Abstract
Background:
The aim of the study was to evaluate familial Mediterranean fever (FMF) mutation analysis in pediatric patients with inflammatory bowel disease (IBD). The relation between MEFV mutations and chronic inflammatory diseases has been reported previously.
Methods:
Children with IBD (334 ulcerative colitis (UC), 224 Crohn’s disease (CD), 39 indeterminate colitis (IC)) were tested for FMF mutations in this multicenter study. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined.
Results:
A total of 597 children (mean age: 10.8 ± 4.6 years, M/F: 1.05) with IBD were included in the study. In this study, 41.9% of the patients had FMF mutations. E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). There was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/heterozygous) in patients with UC (P < .05).
There was a statistically significant difference between colonoscopy findings in patients with or without mutations (P = .031, P = .045, respectively). The patients with UC who had mutations had lower Pediatric Ulcerative Colitis Activity Index (PUCAI) scores than the patients without mutations (P = .007).
Conclusion: Although FMF mutations are unrelated to CD patients, but observed in UC patients with low PUCAI scores, it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease.
Keywords: Children, familial Mediterranean fever, MEFV, mutation analysis, inflammatory bowel disease
INTRODUCTION
Familial Mediterranean fever (FMF) and inflammatory bowel diseases (IBD) are 1 of the most common autoinflammatory diseases characterized by recurrent inflammatory episodes sharing similar symptoms.
FMF is an autosomal recessive disorder caused by mutations in the Mediterranean fever gene (MEFV), first identified in 1997 by French FMF Consortium1 encoded on the short arm of chromosome 16. MEFV gene encodes the pyrin protein, which has a regulatory effect in the inflammasome-related innate immune response.2-8 Also NOD2/CARD15 gene related to Crohn’s disease (CD) is localized on chromosome 16.2-4 The products of both the MEFV and NOD2/CARD15 genes are structurally similar.2
The relation between MEFV mutations and chronic inflammatory diseases such as CD, rheumatoid arthritis, Henoch-Schonlein purpura, polyarteritis nodosa, chronic arthritis, systemic lupus erythematosus has been reported previously.5-23 FMF is more common in people of certain ethnic backgrounds, such as Sephardic Jews, Turks, Arabs, and Armenians. Thus, the aim of this study was to evaluate FMF mutation analysis in Turkish pediatric patients with IBD and define its impact on the clinical course of the disease.
MATERIALS AND METHODS
This was a multicenter study conducted by the Turkish IBD Study Group including 37 institutions in Turkey. Children with IBD diagnosed according to clinical, serological, endoscopic, and histopathological criteria and followed up between 2000 and 2012 at clinics of pediatric gastroenterology were evaluated retrospectively.
The endoscopic examinations and biopsies were performed at the initial diagnosis. All of the patients were tested for common FMF mutations (M694V, M680I, E148Q, R202Q, A744S, V726A, and others). The blood samples drawn into EDTA were collected from all of the patients and DNA was isolated from peripheral blood lymphocytes by PCR. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined.
Pediatric Crohn Disease Activity Index (PCDAI) was used for patients with CD at diagnosis.24,25 The score was determined from items, which included subjective reporting of the degree of abdominal pain, stool pattern, and general well-being; presence of extraintestinal manifestations, such as fever, arthritis, rash, and uveitis; physical examination findings; weight and height; and hematocrit, erythrocyte sedimentation rate, and serum albumin.
Pediatric Ulcerative Colitis Activity Index (PUCAI) was used for patients with ulcerative colitis (UC) at diagnosis.26 It was determined by items including abdominal pain, rectal bleeding, stool consistency of most stools, number of stools per day, nocturnal stools, and activity level.
5-ASA (5-aminosalicylic acid) was used in patients with mild UC, both 5-ASA and oral steroids in patients with moderate UC and 5-ASA, intravenous steroids, and azathioprine in severe UC. Rectal 5-ASA and rectal steroids were used in patients with proctocolitis.
5-ASA and modulen formula was used in patients with mild CD, 5-ASA, modulen formula and oral steroids in moderate CD, and 5-ASA, modulen formula, intravenous steroids, and azathioprine in severe CD. Steroids were reduced gradually before stopping in patients with moderate and severe disease and then immunosuppressant therapy was initiated.
PUCAI and PCDAI scores <10 denotes remission.24-26
Statistical Analysis
Statistical analysis were performed using the SPSS for Windows 15.0 software (IBM Corp., Armonk, NY, USA). Categorical variables were expressed as numbers and percentages. Continuous variables were expressed as mean, standard deviation, median, and minimum-maximum if appropriate. Statistical comparisons were made using the chi-square test for independent groups. The analysis was conducted using Mann–Whitney U test for comparison of 2 independent groups and the Kruskal–Wallis test for more than 2 groups. A value of P < .05 was considered statistically significant.
Ethics
Informed consent was taken from all of the parents before the endoscopy and the other procedures. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by Ege University Ethics Committee (October 12, 2011, No: 11-7/2).
RESULTS
The mean age of 597 patients was 10.8 ± 4.6 (range 2-18 years) and the male:female ratio was 1.05. In this study, 334 patients were diagnosed with UC, 224 CD, and 39 indeterminate colitis (IC). In this study, 41.9% of the patients with IBD (39.2% of UC patients, 44% of CD patients, and 50% of IC patients) had MEFV mutations. The mean follow-up time was 3-5 years. The demographic and clinical characteristics of patients with IBD according to MEFV mutation carriage are shown in Table 1.
Table 1.
The Demographic and Clinical Characteristics of Patients With IBD According to MEFV Mutation Carriage
| Patients With MEFV Mutations (n = 250) | Patients Without MEFV Mutations (n = 347) | P | |
|---|---|---|---|
| Age (years; median) | 10.5 ± 4.9 | 10.5 ± 4.7 | .81 |
| Gender (male/female) | 131/119 | 164/183 | .21 |
| IBD type (n) | |||
| UC | 131 (52.4%) | 203 (58.5%) | .23 |
| CD | 99 (39.6%) | 125 (36%) | |
| IC | 20 ( 8%) | 19 (5.5%) | |
| Median PCDAI (median, range) | 38.5 ± 18.9 | 40.5 ± 16 | .24 |
| Median PUCAI (median, range) | 43.1 ± 19.8 | 49.4 ± 18.8 | .007 |
| Extraintestinal disease | 58 (24%) | 42 (12.5%) | .001 |
| Perianal disease | 60 (24%) | 93 (26.8%) | .20 |
| MEFV mutations | |||
| Homozygous mutation | 50 (25.5%) | ||
| Heterozygous mutation | 146 (74.5%) | ||
| Not mentioned | 23 (2.5%) |
IBD, inflammatory bowel disease; MEFV, Mediterranean fever gene; PCDAI, pediatric Crohn’s disease activity index; PUCAI, pediatric ulcerative colitis activity index.
P < .05 is statistically significant.
Heterozygous E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). The distribution of MEFV genotypes according to disease types are as; M694V 15.3%, M680I 8.5%, E148Q 30.5%, R202Q 28%, A744S 2.5%, V726A 6.8% in patients with UC, M694V 26.2%, E148Q 34.5%, R202Q 32.1%, V726A 2.4% in patients with CD and M694V 47.1%, E148Q 17.6%, R202Q 17.6%, V726A 11.8% in patients with IC.
The colonoscopy findings in patients with mutations according to disease types are shown in Tables 2, 3, and 4. Moderate mucosal fragility was common in patients with MEFV mutations, whereas hemorrhagic ulcer was common in patients without mutations. There was a statistically significant difference between homozygous/heterozygous mutations and colonoscopy findings at cecum in patients with UC (P = .045), at ileum in patients with CD (P = .008) but no difference in patients with IC (P > .05) (Tables 2, 3, and 4).
Table 2.
The Distribution of the Patients According to Mutation Types
| Mutations | Total | Homozygous | Heterozygous | Compound Heterozygous | ||||
|---|---|---|---|---|---|---|---|---|
| n | % | n | % | n | % | n | % | |
| M694V | 48 | 21.4 | 36 | 58.1 | 12 | 7.7 | ||
| M680I | 10 | 4.5 | 3 | 4.8 | 7 | 4.5 | ||
| E148Q | 67 | 29.9 | 9 | 14.5 | 58 | 37.4 | ||
| R202Q | 62 | 27.7 | 5 | 8.1 | 57 | 36.8 | ||
| A744S | 3 | 1.3 | 2 | 3.2 | 1 | 0.6 | ||
| V726A | 12 | 5.4 | 5 | 8.1 | 7 | 4.5 | ||
| Diğer | 15 | 6.7 | 2 | 3.2 | 13 | 8.4 | ||
| M694 V/E148Q | 3 | 1.3 | 3 | 42.9 | ||||
| R202Q/M694 V | 4 | 1.8 | 4 | 57.1 | ||||
| Total | 224 | 100 | 62 | 100 | 155 | 100 | 7 | 100 |
Table 3.
The Distribution of Mutations According to Clinical Features of Patients With IBD
| Total | Homozygous* | Heterozygous* | Compound Heterozygous* | P | |||||
|---|---|---|---|---|---|---|---|---|---|
| N = 224 | n = 62 (27.7%) | n = 155 (69.2%) | n = 7 (3.1%) | ||||||
| n | % | n | % | n | % | n | % | ||
| Age (years) | |||||||||
| ≤5 | 44 | 19.6 | 13 | 21.0 | 29 | 18.7 | 2 | 28.6 | .776 |
| >5 | 180 | 80.4 | 49 | 79.0 | 126 | 81.3 | 5 | 71.4 | |
| Gender | |||||||||
| Male | 116 | 51.8 | 35 | 56.5 | 76 | 49.0 | 5 | 71.4 | .363 |
| Female | 108 | 48.2 | 27 | 43.5 | 79 | 51.0 | 2 | 28.6 | |
| Consanguinity | 44 | 21.1 | 10 | 17.2 | 33 | 22.9 | 1 | 14.3 | .606 |
| Family history of IBD except parents | 9 | 4.7 | 5 | 8.9 | 4 | 3.1 | 0 | 0 | |
| FMF mutation | 219 | 97.8 | 62 | 100 | 155 | 100 | 2 | 28.6 | .247 |
| Perianal disease | |||||||||
| Abscess | 7 | 3.1 | 2 | 3.2 | 5 | 3.2 | 0 | 0 | 1.000 |
| Fissure | 9 | 4.0 | 4 | 6.5 | 4 | 2.6 | 1 | 14.3 | .094 |
| Fistula | 4 | 1.8 | 0 | 0 | 4 | 2.6 | 0 | 0 | .632 |
| Skin Tag | 2 | 0.9 | 0 | 0 | 2 | 1.3 | 0 | 0 | 1.000 |
| Diagnosis | |||||||||
| Ulcerative colitis | 122 | 54.5 | 32 | 51.6 | 86 | 55.5 | 4 | 57.1 | .933 |
| Crohn disease | 85 | 37.9 | 24 | 38.7 | 58 | 37.4 | 3 | 42.9 | |
| Indeterminate colitis | 17 | 7.6 | 6 | 9.7 | 11 | 7.1 | 0 | 0 | |
| PUCAI | 44.2 ± 20.3 | 42.5 ± 18.4 | 43.6 ± 20.7 | 67.5 ± 16.6 | .090 | ||||
| PCDAI | 37.4 ± 17.1 | 41.0 ± 14.1 | 35.9 ± 17.5 | 40.3 ± 30.2 | .344 | ||||
| Crohn Disease | |||||||||
| Distribution | |||||||||
| Localized | 48 | 57.1 | 17 | 70.8 | 30 | 52.6 | 1 | 33.3 | .215 |
| Disseminated | 36 | 42.9 | 7 | 29.2 | 27 | 47.4 | 2 | 66.7 | |
| Colonoscopy Rectum | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 19 | 23.8 | 4 | 17.4 | 15 | 27.3 | 0 | 0 | .838 |
| Ulceration and stricture | 2 | 2.5 | 0 | 0 | 2 | 3.6 | 0 | 0 | |
| Fistula | 2 | 2.5 | 0 | 0 | 2 | 3.6 | 0 | 0 | |
| >5 aphthous lesion | 6 | 7.5 | 3 | 13.0 | 3 | 5.5 | 0 | 0 | |
| <5 aphthous lesion | 9 | 11.3 | 3 | 13.0 | 6 | 10.9 | 0 | 0 | |
| Normal | 42 | 52.5 | 13 | 56.5 | 27 | 49.1 | 2 | 100 | |
| Sigmoid | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 17 | 21.3 | 3 | 13.0 | 14 | 25.5 | 0 | 0 | .881 |
| Fistula | 1 | 1.3 | 0 | 0 | 1 | 1.8 | 0 | 0 | |
| >5 aphthous lesion | 6 | 7.5 | 2 | 8.7 | 4 | 7.3 | 0 | 0 | |
| <5 aphthous lesion | 12 | 15.0 | 4 | 17.4 | 8 | 14.5 | 0 | 0 | |
| Normal | 44 | 55.0 | 14 | 60.9 | 28 | 50.9 | 2 | 100 | |
| Left colon | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 14 | 18.4 | 1 | 4.5 | 13 | 25.0 | 0 | 0 | .84 |
| Ulceration and stricture | 3 | 3.9 | 0 | 0 | 3 | 5.8 | 0 | 0 | |
| >5 aphthous lesion | 4 | 5.3 | 2 | 9.1 | 2 | 3.8 | 0 | 0 | |
| <5 aphthous lesion | 11 | 14.5 | 3 | 13.6 | 8 | 15.4 | 0 | 0 | |
| Normal | 44 | 57.9 | 16 | 72.7 | 26 | 50.0 | 2 | 100 | |
| Right colon | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 11 | 15.1 | 2 | 9.1 | 9 | 18.4 | 0 | 0 | .585 |
| Fistula | 1 | 1.4 | 1 | 4.5 | 0 | 0 | 0 | 0 | |
| >5 aphthous lesion | 9 | 12.3 | 4 | 18.2 | 5 | 10.2 | 0 | 0 | |
| <5 aphthous lesion | 14 | 19.2 | 3 | 13.6 | 11 | 22.4 | 0 | 0 | |
| Normal | 38 | 52.1 | 12 | 54.5 | 24 | 49.0 | 2 | 100 | |
| Cecum | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 14 | 19.4 | 6 | 27.3 | 8 | 16.7 | 0 | 0 | .796 |
| Ulceration and stricture | 3 | 4.2 | 1 | 4.5 | 2 | 4.2 | 0 | 0 | |
| >5 aphthous lesion | 7 | 9.7 | 3 | 13.6 | 4 | 8.3 | 0 | 0 | |
| <5 aphthous lesion | 20 | 27.8 | 5 | 22.7 | 15 | 31.3 | 0 | 0 | |
| Normal | 28 | 38.9 | 7 | 31.8 | 19 | 39.6 | 2 | 100 | |
| Ileum | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 16 | 25.4 | 6 | 30.0 | 10 | 24.4 | 0 | 0 | .426 |
| Ulceration and stricture | 15 | 23.8 | 3 | 15.0 | 11 | 26.8 | 1 | 50.0 | |
| >5 aphthous lesion | 2 | 3.2 | 2 | 10.0 | 0 | 0 | 0 | 0 | |
| <5 aphthous lesion | 15 | 23.8 | 5 | 25.0 | 10 | 24.4 | 0 | 0 | |
| Normal | 15 | 23.8 | 4 | 20.0 | 10 | 24.4 | 1 | 50.0 | |
| Ulcerative colitis | |||||||||
| Distribution | |||||||||
| E1 | 16 | 13.3 | 2 | 6.3 | 14 | 16.7 | 0 | 0 | .057 |
| E2 | 31 | 25.8 | 4 | 12.5 | 26 | 31.0 | 1 | 25.0 | |
| E3 | 73 | 60.8 | 26 | 81.3 | 44 | 52.4 | 3 | 75.0 | |
| Colonoscopy Rektum | |||||||||
| Normal | 8 | 6.3 | 2 | 5.7 | 6 | 6.9 | 0 | 0 | .865 |
| Mild mucosal fragility | 10 | 7.9 | 2 | 5.7 | 8 | 9.2 | 0 | 0 | |
| Moderate mucosal fragility | 34 | 27.0 | 9 | 25.7 | 25 | 28.7 | 0 | 0 | |
| Hemorrhagic ulcers | 74 | 58.7 | 22 | 62.9 | 48 | 55.2 | 4 | 100 | |
| Sigmoid | |||||||||
| Normal | 8 | 6.6 | 1 | 3.0 | 7 | 8.2 | 0 | 0 | .715 |
| Mild mucosal fragility | 13 | 10.7 | 2 | 6.1 | 11 | 12.9 | 0 | 0 | |
| Moderate mucosal fragility | 37 | 30.3 | 9 | 27.3 | 27 | 31.8 | 1 | 25.0 | |
| Hemorrhagic ulcers | 64 | 52.5 | 21 | 63.6 | 40 | 47.1 | 3 | 75.0 | |
| Left colon | |||||||||
| Normal | 15 | 12.8 | 2 | 6.1 | 12 | 15.0 | 1 | 25.0 | .126 |
| Mild mucosal fragility | 13 | 11.1 | 3 | 9.1 | 10 | 12.5 | 0 | 0 | |
| Moderate mucosal fragility | 38 | 32.5 | 7 | 21.2 | 29 | 36.3 | 2 | 50.0 | |
| Hemorrhagic ulcers | 51 | 43.6 | 21 | 63.6 | 29 | 36.3 | 1 | 25.0 | |
| Right colon | |||||||||
| Normal | 31 | 30.4 | 5 | 16.7 | 25 | 36.8 | 1 | 25.0 | .094 |
| Mild mucosal fragility | 11 | 10.8 | 5 | 16.7 | 6 | 8.8 | 0 | 0 | |
| Moderate mucosal fragility | 29 | 28.4 | 6 | 20.0 | 21 | 30.9 | 2 | 50.0 | |
| Hemorrhagic ulcers | 31 | 30.4 | 14 | 46.7 | 16 | 23.5 | 1 | 25.0 | |
| Cecum | |||||||||
| Normal | 44 | 46.3 | 9 | 33.3 | 34 | 53.1 | 1 | 25.0 | .025 |
| Mild mucosal fragility | 15 | 15.8 | 2 | 7.4 | 12 | 18.8 | 1 | 25.0 | |
| Moderate mucosal fragility | 17 | 17.9 | 5 | 18.5 | 11 | 17.2 | 1 | 25.0 | |
| Hemorrhagic ulcers | 19 | 20.0 | 11 | 40.7 | 7 | 10.9 | 1 | 25.0 | |
| Ileum | |||||||||
| Normal | 61 | 80.3 | 14 | 73.7 | 44 | 83.0 | 3 | 75.0 | .300 |
| Mild mucosal fragility | 5 | 6.6 | 2 | 10.5 | 3 | 5.7 | 0 | 0 | |
| Moderate mucosal fragility | 4 | 5.3 | 0 | 0 | 3 | 5.7 | 1 | 25.0 | |
| Hemorrhagic ulcers | 6 | 7.9 | 3 | 15.8 | 3 | 5.7 | 0 | 0 | |
| Indeterminate colitis | |||||||||
| Sigmoid | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 1 | 7.7 | 1 | 33.3 | 0 | 0 | - | - | .335 |
| <5 aphthous lesion | 3 | 23.1 | 0 | 0 | 3 | 30 | - | - | |
| Normal | 9 | 69.2 | 2 | 66.7 | 7 | 70 | - | - | |
| Left colon | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 1 | 7.7 | 1 | 33.3 | 0 | 0 | - | - | .231 |
| Normal | 12 | 92.3 | 2 | 66.7 | 10 | 100 | - | - | |
| Right colon | |||||||||
| >5 aphthous lesion | 1 | 7.7 | 1 | 33.3 | 0 | 0 | - | - | .231 |
| Normal | 12 | 92.3 | 2 | 66.7 | 10 | 100 | - | - | |
| Ileum | |||||||||
| <5 aphthous lesion | 2 | 15.4 | 0 | 0 | 2 | 20 | - | - | 1.000 |
| Normal | 11 | 84.6 | 3 | 100 | 8 | 80 | - | - | |
*The most common homozygous mutation M694V.
*The most common heterozygous mutation E148Q.
*The most common compound heterozygous mutation R202Q/M694 V.
IBD, inflammatory bowel disease; PCDAI, pediatric Crohn’s disease activity index; PUCAI, pediatric ulcerative colitis activity index.
P < .05 is statistically significant.
When colonoscopy findings were examined according to mutation genotypes among patients with CD, the diffuse disease rate was lower in patients who had M694V mutation than the patients with other mutations (Table 3). The rate of normal colonoscopy in the ileum and cecum was low in patients with CD who had R202Q mutation.
There was a significant difference in terms of endoscopic and histopathological findings according to all of the mutation types (homozygous/heterozygous) in patients with UC (P < .05), whereas no significant difference was observed in patients with CD.
No significant difference was observed in terms of histopathological findings (increased plasma cell infiltration, basal plasmacytosis, cryptitis, pyloric metaplasia, paneth cell metaplasia, and granuloma) except crypt abscess (P = .018) at sigmoid colon in patients with UC and except crypt abscess (P = .009) and granuloma (P = .002) at caecum in patients with CD according to MEFV mutations (P > .05).
The patients with UC who had mutations had lower PUCAI scores than the patients without mutations (P = .007) (Table 1). No statistically significant difference was observed in terms of PCDAI between patients with CD whether they had mutations or not (Table 1). When the disease activity indexes were determined according to mutation genotypes among IBD patients, no significant differences were observed (P > .05).
No significant associations were established between remission and response to induction treatment and the presence of mutations, mutation types (homozygous/heterozygous), and genotypes (P > .05). FMF mutation analysis was performed after the diagnosis of IBD in all of the cases. IBD was not screened in the cases diagnosed as FMF.
DISCUSSION
There are a limited number of reports, mostly from Turkey which has studied the association between IBD and FMF in children, but none of those reports have included as many cases as in this multicentric study.2,3,9,13,14,16,23 The prevalence of FMF has been reported to be 1:1000 and the frequency of FMF mutation carrier state 20% in Turkey.12 FMF accompanied 21.1% of the pediatric IBD patients in our country.3 None of the reports about pediatric IBD and FMF has studied the relation between MEFV genotypes and endoscopic findings. We also determined the disease activity indexes according to MEFV genotypes.
In this study, 41.9% of our patients with IBD (39.2% of UC patients, 44% of CD patients, and 50% of IC patients) had MEFV mutations. Uslu et al.3 have examined 33 children with IBD and found that 25.7% of the patients had MEFV mutations (32.1% of CD patients, 9.4% of UC patients). Salah et al.16 reported that 88.1% of the children with IBD (28% of UC patients, 73% of CD patients) had mutations and explained their high prevalence as ethnic differences, genetic heterogeneity, and small sample size.
In this study, E148Q was the most common mutation in patients with UC and CD, and M694V in patients with IC, in contrast with the other studies that M694V was the most common mutation detected in pediatric IBD patients.2,3,9,13,14,23 Only 1 study has reported E148Q as the most common mutation in adult IBD patients.8 Salah et al.16 studied 33 Egyptian children with IBD and found that V627A mutation was the most common one. Beser et al.2,14 also mentioned the high rate of K695R mutation (25%) in their patients with UC which has not been detected in previous studies.
We observed that there was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/heterozygous) in patients with UC, but not in patients with CD. When the colonoscopy findings were examined according to mutation genotypes, the diffuse disease rate was found to be lower in CD patients who had M694V mutation than the patients with other mutations, and no significant differences were obtained among patients with UC.
The impact of MEFV mutations on the clinical course of IBD is controversial. While some of the authors assessed no clinical difference between MEFV mutation carriers and noncarrier IBD patients,8,9,16 the others reported that the presence of MEFV mutations has shown to affect the disease activity and severity and may have an impact on the clinical course of the disease.6 Although Uslu et al.3 reported higher disease activity indexes, (PCDAI: median 40, range 32.5-60; PUCAI: median 47.5, range 35-65), was not statistically significant due to the small number of patients. While the patients with UC who had mutations had lower PUCAI scores than the patients without mutations, no significant difference was observed in terms of PCDAI between patients with CD whether they had mutations or not in our study. The disease activity indexes did not change according to mutation genotypes among IBD patients.
Fidder et al.6 found that extraintestinal disease and the strictures were more frequent among MEFV mutation carriers. Uslu et al.3 found no significant difference in terms of extraintestinal disease whether the patients had mutations or not. Yurtcu et al.8 observed that extraintestinal disease frequencies were higher in patients without mutations. In concomitant with Fidder et al.6 we found that extraintestinal disease (arthritis, arthralgia, edema, erythema nodosum, myalgia, sacroiliitis, pyoderma gangrenosum, clubbing finger, numbness) was more common in patients with mutations.
There is a limited number of studies reporting the relation between response to treatment and accompanying FMF mutations in patients with IBD.3 In this study, no association was established between remission and response to induction treatment and the presence of mutations, mutation types (homozygous/heterozygous), and genotypes.
In conclusion, although colonoscopy findings were shown significantly higher at cecum in patients with UC and at ileum in patients with CD who had FMF mutations and low PUCAI scores were observed in UC patients with mutations, in concomitant with the previous studies it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease, since the effect on treatment was not observed during follow-up as in our study. It is controversial if the routine molecular analysis of the MEFV gene is needed or not in patients with IBD, considering the economic burden and loss of time.
Table 4.
The comparison of homozygous M694Vwith the other mutations
| Homozygous M694V | Heterozygous M694V | Compound Heterozygous | Other Homozygous | P | |||||
|---|---|---|---|---|---|---|---|---|---|
| n = 36 | n = 12 | n = 7 | n = 26 | ||||||
| n | % | n | % | n | % | n | % | ||
| Age (years) | |||||||||
| ≤ 5 | 10 | 27.8 | 4 | 33.3 | 2 | 28.6 | 3 | 11.5 | .281 |
| >5 | 26 | 72.2 | 8 | 66.7 | 5 | 71.4 | 23 | 88.5 | |
| Gender | |||||||||
| Male | 22 | 61.1 | 7 | 58.3 | 5 | 71.4 | 13 | 50.0 | .726 |
| Female | 14 | 38.9 | 5 | 41.7 | 2 | 28.6 | 13 | 50.0 | |
| Consanguinity | 7 | 21.2 | 1 | 8.3 | 1 | 14.3 | 3 | 12.0 | .769 |
| Family history of IBD except parents | 4 | 11.8 | 1 | 8.3 | 0 | 0 | 1 | 4.5 | .918 |
| Perianal disease | 36 | 100 | 12 | 100 | 2 | 28.6 | 26 | 100 | <.001 |
| Abse | 2 | 5.6 | 1 | 8.3 | 0 | 0,0 | 0 | 0 | .543 |
| Fissure | 4 | 11.1 | 1 | 8.3 | 1 | 14.3 | 0 | 0 | .217 |
| Fistula | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Skin Tag | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Diagnosis | |||||||||
| Ulcerative colitis | 15 | 41.7 | 3 | 25.0 | 4 | 57.1 | 17 | 65.4 | .102 |
| Crohn disease | 15 | 41.7 | 7 | 58.3 | 3 | 42.9 | 9 | 34,6 | |
| Indeterminate colitis | 6 | 16.7 | 2 | 16.7 | 0 | 0 | 0 | 0 | |
| PUCAI | 39.5 ± 18.2 | 55.0 ± 7.1 | 67.5 ± 16.6 | .064 | |||||
| PCDAI | 40.3 ± 11.7 | 27.5 ± 11.9 | 40.3 ± 30.2 | .088 | |||||
| Crohn Disease | |||||||||
| Distribution | |||||||||
| Localized | 10 | 6.7 | 6 | 85.7 | 1 | 33.3 | 7 | 77.8 | .392 |
| Disseminated | 5 | 33.3 | 1 | 14.3 | 2 | 66.7 | 2 | 22.2 | |
| Colonoscopy Rectum | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 3 | 21.4 | 1 | 14.3 | 0 | 0 | 1 | 11.1 | .976 |
| Ulceration and stricture | 0 | 0 | 1 | 14.3 | 0 | 0 | 0 | 0 | |
| Fistula | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| >5 aphthous lesion | 2 | 14.3 | 0 | 0 | 0 | 0 | 1 | 11.1 | |
| <5 aphthous lesion | 2 | 14.3 | 1 | 14.3 | 0 | 0 | 1 | 11.1 | |
| Normal | 7 | 50.0 | 4 | 57.1 | 2 | 100 | 6 | 66.7 | |
| Sigmoid | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 3 | 21.4 | 0 | 0 | 0 | 0 | 0 | 0 | .131 |
| Fistula | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| >5 aphthous lesion | 0 | 0 | 1 | 14.3 | 0 | 0 | 2 | 22.2 | |
| <5 aphthous lesion | 4 | 28.6 | 3 | 42.9 | 0 | 0 | 0 | 0 | |
| Normal | 7 | 50.0 | 3 | 42.9 | 2 | 100 | 7 | 77.8 | |
| Leftcolon | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 1 | 7.7 | 0 | 0 | 0 | 0 | 0 | 0 | .726 |
| Ulceration and stricture | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| >5 aphthous lesion | 1 | 7.7 | 0 | 0 | 0 | 0 | 1 | 11.1 | |
| <5 aphthous lesion | 2 | 15.4 | 3 | 50.0 | 0 | 0 | 1 | 11.1 | |
| Normal | 9 | 69.2 | 3 | 50.0 | 2 | 100 | 7 | 77.8 | |
| Right colon | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 1 | 7.7 | 0 | 0 | 0 | 0 | 1 | 11.1 | .834 |
| Fistula | 1 | 7.7 | 0 | 0 | 0 | 0 | 0 | 0 | |
| >5 aphthous lesion | 3 | 23.1 | 0 | 0 | 0 | 0 | 1 | 11.1 | |
| <5 aphthous lesion | 2 | 15.4 | 3 | 50.0 | 0 | 0 | 1 | 11.1 | |
| Normal | 6 | 46.2 | 3 | 50.0 | 2 | 100 | 6 | 66.7 | |
| Cecum | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 4 | 30.8 | 0 | 0 | 0 | 0 | 2 | 22.2 | .432 |
| Ulceration and stricture | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 11.1 | |
| >5 aphthous lesion | 2 | 15.4 | 0 | 0 | 0 | 0 | 1 | 11.1 | |
| <5 aphthous lesion | 2 | 15.4 | 4 | 66.7 | 0 | 0 | 3 | 33.3 | |
| Normal | 5 | 38.5 | 2 | 33.3 | 2 | 100 | 2 | 22.2 | |
| Ileum | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 4 | 36.4 | 1 | 16.7 | 0 | 0 | 2 | 22.2 | .864 |
| Ulceration and stricture | 1 | 9.1 | 1 | 16.7 | 1 | 50.0 | 2 | 22.2 | |
| >5 aphthous lesion | 2 | 18.2 | 0 | 0 | 0 | 0 | 0 | 0 | |
| <5 aphthous lesion | 2 | 18.2 | 3 | 50.0 | 0 | 0 | 3 | 33.3 | |
| Normal | 2 | 18.2 | 1 | 16.7 | 1 | 50.0 | 2 | 22.2 | |
| Ulcerative colitis | |||||||||
| Distribution | |||||||||
| E1 | 1 | 6.7 | 0 | 0 | 0 | 0 | 1 | 5.9 | .739 |
| E2 | 3 | 20.0 | 0 | 0 | 1 | 25.0 | 1 | 5.9 | |
| E3 | 11 | 73.3 | 3 | 100 | 3 | 75.0 | 15 | 88.2 | |
| Colonoscopy Rektum | |||||||||
| Normal | 0 | 0 | 1 | 33.3 | 0 | 0 | 2 | 11.8 | .398 |
| Mild mucosal fragility | 2 | 11.1 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Moderate mucosal fragility | 5 | 27.8 | 0 | 0 | 0 | 0 | 4 | 23.5 | |
| Hemorrhagic ulcers | 11 | 61.1 | 2 | 66.7 | 4 | 100 | 11 | 64.7 | |
| Sigmoid | |||||||||
| Normal | 1 | 5.9 | 0 | 0 | 0 | 0 | 0 | 0 | .570 |
| Mild mucosal fragility | 2 | 11.8 | 1 | 33.3 | 0 | 0 | 0 | 0 | |
| Moderate mucosal fragility | 5 | 29.4 | 0 | 0 | 1 | 25.0 | 4 | 25.0 | |
| Hemorrhagic ulcers | 9 | 52.9 | 2 | 66.7 | 3 | 75.0 | 12 | 75.0 | |
| Left colon | |||||||||
| Normal | 1 | 5.9 | 0 | 0 | 1 | 25.0 | 1 | 6.3 | .251 |
| Mild mucosal fragility | 3 | 17.6 | 1 | 33.3 | 0 | 0 | 0 | 0 | |
| Moderate mucosal fragility | 4 | 23.5 | 0 | 0 | 2 | 50.0 | 3 | 18.8 | |
| Hemorrhagic ulcers | 9 | 52.9 | 2 | 66.7 | 1 | 25.0 | 12 | 75.0 | |
| Right colon | |||||||||
| Normal | 3 | 20.0 | 0 | 0 | 1 | 25.0 | 2 | 13.3 | .316 |
| Mild mucosal fragility | 4 | 26.7 | 1 | 33.3 | 0 | 0 | 1 | 6.7 | |
| Moderate mucosal fragility | 4 | 26.7 | 0 | 0 | 2 | 50.0 | 2 | 13.3 | |
| Hemorrhagic ulcers | 4 | 26.7 | 2 | 66.7 | 1 | 25.0 | 10 | 66.7 | |
| Cecum | |||||||||
| Normal | 5 | 35.7 | 1 | 33.3 | 1 | 25.0 | 4 | 30.8 | .707 |
| Mild mucosal fragility | 2 | 14.3 | 1 | 33.3 | 1 | 25.0 | 0 | 0 | |
| Moderate mucosal fragility | 3 | 21.4 | 0 | 0 | 1 | 25.0 | 2 | 15.4 | |
| Hemorrhagic ulcers | 4 | 28.6 | 1 | 33.3 | 1 | 25.0 | 7 | 53.8 | |
| Ileum | |||||||||
| Normal | 7 | 70.0 | 1 | 33.3 | 3 | 75.0 | 7 | 77.8 | .527 |
| Mild mucosal fragility | 1 | 10.0 | 1 | 33.3 | 0 | 0 | 1 | 11.1 | |
| Moderate mucosal fragility | 0 | 0 | 0 | 0 | 1 | 25.0 | 0 | 0 | |
| Hemorrhagic ulcers | 2 | 20.0 | 1 | 33.3 | 0 | 0 | 1 | 11.1 | |
| Indeterminate colitis | |||||||||
| Sigmoid | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 1 | 33.3 | 0 | 0,0 | 1.000 | ||||
| <5 aphthous lesion | |||||||||
| Normal | 2 | 66.7 | 2 | 100 | |||||
| Left colon | |||||||||
| Mucosal hyperemia, diffuse aphthous lesions | 1 | 33.3 | 0 | 0 | 1.000 | ||||
| Normal | 2 | 66.7 | 2 | 100 | |||||
| Right colon | |||||||||
| >5 aphthous lesion | 1 | 33.3 | 0 | 0 | 1.000 | ||||
| Normal | 2 | 66.7 | 2 | 100 | |||||
| Ileum | |||||||||
| <5 aphthous lesion | 0 | 0 | 0 | 0 | |||||
| Normal | 3 | 100 | 2 | 100 | |||||
Funding Statement
The authors declared that this study has received no financial support.
Footnotes
Ethics Committee Approval: Ethics committee approval was received for this study from the Ege University Ethics Committee (12.10.2011, No:11-7/2).
Informed Consent: Written informed consent was obtained.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept – N.U.; Design – N.U.; Supervision – N.U.; Resource – N.U.; Materials – N.U.; Data Collection and/or Processing – N.U., F.U., K.Z., H.Y., S.S., T.E., Z.O., G.Ç., M.A., D.A., N.U., R.H., A.A., N.B., M.B., G.B., M.C., B.D., Y.D., Ö.D., C.E., M.E., S.G., F.G., F.G., S.H., I.I., A.G.K., A.K., T.K., H.K., E.K., G.K., F.O.H., H.Ö., T.Ö., Y.Ö., Ö.B.S., E.T., G.T., F.U., M.U., G.U., A.Y.; Analysis and/or Interpretation – N.U.; Literature Search – N.U.; Writing – N.U.; Critical Reviews – N.U.
Conflict of Interest: The authors have no conflict of interest to declare.
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