Familial Mediterranean Fever and Behçet's Disease

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 specifically. 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. They were also thoroughly studied for any clinical or with MEFV mutations, while the other group consisted of laboratory support for a concomitant diagnosis of FMF. These included the 37 BD patients with none of the MEFV mutations we were search for 5 MEFV mutations in each BD patient and HLA typing for the B51 antigen. To assess the effect of each of the diseases on one another, we searching for. Both groups were similar for age of onset of divided the BD patients into 2 groups, one with and one without MEFV BD, frequency of HLA-B51, and the number of sites or mutations. We compared both groups for their ethnic origin, and for varying demographic features and clinical manifestations of BD, such as age of Table 1. Ethnic distrubution of 152 patients with FMF. onset, the number of organs involved, and the HLA-B51 frequency. Since there is as yet no accepted severity index for BD, we decided to give a score Ethnic Group No. of Patients % of one point to each organ involved in each BD patient. The total score represented an estimation of the disease spread and a rough estimation of the North-African Jews 79 51.9 disease severity. We also thoroughly investigated the possibility of FMF Jews* 32 21.0 expression in BD patients with a single MEFV mutation. Arabs ** 21 13.8 MEFV mutations analysis. A recently established restriction analysis, PCR Ashkenazi Jews 13 8.5 was used for the identification of the FMF mutations in patients with BD4. Turkish 3 1.97 We searched for the 5 mutations accounting for most of the FMF chromo- Non-Ashkenazi Jews† 3 1.97 somes in our Israeli population: M694V, M694I, M680I, V726A, and Greek 1 0.65 E148Q. Blind screening was carried out for these mutations with a code Total 152 number assigned to each patient. Correlation with other features of patients with BD was subsequently performed. *Iraq, Iran, Syria Lebanon; **Palestinian; † Georgia.

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. Ben-Chetrit, et al: FMF and BD 531 Downloaded on September 24, 2021 from www.jrheum.org Table 2. Ethnic distribution of BD patients with and without FMF mutations.

Ethnic Group BD Patients (%) BD Patients (%) Carrier Rates in Each Group p with FMF Mutations In the Study Expected

Arabs* 22 (41.5) 7 (43.75) 1:3 1:10 0.008 North-African Jews 11 (20.7) 5 (31.2) 1:2 1:5 0.12 Middle Eastern Jews** 10 (18.8) 2 (12.5) 1:5 1:3 0.72 Yemenite Jews 3 (5.6) — — — Ashkenazi Jews† 4 (7.54) 2 (12.5) 1:2 1:5 0.21 Greek 2 (3.5) — — — Turkish 1 (1.8) — — — Total 53 16 — —

*Palestinian; **Iraq, Iran, Syria; † including Russian.

Table 3. Distribution of MEFV gene mutations among the 16 patients with BD.

Allele I M694V M694I V726A V726A M680I E148Q E148Q Allele II — — V726A — — E148Q — No. of patients 5 2 1 1 2 1 4 Ethnic origin A (3), B, D B B D B, C B A (2), B, C

A: North-African Jews, B: Arabs, C: Middle Eastern Jews, D: Ashkenazi Jews. organs involved. Even when we compared each disease coexist. Nevertheless, findings of oral and genital ulcers or manifestation and organ involvement, there was no signifi- uveitis are not features of FMF, whereas the episodic and cant difference between the 2 groups (Table 4). periodic nature of fever and the serositis with spontaneous recovery after 24–96 hours are unique for FMF. DISCUSSION Our screening of 353 patients with FMF and 53 with BD In patients of Mediterranean origin, the manifestations of revealed 2 individuals who had both diseases concomitantly. BD may be confused with those of FMF and vice versa. The The search for BD among the FMF cohort was based fact that both diseases are prevalent among similar popula- primarily upon a chart review of 353 FMF patients, where tions in Turkey and the Middle East and may respond, in we found no FMF patients with concomitant BD. Further, varying degrees, to colchicine treatment, further compli- our thorough interview and examination of 152 patients cates the issue of differentiating between them. This notion (whose ages were above 18) also failed to reveal one with may lead to an impression that both disorders commonly BD. Indeed, only one patient had oral and genital aphthosis,

Table 4. Comparison of various clinical manifesttions between BD patients with and without MEFV mutation.

Clinical Feature BD BD p Without Mutation, With Mutation, n = 37 (%) n = 16 (%)

Fever 6 (16) 3 (18.7) 1.0 Vascular* 11 (30) 6 (37.5) 0.75 Neurological** 6 (16) 5 (31) 0.27 Uveitis 26 (70) 11 (68.7) 1.0 Oral ulcer 37 (100) 16 (100) 1.0 Genital ulcer 30 (81) 12 (75) 0.71 Arthritis/arthralgia 29 (78.3) 12 (75) 0.70 Pathergy 22 (59.4) 8 (50) 1.0 Skin*** 25 (65) 11 (68.7) 1.0 HLA-B51 29 (78) 11 (68.7) 0.49 Age of onset 28.4 + 17.9 29.3 + 5.8 Disease severity 4.73 + 1.42 4.84 + 1.78 0.86†

*Deep vein thrombophlebitis, pulmonary embolism, arterial aneurysms. ** Cerebrovascular accident, memory loss, mononeuritis. *** Erythema nodosum, pustulosis. † Nonpaired t test.

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. 532 The Journal of Rheumatology 2002; 29:3 Downloaded on September 24, 2021 from www.jrheum.org with no additional criterion such as pathergy that would upon a single case. Further, since we have not sequenced the support a diagnosis of BD. Neither did this patient bear the whole 10 exons of the gene — in this case — it is difficult HLA-B51; therefore she was not considered to have BD. to attribute the FMF symptomatology to the E148Q muta- If we assume that the highest prevalence of BD in Turkey tions. Moreover, thorough investigation and clinical evalua- is about 80 to 370/100,000, then we would expect to find 0.4 tion of the 14 BD patients with a single FMF mutation failed to 1.8 patients with BD among 500 individuals12. Our to reveal any with symptomatic FMF. This observation does finding of 2 patients with this disease among 355 (353 + 2 not support a report suggesting that the presence of BD from the BD cohort) patients with FMF is statistically enriches FMF expression in heterozygotes22. similar to the prevalence reported in Turkey. Since Israel is The possibility that the presence of MEFV mutations a country not considered to be permeated with BD patients, may aggravate the clinical expression of BD was not this suggests that the frequency of BD in FMF (2 in 355) is supported by our observation. That is, the group of BD higher than expected by incidental comorbidity, and is at patients with MEFV mutations was almost identical to the least as high as in Turkey. Nevertheless, due to the relatively BD group without them regarding age of onset, organ and small number of patients with both diseases in our study, site of involvement, and the frequency of HLA-B51 (Table one should interpret this observation with caution, since it is 4). As noted, although the organ spread of the disease is not not possible to rule out a coincidental finding. The an accurate measurement for disease severity, the almost frequency of FMF we found — 2 among 53 BD (1:26) — is identical organ distribution in this study suggests that the relatively high. It is about 10 times higher than the presence of MEFV mutations did not affect expression of frequency of FMF among North-African Jews, the popula- BD. tion with the highest frequency of FMF in Israel26. This may Several limitations in this study should be noted. Since serve as further evidence for the relatively high association the pathergy test is one of the diagnostic criteria for BD and between FMF and BD. this was not performed in investigation of the FMF cohort, According to published carrier frequencies of MEFV patients with BD could theoretically be overlooked. mutations, we would expect the following: Israeli Arabs However, as noted, in patients younger than 18 the preva- 1:10, North-African Jews 1:5, Iraqi Jews 1:3, Iranian Jews lence of BD is very low, and among the 152 older patients 1:17, Ashkenazi Jews 1:526,27. From these frequencies it with FMF we searched thoroughly for this phenomenon as seems that the carrier rate of 1:3.2 (16/53) among our BD well as for other BD criteria, and none of these was found. patients is high, especially when we keep in mind that 60% Second, the small number of patients having concomitant of the present BD group were either Arabs or North-African BD and FMF (2 patients only) in this study requires cautious Jews, where the carrier rate is far lower (1:10, 1:5, respec- interpretation of the findings and their statistical analysis. tively) (Table 2). Nevertheless, when we calculated the In summary, we found a mild trend of a higher than carrier rate in each ethnic group in our BD cohort and expected association between BD and FMF, especially compared it with the expected rate in the same ethnic groups among Arabs, but this weak impression should be confirmed in the general population, the only significant value was in a larger study. 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