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Crohn Disease in Patients with Familial Mediterranean Fever



Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p = 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 ± 10.0 yr versus 26.2 ± 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.

From Departments of Gastroenterology and Heller Institute of Medical Research, Chaim Sheba Medical Center, Tel Hashomer, Israel. Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel.

Accessible online at “”. To search for Medicine articles in PubMed, use the journal name “Medicine Baltimore”.

Address reprint requests to: Herma H. Fidder, MD, Department of Gastroenterology, Chaim Sheba Medical Center, 52621 Tel Hashomer, Israel. Fax: 972–3-530–3160; e-mail:

DOI: 10.1097/

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Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. Although the 2 are usually readily distinguishable, the concurrence of the conditions may pose a diagnostic and therapeutic challenge. FMF is recessively inherited and has an increased prevalence among non-Ashkenazi Jews (37). A gene causing FMF—MEFV—has been identified, and genotyping for mutations in the known hotspots has become an important diagnostic and prognostic tool (2,3,6,16).

Crohn disease is believed to occur as a result of a disregulation of the mucosal immune system. Family and twin studies strongly suggest that genetic predisposition is an important factor in the etiology of the disease (7,35). High prevalence is reported for Ashkenazi Jews compared to the non-Jewish population living in the same geographic area (12,31,39,41,42). Crohn disease is also common in Israel, with most studies reporting higher prevalence rates in Ashkenazi than non-Ashkenazi Jews (9,19,21,22). A higher prevalence of 50.6/100,000 in the latter group was reported in a more recent study, approaching the rate for Ashkenazi Jews (23).

Since we were aware of several patients with both FMF and Crohn disease followed in our clinic, we undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize this association clinically and genetically.

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Patients and Methods

Patients and controls

At the time of the study (end of 1999), there were 4978 patients enrolled in the registry of the FMF clinic of our institution. Using a computerized search, the patients were screened for concurrent Crohn disease. Patients identified were interviewed, examined, and their medical charts reviewed.

The diagnosis of Crohn disease was determined according to conventional endoscopic, radiologic, and histologic criteria. Data were obtained on the age of diagnosis, the gastrointestinal sites involved, and the characteristics of the disease, that is, stricturing, fistulizing, or neither. Therapy strategies, need for operations, and family history of inflammatory bowel disease were recorded as well. Data on smoking behavior were not included, since several studies failed to detect an association between smoking and Crohn disease in the Israeli population (20,29,30).

The diagnosis of FMF was made clinically and was consistent with established criteria (18). The following data were obtained: age of onset of FMF, frequency of the febrile attacks, occurrence of extraabdominal attacks (for example, arthritis, erysipelas-like erythema), presence of proteinuria, dose of colchicine needed to control symptoms, use of steroids and nonsteroidal antiinflammatory drugs (NSAIDs) for FMF manifestations, and compliance with the treatment regimen. Severity of FMF was computed according to a previously published severity score (34). Family history of FMF, as well as the ethnic origin of both parents and 4 grandparents of the patients, were also recorded.

Two control groups consisting of ethnically and sex-matched consecutive patients suffering from each of the diseases alone, either FMF (20 patients) or Crohn disease (46 patients), were studied. The control patients underwent clinical and genetic evaluation similar to the study group, and the data obtained were used for comparison.

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Genetic analysis

Blood samples were drawn for genotyping. Genomic DNA was extracted from whole blood according to standard procedures. The 3 predominant mutations in the Israeli population were determined. The V726A and M694V mutations were detected using a commercial kit (Gamidagen, Rehovot, Israel). The third mutation, E148Q, was detected by testing for the presence of a Bstn I restriction site, as previously described (1).

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Statistical analysis

The frequency of Crohn disease in FMF patients and the general population was compared using the Fisher exact test. For comparing patient characteristics in the study and control groups, the chi-square and Student t test were used (as specified in the text).

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Prevalence of Crohn disease in FMF patients

We identified 7 patients with concomitant Crohn disease and FMF (FMF-CD). The observed prevalence of Crohn disease in FMF patients is higher than the expected prevalence of 50.6/100,000 in the general population of African-Asian born Jews living in Israel (p = 0.03) (23). The proportion represented by the age-group at highest risk for contracting Crohn disease (those aged 20–50 years) in the general population and in the FMF registry is similar (50% [Israeli Central Bureau of Statistics] and 60% [unpublished data], respectively), and therefore does not affect the outcome.

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Case reports

The following case reports illustrate the association of FMF and Crohn disease in 2 of our patients.

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Case 1 (Patient 4, Tables 1 and 3):





The patient is a Jewish man of Libyan origin. From early childhood he suffered from FMF febrile attacks, presenting with abdominal or pleuritic chest pain or with arthritis, mainly of the ankle joints. Colchicine in a dose of 1 mg, started at age 23 years, reduced the attack frequency significantly but was ceased because of noncompliance. At the age of 30 years, significant proteinuria was noticed. Colchicine therapy was reinitiated at a dose of 2 mg, which controlled the FMF attacks, but the proteinuria persisted. Several months later the patient noted weakness in his legs. Examination revealed atrophy of the muscles of the lower extremities, elevated serum creatinine phosphatase levels, and electromyography and muscle histology consistent with a diagnosis of muscular dystrophy. At the age of 40 years, the patient was admitted to the hospital for protracted abdominal pain accompanied by diarrhea and a 14-kg weight loss. On examination, the patient was febrile and a tender mass was noted in his right lower abdomen. The erythrocyte sedimentation rate was 96 mm/hr, the hemoglobin was 9.8 mg/dL, the white blood cell count 11,000/μL and the thrombocytes 489,000/μL. Computed tomography revealed thickening of small bowel loops and the ascending colon. Small bowel passage and colonoscopy suggested a diagnosis of Crohn disease. Biopsies taken during colonoscopy showed acute and chronic inflammation of the colonic mucosa with crypt abscesses and granulomata. The patient improved rapidly on steroid therapy, and after discontinuing prednisone, he remained well for many years on mesalamine therapy alone. At age 44 years the patient was admitted to the hospital with severe abdominal pain and fever. Plain abdominal radiograph revealed small bowel obstruction, and abdominal computed tomography showed thickening of the small bowel loops and the colon wall. On colonoscopy, inflamed mucosa and a stricture at the side of the hepatic flexure were noted. High-dose steroids and 6-mercaptopurine failed to control the disease flare, and while awaiting an operation, a perforation of the small bowel occurred, to which the patient eventually succumbed.

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Case 2 (Patient 5, Tables 1 and 3):

The patient is a Jewish male of North African extraction who began to experience FMF attacks at the age of 6 years. The recurrent febrile attacks presented usually as peritonitis, pleuritis, or arthritis of the large joints. Colchicine prophylaxis was initiated at the age of 20 years and soon was increased to a dose of 2 mg/day, a regimen that successfully prevented the febrile attacks. At the age of 23 years, he started complaining of protracted oligoarthritis involving the large joints of the lower and upper extremities. Workup showed bilateral sacroiliitis and features consistent with a diagnosis of spondyloarthropathy. Diclofenac was added with reasonable success in controlling the articular manifestations.

Over the years, the patient had complained of intermittent diarrhea, which usually resolved following transient colchicine dose reduction. At the age of 43 years he was admitted to the hospital with a 6-month history of diarrhea unresponsive to colchicine cessation, diffuse abdominal pain, and a 4-kg weight loss. On admission, he was found to be afebrile, pale, and tachycardic. Examination of joints and abdomen revealed no abnormalities. Laboratory results included hypochromic microcytic anemia, with a hemoglobin concentration of 7.8 g/dL. The white cell count was 11,000/μL and the platelet count 550,000/μL. Computed tomography revealed thickening of the last segment of the ileum, and barium contrast studies showed stricturing and a cobblestone pattern of the terminal ileum. Colonoscopy, during which the terminal ileum was not reached, was unremarkable. A diagnosis of Crohn disease was made and therapy with 40 mg prednisone was initiated, with a rapid improvement of the clinical symptoms.

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Characteristics of Crohn disease in FMF patients

The features of Crohn disease in each of the FMF-CD patients are presented in Table 1. Stricturing disease was encountered in 3 patients, 1 patient suffered from fistulizing disease, and 3 had neither a fistulizing nor stenotic disease pattern. The clinical course of Crohn disease varied. One patient had very resistant disease, leading to treatment with anti-TNF antibodies after failure of several immunosuppressive regimens. One patient died as a result of perforation of the small intestine. The other 5 patients had a relatively mild course of disease that in most instances was easily controlled by mesalamine therapy alone. In most aspects of Crohn disease the FMF-CD patients and the Crohn disease controls were comparable (Table 2). However, the age of onset of Crohn disease was significantly higher in FMF patients than in patients of the control group (40.6 yr in the FMF-CD group versus 26.2 yr in the Crohn disease-only group; p < 0.004, see Table 2). Other disease characteristics, such as localization and complications (that is, strictures or fistulas), did not differ between the 2 groups. Of the control patients, 17.3% had relatives with inflammatory bowel disease, compared with none in the study group (data not shown).



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Features of FMF

Clinical aspects of FMF in individual patients of the study group are shown in Table 3. Most clinical, genetic, and demographic characteristics of FMF in our study group and in the FMF control group were comparable (Table 4). However, FMF-CD patients had a significantly higher attack frequency (p < 0.05) and showed increased prevalence of persistent proteinuria (p < 0.02) compared with FMF control patients. Nevertheless, the overall severity score of the study group was not higher than that of the control group. Interestingly, 4 of 7 patients were diagnosed with a third inflammatory condition (see Table 3). One patient had a concomitant diagnosis of muscular dystrophy.



Genotyping for FMF showed homozygosity for M694V in 3 of 7 patients, compound heterozygosity (M694V/V726A) in 1 patient, and only 1 mutated allele (M694V) in another patient. One patient refused genetic analysis and in 1 patient no mutations were found in the analyzed hotspots. All but 1 patient had a positive family history for FMF. Mutational analysis and history of FMF in the control group were generally comparable.

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Crohn disease appears to be more common in patients suffering from familial Mediterranean fever. Our findings extend the observations made by Cattan et al (4), who reported a more frequent and more severe inflammatory bowel disease in French, non-Ashkenazi, Jewish families with at least 1 member with FMF. The apparent association between the diseases is intriguing. The FMF gene (MEFV) and the recently identified Crohn disease susceptibility gene NOD2 (CARD15) are both located on chromosome 16 (13,24,28). Moreover, the protein products of NOD2 (CARD15) and MEVF (pyrin) both include apoptosis-related domains (14,25). Nonetheless, there are no linkage data to support a role for the FMF gene region as a predisposing loci for Crohn disease. Hence, the unexpected association between these 2 disorders remains to be explained.

Crohn disease is not the only inflammatory disease with a higher prevalence in patients with FMF. Behçet disease, Henoch Schönlein purpura, and polyarteritis nodosa all have been reported to be more common in patients suffering from FMF (10,27,32). The factors underlying these associations are undetermined. In this perspective, one should be puzzled also by the presence of a third inflammatory disease in most our patients.

The above findings raise the possibility that the MEFV gene may act as a modifier affecting the expression of other inflammatory disorders. Alternatively, other inflammation-associated genes may trigger FMF. Recently, it was reported that the MICA (major histocompatibility complex class I chainrelated A gene), which has been associated with a number of inflammatory disorders, including inflammatory bowel disease, may act as a modifier locus in FMF (26,38,40). In addition, Behçet disease was found to induce FMF even in patients who bear only 1 mutated MEFV (15). A third option is that the inflammation induced by FMF may provoke the expression of other inflammatory diseases in genetically predisposed patients who, without FMF, would have remained clinically silent. Finally, NSAID usage, which has been suggested as a etiologic factor in the development of inflammatory bowel disease (8,11), could play a role in the induction of Crohn disease in FMF patients.

Genotyping for FMF showed homozygosity or compound heterozygosity in most patients (see Table 3) with predominance of the M694V mutation, which is generally associated with a more severe clinical picture (33). The M694V mutation is the most frequently found mutation in Jewish FMF patients of North African background, and 4 of 7 of our patients are of North African origin. Therefore, the relatively high prevalence of this allele in our patient population is not unexpected and is not different from the ethnically matched control group (see Table 4). In 1 of our patients genotyping did not reveal a mutation. Another patient showed a mutation in only 1 of the FMF genes. This however, should not raise doubts, as the diagnosis of FMF is based on clinical criteria, and in 20% of patients, mutations are probably located outside the usual hotspots (5).

Crohn disease in patients with FMF follows the same course as Crohn disease in patients without FMF, in all features studied (see Table 2). However, FMF-CD patients diverge from Crohn disease controls by the age of onset of Crohn disease, which was significantly higher in the FMF-CD group. Although significant overlap in the manifestations of Crohn disease and FMF may have caused confusion and delay in the diagnosis of Crohn disease, the observed difference between average age of onset is large, 14 years, and probably represents a true, currently unexplained finding.

The overall disease course of FMF, as measured by the severity score, was similar in the study and the control groups. However, FMF-CD patients reported significantly more frequent attacks than the FMF control group. Although it can be hypothesized that the coexisting second inflammatory condition functions as a trigger for FMF attacks, it is not unlikely that the abdominal symptoms associated with Crohn disease are interpreted by patients as FMF activity.

Persistent proteinuria, suggestive of amyloidosis (16,17,36), was found to be more prevalent in the FMF-CD group. Amyloid deposition develops as a result of continuing inflammatory stimulation, and Crohn disease and FMF are known to be associated with amyloidosis. It is therefore likely that in the FMF-CD group the 2 diseases act synergistically in the development of amyloidosis.

In conclusion, one should be aware of the possibility of FMF-CD in FMF patients with frequent attacks who suffer from chronic arthritis with stigmata of spondyloarthropathy and abdominal pain bearing features atypical for FMF. One should pay special attention to the prevention of amyloidosis, an often fatal complication that seems to be more frequent in patients affected by the complex disease.

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