respect to the activity of CD, but this observation has not been further replicated.104

MEDICAL TREATMENT OF ORAL MANIFESTATIONS IN IBD Medical treatment of oral manifestations in IBD includes topical and/or systemic therapies combined with dietary Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD Table 5 | Treatment of the oral manifestations in inflammatory bowel diseases Medical treatment of oral IBD

Surgical treatment of oral IBD

Effective treatment of intestinal IBD Standard treatment (reported)

Major surgery Oral and oropharyngeal surgery

• Corticosteroids (methlyprednisolone) • Azathioprine • Infliximab • Thalidomide (refractory cases) • Isotretinoin, dapsone (pyostomatitis) • Long-term p.os antibiotics (tetracycline, erythromycin, penicillin, metronidazole)

• Oral surgery • Orthognathic surgery • Maxillofacial surgery Plastic facial and lip surgery • Reconstructive • Elimination

Other possible options (unreported)

Colectomy in intractable oral IBD Minimal or Elective surgery • • • •

Small lesion removal Small fistula repair Abcess drainage Oral biopsies (multiple)

instructions (Tables 5 and 6). Medical treatment strategies can be divided in those treating oral Crohn’s lesions, those for milder and/or unspecific lesions such as apththous ulcers and finally treatments for other lesions. In refractory or intractable cases, the algorithms of management may also include surgical treatment (Figures 9 and 10).

Oral CD The first and foremost step in treating oral lesions in CD is to control intestinal disease.138 The best proven treatment for oral CD includes topical (ointments, mouthwashes, elixirs, intralesional) and systemic steroids139, 140 combined with local analgesics (i.e. lidocaine 2%) for pain relief.141 Immunosuppressive agents (tacrolimus), biological treatments and even antibiotics such as tetracycline have been also used in severe or refractory cases.138 The algorithm of treatment of oral CD includes topical and/or systematic therapy and surgery in selected cases (Figure 9).

• Corticosteroids (1% hydrocortisone) • Tacrolimus • Nonsteroidal antiinflammatory pastes Mouthwash

Topical medical treatment of oral CD. Topical treatment may result in complete remission of oral symptoms in more than half of the patients and includes intralesional injections, ointments and mouthwashes. Local repeated intralesional injections of corticosteroids with or without mandibular blockade, triamcinolone 0.1% up to three times a day, analgesics and lidocaine 2% may provide relief to oral symptoms and are usually used for more refractory cases. Local ointments that may be used – although less effective than intralesional injections – are corticosteroids (1% hydrocortisone), tacrolimus and nonsteroidal antiinflammatory pastes two to three times a day. Topical tacrolimus for intra-oral use at low concentration (0.5 mg/ kg) and for 2–6 months is safe and may be effective in oral CD.142, 143 Mouthwashes of 5-ASA, corticosteroids, antiseptics and dexamethasone elixir (0.5 mg/5 mL spit or swish) or ointment up to three times per day have been described to improve symptoms.144 Topical medical treatment may start with corticosteroid ointments or/and mouthwashes and anti-inflammatory pastes and in case of nonresponse or refractoriness, topical tacrolimus and repeated intralesional injections of corticosteroids can be used. Based on the patient symptoms and oral findings, topical treatment may be also combined with systemic medical therapy.

• 5-aminosalicylic • Corticosteroids • Antiseptic Elixirs (dexamethasone)

Systemic medical therapy of oral CD. Combination of systemic steroids (0.5–1 mg/kg) with azathioprine (2–2.5 mg/kg) is an option145 with a reported efficacy of

• Methotrexate • Adalimumab • Certolizumab Nutrition • Total enteral nutrition (selected cases) • Elemental diet (selected cases) • Elimination diets (special dietary restrictions, i.e. cinnamateand benzoate-free diet) • Supplementation formulas, vitamins (A,B,C) and trace elements (zinc) Topical treatment Local intralesional injections • • • • •

Corticosteroids Triamcinolone 0.1% Infliximab Analgesics Lidocaine 2%, Local ointments

Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Local dental surgery (functional repair and cosmetic) • Dental surgery • Biopsy of small oral lesion • Laser for gingival Crohn’s disease

51

K. H. Katsanos et al. Table 6 | Treatments of oral Crohn’s disease, of aphthous ulcers and of other oral lesions in patients with inflammatory bowel disease (C/U, controlled/uncontrolled trial) Number of Type of trial (controlled/C all patients uncontrolled/U)

Type of oral IBD

Author/year

Oral Crohn’s Oral Crohn’s

Plauth et al.,30 1991 Casson et al.,142 2000

Orofacial franulomatosis/ oral Crohn’s

Mignogna et al.,1392004

Oral Crohn’s

Plauth et al.,30 1991

26

Oral Crohn’s

Williams et al.,145 1991

12

Oral Crohn’s Resistant oral Crohn’s Oral Crohn’s

Litsas,140 2011 Hegarty et al.,153 2003 Campbell et al.,163 2013

1 5 10

Oral Crohn’s

White et al.,161 2006

32

Oral Crohn’s Granulomatous cheilitis Oral Crohn’s Oral Crohn’s Fistulising oral Crohn’s Aphthous ulcers Aphthtous ulcers

Cameron et al.,159 2003 Kano et al.,70 1990 S
anchez et al.,147 2005 Cardoso et al.,149 2006 Staines et al.,151 2007

Aphthtous ulcers Apththous stomatitis Reccurent aphthous ulcers Other oral lesions Pyostomatitis vegetans Pyostomatitis vegetans Pyostomatitis vegetans Pyostomatitis vegetans (resistant) Pyostomatitis vegetans (relapsing) Pyostomatitis/pyovulvitis

7

1 1 1 1 1

Keenan et al.,164 2012

240

Descroix et al.,141 2011

59

Topical steroids/U 7 of 12 (58%) patients Topical tacrolimus ointment/U Marked improvement in 1–6 months Triamcinolone injections Response (2 or /U 3 injection sessions over 14 or 21 days) Azathioprine and/or 13 of 26 (50%) patients systemic steroids/U Systemic steroids/U Improvement in all, 3 steroid-dependent Systemic prednisone/U Response after 6 months Thalidomide/U Response Phenolic acid exclusion diet 7 responded with micronutrient supplementation/U Elimination diets cinnamonResponse after 8 weeks and benzoate-free diet (CB-free diet)/U Elemental diet/U Response but 2 relapses Metronidazole/U Response Adalimumab+dapsone/U Response after 5 months Infliximab/U Successful treatment Infliximab/U Successful treatment Dexamethasone Ointment/C Topical 1% lidocaine/C

83% response vs. 54% placebo Significant efficacy vs. placebo Response after 1 infusion Successful treatment

Kaufman et al.,148 2005 Jacobi et al.,150 2008

3 1

Infliximab/U Infliximab/U

Bens et al.,146 2003 Ficarra et al.,157 1993 Ayangco et al.,23 2002 Mijandrusi
c-Sinci
c et al.,167 2010 Brinkmeier et al.,166 2001

1 1 1 2

Infliximab+methotrexate Oral zinc + prednizolone Topical corticosteroid gel 1 Adalimumab 1 Infliximab Cyclosporine

Complete regression Remission Remission Remission in both

Gatzka et al.,158 2006

1

Methylprednisolone+ isotretinoin +dapsone

Remission

up to 50% oral CD cases with varying severity.30 Satisfactory results have been generally reported with the use of anti-TNFa agents at usual doses.146, 147 In fact, regarding the treatment of orofacial CD, infliximab has demonstrated remarkable efficacy in a series of patients148, 149 and also in some difficult-to-treat cases with pyostomatitis vegetans,150 refractory mucosal aphthosis or fistulising oral CD.151 In refractory oral CD, some authors suggested efficacy of thalidomide.152–154 Long-term use (3–6 weeks) of oral antibiotics (tetracycline, erythromycin, penicillin, met52

12 3

Response rates

1

Remission

ronidazole),155 ketotifen and sulfasalazine at usual doses have been also advocated for such difficult-to-treat cases.85 Pyostomatitis vegetans (PV) is usually resistant to therapy. The use of systemic corticosteroids156 is effective; however, relapses are usual during tapering. Oral zinc supplementation,157 combination therapy with methylprednisolone (0.5–1 mg/kg), isotretinoin and dapsone and therapy with cyclosporin and biologicals at usual doses can also be considered (Table 6). Haemolytic anaemia, hepatitis, leucopenia and allergic reactions are the major side effects of dapsone.158 Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD Management of oral Crohn’s disease (Target in parallel bowel disease remission)

Elimination diets Topical treatment (Cinnamon, benzoate, glutaminate, cocoa)

Antibiotics, tacrolimus ointment, corticosteroids (elixirs, ointments,

Vitamin and trace element supplementation

mouthwashes, intralesional injections), analgesics (lidocaine 2%), antiseptic mouthwashes, NSAID pastes Food restriction, enteral /parenteral nutrition

Systemic treatment Corticosteroids, azathioprine, methotrexate, tacrolimus, biological therapies

Systemic treatment for refractory cases Switch to a 2nd biological therapy, thalidomide, long-term antibiotics, dapsone, cyclosporin A (for pyostomatitis)

Surgical treatment Head-neck surgery, oral surgery (for local repair and cosmesis) Dental surgery

Figure 9 | Algorithm for recommended management for oral Crohn’s disease.

Diet. Exclusive enteral nutrition or elemental diet has been used to alleviate symptoms. Avoiding foods that may cause allergies, elimination diets (i.e. cinnamate- and benzoatefree diet) and vitamin supplements are mostly empirical Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

and they can be of some help particularly in cases of concomitant food allergies or intense oral symptoms.159 Observational studies in paediatric patients with orofacial granulomatosis have demonstrated that dietary 53

K. H. Katsanos et al. Management of oral aphthous ulcers in IBD (Target in parallel bowel disease remission)

Elimination diets Topical treatment Antibiotics, tacrolimus ointment, corticosteroids (elixirs, ointments, mouthwashes, intralesional injections), analgesics (lidocaine 2%), antiseptic mouthwashes, NSAID pastes

(Cinnamon, benzoate, glutaminate, cocoa) Vitamin and trace element supplementation

Systemic treatment Corticosteroids, azathioprine, methotrexate, tacrolimus

Systemic treatment for refractory cases Biological therapy, thalidomide, long-term antibiotics

elimination of some triggering elements (cinnamaldehyde, benzoate additives, carnosine, monosodium glutamate, cocoa and sunset yellow) are effective in the treatment of oral lesions.160, 161 The cinnamon- and benzoate-free diet has been shown to provide benefit in 54–78% of patients after 8 weeks with 23% of them requiring no adjunctive therapies.161, 162 The most concentrated source of benzoate exposure is from food preservatives. Use of liquid enteral formulas can offer a further dietary therapy, particularly in children. A low phenolic acid diet with micronutrient supplementation also holds promise.163

Aphthous ulcers The best proven treatment for aphthous ulcers includes topical (ointments, mouthwashes, elixirs) steroids combined with local analgesics (i.e. lidocaine) for pain relief.164 There is usually no need for specific treatment for these lesions, they will resolve over time in association with the treatment of gastrointestinal disease, but when indicated in refractory cases, treatment may also comprise systemic steroids, immunosuppressive drugs, antibiotics, and even biological treatment in more severe cases (Figure 10).165

54

Figure 10 | Algorithm for the management for oral aphthous ulcers in IBD.

Other lesions Treatment of other oral lesions includes topical and/or systematic therapy and should be individualised and escalated in refractory cases accordingly and by using the above described algorithms of treatment.166, 167 SURGICAL TREATMENT OF ORAL MANIFESTATIONS IN IBD Surgical intervention may be needed for severe complications refractory to medical therapy. Minimal or elective surgery includes removal of small lesions, small fistula repair and drainage of small abscesses. Local dental surgery aims to functional repair and cosmesis of teeth and gingiva and to targeted biopsies of the oral mucosa.168 Major surgical interventions include oral and oropharyngeal surgery (orthognathic and/or maxillofacial surgery), and plastic surgery (reconstructive, elimination, i.e. for hyperplastic gingiva). Colectomy is reserved as an ultimate option for patients with UC and intractable or highly resistant oral lesions that significantly affect oral feeding and overall quality of life. For example, colectomy has been reported to produce promising results in pyostomatitis vegetans (PV) associated with UC.47, 91, 169 In such a patient, complete remission of PV was

Aliment Pharmacol Ther 2015; 42: 40–60 ª 2015 John Wiley & Sons Ltd

Review: non-malignant oral manifestations in IBD achieved immediately after a total colectomy due to a diagnosis of adenocarcinoma of the colon.169 Orofacial surgery in patients with oral IBD requires expertise and high level of alert for atypical findings and potential complications or failures. Patients with CD on systemic medications may show a delayed and altered buccal mucosa170 or bone healing.171 They must be closely monitored after periodontal or mucogingival surgery. Even in a remission state, patients require careful perioperative management. Special attention must be paid to the patient’s diet and maintenance medications in collaboration with the treating physician.172 Endosseous dental implants are challenging especially in cases of glucocorticoid-dependency and osteoporosis173 and early implant failures have been reported.174, 175 Finally, the risk of oropharyngeal perforation during intubation seems to be higher either because of oral lesions and ulcers are changing the local soft tissue176 or because chronic corticosteroid therapy may lessen tissue resistance to perforation.177

CONCLUSION The list of oral lesions that may affect IBD patients is extensive. Lesions affecting orofacial regions may have devastating consequences, not only because of disabling symptoms and impairment in eating but also because of the cosmetic consequences in young patients. While most lesions are easily handled and respond to the treatment of intestinal IBD, others may face real challenges and require escalation of medical therapy or even surgery. A multidisciplinary approach is essential for the correct diagnosis and management.

AUTHORSHIP Guarantor of the article: J.-F. Colombel Author contributions: KHK, GR and JT performed the research and wrote the paper, AB and ED collected and analyzed the figures, and JFC contributed to the concept, design and general layout of the study. All authors approved the final version of the manuscript. ACKNOWLEDGEMENT Declaration of personal and funding interests: K.H. Katsanos: none, G. Roda: none, J. Torres: none, A. Brygo: none, Emmanuel Delaporte: has been occasionally speaker for, and have been invited to conferences by, Abbott, Janssen, Merck and Pfizer, J-F Colombel: has served as consultant or advisory board member for Abbvie, ABScience, Amgen, Bristol Meyers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, Medimmune, Merck & Co., Millenium Pharmaceuticals Inc., Neovacs, Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co and has served as speaker for Abbvie, Ferring, Janssen, Merck & Co., Nutrition Science Partners Ltd., Takeda. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Appendix S1. Search strategy.

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