Familial Mediterranean fever (FMF) is one of most common forms of autoinflammatory diseases, characterized by periodic fever accompanied by sterile peritonitis, pleuritis, arthritis or erysipelas-like erythema affecting the lower limbs.[1–3] FMF is an autosomal recessive disorder caused by mutations in the Mediterranean fever gene (MEFV) encoded on the short arm of chromosome 16. It has also been known that mutations in exons 1–3, 5, and 10 of MEFV are involved for the pathogenesis of FMF.[4,5]
MEFV gene encodes the pyrin protein, which has a regulatory effect in the inflammasome-related innate immune response. The symptoms of FMF often resemble those of inflammatory bowel disease (IBD), such as Crohn disease (CD), ulcerative colitis (UC), and intestinal Behçet disease (BD).[6–10] To date, however, only a few endoscopic findings of gastrointestinal lesions in patients with FMF have been described so far.[6–12] In the present article, we report a case of FMF in which both the clinical symptoms and endoscopic findings resembled those of CD.
2 Case report
A 21-year-old Japanese man visited a proctology clinic because of anal pain in July 2015. The patient was diagnosed as having anal fistulas, and was subsequently treated with seton drainage. He had been suffering from recurrent diarrhea and weight loss of 14 kg during the past 2 years. His father and one of his brothers had been diagnosed as having UC. In September 2015, the patient visited a gastroenterological clinic because of severe abdominal pain with high fever of 39°C. Colonoscopy showed longitudinal ulcers in the terminal ileum and aphthous erosions in the colorectum. Since he was suspected as having CD, 1.5 g/day of oral mesalazine was initiated and then he was referred to our hospital.
At the time of the first visit, the patient presented with fever of 39°C, abdominal pain and recurrent stomatitis. His body mass index was 14.9 kg/m2. Physical examination revealed tenderness in his epigastrium. The laboratory data showed a white blood cell (WBC) count of 14,040/μL (neutrophils: 90.0%), serum C-reactive protein (CRP) 13.16 mg/dL, total protein 6.9 g/dL and albumin 3.8 g/dL. The interferon-gamma release assay (T-SPOT tuberculosis blood test) and cytomegalovirus antigenemia test showed negative results. The bacterial cultures from blood and fecal samples detected no infectious pathogens. Because of the possibility of mesalazine allergy, we ceased the medication of mesalazine. Three days later, however, both his fever and abdominal pain had resolved spontaneously with laboratory data of 4970/μL (neutrophils: 58.4%) in WBC count and 0.52 mg/dL in serum CRP value.
Colonoscopy revealed longitudinal ulcers in the terminal ileum and multiple aphthous erosions in all areas of the colorectal mucosa (Fig. 1A, B). These endoscopic findings suggested a diagnosis of CD. Esophagogastroduodenoscopy (EGD) revealed multiple linear erosions in the gastric corpus (Fig. 1C) and circular erosions in the duodenal second portion. Although none of the biopsy specimens from these erosions, ulcerative lesions and normal-appearing mucosa revealed any evidence of epithelioid cell granulomas (Fig. 1D), we clinically diagnosed the patient as having CD, and intravenous administration of infliximab 5 mg/kg was started. However, his symptoms of fever and abdominal pain recurred 5 days after the start of infliximab. Both WBC count (38,800/μL and serum CRP level (6.56 mg/dL) further increased.
Thereafter, we suspected the possibility of FMF because his symptoms met the Tel-Hashomer major criteria of 3 recurrent typical attacks. The patient was subsequently given 0.5 mg of colchicine per day. His fever and abdominal pain promptly subsided. We subsequently searched for mutations in exons 1–3, 5, and 10 in MEFV. As a result, he was found to have compound heterozygous mutations of E148Q/L110P in exon 2 of MEFV. Based on these findings, we finally made a definitive diagnosis of FMF in this patient. Oral administration of colchicine was continued, whereas infliximab was discontinued after 4 times administration (0, 2, 6, 14 weeks). Follow-up colonoscopy 6 months later demonstrated that both the longitudinal ulcers in the terminal ileum and aphthous lesions in the colorectum had completely disappeared (Fig. 2A, B).
In patients with FMF, the mutations in MEFV result in loss of pyrin-mediated regulation of apoptosis-associated speck-like protein containing caspase recruitment domain and caspase 1 activity in the inflammasome and in systemic increase in IL-1β. In Japanese patients with FMF, major mutations in MEFV have been found at E148Q in exon 2 and M694I in exon 10.[4,5] In our present case, compound heterozygous mutations of E148Q/L110P in exon 2 was detected. It has been shown that the compound heterozygous mutation of MEFV were found in 8.4% of Japanese patients with FMF.
There have been several publications regarding the endoscopic findings of gastrointestinal lesions in patients with FMF. Arasawa et al first reported a case of FMF who had the circumferentially erythematous mucosa with erosion in the cecum and longitudinal erosions with pseudopolyposis-like lesions in the right side of the colon, and they suggested a similarity in the intestinal lesions between CD and FMF. Subsequently, Takahashi et al reported another case of FMF with multiple nonspecific ulcers in the terminal ileum, which apparently suggested a diagnosis of intestinal BD. In a study by Beser et al, 12 of 20 (60%) pediatric FMF patients with abdominal pain, diarrhea, or bloody stool were endoscopically diagnosed as having IBD of any form (11 patients mimicking UC and 1 CD). In another study of 10 patients with FMF, colonoscopy revealed findings compatible with IBD including hyperemia, fragility, and patchy ulcerations (n = 5); aphthous ulcers (n = 3); and follicular lymphoid hyperplasia (n = 2). Matsumoto et al, reported a case of FMF in which CD was suspected because of the wall thickening and increased density of mesenteric adipose tissue in the jejunum, but oral double-balloon endoscopy revealed only mild edema of the jejunum.
More recently, small bowel lesions in FMF have been rigorously investigated by enteroscopy. Demir et al, examined 41 patients with FMF by capsule endoscopy and found mucosal defects (erosions or ulcers) in the small bowel in 44% of patients. Kitade et al reported a case of FMF with multiple jejunoileal lesions of petal-shaped redness and white hemming detected by capsule endoscopy and double-balloon endoscopy. Thus, patients with FMF are presumed to have variable small bowel lesions. In our present case, colonoscopy revealed longitudinal ulcers in the terminal ileum and multiple aphthous erosions in all areas of the colorectal mucosa, which resembled CD. In contrast, we presume that EGD findings of our case, namely multiple linear erosions in the gastric corpus and circular erosions in the duodenal second portion, are distinctive of those in CD.
Colchicine is recommended to be the first choice medication for treatment of FMF, as it is highly effective.[13,14] Also in our patient, fever and abdominal pain subsided immediately after administration of colchicine. It is of interest that ileal longitudinal ulcers and aphthous erosions in the colorectum also disappeared after taking colchicine. In patients with FMF, who are resistant to colchicine, anti-IL-1β1 monoclonal antibody canakinumab is effective.
We presented detailed endoscopic findings in a case of FMF, which was initially diagnosed as CD. It should be noted that there are considerable overlaps in clinical symptoms and in gastrointestinal lesions in FMF and CD.
. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever
. Arthritis Rheum 1997;40:1879–85.
. Chae JJ, Komarow HD, Cheng J, et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 2003;11:591–604.
. Masters SL, Simon A, Aksentijevich I, et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 2009;27:621–68.
. Tomiyama N, Higashiuesato Y, Oda T, et al. MEFV mutation analysis of familial Mediterranean fever
in Japan. Clin Exp Rheumatol 2008;26:13–7.
. Migita K, Agematsu K, Yazaki M, et al. Familial Mediterranean fever
: genotype-phenotype correlations in Japanese patients. Medicine 2014;93:158–64.
. Arasawa S, Nakase H, Ozaki Y, et al. Mediterranean mimicker. Lancet 2012;380:2052.
. Takahashi T, Tsukuda H, Itoh H, et al. An atypical familial Mediterranean fever
patient who developed ulcers in the terminal ileum and recurrent abscess-like lesions in multiple organs. Intern Med 2012;51:2239–44.
. Beser OF, Kasapçopur O, Cokugras FC, et al. Association of inflammatory bowel disease with familial Mediterranean fever
in Turkish children. J Pediatr Gastroenterol Nutr 2013;56:498–502.
. Gurkan OE, Dalgic B. Gastrointestinal mucosal involvement without amyloidosis in children with familial Mediterranean fever
. J Pediatr Gastroenterol Nutr 2013;57:319–23.
. Matsumoto S, Urayoshi S, Yoshida Y. Familial Mediterranean fever
in which Crohn disease
was suspected: a case report. BMC Res Notes 2014;7:678.
. Demir A, Akyüz F, Göktürk S, et al. Small bowel mucosal damage in familial Mediterranean fever
: results of capsule endoscopy
screening. Scand J Gastroenterol 2014;49:1414–8.
. Kitade T, Horiki N, Katsurahara M, et al. Usefulness of small intestinal endoscopy
in a case of adult-onset familial Mediterranean fever
associated with jejunoileitis. Intern Med 2015;54:1343–7.
. Demirkaya E, Erer B, Ozen S, et al. Efficacy and safety of treatments in Familial Mediterranean fever
: a systematic review. Rheumatol Int 2016;36:325–31.
. Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever
. Ann Rheum Dis 2016;75:644–51.
. Gül A, Ozdogan H, Erer B, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever
. Arthritis Res Ther 2015;17:243.