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.
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.
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.
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.
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.
1. Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64: 949–62, 1999.
2. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90: 797–807, 1997.
3. A candidate gene for familial Mediterranean fever. The French FMF Consortium. Nat Genet 17: 25–31, 1997.
4. Cattan D, Notarnicola C, Molinari N, Touitou I. Inflammatory bowel disease in non-Ashkenazi Jews with familial Mediterranean fever. Lancet 355: 378–9, 2000.
5. Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, Delpech M, Amselem S, Grateau G. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet 92: 241–6, 2000.
6. Eisenberg S, Aksentijevich I, Deng Z, Kastner DL, Matzner Y. Diagnosis of familial Mediterranean fever by a molecular genetics method. Ann Intern Med 129: 539–42, 1998.
7. Farmer RG, Michener WM, Mortimer EA. Studies of family history among patients with inflammatory bowel disease. Clin Gastroenterol 9: 271–7, 1980.
8. Felder JB, Korelitz BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim G. Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: A case-control study. Am J Gastroenterol 95: 1949–54, 2000.
9. Fireman Z, Grossman A, Lilos P, Eshchar Y, Theodor E, Gilat T. Epidemiology of Crohn’s disease in the Jewish population of central Israel, 1970–1980. Am J Gastroenterol 84: 255–8, 1989.
10. Flatau E, Kohn D, Schiller D, Lurie M, Levy E. Schonlein-Henoch syndrome in patients with familial Mediterranean fever. Arthritis Rheum 25: 42–7, 1982.
11. Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature. Arch Intern Med 152: 625–32, 1992.
12. Gilat T, Grossman A, Fireman Z, Rosen P. Inflammatory bowel disease in Jews. In: Mc Connell R, Rosen P, Langman M, and Gilat T, eds. The genetics and epidemiology of inflammatory bowel disease. Karger: Basel, pp 135–40, 1986.
13. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411: 599–603, 2001.
14. Kastner DL, O’Shea JJ. A fever gene comes in from the cold. Nat Genet 29: 241–2, 2001.
15. Livneh A, Aksentijevich I, Langevitz P, Torosyan Y, Shoham N, Shinar Y, Pras E, Zaks N, Padeh S, Kastner DL, Pras M. A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behcet’s disease (FMF-BD). Eur J Hum Genet 9: 191–6, 2001.
16. Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol 14: 477–98, 2000.
17. Livneh A, Langevitz P, Zemer D, Padeh S, Migdal A, Sohar E, Pras M. The changing face of familial Mediterranean fever. Semin Arthritis Rheum 26: 612–27, 1996.
18. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40: 1879–85, 1997.
19. Niv Y, Abuksis G, Fraser GM. Epidemiology of Crohn’s disease in Israel: A survey of Israeli kibbutz settlements. Am J Gastroenterol 94: 2961–5, 1999.
20. Odes HS, Fich A, Reif S, Halak A, Lavy A, Keter D, Eliakim R, Paz J, Broide E, Niv Y, Ron Y, Villa Y, Arber N, Gilat T. Effects of current cigarette smoking on clinical course of Crohn’s disease and ulcerative colitis. Dig Dis Sci 46: 1717–21, 2001.
21. Odes HS, Fraser D, Hollander L. Epidemiological data of Crohn’s disease in Israel: Etiological implications. Public Health Rev 17: 321–35, 1989.
22. Odes HS, Fraser D, Krawiec J. Inflammatory bowel disease in migrant and native Jewish populations of southern Israel. Scand.J. Gastroenterol Suppl 170: 36–8, 1989.
23. Odes HS, Locker C, Neumann L, Zirkin HJ, Weizman Z, Sperber AD, Fraser GM, Krugliak P, Gaspar N, Eidelman L. Epidemiology of Crohn’s disease in southern Israel. Am J Gastroenterol 89: 1859–62, 1994.
24. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411: 603–6, 2001.
25. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276: 4812–8, 2001.
26. Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP. MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy. Clin Exp Immunol 126: 437–40, 2001.
27. Ozen S, Ben Chetrit E, Bakkaloglu A, Gur H, Tinaztepe K, Calguneri M, Turgan C, Turkmen A, Akpolat I, Danaci M, Besbas N, Akpolat T. Polyarteritis nodosa in patients with familial Mediterranean fever (FMF): A concomitant disease or a feature of FMF? Semin Arthritis Rheum 30: 281–7, 2001.
28. Pras E, Aksentijevich I, Gruberg L, Balow Jr, JE Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326: 1509–13, 1992.
29. Reif S, Klein I, Arber N, Gilat T. Lack of association between smoking and inflammatory bowel disease in Jewish patients in Israel. Gastroenterology 108: 1683–7, 1995.
30. Reif S, Lavy A, Keter D, Fich A, Eliakim R, Halak A, Broide E, Niv Y, Ron Y, Patz J, Odes S, Villa Y, Gilat T. Lack of association between smoking and Crohn’s disease but the usual association with ulcerative colitis in Jewish patients in Israel: A multicenter study. Am J Gastroenterol 95: 474–8, 2000.
31. Roth MP, Petersen GM, McElree C, Vadheim CM, Panish JF, Rotter JI. Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology 96: 1016–20, 1989.
32. Schwartz T, Langevitz P, Zemer D, Gazit E, Pras M, Livneh A. Behcet’s disease in familial Mediterranean fever: Characterization of the association between the two diseases. Semin. Arthritis Rheum 29: 286–95, 2000.
33. Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE, Kastner DL, Pras M, Pras E. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 27: 1703–7, 2000.
34. Sidi G, Shinar Y, Livneh A, Langevitz P, Pras M, Pras E. Protracted febrile myalgia of familial Mediterranean fever. Mutation analysis and clinical correlations. Scand J Rheumatol 29: 174–6, 2000.
35. Singer HC, Anderson JG, Frischer H, Kirsner JB. Familial aspects of inflammatory bowel disease. Gastroenterology 61: 423–30, 1971.
36. Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43: 227–53, 1967.
37. Sohar E, Merker HJ, Missmahl HP, Gafni J, Heller H. Electron-microscope observations on peri-reticulin and peri-collagen amyloidosis in rectal biopsies. J Pathol Bacteriol 94: 89–93, 1967.
38. Sugimura K, Ota M, Matsuzawa J, Katsuyama Y, Ishizuka K, Mochizuki T, Mizuki N, Seki SS, Honma T, Inoko H, Asakura H. A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behavior in ulcerative colitis. Tissue Antigens 57: 9–14, 2001.
39. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: Results of a British twin study. BMJ 312: 95–6, 1996.
40. Touitou I, Picot MC, Domingo C, Notarnicola C, Cattan D, Demaille J, Kone-Paut I. The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 44: 163–9, 2001.
41. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29: 990–6, 1988.
42. Yang H, McElree C, Roth MP, Shanahan F, Targan SR, Rotter JI. Familial empirical risks for inflammatory bowel disease: Differences between Jews and non-Jews. Gut 34: 517–24, 1993.