Familial Mediterranean Fever and Behçet’s Disease — Are They Associated? ELDAD BEN-CHETRIT, RONIT COHEN, and TOVA CHAJEK-SHAUL ABSTRACT. Objective. To test whether the coexistence of familial Mediterranean fever (FMF) and Behçet’s disease (BD) is more frequent than expected and whether each disease affects the severity of the other. Methods. We screened 353 charts of patients with FMF to detect individuals with concomitant BD. Of these, 152 patients with FMF over the age of 18 years were also interviewed and examined specif- ically. We also studied 53 patients with BD, looking for FMF and for their MEFV mutations. We compared BD patients with MEFV mutations to those without them. Results. None of 353 patients with FMF was found to have concomitant BD. Sixteen patients with BD bore MEFV mutations, 2 of whom were symptomatic homozygotes and had concomitant FMF. No patient with BD with a single MEFV mutation had FMF. Both BD groups (with or without MEFV mutations) were similar in their clinical manifestations and disease course. Conclusion. BD and FMF are 2 separate entities that have a mild trend toward a higher than expected association. However, there was no mutua1 effect of FMF on BD or vice versa. (J Rheumatol 2002;29:530–4) Key Indexing Terms: FAMILIAL MEDITERRANEAN FEVER BEHÇET’S DISEASE MEFV GENE Familial Mediterranean fever (FMF, recurrent polyserositis) Turkey, the disease is quite common in Japan, Korea, Iran, is an autosomal recessive disease primarily affecting popu- and Saudi Arabia12. lations surrounding the Mediterranean Basin: mainly non- Both diseases are considered rare and share some Ashkenazi Jews, Arabs, Armenians, and Turks1,2. Typically, common symptoms and laboratory findings. FMF and BD it presents as acute episodes of fever, accompanied by patients may have fever, arthritis, abdominal pain, and acute complaints of abdominal pain, chest pain, arthritis, or scrotum due to orchitis or epidydimitis. In both diseases erysipelas-like skin eruptions. Four years ago, the gene increased chemotaxis of neutrophils and elevated serum associated with FMF, MEFV, was mapped and cloned from interleukin 8 have been described13,14. Further, colchicine the short arm of chromosome 16 and about 30 mutations was found to be an effective medication in preventing FMF have been identified3-9. attacks and ameliorating some of the clinical manifestations Behçet’s disease (BD) is an inflammatory disorder with a of BD15. Three years ago, Birlik, et al described a patient genetic background, characterized by oral and genital with FMF and BD16. The authors suggested that both ulcers, uveitis, pustular erythematous cutaneous lesions, diseases may have common etiopathogenetic mechanisms, arthritis, central nervous system involvement, and/or due to their resemblance. Several vasculitic diseases, such vascular manifestations such as venous thrombosis, arteritis as polyarteritis nodosa and Henoch-Schönlein purpura, have and aneurysms10,11. BD is not a chronic persistent inflam- been found in increased rates among FMF patients matory disorder, but rather one consisting of recurrent compared with the normal healthy population17,18. Since BD attacks of acute inflammation. Cases of BD are prevalent is also a type of vasculitic disorder, it was postulated that its along the ancient Silk Road, which extends from Eastern coexistence with FMF is higher than expected19,20. Asia to the Mediterranean Basin. While the highest preva- Nevertheless, in a recent study, Fresko, et al did not find a lence of BD (80 to 370/100,000) has been reported in higher prevalence of FMF in a cohort of 344 patients with BD21. In another study it was found that about 60% of FMF patients with BD bear only a single mutated MEFV gene22. From the Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. The authors suggested that the concomitant presence of BD Supported by a grant for FMF research from the Hadassah Medical in these patients leads to a complete expression of FMF, Relief Association, UK. despite their being heterozygotes. Further, Touitou, et al, E. Ben-Chetrit, MD, Professor of Medicine; R. Cohen, MD, Insructor in who screened a cohort of 114 patients with BD for MEFV Medicine; T. Chajek-Shaul, MD, Professor of Medicine. mutations, found that some of these mutations were more Address reprint requests to Dr. E. Ben-Chetrit, Department of Medicine, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel. frequent in this group, suggesting that they may act as an E-mail: [email protected] additional susceptibility factor in BD23. Submitted April 27, 2001; revision accepted September 11, 2001. We examined whether the frequency of FMF is increased Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. 530 The Journal of Rheumatology 2002; 29:3 Downloaded on September 24, 2021 from www.jrheum.org among patients with BD and vice versa. We also compared Statistical analysis. Results are reported as mean ± SD. Fisher’s exact test the severity of BD in patients with and without MEFV muta- (2 sided) was used for comparison of proportions, while nonpaired t test tions to verify whether BD patients heterozygous for a was employed for comparison of means. single MEFV mutation will express symptomatic FMF. RESULTS At the beginning we screened the charts of 353 patients with MATERIALS AND METHODS Patients. In our outpatient clinic at the Hadassah Medical Center we regu- FMF at the Hadassah Medical Center and were unable to larly follow more than 350 patients with FMF. Diagnosis of FMF was based find any patient who suffered concomitantly from BD. Then upon published criteria, including typical clinical manifestations and a we interviewed and examined all the patients over the age of response to colchicine24. We have also looked for a family history of the 18. We found 152 patients whose ages ranged between 18 disease to support the FMF diagnosis, although it is not a diagnostic crite- and 71 years (mean 33.81 ± 12.28); 79 of them were male. rion. The diagnosis of FMF was reassessed in many of these patients (about 120) by genetic analysis using polymerase chain reaction (PCR). More than Their ethnic distribution is shown in Table 1. Five of these 70% of them were either homozygous or compound heterozygous for the patients had aphthous stomatitis, one of whom also had M694V, V726A, M694I, M680I, or E148Q mutations. FMF patients are genital ulcers with no concomitant eye, vascular, or nervous followed regularly every 6 months unless they have uncontrolled attacks. system involvement or positive pathergy test or erythema During each visit we examine them and check complete blood count, serum nodosum. This patient was homozygous for the M694V electrolytes, liver and kidney functions, and urinalysis, in order to exclude proteinuria usually induced by amyloidosis. Fifty-three patients having BD mutation and did not bear the HLA-B51. Two patients had are also routinely followed in our Behçet’s clinic. Diagnosis of BD was uveitis, with no aphthosis or any other clinical feature (not based on the criteria proposed by the International Study Group for even arthritis) suggesting BD. Behçet’s Disease in 199025. All the patients had recurrent aphthous stom- Fifty-three patients with BD were studied; 37 were male atitis and 2 more sites of organ involvement such as genital ulcers, uveitis, and 16 female. Twenty-two were Palestinian Arabs and 31 erythema nodosum, or skin pustulosis. Thirty of them were also positive for the pathergy test. The age of onset was defined as the time of the presenting were Jews from various ethnic groups (Table 2). Their ages symptom of BD, even if it was only aphthosis. ranged from 20 to 73, mean 48.8 ± 11.5 years. Analysis of To estimate the prevalence of BD among patients with FMF, we used their genomic DNA for FMF mutations revealed that 16 the Hadassah Hospital medical archives. We reviewed the charts of 353 bore MEFV gene mutations, 2 of whom were homozygotes patients with FMF for evidence, signs, or criteria suggesting a diagnosis of (Table 3). Most of the patients who had the M694V muta- BD. We then interviewed and examined all FMF patients over the age of 18 (152 patients). Again we looked specifically for any clue suggesting BD tion were Jews of North-African origin. Two patients from (including oral or genital ulcers, vascular, gastrointestinal, ophthalmic, this cohort were homozygous for the V726A and E148Q nervous system involvement, or pathergy phenomenon). We chose this age mutations, and they were symptomatic. They displayed group for several reasons: first, the onset of BD typically occurs during the FMF manifestations, including episodic peritonitis with third or fourth decade of life. Thus by including patients 5–10 years younger, we decrease the chances of overlooking those who have concomi- fever and arthritis. None of the remaining 14 BD patients tant BD with earlier than usual age of onset. Second, we wanted to inter- with a single MEFV mutation had any FMF manifestation view the patients personally and to get clear clinical information from them such as short episodes of fever, polyserositis, or erysipelas- rather than hearing the medical history of younger patients from their like skin lesion. The carrier rate in this BD population was parents. Third, the prevalence of BD among children in Israel is relatively 1:3.2 (16/53). In this study 2 patients out of 53 had BD and low. Therefore, it seems very unlikely that we would overlook BD in patients younger than 18. FMF (symptomatic homozygotes) concomitantly. To assess Concomitantly, all the 53 patients with BD were interviewed and a ques- the effect of the presence of FMF mutations on BD severity tionnaire concerning their demographic background and clinical manifesta- we compared 2 groups. Group 1 consisted of 16 BD patients tions was completed.