Familial Mediterranean fever (FMF) is an inflammatory disease that occurs as a result of uncontrolled immune response. In the Turkish population, the frequency of FMF is higher than that in Western populations. The disease is characterized by acute attacks of fever and inflammatory abdominal, chest, and joint pain. The MEFV gene encodes pyrin, which acts to regulate neutrophil activity. It is the gene responsible for FMF and is localized on chromosome 16p13 (1–3). In many studies, the anti-inflammatory properties of pyrin have been demonstrated; however, not all actions of pyrin are known at present (4,5).
Two major conditions, Crohn disease (CD) and ulcerative colitis (UC), are inflammatory bowel diseases (IBDs), which are a chronic and recurrent disease group. The differentiation between these 2 conditions is made by clinical, endoscopic, radiological, and histopathological findings (6). In CD, inflammation can involve any part of the digestive tract from the oral cavity to the anus, without continuity, and can affect all mucosal layers; however, UC is limited to the colonic mucosa, has a typical continuous distribution, involves the rectum, and shows a variable proximal extension from the rectum (7).
Additional clinical and epidemiological evidence supports MEFV as a potential IBD candidate gene. IBD and FMF share common clinical and biological features; both are inflammatory disorders characterized by the same chronic relapsing behavior, infiltration by neutrophils at the site of injury, and abnormal regulation of apoptosis (8,9). The prevalence of inflammatory diseases, including IBD, is increased in FMF (10–12). Different mutations detected in the MEFV gene are related to other diseases. Molecular analysis of MEFV is a useful tool in clinical practice. MEFV gene mutations in patients with IBD have been investigated in a few studies (13).
In the present study, we aimed to establish the presence of accompanying IBD in patients who were being followed up for a diagnosis of FMF on outpatient visits and the relation between IBD and MEFV gene mutations.
A total of 78 children diagnosed by a new set of criteria for diagnosis of FMF in childhood were enrolled between September 2011 and February 2012 at Pediatric Rheumatology Unit, Istanbul University (14). After obtaining consent from their families, patients were included in the study independent of the presence of complaints when they were diagnosed as having FMF and presented to the outpatient clinic for follow-up. Colonoscopy for IBD was performed if any of the following was present: blood mixed with mucus in the stools; chronic diarrhea (loose and frequent stools that lasted >4 weeks); abdominal pain incompatible with FMF (localized in a certain part of the abdomen, not occurring during attacks, duration >3 days); positive for IgA and IgG anti-Saccharomyces cerevisiae antibodies (ASCAs) and perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs). (Actually, we wanted to perform colonoscopy for IBD in all patients with FMF; however, because colonoscopy is an invasive procedure and it would not be ethical to conduct the procedure unnecessarily, we identified the above criteria for performing a colonoscopy). We were aware of the need to perform a colonoscopy in patients with FMF and to confirm the diagnosis of IBD by a histopathological biopsy; however, because it would not be ethically acceptable to perform a colonoscopy in all patients with FMF included in the study (78 cases), we had to determine some criteria. The clinical symptoms, suggestive of IBD, were as follows:
1. Blood mixed with mucus in the stools
2. Chronic diarrhea (loose and frequent stools that lasted >4 weeks)
3. Abdominal pain incompatible with FMF (localized in a certain part of the abdomen, not occurring during attacks, duration >3 days)
Because these are the most common and the most fundamental findings of IBD, we think that a colonoscopy should be performed to verify the diagnosis of IBD in individuals with these symptoms in the general population (even if it is not accompanied by FMF), after the exclusion of other organic causes (eg, bacterial enterocolitis, parasitic infections) (15).
The ASCA positivity was another criterion used to identify the patients with suspected IBD in our study. It is encountered in 50% to 70% of patients with CD and 5% to 15% of those with UC (16,17).
Another criterion used to identify the accompanying IBD in patients with FMF was pANCA. Winter et al (18) have reported that pANCA positivity has a specificity of 90% and sensitivity of 83% in UC starting in childhood.
Although we initially considered determining the fecal calprotectin levels before the colonoscopy, we gave up this idea because calprotectin levels can also be elevated due to diseases other than IBD (19,20).
Inflammation was classified as mild, moderate, or severe in the patients who were diagnosed as having IBD by colonoscopy and histopathological examination of biopsy samples. Gastroscopy, ophthalmological examination, and computed tomography enterography (CTE) were performed in the patients with IBD. At the time of inclusion in the study, height, weight z scores, follow-up periods, complete blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and immunoglobulin were examined in all patients.
Some demographic and laboratory findings of patients with FMF with and without IBD were analyzed by the Mann-Whitney U test. In all tests, P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS for Windows version 10.0 (SPSS Inc, Chicago, IL). The comparison of symptoms and laboratory findings between patients with only FMF and those with IBD and FMF was done by χ2 test.
Demographic and clinical features of the patients at the time of first diagnosis of FMF are shown in Table 1. MEFV gene mutation was found in 84.6% of the patients at the time of FMF diagnosis. M694 V mutation was the most common mutation among patients who were followed up with a diagnosis of FMF and was present in 51.3% of the patients.
Among the 78 patients with a diagnosis of FMF, colonoscopy was performed and biopsy samples were taken in 20 patients who had abdominal pain incompatible with FMF, chronic diarrhea, bloody stools, and/or positive pANCA or ASCA (Table 2). Histopathological examination confirmed a diagnosis of UC in 11 of 20 patients and CD in 1 patient. Moderate UC was found in 7 patients and mild UC in 4.
Eight of the 20 patients who underwent colonoscopy had no complaint at the time of inclusion in the study, and colonoscopy was performed in these patients because of positive pANCA, ASCA, and/or positive familial history of IBD. In 4 of these, IBD was found histopathologically, and no pathology was found in 4.
MEFV gene mutations were present in all 12 patients who were diagnosed as having IBD. We observed M694 V mutations in 5 of 12 patients (41.7%), M680I mutations in 3 (25%), K695R mutations in 3 (25%), and E148Q mutations in 1 (8.3%) (Fig. 1).
Laboratory and histopathological properties of 12 patients who were diagnosed as having IBD as a result of colonoscopy and histopathological examination are shown in Table 3. Of 20 patients with suspected IBD, the cases with complaints of abdominal pain incompatible with FMF underwent ultrasound of the ileum before the colonoscopy; however, they all revealed normal results. Twelve patients, who were diagnosed as having IBD by colonoscopy, underwent a (oral and intravenous contrast-enhanced) CTE to evaluate the involvement of the ileum and/or small intestine. Wall thickening in the ileum and lymphadenopathy in the pericecal region were observed on CTE in 1 patient who was diagnosed as having CD. Ophthalmological examinations were performed in all of these patients. Ophthalmological examination was found to be normal in all patients. Gastroscopy was performed in all patients who were found to have IBD, and antral gastritis was found additionally in 7 patients. The differences between patients with only FMF and patients with FMF and IBD in terms of demographic, clinical, and laboratory findings are shown in Table 4.
Throughout Europe, IBD affects 0.5% to 1.0% of the population at any given time, and the disease begins in childhood in 30% of patients (21,22). In the study performed by Sawczenko et al (23), 3.1:100,000 new patients were diagnosed as having CD and 1.4:100,000 as having UC each year.
In Turkey, FMF is a common disease, with a predicted incidence of 1:1000 (24). In the study by Uslu et al (25), FMF was found in 21.2% of Turkish children with a diagnosis of IBD, a rate higher than that in the general population.
We investigated the presence of IBD in patients who were followed up with a diagnosis of FMF and found that IBD accompanied FMF in 12 (11 UC, 1 CD) of 78 patients (15.4%) with a diagnosis of FMF. Considering that the frequency of IBD in Europe is 0.5% to 1% and 30% of these start in childhood, the rate in our patients with FMF was much higher compared with the frequency of IBD in the general population.
In previous studies, it has been found that IBD (CD and UC) is frequent and has a severe course in patients with FMF (26). Again, CD is more prevalent in patients with a diagnosis of FMF, and when CD accompanies FMF, attacks of FMF are more severe (27). The association between CD and FMF has been better elucidated using information about mutations found in genetic studies. In a study of 33 patients with IBD (16 UC, 14 CD, and 3 indeterminate colitis), a diagnosis of FMF was made in 21.2% of the patients, and FMF was found to be especially common among those with CD (28.6%). The most common mutation has been found to be M694 V when FMF accompanies CD (23). Both the MEFV and NOD2/CARD15 genes, which are suspicious for CD, are localized on chromosome 16. Additionally, their genetic products are structurally similar (pyrin and NOD2/CARD15), and both belong to the family that regulates apoptosis. They play a key role in processing cytokines and regulation of inflammation. Pyrin has been shown to have an important role in interleukin-1 production and regulation of inflammation (28).
This is not the case for UC, however. In our study, UC was found in 11 of 12 patients who were diagnosed as having IBD. In the study performed by Giaglis et al (29), MEFV mutations were found in 7 of 25 patients (28%) with a diagnosis of UC. This rate was found to be higher compared with that in patients with rheumatoid arthritis and the control group. Among these 7 patients, M694 V mutations were found in 3, M680 V mutations in 2, and E148Q and A744S mutations in 1 each. In another study, MEFV mutations were found in 19 of 54 patients (35.2%) with a diagnosis of UC, and the most common mutation was E148Q (30). Sari et al (12) found M694 V mutations in 3 children with a diagnosis of treatment-resistant infantile UC, and they diagnosed FMF in these patients.
The most common mutation is M694 V (51.55%) among patients with a diagnosis of FMF in the Turkish population. This is followed by M680I (9.22%), E148Q (3.55%), and V726A (2.88%) (31). In our study, 51.3% of all patients with a diagnosis of FMF carried the M694 V mutation, which is compatible with the findings in the literature.
In the study by Uslu et al (25), in Turkish children with a diagnosis of IBD, M694 V mutation was found at a rate of 43.7% in patients with a diagnosis of FMF in association with IBD. In our study, M694 V mutation was found in 5 of 12 patients (41.7%) with a diagnosis of FMF and IBD, M680I mutation was found in 3 (25%), K695R mutation was found in 3 (25%), and E148Q mutation was found in 1 (8.3%). When IBD accompanies FMF, the most common mutation is M694 V. The results of our study also supported this; however, the high rate (25%) of K695R mutation in our patients with FMF and IBD has not been observed in previous studies.
ASCA is an antibody that is produced against the oligomannoside epitopes of S cerevisiae(32). In previous studies, ASCA has been found in 50% to 70% of patients in Western countries with a diagnosis of CD and in 5% to 15% of those with a diagnosis of UC (16,17). In our study, ASCA was found in 4 of 78 patients with a diagnosis of FMF. In one of these patients, pANCA was also positive, and a diagnosis of CD was made in this patient. In the study by Ruemmele et al (33), the possibility of CD increased specifically when pANCA and ASCA were both positive, similar to our patient. A diagnosis of UC was made in the other 3 patients in whom only ASCA was found to be positive. In 1 patient, IBD was not found, although ASCA was found to be positive. When we compared patients with FMF alone and those with FMF and IBD, ASCA positivity was significantly higher in patients with both diseases (P = 0.0019).
In the study by Winter et al (18), the specificity of pANCA positivity was found to be 90%, and the sensitivity was found to be 83% in UC that had started in childhood. In our study, pANCA was found to be positive in 14 of 78 patients, and UC was found in 10 of these by colonoscopy and histopathological study. Although pANCA was positive in 4 of 66 patients who had only FMF, it was positive in 10 of 12 patients with FMF and IBD. The specificity and sensitivity of pANCA positivity and its difference between the patients with FMF alone and those with FMF and IBD were statistically significant (P ≤ 0.00001).
Although mean ESR and CRP values, which may be high in the presence of inflammation, were found to be 22.4 (4–72 mm/h) and 0.38 (<0.3–5.6 mg/dL), respectively, in the group with FMF alone, they were found to be 25.5 (5–66 mm/h) and 0.40 (<0.3–2.4 mg/dL) in the group with FMF and IBD. This difference between the 2 groups was statistically insignificant (P = 0.97). The presence of high ESR and CRP values in both groups with no significant difference between the groups may be explained by the fact that both FMF and IBD are inflammatory diseases.
When z scores for weight for age at the time when the patients were included in the study were evaluated, −2 SD was found in 10 of 66 patients (15.1%) with FMF alone and in 8 of 12 patients (66.6%) with FMF and IBD. Among these patients who had low weight for age, the mean follow-up time from the first diagnosis of FMF was 4.8 years (3–8 years) in the group with FMF alone and 1.4 years (6 months–2.4 years) in the group with FMF and IBD. These findings demonstrated that IBD caused statistically significant low weight for age (P = 0.00009). Again, when z scores for height for age were evaluated, −2 SD was found in 6 of 66 patients (9%) with FMF alone and in 4 of 12 patients (33.3%) with FMF and IBD. The mean follow-up time from first diagnosis of FMF was 5.1 years (2–9.2 years) in the group with FMF alone and 1.8 years (1–2.8 years) in the group with FMF and IBD. Despite a shorter disease period, the reduction in z scores for height for age was significantly greater in patients with FMF and IBD compared with those with only FMF (P = 0.02).
Colonoscopy was performed in 20 of 78 patients included in the study, including 8 who had no complaints. Colonoscopy was performed in these 8 patients because of positive pANCA and ASCA and/or positive familial history of IBD. Although IBD was found histopathologically in 4 of 8 patients (50%), no pathology was found in the other 4 patients (50%). In the light of these results, it should be kept in mind that IBD may accompany FMF when pANCA and ASCA are positive and/or there is a positive familial history of IBD in patients who are followed up with a diagnosis of FMF even though the patients have no complaints.
In our study, we observed that the K695R mutation was found at a particularly higher rate when UC accompanied FMF compared with FMF alone. When compared with the frequency of IBD in childhood, this rate was observed to be increased in patients with FMF. This result suggests that these 2 conditions frequently accompany each other or are parts of a whole occurring against a background of the same genetic mutation.
In patients with FMF accompanied by IBD, in addition to the treatment of FMF, IBD treatment should also be given. Next to colchicine used for FMF, steroid, azathioprine, 5-aminosalicylic acid, infliximab, and adalimumab are the agents that can be used in the treatment, depending on the type of IBD, the involvement, the severity, and the clinical course (12,34).
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Keywords:© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
children; familial Mediterranean fever; inflammatory bowel disease; K695R mutation; MEFV mutation