Στοματική κοιλότητα και IBD

Στοματική κοιλότητα και IBD Κωνσταντίνος Χ. Κατσάνος Ιωάννινα, Ιούνιος 2016

Στοματική κοιλότητα και IBD ΚΑΛΟΗΘΕΙΣ ΕΚΔΗΛΩΣΕΙΣ ΠΡΟ-ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ

ΚΑΛΟΗΘΕΙΣ ΕΚΔΗΛΩΣΕΙΣ

ΙBD & ΣΤΟΜΑΤΚΗ ΚΟΙΛΟΤΗΤΑ A significant proportion of patients may have one or more manifestations in the oral cavity and in the perioral skin area. The prevalence of oral lesions in IBD has been reported to range from 5-50%. oral lesions are more common in CD as compared to UC more prevalent in children as compared to adults.

ΙBD & ΣΤΟΜΑΤΚΗ ΚΟΙΛΟΤΗΤΑ Oral manifestations may be associated with the disease itself with nutritional deficiencies with complications from therapy. may precede IBD diagnosis may or not be associated with active disease may involve any part of the oral cavity They may cause significant symptoms and disability

ΙBD & ΣΤΟΜΑΤΚΗ ΚΟΙΛΟΤΗΤΑ two common clinical scenarios: 1) oral lesions associated with altered bowel habits 2) established IBD but complaining of new oral lesions.

Oral lesions in CD Oral lesions have a prevalence rate between 20-50%. higher in proximal gastrointestinal tract and/or perianal involvement. Aphthous ulcers, the most common preceding GI symptoms in 5%-10% of patients.

Oral lesions in children with CD The highest reported rate almost 50% 30% may continue to manifest oral lesions despite intestinal disease control. Paediatric doctors and dentists play a critical role

Oral manifestations in UC Aphthous ulcers in 10% of UC. in pediatric patients with UC in up one third and are usually non-specific.

DIAGNOSIS OF ORAL LESIONS IN IBD Oral lesions in IBD can be specific non-specific

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

Table Clinical signs of oral involvement in IBD by oral anatomic location. Oral involvement in IBD Orofacial Crohn disease Oral mucosa [masticatory or lining (labial / buccal)] Lip(s) Gingiva Hard palate Teeth Tongue Tonsills Salivary glands Clinical Signs 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 edema 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 non specific gingivitis hyperplastic granular gingivitis palatal ulcer(s) parodontal lesions paraodontosis reduction of the alveolar bony tissue erosions glossitis ulcers granulomatous tonsillitis tonsillar granulomas Fistula,granulomatous inflammation, minor salivary gland enlargement reduced salivation sicca syndrome

Table Oral symptoms in patients with inflammatory bowel disease. Dental symptoms Oral symptoms Discomfort, pain, infections, dental caries, decay, periodontal involvement dry mouth (sicca syndrome), reduced salivation,difficulty in speaking and/or swallowing, halitosis Gingiva Lip changes Oral mucosa changes Perioral skin changes Lymphadenopathy Tongue changes gingival hypertrophy, swelling, pain, bleeding swelling, macrocheilia, redness, scaling, fissures ulcer(s), cobblestoning, polypoid tags, buccal swelling, leukoplakia, mucosal discoloration 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

Table Differential diagnosis of oral aphthous and oral granulomatous lesions in patients with inflammatory bowel disease. Oral aphthous or ulcerous or edematous lesions Recurrent aphthous stomatitis (RAS) Autoimmune rheumatic diseases (Reiter's syndrome, systemic lupus erythematosus, Adamandiadis-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 edema, lymphangioma, vascular edema, Neutropenias Desquamative gingivitis Precancerous lesions (lichen planus) Cancer (mouth T-cell lymphoma) Oral granulomatous lesions Orofacial granulomatosis (OFG) Melkersson-Rosenthal syndrome Cheilitis granulomatosa (Miescher cheilitis) Foreign body reaction-sarcoid-like (Polishing-paste-induced silica granuloma, delayed hypersensitivity to cobalt, oral cavity piercing) Sarcoidosis Sjögren syndrome Wegener s granulomatosis Tuberculosis Tuberculoid leprosy Traumas and Allergies

Spectrum of oral manifestations and lesions in inflammatory bowel disease Crohn s disease Ulcerative colitis Highly specific - Metastatic -Orofacial -Granulomatous cheilitis Highly suspicious -Tag-like lesions -Cobblestoning -Mucogingivitis -Lip swelling & vertical fissuring -Deep linear oral ulcers (buccal sulci) Non-specific oral lesions In IBD and non-ibd patients -Malabsorption related -Medication related -Other Highly specific -pyostomatitis vegetans

a. Highly specific oral lesions Highly specific oral lesions are almost pathognomonic for IBD diagnosis orofacial and granulomatous cheilitis in CD pyostomatitis vegetans in UC and CD

Orofacial Crohn s disease oral ulcers and cobblestoning appearance in the mouth of patients with CD CD of the mouth. Orofacial CD is a specific manifestation of CD (5-15% ) relapsing aphthous ulceration with coexisting edema of the oral cavity and of the lips Usually the bowel disease develops within a few months of the orofacial condition, but delays of up to nine years have also been reported.

Orofacial Crohn s disease 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) Melkersson-Rosenthal syndrome

Orofacial granulomatosis Granulomatous cheilitis Melkerson-Rosenthal syndrome Other causes (i.e sarcoidosis, allergy) Orofacial Crohn s (preceeding bowel symptoms) Orofacial Crohn s (extraintestinal manifestation) Absence of bowel disease Bowel disease

Granulomatous cheilitis Granulomatous cheilitis (or cheilitis granulomatosa or Miescher cheilitis) Changes are restricted to the lip, mostly focal granulomatous inflammation of the lower lip.

Pyostomatitis vegetans Pyostomatitis vegetans (PV) is a rare condition characterized by erythematous and thickened oral mucosa with multiple pustules and superficial erosions. PV is associated with IBD in 75% of cases Other differential diagnoses include autoimmune pemphigoid diseases and sometimes infections.

b. Highly suspicious oral lesions for IBD are highly suggestive of underlying IBD, especially CD The most common affected portions are the buccal mucosa, gingiva, lips

c. Non-specific lesions in IBD

Recurrent aphthous stomatitis Any patient with recurring or insisting oral ulcers should be evaluated medically for the possible presence of a more serious systemic disease. Aphthous-like lesions may be seen in 4-5% of patients with IBD. Colonic, rather than small intestinal, CD is more often associated with oral The list of differential diagnosis is long

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. Granulomatous inflammation of minor salivary gland ducts has been suggested as another oral manifestation of active intestinal CD.

Tongue involvement in IBD Rare cases of non-neoplastic tongue involvement in IBD have been described Alterations of taste (metallic dysgeusia) may be related with disease activity, nutritional habits therapy with metronidazole.

Dental and gingival manifestations in IBD dental infections and dental alterations related to malabsorption and to disease activity of IBD. Gingival involvement in CD is infrequent. Gingival biopsy may be helpful for early diagnosis of an underlying CD.

Oral lesions secondary to nutritional deficiencies Nutritional deficiencies may cause oral lesions, the most common being angular cheilitis associated with iron deficiency. deficiencies in iron, folic acid, vitamin B12, potassium, calcium, magnesium, vitamin A, vitamin C, vitamin D, zinc and selenium.

Therapy-related oral lesions All medications may cause oral lesions or symptoms Oral paradoxical reactions to biologicals include oral lichenoid reaction to infliximab and new onset of oral lichen planus during certolizumab pegol use.

MEDICAL TREATMENT OF ORAL MANIFESTATIONS IN IBD topical and/or systemic therapies combined with dietary instructions In refractory or intractable cases the algorithms of management may also include surgical treatment

Table Treatment of the oral manifestations in inflammatory bowel diseases. Medical treatment of oral IBD Effective treatment of intestinal IBD Standard treatment (reported) -Corticosteroids (methlyprednisolone) -Azathioprine -Infliximab -Thalidomide (refractory cases) -isotretinoin, dapsone (pyostomatitis) -Long-term p.os antibiotics (tetracycline, erythromycin, penicillin, metronidazole) Other possible options (unreported) -Methotrexate -Adalimumab -Certolizumab Nutrition -Total enteral nutrition (selected cases) -Elemental diet (selected cases) -Elimination diets (special dietary restrictions i.e cinnamate- and benzoatefree diet) -Supplementation formulas, vitamins (A,B,C) and trace elements (zinc) Topical treatement Local intralesional injections -corticosteroids - triamcinolone 0.1% -Infliximab -analgesics -lidocaine 2%, Local ointments -corticosteroids(1% hydrocortisone) -tacrolimus -non-steroidal anti-inflammatory pastes Mouthwash -5-aminosalicylic,-corticosteroids,-antiseptic,Elixirs (dexamethasone) Surgical treatment of oral IBD Major surgery Oral and oropharyngeal surgery -Oral surgery -Orthognathic surgery -Maxillofacial surgery Plastic facial and lip surgery -Reconstructive -Elimination Colectomy in intractable oral IBD Minimal or Elective surgery -small lesion removal -small fistula repair -abcess drainage - oral biopsies (multiple) Local dental surgery (functional repair and cosmetic) -Dental surgery -Biopsy of small oral lesion -Laser for gingival Crohn's disease

Treatments of oral IBD Type of oral IBD Author/Year Number of all patients Type of trial (controlled/c Uncontrolled/U) Response rates Oral Crohn s Plauth et al, 30 1991 12 Topical steroids/ U 7 of 12 (58%) patients Oral Crohn s Casson et al, 142 2000 Orofacial Mignogna et al, 139 franulomatosis/ora 2004 l Crohn s 3 Topical tacrolimus ointment /U Marked improvement in 1-6 months 7 Triamcinolone injections Response (2 or 3 injection / U sessions over 14 or 21 days) Oral Crohn s Plauth et al, 30 1991 26 Azathioprine and/or systemic 13 of 26 (50%) patients steroids / U Oral Crohn s Williams J et al, 145 12 Systemic steroids / U Improvement in all, 3 1991 steroid-dependent Oral Crohn s Litsas 140, 1 Systemic prednisone / U Response after 6 months 2011 Resistant oral Hegarty et al, 153 5 Thalidomide/ U Response Crohn s 2003 Oral Crohn s Campbell et al, 163 10 Phenolic acid exclusion diet 7 responded 2013 with micronutrient supplementation/ U Oral Crohn s White et al, 161 2006 32 Elimination diets cinnamon- and benzoate-free diet (CB-free diet) / U Response after 8 weeks Oral Crohn s Cameron et al, 159 1 Elemental diet/ U Response but 2 relapses 2003 Granulomatous Kano et al, 70 1992 1 Metronidazole / U Response cheilitis Oral Crohn s Sánchez et al, 147 1 Adalimumab+dapsone/ U Response after 5 months 2005 Oral Crohn s Cardoso et al, 149 2006 1 Infliximab/ U Successful treatment Fistulizing oral Staines et al, 151 1 Infliximab/ U Successful treatment Crohn s 2007

Figure. Algorithm for management for oral aphthous ulcers in IBD. Management of oral aphthous ulcers in IBD (Target in parallel bowel disease remission) Topical treatment Antibiotics, tacrolimus ointment, corticosteroids (elixirs, ointments, mouthwashes, intralesional injections), analgesics (lidocaine 2%), antiseptic mouthwashes, NSAID pastes Elimination diets (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

Figure. Algorithm for recommended management for oral Crohn s disease. Management of oral Crohn s disease (Target in parallel bowel disease remission) Topical treatment Antibiotics, tacrolimus ointment, corticosteroids (elixirs, ointments, mouthwashes, intralesional injections), analgesics (lidocaine 2%), antiseptic mouthwashes, NSAID pastes Elimination diets (Cinnamon, benzoate, glutaminate, cocoa) Vitamin and trace element supplementation Systemic treatment Corticosteroids, azathioprine, methotrexate, tacrolimus, biological therapies Food restriction, Enteral / Parenteral nutrition 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

SURGICAL TREATMENT OF ORAL MANIFESTATIONS IN IBD for severe complications refractory to medical therapy. Minimal or elective surgery Local dental surgery Major surgical interventions include oral and oropharyngeal surgery, (orthognathic and/or maxillofacial surgery) 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.

ΠΡΟ-ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ

Figure. The puzzle of mechanisms and conditions leading to the development of oral precancerous lesions and oral cancer in inflammatory bowel diseases. Environmental factors Sun exposure (UV light), passive smoking(?) Demographics (age>40, males, African-American (oral cavity cancer), fair skin (lip cancer) Life style (smoking, smokeless tobacco use, pipe smoking, marijuana use, heavy alcohol use, access to medical care or dental care, low consumption of fruits and vegetables) Chronic irritation in oral cavity (traumatic ulcers, poor fitting denture, broken or sharp-edged teeth or fillings) Infections (HPV E6 and E7 oncogenes, HIV, syphilis DNA detected from CMV and EBV in oral cancerous lesions, chronic candidiasis) Drugs (immunosuppressants, anti-tnfa?, others?) Education level (Absence of oral screening, no annual oral exam, poor oral hygiene) Nutrition deficiencies (low vitamin A, B12, folic acid levels, iron deficiency) Underlying conditions (immunodeficiency, transplantation, Plummer-Vinson) Alterations in oral homeostasis (xerostomia, reduced salivary flow, candida colonization) Precancerous oral lesions unrecognized and untreated (leukoplakia, erythroplakia, leukoerythroplakia, chronic candidiasis (?) p53 gene alterations-dysplasia-cancer in situ-invasive cancer

Table. Oral precancerous lesions reported in the form of case reports in patients with inflammatory bowel disease. Author Drug Patient Disease Type of oral lesion Mocciaro et al. 54 Certolizumab 1 Crohn s Oral lichen pegol planus Fluckiger et al. 55 Azathioprine 1 Ulcerative Oral hairy colitis leukoplakia Worsnop et al. 52 Infliximab 1 Crohn s Oral lichen planus (probable) Moss et al. 53 Infliximab 1 Crohn s Oral lichenoid reaction to IFX Outcome Non evolution to Ca Non evolution to Ca, HIV(-) Non evolution to Ca (Paradoxical reaction to IFX) Non evolution to Ca (Paradoxical reaction to IFX)

a. Typical oral lichen planus (OLP) of the tongue s right side. (AB) b. Diffuse OLP, plaque form, of the entire oral mucosa. Note the leukokeratotic aspect to be distinguished from a leukokeratosis. (AB) c. Cheek s OL erosive and planus. (AB & ED) d. Tongue s atrophic OLP after a long time evolution. Note the typical network of overlapping white striae of the point. (AB)

ΝΕΟΠΛΑΣΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ The incidence and prevalence of oral cancerous and pre-cancerous lesions in IBD is currently unknown. No routine oral screening is performed or is advised so far. HPV infection!

a.squamous cell carcinoma (SCC) of the tongue s point arising on an atrophic oral lichen planus. (ED) b.scc of the tongue in a 19-year-old smoker female. The question of the responsability of HPV as cofactors is raised in such a case. (AB & ED) c.typical SCC of the lower lip in a smoker patient arising on a leukokeratosis. (ED) d.scc of the lower lip in a young male, rapidly appeared after a kidney transplantation. (ED)

Melanoma of the soft palate in non-ibd non-hiv patient

Kaposi sarcoma of the hard palate in non-ibd non-hiv patient

Table. Oral cancers reported in patients with inflammatory bowel disease. Author Drug Patient(s) with oral Ca Vilas-Boas et al. 61 (case report) Li et al. 60 (case report) Dulai et al. 39 (case report) Biancone et al. 26 (multicenter study) Lichtenstein et al. 42 (TREAT cohort registry n=6,773) Cottone et al. 43 (cohort study) Pasternak et al. 62 (Danish IBD cohort database n=45,986) Nyboe- Andersen et al. 50 (Danish IBD cohort database) Colombel et al. 44 (Adalimumab cohort trials) Sandborn et al. 45 (ULTRA cohort study) Beaugerie et al. 57 (CESAME cohort n=17,047) Fidder et al. 46 cohort n=734 ) Katsanos et al. 47 cohort n=681) (Leuven IFX (EC-IBD Katsanos et al. 48 (Leuven cohort n=1815) Fraser et al. 49 n=2204) (Oxford cohort AZA (9 years) Disease Location / Type of oral cancer 1 CD Right superior retromollar trigone, SCC / HPV (-) AZA (3 years) 1 CD Tongue SCC (ulcerous in situ) IFX+AZA 1 IBD Parotid Non-Hodgkin lymphoma non-biological therapies 1 CD Oropharyngeal (larynx) IFX 6 CD Oral cavity or (3 patients on IFX) Any other therapy Details Surgery Surgery Unknown Death SIR (95%(CI) IFX-treated 1.77 (0.37, 5.17) Any other therapy 1.78 (0.37, 5.21) IFX=2,475 ADA=604 1 0 CD Pharyngeal 18 months after IFX (died) AZA= 5,197 69 IBD Lip/oral cavity/pharynx non-aza=60 RR 95%(CI) former AZA=4 Non-users (referrent) current AZA=5 Former users 1.70 (0.63-4.60) Users 1.69 (0.57-5.00) antitnf=4,553 3 IBD Lip/oral cavity/pharynx Crude non -antitnf 1.24 (0.39-3.93) =51,593 Adjusted 1.47 (0.43-5.00) Adjusted for use of azathioprine 1.08 (0.31-3.70) ADA=3,160 1 CD Oral cavity SCC ADA=494 1 UC Oral cavity 1 of total 35 Ca on ADA <0.1% of the cohort AZA=7,844 15 IBD 15 ear-nose-throat Ca 3.6% of all Ca (n=428) AZA (any use pre- or combo- to IFX)=501 1 IBD Lip SCC patient on combo AZA+IFX AZA=174 2 IBD Lip AZA =725 0 IBD No oral cancer (1 BCC in UC on AZA and 1 SCC in UC not on AZA) AZA= 626 2 IBD 1 SCC oral on AZA 1 SCC oral not on AZA 31 Ca in AZA 77 Ca not in AZA

CONCLUSIONS The list of oral lesions is extensive. may have devastating consequences most lesions are easily handled and respond to the treatment of intestinal IBD A multidisciplinary approach is essential for the correct diagnosis and management.

+ JAN 12 th, 2016 The Henry D. Janowitz Division of Gastroenterology at Mt Sinai, NY, USA