The Familial Mediterranean Fever Gene as a Modifier of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome

PFAPA SYNDROME

The Familial Mediterranean Fever Gene as a Modifier of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome Yackov Berkun, MD,* Ran Levy, MD,† Adam Hurwitz, MD,† Michal Meir-Harel, MD,† Merav Lidar, MD,‡ Avi Livneh, MD,§ and Shai Padeh, MD* Objective: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA. Patients and Methods: The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M⫹ and M⫺, respectively) were compared. Results: PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 ⫾ 1.7 versus 4.8 ⫾ 1.9 days, P ⬍ 0.01). The difference was more pronounced in those carrying the M694V mutation. In M⫹ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M⫺ patients (74.5% and 43.9%, respectively, P ⬍ 0.05 for each of the 2 comparisons). M⫹ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 ⫾ 0.07mg/kg versus 0.19 ⫾ 0.08, P ⫽ 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years. Conclusion: In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity. © 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 40:467-472 Keywords: periodic fever, aphthous stomatitis, PFAPA, familial Mediterranean fever, children, phenotype, mutations, MEFV, autoinflammatory disorder

P

eriodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a chronic disease of unknown cause, characterized by periodic, sometimes regularly recurring attacks of high fever lasting

*Senior Lecturer in Pediatrics, Department of Pediatrics, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. †Department of Pediatrics, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel. ‡Lecturer in Internal Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel and Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer, Israel. §Professor of Internal Medicine, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel and Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer, Israel. Address reprint requests to Berkun Yackov, MD, Rheumatology Clinic, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: [email protected].

0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2010.06.009

3 to 6 days, often accompanied by aphthous stomatitis, chills, headache, and abdominal or musculoskeletal pain. Pharyngitis and cervical adenopathy, resembling streptococcal tonsillitis but with negative throat cultures, typify the syndrome. Attacks recur every 4 to 6 weeks with a complete resolution of all symptoms between episodes. All patients report a dramatic resolution of fever within few hours after 1 dose of corticosteroids at each episode (1,2). Although PFAPA has its onset mainly before 5 years of age, this syndrome is not restricted to pediatric patients (3). PFAPA belongs to a growing group of autoinflammatory disorders of innate immunity, characterized by selflimiting attacks of seemingly unprovoked inflammation, in the absence of known autoreactive T cells or autoantibodies. While most of these periodic autoinflammatory diseases, such as familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome, and hyper467

468

IgD syndrome (4-6), are hereditary monogenic syndromes, in PFAPA, studies trying to establish a genetic basis have failed (1,7). FMF (OMIM#249100), the prototype of the autoinflammatory disorders, is an autosomal-recessive disease, mainly affecting ethnic groups living around the Mediterranean basin: Sephardic Jews, Armenians, Turks, and Arabs (8). FMF is characterized by irregular inflammatory episodes of fever, accompanied by serositis and synovitis. The MEditerranean FeVer gene (MEFV), associated with FMF, was cloned in 1997 (9,10). So far, more than 50 disease-causing mutations in MEFV have been identified (http://fmf.igh.cnrs.fr/infevers). Pyrin, the product of the MEFV gene, appears to play a pivotal role in the regulation of the systemic inflammatory response and apoptosis (11,12). Thus, aside from causing FMF, mutations in MEFV may lead to a proinflammatory state, resulting in a subclinical inflammation in asymptomatic carriers (13-15) and a deleterious effect in the phenotype of some inflammatory and autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, vasculitides, Crohns, and Behçet disease (1620). Since carriage of MEFV mutations in Israel is common, with a rate of up to 30% (21) in certain populations, many of the PFAPA patients are expected to carry MEFV mutations. The aim of the present study was to investigate the effect of MEFV mutations on the clinical and laboratory manifestations, and on the course of the disease, in a large cohort of children with PFAPA syndrome. METHODS In January 2000, we initiated an ongoing prospective study for PFAPA patients, focusing on demographic, clinical, and laboratory features of the disease. For that aim, we have established a computerized database for PFAPA patients, referred to the pediatric rheumatology clinic, at the Edmond and Lily Safra Children’s Hospital, Sheba Medical Center. Demographic data, family history, clinical manifestations, and routine laboratory data were obtained initially and over the course of the disease. Response to therapy and changes in the basic data were documented for each patient visit and entered into the patient computerized records. This database served as the source data for the current study. The ethical committee of our institute approved the study protocol. During the study time (January 2000 to January 2009), 450 children, 16 years old or younger, with PFAPA syndrome, were included in our registry. Of these, 143 were tested for MEFV mutations. In 19 of the 143 patients the data were incomplete or the patients were lost to follow-up, and they were excluded, making the study group 124 patients (71 males, 57.2%). The diagnosis of PFAPA was established according to a set of clinical criteria, requiring the presence of regularly recurring febrile attacks, with early age of onset, exudative tonsillitis

MEVF as a modifier of PFAPA syndrome

with negative throat culture, associated with aphthosis or cervical adenitis, constitutional symptoms in the absence of upper respiratory tract infection signs, exclusion of cyclic neutropenia, completely asymptomatic interval between episodes, normal growth and development, and a prompt response to a single dose of corticosteroid (1,8). A diagnosis of FMF was ruled out clinically in all patients, based on the criteria formulated for the diagnosis of FMF, with a sensitivity and specificity of ⬎95% (22). The computerized database and clinical charts of all patients were reviewed, focusing on demographic data, laboratory tests, family history, course of the disease, and response to therapy. Genetic Analysis Mutation analysis for Jewish patients was performed for the 3 most common FMF mutations found in the Jewish FMF population: M694V, V726A, and E148Q, using a commercial kit (Gamidigen, Rehovot, Israel), or polymerase chain reaction amplification and restriction enzyme analysis, as previously published (23). In the nonJewish patient population, the M680I and the M694I mutations were studied in addition to the above mutations, using a similar technology. In some patients, a wider range of mutations was tested, usually due to a different laboratory routine outside our institution. Statistical Analysis Results are given as a mean ⫾ SD or proportion, as appropriate. Differences between the groups in discrete variables were evaluated by ␹2 or Fisher’s exact test (according to the cell size). Comparisons of continuous variables were done by unpaired Student’s t test. All P values given are 2-sided. P values less than 0.05 were considered significant. RESULTS Of the total study cohort of 124 patients, 65 (36 males, 55.4%) had a single MEFV (M⫹ group). The M694V mutation was found in 48 (73.8%) patients; the E148Q in was found in 9 (13.8%) patients, and the V726A was found in 6 (9.2%) patients. In the other 2 (3.1%) patients, uncommon mutations were found. In 59 of the 124 patients (35 males, 59.3%), no MEFV mutations were found (M⫺ group). The demographic data were comparable in both groups (Table 1), with the only exception being a higher prevalence of family history of FMF in the M⫹ patients. Patients carrying a MEFV mutation had shorter duration of attacks than patients without mutations (3.8 ⫾ 1.7 days versus 4.8 ⫾ 1.9 days, P ⫽ 0.0015, Table 2). This difference was even larger, when compared with carriers of the M694V mutation, which in FMF patients is associated with a more severe disease (3.3 ⫾ 1.5 days in M694V carriers versus 4.8 ⫾ 1.9 days in patients of the

Y. Berkun et al.

469

Table 1 Demographic Data of PFAPA Patients with (M⫹) and Without (M⫺) a Mutation in the MEFV Gene

Age at onset (yr)a Age at first visit (yr)a Male:female ratio North African Jews Other Sephardic Jews Mixed Sephardic Jews Mixed Sephardic Ashkenazi Jews Arabs Family history of FMFb

All Patients n ⫽ 124 N (%)

Patients with MEFV Mutation (M⫹, n ⫽ 65) n (%)

Patients Without MEFV Mutation (M⫺, n ⫽ 59) n (%)

2.9 ⫾ 2.0 6.1 ⫾ 2.9 1.34:1 60 (48.4) 3 (2.4) 38 (30.6) 18 (14.5) 2 (1.6) 44 (35.5)

3.0 ⫾ 2.1 6.1 ⫾ 3.0 1.16:1 33 (50.8) 0 (0) 20 (30.8) 9 (13.8) 2 (3.1) 31 (47.7)

2.9 ⫾ 1.9 6.0 ⫾ 2.9 1.46:1 27 (45.8) 3 (5.1) 18 (30.5) 9 (15.3) 0 (0) 13 (22.0)

expressed as mean ⫾ SD. significant differences were found between the groups with the exception of familial history of FMF (P ⫽ 0.0046).

aValues bNo

M⫺ group, P ⫽ 0.0001). The regular cyclic pattern of the attacks and the occurrence of oral aphthae during these bouts, characteristic of PFAPA, were less common in patients of the M⫹ than in the M⫺ group (Table 2). No differences were found between the 2 groups in all other clinical and laboratory parameters (Table 2). Of note, consistent with published studies, abdominal, chest, and joint pain accompanied PFAPA attacks. However, in no cases were these manifestations severe, made patients bedridden, or had features compatible with peritonitis, pleuritis, or arthritis. The course of the disease, during a follow-up of 4.3 ⫾ 3.1 years, is summarized in Table 3. The dose of corticosteroids used to abort the attacks was significantly lower in the M⫹ patients, but the time to achieve the response was clinically insignificant longer (4.0 ⫾ 2.4 versus 3.4 ⫾ 3.9 hours). About half of the patients of each group reported a transitory increase in the attack rate, following initiation of corticosteroids therapy. In 19 (29.2%) patients from the M⫹ group and 11 (18.6%) from the M⫺ group, colchicine prophylaxis for possible FMF was tried but

failed, and colchicine was discontinued (Table 3). Three patients from the M⫹ group and 4 from the M⫺ group underwent tonsillectomy. Following the operation, the attacks recurred in 1 patient of the M⫹ group and 3 in the M⫺ group. The numbers, however, were too small for statistical evaluation. The frequency of attacks, length of attack-free periods, and disease duration were comparable in the 2 groups. DISCUSSION The major finding of our study is that carriage of a MEFV mutation may favorably affect the PFAPA phenotype. Carriers have shorter and less regular attacks, a lower rate of aphthae during attacks, and respond to a lower dose of corticosteroids. In all other clinical and laboratory parameters M⫹ and M⫺ patients have a comparable disease. Since in FMF the attacks are irregular and sterile pharyngitis is not a feature of FMF, one may also view our findings as if carriage of MEFV mutation may impose a FMF visage on PFAPA. To the best of our knowl-

Table 2 PFAPA Manifestations in Patients with and Without a Mutation in the MEFV Gene Symptoms and Signs

Patients with MEFV Mutation (M⫹, n ⫽ 65) N (% of pts.)

Patients Without MEFV Mutation (M⫺, n ⫽ 59) N (% of pts.)

P Value

Attack duration (days)a Interval between attacks (wk)a Cyclic periodic attacks Pharyngitis Enlarged tonsils Aphthae Abdominal pain Musculoskeletal pain Headaches Chest pain WBCa ESR mm/ha CRP levels mg/dLa,b

3.8 ⫾ 1.7 4.1 ⫾ 3.0 32 (49.2) 65 (100) 53 (81.5) 16 (24.6) 48 (73.8) 24 (36.9) 17 (26.1) 5 (7.7) 12.1 ⫾ 4.0 34.2 ⫾ 15.1 46.3 ⫾ 64.0

4.8 ⫾ 1.9 4.3 ⫾ 2.0 44 (74.5) 59 (100) 48 (81.3) 26 (43.9) 44 (74.6) 28 (47.4) 14 (23.8) 2 (3.4) 11.6 ⫾ 4.5 31.0 ⫾ 20.9 25.7 ⫾ 30.7

0.0015 NS 0.0104 NS NS 0.035 NS NS NS NS NS NS NS

NS, not statistically significant (P ⬎ 0.05); WBC, white blood cell count. aValues expressed as mean ⫾ SD. bNormal value ⬍5 mg/dL.

470

MEVF as a modifier of PFAPA syndrome

Table 3 Treatment and Course of PFAPA Patients with and Without a Mutation in the MEFV Gene Symptoms and Signs Disease duration (yr) Duration of follow-up (yr) Age at attacks cessation (yr) Length of maximal remission (wk) Long remission in attacks (no. of pts.) Relapse after tonsillectomya Colchicine trialb Bethamethasone dose (mg/kg)c Time of response (h) Increased frequency of attacks following treatment

Patients with MEFV Mutation (M⫹, n ⫽ 65) N (% of pts.)

Patients Without MEFV Mutation (M⫺, n ⫽ 59) N (% of pts.)

P Value

5.0 ⫾ 2.7 (n ⫽ 28) 4.3 ⫾ 2.7 8.7 ⫾ 2.4 (n ⫽ 28) 18.1 ⫾ 20.0 29 (44.6) 1/3 of pts. 19 (29.6) 0.16 ⫾ 0.07 4.0 ⫾ 2.4 49 (75.4)

5.1 ⫾ 3.0 (n ⫽ 24) 4.3 ⫾ 3.5 8.7 ⫾ 3.3 (n ⫽ 24) 17.0 ⫾ 12.3 31 (52.5) ¾ of pts 11 (18.6) 0.19 ⫾ 0.08 3.4 ⫾ 3.9 48 (81.4)

NS NS NS NS NS NS NS 0.028 0.039 NS

Values expressed as mean ⫾ SD. NS, not statistically significant (P ⬎ 0.05). aThree patients underwent tonsillectomy in the M⫹ group and 4 in the M⫺ group. bNumber of patients who were prescribed colchicine. All failed to respond. cBethamethasone-equivalent dose needed to abort PFAPA attacks.

edge, this is the largest cohort of PFAPA patients reported, and the association of PFAPA phenotype with MEFV mutations has not been previously reported. The possibility that the M⫹ PFAPA patients actually suffer from FMF could safely be excluded, as the diagnosis of FMF is based on strict clinical criteria, including recurrent attacks of peritonitis, pleuritis, monoarthritis, or fever alone, with a sensitivity and specificity of ⬎95% (22). As none of our patients, either M⫹ or M⫺ PFAPA, experienced even a single attack of serositis, they failed to fulfill these criteria. Moreover, colchine was ineffective in the prevention of the attacks. In contrast, our patients’ manifestations were similar to those reported for PFAPA (1,3,24). Of note, all our patients presented with bouts of sterile exudative tonsillitis, which favorably responded to a single dose of corticosteroids, a phenomenon unique for the PFAPA syndrome that has never been reported in FMF patients. The rate of MEFV mutation carriage in our cohort of PFAPA patients was as high as 52%. However, for selec-

tion bias reason, this study cannot be used to examine the prevalence of MEFV mutations in PFAPA syndrome; as this patient cohort consists of hospital referrals, undergoing MEFV mutation analysis is not at random. Indeed, in a recent Israeli study of unselected PFAPA patients, a rate of 27% of MEFV mutation, close to the figure expected in the general population, was detected (25). At present, a predisposition for PFAPA syndrome in MEFV mutation carriers cannot be claimed. The distribution of the different MEFV mutations among the M⫹ group, particularly of M694V mutation (73%), is close to the rates of these mutations previously reported in the Israeli FMF population (M694V—75%) (26) and significantly different from the carriage of MEFV mutations in the general Israeli population (M694V— 40%) (21,27,28). This supports a role for MEFV, notably in patients carrying the M694V mutation, as a modifier gene in PFAPA. Indeed, the more significant differences in the clinical

Table 4 Incidence and Phenotype of Inflammatory Diseases in MEFV Mutations Carriers Disorder

Incidence

Phenotype Compared to Noncarriers

Idiopathic recurrent pericarditis Behcet Crohns

Normal (32) Increased (17,33-35) Increased (36), normal (19,37,20)

Ulcerative colitis Rheumatoid arthritis Asthma Multiple sclerosis AS Systemic JIA Childhood polyarteritis nodosa Henoch Shoenlein Purpura

Increased (38) Normal (16,39,40) Decreased (29) Increased (41), NA (18) Increased (40,42), Normal (43) Increased (44) Increased (45) Increased (46,47)

NS (32) NS (33-35), increased thrombosis, uveitis (17) Comparable (20,36), NS (37), stricturing, extraintestinal disease (19) More arthritis (38) More severe (16), NS (39,40) Milder (29) More severe (41,18) More severe (43), comparable (40,42) More severe (44) NS (45) More severe (47), NS (46)

NS, not studied.

Y. Berkun et al.

presentation of the M⫹ population were noted in the M694V mutation carriers. How MEFV modifies PFAPA is unclear, as is the case with ample other inflammatory diseases, which seem to be modified by MEFV (Table 4) (16-20, 29-47). Since carriage of MEFV differentially affects various disease entities, the mechanism in each disease could be distinct. Moreover, PFAPA diverge from most other conditions by being favorably affected. Asthma and systemic lupus erythematosus are also clinically improved, or their rate is reduced in association with MEFV carriage, either by Th1 polarization in asthma or by increased apoptosis in SLE (29,30). Such an individual impact of mutation carriage is even more obscure. Since carriage of MEFV mutation confers elevation in markers of inflammation (31), one may say that in PFAPA and in other situations “protected” by MEFV mutations, the proinflammatory state sets up a higher threshold for the mechanisms that trigger attacks. Yet, even this noncommitted interpretation should be considered speculative. In summary, PFAPA patients carrying a MEFV mutation have an attenuated disease, with a higher rate of patients with shorter and irregular attacks, oral aphthae, and a favorable response to a lower corticosteroid dose. The mechanism of the “protection” conferred by MEFV mutation in PFAPA is yet to be elucidated. REFERENCES 1. Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 1999;135(1):98-101. 2. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr 1999;135(1):15-21. 3. Padeh S, Stoffman N, Berkun Y. Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults. Isr Med Assoc J 2008;10(5):358-60. 4. Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum 2009;60(6): 1862-6. 5. Harel-Meir M, Bujanover Y, Berkun Y, Goldstein N, Anikster Y. Mevalonic aciduria in a child featuring hepatic fibrosis and novel mevalonate kinase mutations. Open Pediatr Med J 2009;3(3): 45-7. 6. Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 2002;70(6): 1498-506. 7. Cazeneuve C, Genevieve D, Amselem S, Hentgen V, Hau I, Reinert P. MEFV gene analysis in PFAPA. J Pediatr 2003;143(1):140-1. 8. Padeh S, Berkun Y. Auto-inflammatory fever syndromes. Rheum Dis Clin North Am 2007;33(3):585-623. 9. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17(1):25-31. 10. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90(4):797-807. 11. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, et al. The familial Mediterranean fever protein, pyrin, is cleaved

471

12. 13. 14.

15.

16.

17.

18.

19.

20.

21.

22. 23. 24. 25. 26.

27. 28.

29.

by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 2008;112(5):1794-803. Berkun Y, Ben-Chetrit E. Pyrin and cryopyrin—similar domain sequence but opposite inflammatory consequence. Clin Exp Rheumatol 2007;25(4 Suppl 45):S6-8. Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, Soyturk M, et al. The genetic basis of autosomal dominant familial Mediterranean fever. QJM 2000;93(4):217-21. Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar M, et al. A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin Arthritis Rheum 2007;37(3):182-8. Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N, et al. The efficacy of interferon alpha on colchicine-resistant familial Mediterranean fever attacks: a pilot study. Br J Rheumatol 1997; 36(9):1005-8. Rabinovich E, Livneh A, Langevitz P, Brezniak N, Shinar E, Pras M, et al. Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis 2005;64(7):1009-14. Rabinovich E, Shinar Y, Leiba M, Ehrenfeld M, Langevitz P, Livneh A. Common FMF alleles may predispose to development of Behcet’s disease with increased risk for venous thrombosis. Scand J Rheumatol 2007;36(1):48-52. Shinar Y, Livneh A, Villa Y, Pinhasov A, Zeitoun I, Kogan A, et al. Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun 2003; 4(3):197-203. Fidder H, Chowers Y, Ackerman Z, Pollak RD, Crusius JB, Livneh A, et al. The familial Mediterranean fever (MEVF) gene as a modifier of Crohn’s disease. Am J Gastroenterol 2005;100(2): 338-43. Karban A, Dagan E, Eliakim R, Herman A, Nesher S, Weiss B, et al. Prevalence and significance of mutations in the familial Mediterranean fever gene in patients with Crohn’s disease. Genes Immun 2005;6(2):134-9. Kogan A, Shinar Y, Lidar M, Revivo A, Langevitz P, Padeh S, et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet 2001;102(3):272-6. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997;40(10):1879-85. Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, et al. MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 1999;6(1):1-6. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 1987;110(1):43-6. Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int 2010;30(5):633-6. Padeh S, Shinar Y, Pras E, Zemer D, Langevitz P, Pras M, et al. Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean fever. J Rheumatol 2003; 30(1):185-90. Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 2001;9(8):634-7. Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, et al. Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 2000; 8(4):307-10. Rabinovitch E, Harats D, Yaron P, Luvish T, Lidar M, Kedem R, et al. Familial Mediterranean fever gene and protection against asthma. Ann Allergy Asthma Immunol 2007;99(6):517-21.

472 30. Lidar M, Zandman-Goddard G, Shinar Y, Zaks N, Livneh A, Langevitz P. Systemic lupus erythematosus and familial Mediterranean fever: a possible negative association between the two disease entities–report of four cases and review of the literature. Lupus 2008;17(7):663-9. 31. Lachmann HJ, Sengul B, Yavuzsen TU, Booth DR, Booth SE, Bybee A, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford) 2006;45(6):746-50. 32. Brucato A, Shinar Y, Brambilla G, Robbiolo L, Ferrioli G, Patrosso MC, et al. Idiopathic recurrent acute pericarditis: familial Mediterranean fever mutations and disease evolution in a large cohort of Caucasian patients. Lupus 2005;14(9):670-4. 33. Ayesh S, Abu-Rmaileh H, Nassar S, Al-Shareef W, Abu-Libdeh B, Muhanna A, et al. Molecular analysis of MEFV gene mutations among Palestinian patients with Behcet’s disease. Scand J Rheumatol 2008;37(5):370-4. 34. Imirzalioglu N, Dursun A, Tastan B, Soysal Y, Yakicier M. C. MEFV gene is a probable susceptibility gene for Behcet’s disease. Scand J Rheumatol 2005;34(1):56-8. 35. Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, Picco P, et al. MEFV mutations in Behcet’s disease. Hum Mutat 2000; 16(3):271-2. 36. Uslu N, Yuce A, Demir H, Saltik-Temizel IN, Usta Y, Yilmaz E, et al. The Association of Inflammatory Bowel Disease and Mediterranean Fever Gene (MEFV) Mutations in Turkish Children. Dig Dis Sci 2010 Mar 21. [Epub ahead of print] 37. Villani AC, Lemire M, Louis E, Silverberg MS, Collette C, Fortin G, et al. Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn’s disease and ulcerative colitis. PLoS One 2009;4(9):e7154. 38. Giaglis S, Mimidis K, Papadopoulos V, Thomopoulos K, Sidiropoulos P, Rafail S, et al. Increased frequency of mutations in the

MEVF as a modifier of PFAPA syndrome

39. 40.

41.

42.

43. 44. 45. 46. 47.

gene responsible for familial Mediterranean fever (MEFV) in a cohort of patients with ulcerative colitis: evidence for a potential disease-modifying effect? Dig Dis Sci 2006;51(4):687-92. Migita K, Nakamura T, Maeda Y, Miyashita T, Koga T, Tanaka M, et al. MEFV mutations in Japanese rheumatoid arthritis patients. Clin Exp Rheumatol 2008;26(6):1091-4. Akkoc N, Sari I, Akar S, Thomas MG, Binicier O, Weale ME, et al. Increased prevalence of M694V in patients with ankylosing spondylitis; Additional evidence for a link with familial Mediteranean Fever. Arthritis Rheum 2010 Jun 8. [Epub ahead of print] Unal A, Dursun A, Emre U, Tascilar NF, Ankarali H. Evaluation of common mutations in the Mediterranean fever gene in multiple sclerosis patients: Is it a susceptibility gene? J Neurol Sci 2010; 294(1-2):38-42. Cinar M, Dinc A, Simsek I, Erdem H, Koc B, Pay S, et al. The rate and significance of Mediterranean fever gene mutations in patients with ankylosing spondylitis: a three-month, longitudinal clinical study. Rheumatol Int 2008;29(1):37-42. Durmus D, Alayli G, Cengiz K, Yigit S, Canturk F, Bagci H. Clinical significance of MEFV mutations in ankylosing spondylitis. Joint Bone Spine 2009;76(3):260-4. Ayaz NA, Ozen S, Bilginer Y, Erguven M, Taskiran E, Yilmaz E, et al. MEFV mutations in systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford) 2009;48(1):23-25. Yalcinkaya F, Ozcakar ZB, Kasapcopur O, Ozturk A, Akar N, Bakkaloglu A, et al. Prevalence of the MEFV gene mutations in childhood polyarteritis nodosa. J Pediatr 2007;151(6):675-8. Gershoni-Baruch R, Broza Y, Brik R. Prevalence and significance of mutations in the familial Mediterranean fever gene in HenochSchonlein purpura. J Pediatr 2003;143(5):658-61. Ozcakar ZB, Yalcinkaya F, Cakar N, Acar B, Kasapcopur O, Uguten D, et al. MEFV mutations modify the clinical presentation of Henoch-Schonlein purpura. J Rheumatol 2008;35(12):2427-9.