BASIC/CLINICAL SCIENCE

Mucocutaneous Manifestations of Inflammatory Bowel Disease in Turkey Filiz Topalogˇlu Demir, Emek Kocatu¨rk, Elif Yorulmaz, Gupse Adalı, and Mukaddes Kavala Background: Mucocutaneous manifestations of inflammatory bowel diseases are relatively common; the mean incidence is around 10% at the time of diagnosis. However, during follow-up, an increased variety of skin lesions, granulomatous cutaneous disease, reactive skin eruptions, nutritional defiencies, and other associated conditions may develop. Objective: The objective of this study was to evaluate the prevalence of the mucocutaneous manifestations and their association with gender, duration of disease, arthritis, location of the bowel disease, and disease activity. Methods: Fifty-six patients with ulcerative colitis (UC) and 36 patients with Crohn disease (CD) who were in follow-up in the Istanbul Medeniyet University Go¨ztepe Training and Research Hospital Department of Gastroenterology were included in the study. Whole-body dermatologic examinations were performed for all patients, and patient files were evaluated for mucocutaneous manifestations. Results: Of the 92 patients, 49 (53.26%) presented with at least one mucocutaneous manifestation (58.9% of patients with UC and 44.4% of patients with CD). Of these, 38 (41.3%) had at least one reactive skin eruption. Aphthous stomatitis was noted in 33 patients (35.86%) and became the most common mucocutaneous manifestation. Granulomatous cutaneous diseases were detected in 18 patients (19.57%), and none of the patients had a nutritional deficiency–associated skin condition. Only 3 patients (3.26%) had erythema nodosum and 2 patients (2.17%) had pyoderma gangrenosum. Conclusions: We found that mucocutaneous manifestations of inflammatory bowel diseases are more common than thought and are more common in UC than in CD. No association was detected between mucocutaneous manifestions and gender, duration of disease, arthritis, location of the bowel disease, and activity of the disease. Contexte: Les manifestations mucocutane´es des maladies inflammatoires de l’intestin sont relativement fre´quentes; l’incidence moyenne est d’environ 10% au moment de la pose du diagnostic. Toutefois, pendant le suivi, peuvent apparaıˆtre diverses le´sions cutane´es, des affections cutane´es granulomateuses, des e´ruptions cutane´es re´actionnelles, des carences nutritionnelles, et d’autres troubles associe´s a` ces maladies. Objectif: L’e´tude visait a` e´valuer la pre´valence des manifestations mucocutane´es ainsi que leur association avec le sexe, la dure´e de la maladie, l’arthrite, le sie`ge de la maladie intestinale, et le degre´ d’activite´ de la maladie. Me´thode: Ont participe´ a` l’e´tude 56 patients souffrant de rectocolite he´morragique (RH) et 36 patients atteints de la maladie de Crohn (MC), qui faisaient l’objet de suivi au service de gastroente´rologie de l’hoˆpital de recherche et d’enseignement Go¨ztepe de l’Universite´ Medeniyet d’Istanbul. Tous les patients ont e´te´ soumis a` un examen dermatologique du corps entier, et il y a eu e´valuation des dossiers a` la recherche de manifestations mucocutane´es. Re´sultats: Sur les 92 patients, 49 (53.26%) pre´sentaient au moins une manifestation mucocutane´e (58.9% des patients atteints de RH et 44.4% des patients atteints de la MC); sur ce nombre, 38 (41.3%) avaient fait au moins une e´ruption cutane´e re´actionnelle. Une stomatite aphteuse a e´te´ observe´e chez 33 patients (35.86%), ce qui en a fait la manifestation mucocutane´e la plus fre´quente. Des affections cutane´es granulomateuses ont e´te´ releve´es chez 18 patients (19.57%), et aucun patient ne pre´sentait d’affection cutane´e

From the Istanbul Medeniyet University School of Medicine, Departments of Dermatology and Gastroenterology, Go¨ztepe Training and Research Hospital; Department of Dermatology, Okmeydanı Training and Research Hospital; and Department of Gastroenterology, Bagcılar Training and Research Hospital, Istanbul, Turkey. Presented as a poster at the 22nd European Academy of Dermatology and Venereology Congress, Istanbul, October 2–6, 2013.

Address reprint requests to: Emek Kocatu¨rk, MD, Department of Dermatology, Okmeydanı Training and Research Hospital, Nadiraga Sok. No: 25/9 Go¨ztepe, 34730, Istanbul, Turkey; e-mail: [email protected].

DOI 10.2310/7750.2014.13209 # 2014 Canadian Dermatology Association

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associe´e a` des carences nutritionnelles. Trois patients seulement (3.26%) pre´sentaient un e´rythe`me noueux et 2 patients (2.17%) souffraient de pyodermite gangre´neuse. Conclusions: Les manifestations mucocutane´es des maladies inflammatoires de l’intestin sont plus fre´quentes que ce qui avait e´te´ envisage´ au de´part et e´galement plus fre´quentes dans la RH que dans la MC. Aucune association n’a e´te´ e´tablie entre les manifestations mucocutane´es et le sexe, la dure´e de la maladie, l’arthrite, le sie`ge de la maladie intestinale, et le degre´ d’activite´ de la maladie.

NFLAMMATORY BOWEL DISEASE (IBD) is a chronic systemic disorder that is triggered and sustained by a variety of genetic and environmental factors and represents the chronic relapsing and remitting disorders of the gastrointestinal tract.1 The major forms of IBD are ulcerative colitis (UC) and Crohn disease (CD). Although inflammation begins in the rectum and extends to the proximal colon in UC, CD affects any portion of the gastrointestinal tract, from the mouth to the anus. According to recent reports, the incidence of IBD is increasing in developing countries.2,3 Tozun and colleagues reported that the incidence of IBD was 4.4 in 100,000 and 2.2 in 100,000 for UC and CD, respectively, in their multicenter epidemiologic survey in Turkey.4 IBD incidence in our country was found to be lower than in northern and western Europe but close to that in the Middle East.4 A broad spectrum of extraintestinal manifestations in various organ systems have been reported to be associated with IBD. Extraintestinal manifestations (cutaneous, musculoskeletal, hepatobiliary, ocular, and metabolic conditions) may occur in one-third of patients with IBD, among whom cutaneous manifestations are the most common.5 The mean incidence of cutaneous manifestations is around 10% at the time of diagnosis. However, many other skin lesions may develop during follow-up.6 They occur in many different clinical forms, are sometimes painful or disabling, and may be the harbinger of the disease.7 The mucocutaneous manifestations of IBD are classified into three main groups: granulomatous cutaneous diseases (GCDs), reactive skin eruptions (RSEs), and manifestations that are secondary to nutritional deficiency.8 Perianal and peristomal ulcers and fistulas, metastatic CD, and oral granulomatous changes are the disorders that histologically resemble inflamed bowel and form GCDs.9 RSEs, such as aphthous ulcers, erythema nodosum (EN), pyoderma gangrenosum (PG), and Sweet syndrome, are strongly associated with IBD.10 Acrodermatitis enteropathica may manifest due to a zincdeficient diet, total parenteral nutrition, or malabsorption in IBD.11 An association between IBD and many cutaneous autoimmune diseases, such as psoriasis, vitiligo, lupus

I

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erythematosus (more rarely), polymyositis, and scleroderma, has also been reported in the literature.12 In the literature, there are vast differences in the prevalence of these various mucocutaneous manifestions.13,14 Therefore, we aimed in this study to evaluate the prevalence of mucocutaneous manifestations in our country and their association with gender, duration of disease, arthritis, and the location and activity of the bowel disease.

Materials and Methods Fifty-six patients with UC and 36 patients with CD who were in follow-up at the Istanbul Medeniyet University Go¨ztepe Training and Research Hospital Department of Gastroenterology were included in the study. The diagnosis of IBD was based on clinical, endoscopic, radiologic, and histopathologic features. The extent of UC was defined at the first visit by endoscopy and categorized into four groups: distal type, involvement of the left colon, extensive colitis, and pancolitis. The severity of UC was measured as severe, moderate, or mild according to the Truelove and Witt criteria.15 The Montreal classification was used to classify CD patients, according to age at diagnosis (A1 , 16 years, A2 17–40 years, A3 . 40 years), location of disease (L1 ileal, L2 colonic, L3 ileocolonic, L4 isolated upper disease), and disease behavior (B1 nonstricturing, nonpenetrating; B2 stricturing; B3 penetrating, perianal disease).16 Wholebody dermatologic examinations were performed on all patients, and patient files were evaluated for mucocutaneous manifestations from December 2010 to January 2012. The presence of rheumatologic disease was also examined. We categorized the skin lesions into three groups: GCDs, RSEs, and nutritional defiency–associated skin conditions (NDSCs). The skin diseases that could not be classified were gathered under another group as other associated skin conditions (OSCs). GCDs consisted of perianal and peristomal ulcers and fistulas, metastatic CD, and oral granulomatous changes. Aphthous ulcers, EN, and PG formed the RSE group. Diseases associated with a zinc-deficient diet, total parenteral nutrition, or

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Table 1. Mucocutaneous Manifestations of Inflammatory Bowel Disease

Age, yr (mean 6 SD) Gender, n (%) Female Male Duration of illness, mo (range) GCD, n (%) None Fissure Fistulas Perianal and peristomal ulcers Oral granulomatous lesions Oral granulomatous lesions + fissures RSE, n (%) None Aphthous ulcers Pyoderma gangrenosum Aphthous ulcers with erythema nodosum Aphthous ulcers with pyoderma gangrenosum NDSC, n (%) None OSC, n (%) None Psoriasis Acne rosacea Chronic urticaria Sarcoidosis Alopecia areata Oral lichen Hidradenitis Fordyce disease

29 27

UC

CD

p

44.66 6 13.36

34.5 6 11.72

.0001

(51.79) (48.21) 44 (15.25–81)

19 17

(52.78) (47.22)

46 3 2 1 4 0

(82.14) (5.36) (3.57) (1.79) (7.14) (0.00)

28 5 2 0 0 1

(77.78) (13.89) (5.56) (0.00) (0.00) (2.78)

.258 .636 .998 .291 .387

30 22 1 2 1

(53.57) (39.29) (1.79) (3.57) (1.79)

24 11 0 1 0

(66.67) (30.56) (0.00) (2.78) (0.00)

.371 .998 .998 .998

56

(100.00)

36

(100.00)

45 2 4 2 1 1 1 0 23

(80.36) (3.57) (7.14) (3.57) (1.79) (1.79) (1.79) (0.00) (41.07)

33 0 1 1 0 0 0 1 8

(91.67) (0.00) (2.78) (2.78) (0.00) (0.00) (0.00) (2.78) (22.22)

21 (7–48)

.926 .044

.509 .644 .998 .999 .999 .999 .430 .101

CD 5 Crohn disease; GCD 5 granulomatous cutaneous disease; NDSC 5 nutritional defiency–associated skin condition; OSC 5 other skin condition; RSE 5 reactive skin reaction; UC 5 ulcerative colitis.

malabsorption were categorized as NDSCs. Acne rosacea, psoriasis, chronic urticaria, sarcoidosis, alopecia areata, oral lichen, and hidradenitis were categorized as OSCs. Statistical analysis were performed with the NCSS 2007 statistical software (Kaysville, UT). Descriptive statistical methods (mean, standard deviation) for the comparison of two independent groups was detected by t-test. Chi-square and Fisher exact tests were used to compare the qualitative data. The significance level was set at p , .05.

Results Of 92 patients with IBD (mean age 40.68 6 13.63 years, range 19–72 years; 48 females, 44 males), 56 had UC

and 36 had CD. The mean IBD duration was 47.44 6 48.90 months (range 1–240 months). The epidemiologic characteristics and mucocutaneous manifestations of these patients are shown in Table 1. We found that 53.3% of patients with IBD (58.9% of patients with UC and 44.44% of patients with CD) had at least one mucocutaneous manifestation. At least one RSE in 38 patients (41.3%) and at least one granulomatous cutaneous lesion in 18 patients (19.6%) were detected. Eight patients (8.7%) had both granulomatous cutaneous lesions and RSEs. No patient had an NDSC such as acrodermatitis enteropathica. Aphthous stomatitis (40.2%) was the most common mucocutaneous manifestation for both UC (44.6%) and CD (33.3%).

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Table 2. Comparison of Patients’ Features with Mucocutaneous I˙nvolvement Mucocutaneous Involvement

Age, yr (mean 6 SD) Duration of illness, yr (range) Gender, n (%) Female Male UC localization, n (%) Distal type Left colon involvement Extensive type Pancolitis UC activity, n (%) Mild Medium Severe CD localization, n (%) IIeal Colonic Ileocolonic CD behavior, n (%) Nonstricturing, nonpenetrating type Stricturing type Penetrating type CD activity indices, n (%) Remission Medium

Negative

Positive

p

40.56 6 14.86 18 (7–60)

40.79 6 12.59 36 (18–69)

.934 .068

14 29

(32.56) (67.44)

34 15

(69.39) (30.61)

.0001

5 4 4 10

(21.74) (17.39) (17.39) (43.48)

7 8 4 14

(21.21) (24.24) (12.12) (42.42)

.904

16 7 0

(69.57) (30.43) (0.00)

23 9 1

(69.70) (27.27) (3.03)

.689

8 0 12

(40.00) (0.00) (60.00)

3 3 10

(18.75) (18.75) (62.50)

.079

9 10 1

(45.00) (83.30) (25.00)

11 2 3

(55.00) (16.70) (75.00)

.045

15 5

(75.00) (25.00)

11 5

(68.75) (31.25)

.677

CD 5 Crohn disease; UC 5 ulcerative colitis.

Whereas fissure and fistulas were more common in CD (19.4%) than in UC (8.9%), aphthous ulcers, EN, PG, and oral granulomatous lesions were more common in UC (44.6%, 3.5%, 3.5%, and 7.1%, respectively) than in CD (33.3%, 2.7%, 0.00%, and 2.7%, respectively). However, these rates were not significantly different (p . .05). OSCs were as follows: 2 (2.2%) psoriasis, 5 (5.4%) acne rosacea, 3 (3.3%) chronic urticaria, 1 (1.1%) sarcoidosis, 1 (1.1%) alopecia areata, 1 (1.1%) oral lichen, and 1 (1.1%) hidradenitis suppurativa. These findings were not more frequent than would be expected in the general population. Thirty-one patients (33.7%) had Fordyce spots, of whom 23 (41.07%) had UC and 8 (22.22%) had CD. We found no relationship between Fordyce spots and gender, age, and type of IBD (see Table 1), and the frequency was the same as in the normal population. Only 7 patients (7.6%) had arthritis. Although arthritis was more common among patients with CD (13.8%) than with UC (3.5%), these rates were not significantly different 400

(p . .05). No relationship between mucocutaneous manifestations and arthritis was found. Twenty-eight of our patients were smokers, 23 were exsmokers, and 41 were nonsmokers. We compared these three groups for the presence of aphthous ulcers and found that the frequency of aphthous ulcers was less in the smokers group. This difference was statistically significant (p 5 .012). We found no relationship between the frequency of mucocutaneous manifestations and age, duration of disease, activity indices, and location of IBD. Mucocutaneous manifestations were more common in females (69.4%) than in males (30.6%), and this difference was statistically significant (p 5 .0001) (Table 2). CD behavior has three categories: nonstricturing, nonpenetrating type; stricturing type; and penetrating type. In the stricturing type, mucocutaneous manifestations were lower (16.7%) than in the nonstricturing, nonpenetrating type (55%) and the penetrating type

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(75%), and these findings were statistically significant (p 5 .045) (see Table 2).

Discussion IBD is often associated with extraintestinal manifestations, complications, and other autoimmune disorders.17,18 Cutaneous manifestations are the most frequent extraintestinal manifestations associated with IBD.19 These findings can either be contiguous with the bowel or a reactive cutaneous eruption or may be related to drug reactions or other etiologies that are not well understood. They can occur before, during, or after the manifestations of the gastrointestinal problems.20,21 In the literature, there is a significant variation between reported rates and types of dermatologic manifestations. Their prevalence varies from 2 to 36%.13,14 In our study, 53.3% of patients with IBD (58.9% of patients with UC and 44.44% with CD) had at least one mucocutaneous manifestation. We found that the prevalence of mucocutaneous manifestations (53.3%) was higher than the recent prevalences reported in the literature. There were different results regarding which form of IBD was associated with more frequent cutaneous manifestations. Christodoulou and colleagues reported the incidence of skin signs in 13% of UC patients and in 24.3% of CD patients.13 They also reported that cutaneous manifestations were more common in CD than in UC. The frequency of dermatologic complications was stated to be 2 to 35% in patients with UC and 9 to 23% in patients with CD in other reports.22,23 In our study, patients with UC had far more mucocutaneous manifestations than patients with CD, but this difference was not statistically significant. Of 49 patients with mucocutaneous involvement (69.39%), 14 were female and 15 were male in our study. We found that mucocutaneous manifestations occurred more often in women than in men. This finding was statistically significant and was consistent with the literature.22,23 We found that aphthous ulcer was more common than other mucocutaneous manifestations, such as EN, PG, and perianal fissure and fistula. The prevalence was 40.2% (44.6% in UC and 33.3% in CD). Aphthous ulcer has been reported in 10% of patients with UC and 20 to 30% of patients with CD in the literature.8 On reviewing the literature, we realized that in studies originating from Turkey, the prevalence of aphthous ulcer was higher than in the studies performed in other countries.24,25 Turkc¸apar and colleagues reported a prevalence of 47.5% (42.9% in UC and 52.6% in CD patients),24 whereas Yu¨ksel and colleagues found a frequency of 37.5%, with a dominance

in UC patients.26 It was interesting that the frequency of recurrent aphthous ulcers has been reported to be the same as that in other countries (< 25%).27 But the increased prevalence of aphthous ulcers in IBD patients was remarkable; therefore, we emphasize that in patients with recurrent aphthous ulcerations, an approach to seeking underlying IBD must be sought. Some studies report that EN is the most frequent cutaneous manifestation of IBD.20,28,29 It has been reported at rates of 1.9 to 7.2% and 0.9 to 4% in CD and UC, respectively.30–32 In our study, the prevalence of EN in IBD patients (3.3%) was similar to that reported in the literature. But we observed that EN was more common in patients with UC (3.57% vs 2.78%), although this was not statistically significant.30–33 EN occurs in women three to six times more often than in men.34 All of our patients with EN were women, and this finding was supported by the literature.34 We found no differences for location of intestinal disease between IBD patients with or without EN, which was consistent with the literature.26,33 Some studies reported an association between EN and colonic CD.31,33 We found no relationship between EN and arthritis, which was incompatible with the literature.6,26,35 PG has been reported to be more prevalent in UC patients, with rates between 0.5 and 5%.9,20,21,31,36 We found similar rates (2.2% [3.58% in UC and 0.0% in CD]) in our study. The frequency of PG in CD has been found to be 0.6 to 2.0%, but we observed no PG in our patients with CD.30,31 All of our patients with PG were also female, as were patients with EN. A slight female preponderance was reported in the literature, as in our study.37 Yu¨ksel and colleagues reported that the location of bowel disease was similar between IBD patients with or without PG. We also found no difference between the two groups regarding the location of bowel disease.26 In our study, there was no relationship between age, duration of disease, activity indices, and location of IBD with any of the mucocutaneous manifestations. But mucocutaneous manifestations were found to be associated with female gender and CD behavior. In patients with CD, mucocutaneous manifestations were found less (16.7%) in the stricturing type than in the nonstricturing, nonpenetrating (55%) and penetrating (75%) types, and this finding was statistically significant. Such a relationship between CD behavior and mucocutaneous manifestations has not been reported before. Perianal fissures and fistulas, usually one of the most common skin findings of IBD, occur mainly in CD (20–60%) and rarely in UC.38 Fissures and fistulas (Figure 1) were more common in CD (19.4%) than in UC (8.9%) in

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Figure 1. Perianal fistulas of a patient with Crohn disease.

our series, but they were not among the most common mucocutaneous manifestations in our population. In fact, in our study, fissures and fistulas were the only mucocutaneous manifestations seen more often in CD than in UC. Aphthous ulcers, EN, PG, and oral granulomatous lesions were detected more often in UC (44.6%, 3.5%, 3.5%, and 7.1%, respectively) than in CD (33.3%, 2.7%, 0.00%, and 2.7%), which was not consistent with the literature.10,13 However, these rates were not significantly different (p . .05). No metastatic skin lesions were observed. Oral granulomatous lesions were observed in five patients (5.4%) (Figure 2), but only one had the diagnosis of Melkersson-Rosenthal syndrome. None of our patients had manifestations secondary to nutritional deficiency such as acrodermatitis enteropathica. Arthritis has been reported as the most common extraintestinal manifestation of IBD in some studies,

Figure 2. The cobblestone appearance of the upper gingiva of a patient with Crohn disease.

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appearing in 4 to 22% of patients with UC and in 2 to 22% of patients with CD.24,31,39 Fahri and colleagues reported that articular involvement was the most common extraintestinal manifestation (14.6%), followed by dermatologic (5.8%), oral (5.8%), and ocular (3.1%) involvement.39 They found these manifestations to be significantly more frequent in patients with CD than with UC. Arthritis was more common among patients with CD (13.8%) than among patients with UC (3.5%) in our study, which concurs with the literature. However, these rates were not statistically significant. Turkc¸apar and colleagues reported musculoskeletal manifestations as the most common extraintestinal manifestations of IBD and detected that about half of all patients had musculoskeletal involvement.24 They found no association between the severity of IBD and spinal involvement, which was the same finding in our study. Yu¨ksel and colleagues reported that the prevalence of arthritis was significantly higher in IBD patients with EN than in IBD patients without EN.26 They also found that arthritis was more common in IBD patients with PG than in IBD patients without PG. Fahri and colleagues reported that among all patients with IBD, aphthous ulcers were significantly associated with joint involvement.39 In contrast to the literature, we found no relationship between mucocutaneous manifestations and arthritis.26,39 Mucocutaneous involvement was more common than articular involvement in our study. Autoimmune skin disorders such as vitiligo, polymyositis, lupus erythematosus, scleroderma, and bullous pemphigoid have been reported to be associated with CD and UC in a similar frequency.7,40,41 We found no relationship between IBD and autoimmune diseases. An increased association between IBD and psoriasis has been reported in previous studies.42–44 Psoriasis occurs in 7 to 11% of patients with IBD compared to about 1 to 2% of the normal population.43 The association with CD (11.2%) is higher than that with UC (5.7%).44 Passarini and colleagues found that the percentage of patients with psoriasis (17%) almost doubled the percentage expected in IBD and was much more than that of the general population.45 All patients with psoriasis in their study had received tumor necrosis factor a (TNF-a) blocker drugs. They indicated that such a high incidence could not be explained solely by genetic or immune imbalance or alterations associated with the basic disease. They supported the hypothesis of psoriasis induced by anti-TNF-a agents. In our study, the percentage of patients with psoriasis (2.2%) was the same as that of the general population. In our series, only one patient had received

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anti-TNF-a agents. Therefore, we do not have the data to comment on psoriasis induced by anti-TNF-a agents. In the literature, there are conflicting results regarding the association between tobacco use and dermatologic signs.39,46,47 Barreiro-de Acosta and colleagues found a positive association between smoking habits and EN in a series of 173 consecutive CD patients.46 This was not reported for other extraintestinal manifestations. Manguso and colleagues examined the relationship between tobacco use and extraintestinal manifestations and found increased dermatologic manifestations in smokers.47 Fahri and colleagues did not find an association between tobacco use and dermatologic signs.39 In our study, we examined the relationship between tobacco habits and aphthous ulcers. The frequency of aphthous ulcers was found to be decreased in the smokers group. A lower prevalence rate of recurrent aphthous stomatitis has been found in smokers when compared to nonsmokers.48–50 We observed a decreased prevalence rate of aphthous ulcers in the smokers group with IBD, in accordance with previous studies.

Conclusion We found that mucocutaneous manifestations were more common than expected in IBD. They were not associated with a more aggressive intestinal disease. Although there was no relationship between age, duration of disease, activity indices, and location of IBD with mucocutaneous manifestations, female gender and CD behavior affected mucocutaneous manifestations. The prevalence of aphthous stomatitis was found to be much higher than previously reported. We believe that regional variances may explain such clinical discrepancies.

Acknowledgment Financial disclosure of authors and reviewers: None reported.

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Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 18, No 6 (November/December), 2014: pp 397–404

Mucocutaneous manifestations of inflammatory bowel disease in Turkey.

Mucocutaneous manifestations of inflammatory bowel diseases are relatively common; the mean incidence is around 10% at the time of diagnosis. However,...
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