Orofacial Crohn's Disease: an Oral Enigma

Acta Dermatovenerol Croat 2009;17(4):289-300 CLINICAL ARTICLE

Orofacial Crohn’s Disease: An Oral Enigma

Mahnaz Fatahzadeh, Robert A. Schwartz, Rajendra Kapila, Christopher Rochford

New Jersey Dental School, New Jersey Medical School, University of Medicine & Dentistry of New Jersey, Newark, NJ, USA

Corresponding author: Summary Crohn’s disease is a chronic, relapsing, inflam- Assoc. Prof. Mahnaz Fatahzadeh, DMD matory disorder which may involve any segment of the bowel from mouth to anus. The mucocutaneous manifestations of Division of Oral Medicine Crohn’s disease in the orofacial region are multiple, including Department of Diagnostic Sciences, D-855 oral Crohn’s disease, metastatic Crohn’s disease in sites non- New Jersey Dental School contiguous with the bowel system, and reactive disorders such as pyoderma gangrenosum. Clinicians should be familiar with University of Medicine & Dentistry of New Jersey these extraintestinal manifestations and include this important 110 Bergen Street and often serious disease in the evaluation of patients with Newark, NJ 07103, USA selected orofacial disorders. The recognition of these manifes- [email protected] tations may help prevent misdiagnosis and unnecessary treatment, and facilitates timely diagnosis, palliation and definitive therapy. Received: November 28, 2009 Accepted: May 15, 2009. Key words: Crohn’s disease, pyoderma gangrenosum, oral disease

Introduction Crohn’s disease (CD) is a chronic, transmural ence of extraintestinal manifestations which may inflammatory bowel disease which may involve obscure the underlying bowel involvement (11). any segment of the gut, including oral cavity (1-3). Extraintestinal manifestations may occur pri- First described by Crohn et al. in 1932 as regional or to the onset or throughout the course of CD ileitis (4), the disease primarily affects whites, often and have been reported in 25%-36% of patients in early adulthood, and has a slight predilection for (5,12,13). Examples include anemia, inflammato- females (5-8). The precise etiology is unknown, but ry arthropathies, hepatobiliary disease, metabolic is thought to be multifactorial and include potential osteopathy, ocular problems, renal disorders, and aberrations in the immune system, heredity, infec- mucocutaneous lesions. (8,14,15). We present a tious and environmental factors (9,10). A number case of a 49-year-old male with a history of CD of factors contribute to missed or delayed diagno- who developed right-sided face and lip swelling sis of CD. These include mild or nonspecific symp- and mucocutaneous ulcers unresponsive to ad- toms, relapsing pattern of the disease and pres- ministration of multiple antibiotics. The patient’s

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cutaneous findings improved with corticosteroid Potential etiologies for sudden onset facial therapy. Orofacial presentations of CD are dis- swelling were considered and included infectious cussed and inclusion of a systemic disease in the and drug-related disorders. The work up for sep- differential diagnosis of these orofacial manifesta- sis was initiated with the patient empirically started tions is emphasized. on intravenous vancomycin and piperacillin-tazo- bactam for cellulitis and possible abscess. After Case Report transfusion with 2 units of packed red blood cells, A 49-year-old African-American male informa- hemoglobin increased to 9.0 g/dL with improve- tion technologist was admitted to the University ment in the symptoms of weakness and fatigue, Hospital for evaluation of a sudden onset right- but following an episode of melena a day after ad- sided tender face and lip swelling. The onset was mission it dropped again to 7.9 g/dL. The anemia 5 days prior to admission with right lower lip swell- was considered to be related to bleeding from the ing, which gradually progressed to involve the chin oral ulcer and most likely the cause of melena. En- and cheek, resulting in limitation of mouth opening doscopy under sedation to rule out upper gastroin- as he developed fever, light headedness and fa- testinal bleeding was deferred due to trismus, risk tigue throughout that time. of bleeding from oral ulcer and anticipated pha- ryngeal swelling until when the patient stabilized His past medical history was significant for ane- or deemed suitable for endoscopy under general mia and minimally active left-sided CD diagnosed anesthesia. However, he was closely monitored by intestinal biopsy 10 years earlier. There was no with sequential CBC for the status of anemia and history of Crohn’s-related complications or surger- possible blood loss. ies. His last endoscopy and colonoscopy were per- formed 1.5 years prior to admission. During his last Clinical examination and panoramic radiog- flare-up three months before, he developed ab- raphy ruled out dental pathology as the cause dominal pain, diarrhea and fresh bright red blood of right-sided facial swelling. The head and neck per rectum which responded to therapy with sys- imaging with contrast was suggestive of cellulites temic corticosteroids. He was taking mesalamine and extensive inflammation, but no abscess cav- 400 mg bid for maintenance of remission. He had ity formation in the right mandibular subcutaneous a baseline Hg of 12-13 g/dL, prior history of rectal soft tissues was observed. Nevertheless, the fa- bleeding, poor compliance with medical therapy cial swelling persisted and lower lip fissuring and and follow-up. He was a lifelong resident of his cheilitis became more prominent (Fig. 1). The dis- area and denied a history of foreign travel. He de- colored, intraoral patch progressed to form sur- nied tobacco, alcohol and drug abuse, weight loss, face corrugations, focal erosions and necrosis on trauma, recent dental work, visual changes or yel- the buccal mucosa (Fig. 2), along with a tender, lowing of the eyes, abdominal pain or bright red deep, linear ulceration with raised borders on the blood per rectum at presentation. lower right vestibule (Fig. 3). In addition, a solitary aphthous-like ulcer developed on the right floor of On initial examination, he had a fever of 102.9 F, but was not in acute distress. The patient had a tender, non-fluctuant, right-sided facial edema extending from the right mandibular angle to the right lower lip, submandibular and submental area. There was cervical lymphadenopathy and trismus with maximal interincisal opening of 30 mm. Lim- ited intraoral examination revealed that the patient was dentate with no obvious dental caries. Notable was a firm, dark, adherent patch extending from the right posterior buccal and vestibular mucosa to the lower lip midline. There was no elevation of the floor of the mouth. His laboratory values showed significant anemia (Hemoglobin (Hg)=6.2 g/dL, nl=13.8-17.2 g/dL and hematocrit (Hct)=17.9%, nl=42-52%), elevated liver function tests, high C- reactive protein (CRP=208 mg/L, nl=0-9 mg/L), Figure 1. Right sided facial swelling and lower lip renal insufficiency (elevated BUN/creatinine), and macrocheilia. Note mild cheilitis and fissuring of positive stool guaiac. the lower lip.

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Figure 2. Erythematous, boggy left buccal mucosa with corrugated surface features, focal ero- Figure 3. Deep linear ulceration with raised bor- sions and necrosis. ders on the right mandibular vestibule and focal hyperplastic gingivitis. the mouth, and localized hyperplastic gingivitis in the canine-premolar region became apparent. A levels and return of normal renal function. The few days after admission, the patient also devel- high index of suspicion for relapse of CD and re- oped a pustule on his left cheek which gradually evaluation of presumptive diagnosis led to a con- enlarged to form a tender, indurated, grey plaque sideration that the patient’s orofacial changes may of nearly 4 cm in diameter with superficial ulcer- have represented extraintestinal manifestations of ation at the center (Fig. 4). The patient reported CD. The patient was started on 60 mg of oral pred- a prior incidence of ingrown hair, but denied re- nisone daily. Over the four ensuing days, facial cent insect bites, or a history of exaggerated scar- swelling, mucocutaneous findings and diarrhea ring. The differential diagnosis of the cutaneous improved, and hemoglobin stabilized. The patient ulcer included atypical pyoderma gangrenosum, was subsequently discharged to be followed up by deep fungal infection and atypical mycobacterial his gastroenterologist. infection. Biopsy specimens were obtained from both cu- Discussion taneous and vestibular ulcers and submitted for Mucocutaneous changes are the most com- histopathologic evaluation and culture studies. mon type of extraintestinal manifestations in CD. The left cheek biopsy specimen revealed massive Their prevalence varies between 15% and 75% neutrophil infiltration of the dermis with negative (8,12,16-20). In a quarter of patients, dermato- staining with periodic acid-Schiff, Gomori, Gram, and acid fast stains for microorganisms. Incisional biopsy of vestibular ulcer demonstrated granulation tissue and abscess formation, while special stains were negative for fungal organisms. The abscess culture failed to grow any microorganism including fungi and bacteria or demonstrate any ova or parasite. The urine and blood cultures were also negative. In spite of broad spectrum antibiotic therapy, facial swelling and oral ulceration persisted. The cutaneous ulceration continued to expand through the course of hospitalization. The absence of obvious fluid collections on the head and neck imaging, the histopathologic findings on biopsy and negative growth on culture of collected specimens were all supportive of a noninfectious etiology. Follow- Figure 4. Crusted ulcerative lesion on the lower up blood work revealed normalized transaminase left cheek.

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logic changes may precede Crohn’s diagnosis by ulcerations (36). Edema and ulceration may also 3-8 years (21). They may be solitary or multiple affect subcoronal penis and scrotum, although and often associated with minimal symptoms (8). less frequently (37). Nearly a quarter of patients Although mucocutaneous changes may occur in- experience genital changes prior to the onset of dependently of the activity or quiescence of the bowel symptoms (19). MCD may rarely cause dis- intestinal disease, they are more common in the figuring facial lesions with attendant psychosocial context of colonic CD (12,13,22,23). stress (22,28,31,32). Although the etiology of MCD There are three types of mucocutaneous find- is not well-defined, cutaneous immune complexes ings in CD depending on the origin: 1) granuloma- and cell-mediated hypersensitivity reactions have tous oral and perianal changes caused by direct been implicated in the pathogenesis of granuloma- extension of intestinal disease as well as granu- tous inflammation and vascular damage (38,39). lomatous skin findings non-contiguous with gas- The clinical spectrum of MCD is varied and trointestinal tract (8,15); 2) reactive conditions in shared by many other skin disorders (40). This association with CD such as pyoderma gangreno- often leads to diagnostic delay and mandates sum, erythema nodosum, Sweet’s syndrome, prompt evaluation of cutaneous lesions in patients erythema multiforme, and cutaneous vasculitis with CD (40). When MCD is suspected, a biopsy (8,15,16,24,25); and 3) changes related to therapy specimen should be obtained, with special stains directed against CD or disease-induced nutritional such as Gram, periodic acid-Schiff, and acid fast deficiencies such as acrodermatitis enteropathica and evaluated for the presence of granulomatous and marasmic striae (12,14,16). inflammation, perivascular lymphocytes, mono- cytes and necrobiosis (26,38-42). Additional work Metastatic Crohn’s disease (MCD) up may include tissue culture, polarized micros- copy, tuberculin skin test, and chest radiography Metastatic CD refers to rare skin changes, with to exclude other causes of granulomatous inflam- non-caseating granulomas on histology, separated mation such as tuberculosis, deep fungal infec- and distant from the intestinal tract in patients with tions, sarcoidosis, erysipelas and foreign body known intestinal disease (26,27). MCD may de- reactions (8,40). Reactive cutaneous conditions velop independently of the status of intestinal dis- such as pyoderma gangrenosum, erythema no- ease activity and even prior to the onset of bowel dosum and erythema multiforme associated with symptoms; however, they occur more frequently CD should also be considered.(12,16). In addition, when colon is involved by CD (22,23,28,29). MCD when evaluating genital manifestations of MCD, may affect genital and non-genital sites. Although sexually transmitted diseases with similar clinical cutaneous ulcerations are the most common form features should be excluded (8,40). of MCD, cutaneous plaques, papules, nodules and chronic edematous infiltration affecting differ- Oral manifestations of Crohn’s disease ent body regions have also been reported (30,31). These cutaneous changes are hard to heal and Oral Crohn’s disease comprises a variety of have a predilection for the intertriginous areas cutaneous manifestations in the orofacial region (26,32). associated with CD (18,43). The involvement of oral cavity in CD may occur in all age groups, but In adults, MCD usually appears following CD is more common in pediatric population (44). Oral diagnosis and is frequently evident as plaques changes may occur prior to, concurrently with or with or without ulcerations on extremities (8). In following the onset of bowel disease and inde- contrast, MCD in children often develops at the pendently of the extent and severity of intestinal onset of intestinal disease, is of shorter dura- symptoms (8,45-47). They may precede intes- tion, and frequently affects genitalia (8). Genital tinal disease in up to 60% of patients (18). The changes in MCD are distinct from perineal and reported symptoms associated with oral Crohn’s parastomal changes caused by direct extension of include pain, difficulty with oral functions, cosmetic intestinal lesions (33). Perianal changes develop concerns and psychological stress (18,22). The in and around anus as fissures, fistulas, abcesses, prevalence of oral manifestations in the context ulcers and chronic edematous infiltration affecting of CD ranges from 0.5% to 80% (3,12,18,44,48- children and females (8,34,35). 52). This variability may be related to specific and Genital changes are also more common in chil- nonspecific oral changes reported in the context dren (19), often presenting as vulvar swelling, in- of CD. Table 1 lists a variety of oral findings asso- duration, fissures, fistulas, abcesses, skin tags or ciated with CD including gingivitis, mucosal tags,

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and histopathologic features (57,61). In nearly Oral manifestations of Crohn’s disease Table 1. 10% of patients with signs and symptoms of OFG, CD is the underlying etiology (55,61). Pathognomonic: Diagnostic work up includes tissue sampling • Macrocheilia with/without fissuring of the involved orofacial region for histopathologic • Cobblestoning of oral mucosa examination (57). Microscopic features of orofacial • Linear ulcerations of oral vestibules CD resemble those identified in intestinal CD and • Mucosal tags include non-caseating granulomas in the setting of acute and chronic inflammation (38,62). Evalua- Non-pathognomonic: tion with special stains helps rule out other causes • Facial swelling of granulomatous inflammation and establish the • Perioral erythema • Angular cheilitis definitive diagnosis. • Aphthous stomatitis • Pyostomatitis vegetans Facial pyoderma gangrenosum • Diffuse oral edema Pyoderma gangrenosum (PG) is an uncom- • Hyperplastic granular gingivitis mon, noninfectious, inflammatory, neutrophilic der- Based on references 3,9,14,16,18,43,44,50,54-56,58,60 matosis (63). It often starts as a follicular pustule which enlarges rapidly to form a painful, necrotic aphthous ulceration, labial swelling, cobblestoning ulcer with mucopurulent or hemorrhagic exudate of buccal mucosa, and linear ulcers of oral ves- and peripheral erythema (63,64). The condition tibules (3,9,14,16,18,43,44,50,54-56,58,60). The often affects the lower extremity, but may occur subtle and nonspecific nature of many of these on other boda areas, including the face (63,64). It findings, especially when developed prior to the was initially thought to be infectious in nature, but onset of intestinal symptoms, often creates a di- cultures have been repeatedly found to be sterile. agnostic dilemma (57). Although recurrent, severe Aberrations in humoral or cell-mediated immune aphthous stomatitis does affect Crohn’s patients, response to an unknown antigen may be respon- aphthous ulcers are frequently seen in general sible (65). PG often affects patients with an associ- population and are not considered a specific oral ated systemic illness, of which inflammatory bowel finding for CD (50). Another nonspecific oral find- disease is the most frequent culprit (63,64,66-68). ing in Crohn’s patients is pyostomatitis vegetans. PG has been reported in 1%-2% of CD patients This condition is more often associated with ulcer- (12,69,70), in whom cross-reaction of cutaneous ative colitis and is characterized by multiple oral and intestinal antigens may lead to reactive der- pustules, erosive vegetations, labil and gingival matosis such as PG (68). erythema and mucosal folds (58,59). In contrast Diagnosis depends on thorough medical his- to the above findings, oral changes such as labil tory unraveling the underlying systemic disease, swelling linear fissures, mucosal tags and cobble- clinical signs and symptoms, histopathology and stoning are considered specific and pathogno- exclusion of similar ulcerative conditions (63,64). monic for CD (3,58,60). “Cobblestoning” is char- Although histopathologic findings in PG are not acterized by nodular, granulomatous swellings of diagnostic and vary with stage of the disease, a labial and buccal mucosa resulting in a specific skin biopsy for culture and staining is essential to clinical appearance. (58) Deep, linear ulcers of exclude bacterial, fungal, viral and mycobacterial oral Crohn’s often develop in oral vestibules and infections (64). On microscopic examination, PG have hyperplastic extensions at the edges (58). resembles an abscess or cellulitis (71), as it con- The descriptive term orofacial granulomatosis tains dense neutrophil infiltration, hemorrhage and (OFG) is often used to describe a variety of con- epidermal necrosis (63-65). Local wound care, ditions in which granulomatous inflammation -af topical antibiotics, and corticosteroids are pallia- fects oral cavity and face (61). The spectrum of tive, prevent superinfection and accelerate heal- OFG is broad and includes Melkersson-Rosenthal ing; however, these strategies do not address the syndrome (MRS), cheilitis granulomatosa, foreign underlying systemic disease (64). Immunosup- body reaction, certain infections, and systemic pressive therapy is often necessary to manage diseases such as Crohn’s disease, tuberculosis, extensive or progressive pyoderma gangrenosum sarcoidosis, and granulomatous processes of un- (63,64,68,72). known etiology, all of which share similar clinical In our patient, the oral biopsy specimen demon-

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strated ulceration, granulation tissue and abscess could not be entirely ruled out. He was anemic on formation. The culture from the abscess failed to admission and his baseline Hg hovered around grow any microorganism. Special stain for fungus 12-13 g/dL. Nevertheless, he was not taking any was negative. The failure to detect granulomas vitamin, iron or other types of supplements. On histologically does not exclude CD and may be admission, his methylmalonic acid level was nor- consequence of size of the sample (9,18,43,57). mal (MMA= 0.1 μmol/L, nl <0.4 μmol/L), which did In analogy with the skip region of intestinal CD, not support vitamin B-12 deficiency as an etiology the distribution of oral findings is patchy, so the for his mucocutaneous symptoms. sampling may reflect normal rather than diseased The patient was taking mesalamine daily for mucosa (73). Also, the incidence of granuloma maintenance for months prior to admission. Al- is variable in different tissues (9). Non-caseating though possible, mesalamine is not known to granulomas have been reported in 60% of the cause nutritional deficiency, hematologic or hepatic gut tissue resected (74,75). In contrast, giant cell alterations leading to the mucocutaneous manifes- granulomas have been reported in 67%-85% of tations observed in our patient. On admission, the oral findings associated with CD (18,44,55,58,60). patient had elevated liver function tests and renal The skin biopsy in our patient revealed massive insufficiency both of which normalized with hydra- neutrophil infiltration of the dermis with staining tion, transfusion and supportive medical care, indi- negative for microorganisms, indicating that the ul- cating that renal and liver abnormalities were likely cer was not infectious in nature and that an acute acute rather than chronic (i.e. changes caused by neutrophilic dermatosis such as PG in the context CD or toxic effect of drugs used to treat it). of CD was a potential diagnosis. Reactivation of CD in this case may have re- The patient presented was the first one seen flected suboptimal maintenance therapy or the with a combination of two extraintestinal cutane- patient’s lack of compliance with taking his medi- ous manifestations affecting the orofacial region, cations. In our opinion, the addition of corticoste- namely oral findings and a reactive cutaneous ul- roids to the patient’s maintenance therapy helped cer, i.e. PG. Macrocheilia, linear fissuring of the resolve the ulcerative, bleeding oral ulcer (presum- vestibule, and cobblestoning of the buccal mucosa ably the source of melena and anemia) and abort- noted in this patient are pathognomonic cutane- ed a full relapse with resolution of gastrointestinal ous manifestations of CD in the orofacial region. symptoms (i.e. diarrhea, rectal bleeding). He had The failure to establish an infectious etiology for responded favorably to steroid therapy during his the abscess identified on both oral and facial tis- previous flare-ups of CD. This case illustrates the sue biopsy specimens, as well as the resolution of importance of historical data in the evaluation of orofacial findings with corticosteroid therapy, fur- current orofacial findings. A positive history of CD ther supported this notion. and prior relapses in spite of medical therapy in a Mucocutaneous manifestations of CD may also patient with specific orofacial findings should alert be related to nutritional deficiency. The latter may the clinician to the possible reactivation of intesti- result from chronic diarrhea, reduced oral feed- nal disease. In patients with ongoing gastrointesti- ing, overgrowth of bowel flora, intestinal resection, nal complaints, weight loss and fatigue, detection malabsorption, or drug therapy (76-80). Specific of pathognomonic orofacial lesions unresponsive mucocutaneous changes such as stomatitis, aph- to routine therapy should also prompt a thorough thous ulceration, glossitis, cheilitis, perioral derma- diagnostic work up, including endoscopy to ex- titis and acrodermatitis enteropathica have been clude underlying CD (12,57,83). linked to low levels of albumin, zinc, folic acid, Orofacial CD may develop prior to the onset or niacin, vitamin B-12 and other essential nutrients throughout the course of intestinal disease, often (76-78,81,82). Deficiency of folic acid, niacin and independently of disease activity (55,58,60,84,85). fat-soluble vitamins has also been reported in A diagnosis of CD prompted by oral manifestations association with medications such as sulfasala- was first reported by Varleyet al. in 1972, followed zine/sulfapyridine, azathioprine, and cholestyr- by others (86,87). The predictive value of orofa- amine, respectively (76-78). In addition, patients cial findings to the future onset of CD is subject to undergoing corticosteroid or immunosuppressive controversy (88). However, even in the absence of therapy are at risk for acneiform eruptions and op- gastrointestinal complaints, certain orofacial find- portunistic mucocutaneous infections (82). ings should raise sufficient suspicion to warrant The role of CD-induced malabsorption in the tissue biopsy from this easily accessible area. It etiology of the patient’s mucocutaneous findings is also warranted to question patients about intes-

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tinal complaints, to examine them for genital and It is unclear whether benefits of infliximab, a perianal changes or presence of occult blood in chimaeric monoclonal anti-TNF-alpha antibody, is the stool, to perform screening blood work (CBC, the result of its inhibitory effect on TNF-α or in- iron levels, ESR, albumin), and to closely follow direct consequence of improvement in CD (59). them for potential development of CD in the future Concurrent administration of methotrexate may (8,58). diminish the incidence of anti-infliximab antibodies management strategies and extend remission in responsive patients (53). While highly efficacious, infliximab therapy may Medical therapy aimed at the underlying CD often be associated with serious complications such results in resolution of extraintestinal signs and as hypersensitivity reactions, opportunistic infec- symptoms (45,89). A variety of systemic anti-in- tions, lymphoproliferative disorders and reactiva- flammatory drugs, immunomodulators, and bio- tion of latent tuberculosis (53,100). Adaluminab, a logical agents have been used, with variable suc- newer non-chimeric monoclonal antibody against cess, in the treatment of orofacial CD. TNF-alpha TNF-alpha, may be an alternate biological agent has been implicated in the pathogenesis of CD in patients who are intolerant or unresponsive to (90). Anti-TNF agents such as infliximab and tha- infliximab (101,102). lidomide have been utilized in the treatment of refractory CD and its orofacial manifestations (27,31 The efficacy of thalidomide in the treatment 53,59,85,90-99). of CD and its orofacial manifestations may be

Table 2. Therapeutic approaches to orofacial Crohn’s disease and patient response Ref. No. Orofacial manifestation Therapy Response 45 Gingival bleeding, metallic dysguesia Tetracycline + steroid mouthwash Yes 110 Cobblestoning, mucosal tags Intralesional steroid injection Yes 111 Lip swelling and fissuring Topical tacrolimus Yes 112 Oral swelling and ulceration Prednisone Yes 113 Palatal ulceration Steroids + mesalamine Yes 92 Lingual ulceration Steroids + mesalamine No Infliximab Yes 85 Oral vestibule cobblestoning Steroids + antibiotics No Infliximab + azathioprine Yes 115 Oral pyostomatitis vegetans and tongue lesions Prednisone + zinc supplementation Yes

58 Oral ulcers, hyperplastic gingival folds 6-Mercaptopurine Yes 58 Lip swelling, gingival edema 6-Mercaptopurine + metronbidazole No Infliximab Yes 58 Lip swelling and discoloration Prednisolone + metronidazole +6- Yes MP 31 Perioral erythema, labial swelling and ulceration Infliximab + topical steroids Yes

27 Facial swelling and oral ulceration Systemic steroids + mesalamine No Infliximab + azathioprine Yes 59 Oral pyostomatitis vegetans Infliximab + methotrexate Yes 53 Lip swelling and mucosal tags Prednisolone + azathioprine Yes Fistulizing oral Crohn’s Infliximab + methotrexate Yes 115 Labial and gingival swelling, oral aphthous Total enteral nutrition Yes ulcers 116 Oral cobblestoning and esophageal ulcers Prednisone + 6-MP + Infliximab No Adalimumab + 6-MP + dapsone Yes 90 Oropharyngeal ulcerations Prednisolone, topical steroids No Thalidomide Yes 95 Peritonsillar, oropharyngeal and esophageal Infliximab No ulcers Thalidomide + steroids Yes 98 Oral aphthous ulceration Thalidomide Yes

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related to its inhibitory effect on TNF-α (90), its study of the oral manifestations of Crohn’s dis- antiphagocytic (103) and antiangiogenic actions ease. Clin Gastroenterol Hepatol 2005;3:886- (104), or its influence on cell-mediated immunity 91. (90). The well-known side effects of thalidomide 4. Crohn BB, Ginzbur L, Oppenheimer GD. Re- include teratogenicity, peripheral neuropathy and gional ileitis. JAMA 1932;99:1323-9. severe somnolence (90,103), mandating appropri- 5. Karlinger K, Gyorke T, Mako E, Mester A, ate counseling prior to administration. Tarjan Z. The epidemiology and the patho- Cutaneous CD is potentially responsive to topi- genesis of inflammatory bowel disease. Eur cal therapy and application of topical steroids, ta- J Radiol 2000;35:154-67. crolimus and cyclosporine, for this purpose has 6. Jacobsen BA, Fallingborg J, Rasmussen HH, been described. The immunosuppressive agents Nielsen KR, Drewes AM, Puho E, et al. In- tacrolimus and share the same mechanism of crease in incidence and prevalence of inflam- action, but differ in potency and cutaneous ab- matory bowel disease in northern Denmark: sorption (45,105-107,111). Each drug dampens a population-based study, 1978-2002. Eur J generation of cytokines and activation of T cells Gastroenterol Hepatol 2006;18:601-6. (108); however, cyclosporine is not as efficacious as tacrolimus for the management of cutaneous 7. Podolsky DK. Inflammatory bowel disease. N changes in CD (109). Engl J Med 2002;347: 417-29. Table 3 provides a summary of therapeutic ap- 8. Palamarus I, El-Jabbour J, Pietropaolo N, proaches to orofacial CD (27,31,45,53,58,59,90,9 Thompson P, Mann S, Robles W, et al. Meta- 2,95,98,110-116). Patients at risk for opportunistic static Crohn’s disease: a review. J Eur Acad infections related to immunosuppressive therapy Dermatol Venereol 2008;22:1033-43. may also benefit from preventive or therapeutic 9. Basu MK, Asquith P, Thompson RA, Cooke antimicrobial interventions. Nutritional support, WT. Oral manifestations of Crohn’s disease. elimination of exacerbating factors and palliative Gut 1975;16:249-54. measures should also be considered in the man- 10. Yamamoto-Furusho JK, Korzenik JR. Crohn’s agement on individual basis. disease: innate immunodeficiency? World J Gastroenterol 2006;12:6751-5. Overview 11. Ricci C, Lanzarotto F, Lanzini A. The multidis- The clinician should be familiar with the spec- ciplinary team for management of inflamma- trum of CD manifestations in the orofacial region, tory bowel diseases. Dig Liver Dis 2008;40 include CD in the differential diagnosis of specific Suppl 2:S285-8. lesions affecting oral cavity, and initiate a thorough 12. Greenstein AJ, Janowitz HD, Sachar DB. diagnostic work up, particularly in the presence of The extraintestinal complications of Crohn’s prior or current gastrointestinal complaints and disease and ulcerative colitis: a study of 700 lack of response to routine therapy. Even in the patients. Medicine 1976;55:401-12. absence of bowel symptoms, biopsy specimens 13. Rankin GB, Watts HD, Melnyk CS, Kelley should be obtained from oral changes and patient ML. National Cooperative Crohn’s Disease closely followed for possible development of intes- Study: extraintestinal manifestations and tinal disease. perianal complications. Gastroenterology 1979;77:914-20. References 14. Bernstein CN, Blanchard JF, Rawsthorne 1. Hanauer SB, Sandborn W, Practice Param- P, Yu N. The prevalence of extraintestinal eters Committee of the American College of diseases in inflammatory bowel disease: a Gastroenterology. Management of Crohn’s population-based study. Am J Gastroenterol disease in adults. Am J Gastroenterol 2001;96:1116-22. 2001;96:635-43. 15. Danese S, Semeraro S, Papa A, Roberto I, 2. Kornbluth A, Sacher DB. Ulcerative Colitis Scaldaferri F, Fedeli G, et al. Extraintestinal Practice Guidelines in Adults. Am J Gastro- manifestations in inflammatory bowel dis- enterol 2004;99:1371-85. ease. World J Gastroenterol 2005;11:7227- 3. Harty S, Fleming P, Rowland M, Crushell E, 36. McDermott M, Drumm B, et al. A prospective 16. Burgdorf W. Cutaneous manifestations

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