תרומתי לרפואה

מחקרים קליניים בנושא FMF

מחקר קליני נרחב בנושאים שונים ב- FMF ניתן למצוא ברשימת המאמרים המלאה, במאמרים הבאים: 39, 61, 63, 71, 77, 120, 134, 135, 137, 139, 143, 144, 172, 198, 200, 203, 214, 216, 255, 257, 260, 262, 264, 268, 271, 274, 276, 298, 302, 306, 333, 337, 349, 351, 370, 371, 396, 397, 400, 409, 412, 422, 424, 425, 427, 432, 436, 449, 450, 458, 466, 467, 469, 472, 475, 496, 497 ,499, 501, 502, 503, 513, 514, 517, 518, 534, 536, 537, 542  (לרשימת המאמרים המלאה). להלן, מובאים תקצירים של 11 מאמרים נבחרים:

QJM. 1997 Oct;90(10):643-7.
Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF).
Kees S, Langevitz P, Zemer D, Padeh S, Pras M, Livneh A.

Abstract
Familial Mediterranean fever (FMF) is characterized by recurrent attacks of febrile serositis. While arthritis, pleuritis and peritonitis are common in FMF, no association of pericarditis with FMF has been described in detail. We retrospectively studied about 4000 FMF patients, using a computer chart review. Pericarditis was diagnosed when patients sustained attacks of pleuritic retrosternal chest pain and had typical findings in the electrocardiogram,
echocardiogram or chest radiogram. The incidence and features of pericarditis in FMF were compared to published data. Over a period of 20 years, one or more episodes of pericarditis were recorded in 27 patients, a significantly higher incidence than in the general population (68 vs. 6 per 10(5) per year, p < 0.001). Each patient experienced 1-3 pericarditis attacks, lasting a mean of 4.2 days, accompanied by high temperature and symptoms of FMF attack at another site. The pericarditis attack resolved spontaneously and left no sequelae. FMF patients with pericarditis were comparable to other FMF patients in most demographic and
clinical parameters. Pericarditis may be considered another rare manifestation of FMF.

Arthritis Rheum. 1997 Oct;40(10):1879-85.
Criteria for the diagnosis of familial Mediterranean fever.
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M.

Abstract    
OBJECTIVE: To establish a new set of criteria for the diagnosis of familial Mediterranean fever (FMF).
METHODS: Twenty-seven features and manifestations typical of FMF were studied to determine their prevalence in 105 patients with FMF and 106 controls. Diagnosis of FMF in the study group was based on clinical judgment. Controls were patients with a variety of other diseases who presented to the emergency room or outpatient clinics with recurrent episodes of pain in body sites usually involved in FMF attacks. Manifestations observed to be significantly more common in FMF patients than in controls were incorporated into the rule proposed for diagnosis of FMF, based on a model of major, minor, and supportive criteria.
RESULTS: Two sets of diagnostic criteria were established. A conservative criteria set for diagnosis of FMF was based on the presence of 1 major or 2 minor criteria, or 1 minor plus 5 supportive criteria, and a simple criteria set for diagnosis of FMF required 1 major or 2 minor criteria. The sensitivity and specificity of these 2 criteria sets were >95% and >97%, respectively.
CONCLUSION: The proposed new sets of criteria were highly sensitive and specific, and could be used to readily diagnose FMF and to distinguish FMF from other periodic febrile diseases.

Semin Arthritis Rheum. 2000 Apr;29(5):286-95.
Behçet's disease in Familial Mediterranean fever: characterization of the association between the two diseases.
Schwartz T, Langevitz P, Zemer D, Gazit E, Pras M, Livneh A.

Abstract
OBJECTIVES: Familial Mediterranean fever (FMF) is a genetic disease, characterized by attacks of fever and painful manifestations. Several vasculitides are more common in FMF than in the general population. The aim of the study was to define and characterize the association between FMF and Behcet's disease (BD), a form of vasculitis not previously related to FMF.
METHODS: We conducted a retrospective study in which FMF patients, also suffering from BD (FMF-BD), were recruited from about 4,000 patients registered in our clinic, using a computer survey. Patients identified by the screening process were examined, and those meeting the published criteria for the diagnoses of FMF and BD were classified as FMF-BD cases and compared with unselected FMF and BD controls.
RESULTS: The prevalence of BD was higher in FMF than in populations known to be rich in BD (eg, 16 per 4,000 in FMF compared with 1 per 104 in Japan, P < .001). FMF-BD cases and FMF or BD controls were comparable in most demographic, clinical, and laboratory aspects studied. However, more cases than FMF-controls were of Iraqi/Turkish origin and responded less favorably to colchicine. A higher proportion of cases than BD controls had skin, central nervous system, and gastrointestinal manifestations, originated from North Africa, and had family history of BD. In most cases, as in most respective controls, the severity of FMF was of intermediate grade and the extensiveness of BD was limited. The HLA B5 antigen was present in 53% of BD cases and 40% of BD controls.
CONCLUSIONS: BD should be included among the vasculitides complicating FMF. BD and FMF in patients with FMF-BD, and in patients suffering from each of these entities alone, are clinically and demographically comparable.

Medicine (Baltimore). 2002 Nov;81(6):411-6.
Crohn disease in patients with familial Mediterranean fever.
Fidder HH, Chowers Y, Lidar M, Sternberg M, Langevitz P, Livneh A.

Abstract
Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of
ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p = 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 +/- 10.0 yr versus 26.2 +/- 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.

J Rheumatol. 2003 Dec;30(12):2620-3.
Intravenous colchicine for treatment of patients with familial Mediterranean fever unresponsive to oral colchicine.
Lidar M, Kedem R, Langevitz P, Pras M, Livneh A.

Abstract
OBJECTIVE: To evaluate the efficacy and safety of weekly intravenous (IV) colchicine, in addition to oral colchicine therapy, in a subset of patients with familial Mediterranean fever (FMF) unresponsive to oral colchicine prophylaxis. 
METHODS: Thirteen patients with frequent FMF attacks, despite oral doses of 2-3 mg/day colchicine, were treated with weekly IV injections of 1 mg colchicine for 12 weeks in an open-label pilot study. Patients were evaluated periodically for the number and severity of their attacks, use of analgesics, and erythrocyte sedimentation rate (ESR).
RESULTS: A 50% reduction in attack frequency and attack severity in at least one site was achieved by 10 and 6 of the 13 study patients, respectively (p < 0.001 and p < 0.01). Mean number of abdominal attacks declined significantly from 4.2 +/- 3.0 per patient at baseline to 1.9 +/- 2.6 attacks at the end of the third month of the study (p = 0.0002). The mean severity of abdominal attacks declined from a baseline of 6.1 +/- 0.95 to 3.9 +/- 2.8 after 3 months (p = 0.02). Comparable significant change was observed in chest attacks, ESR, and number of analgesic tablets used. Joint attacks were unrelieved during the study period.
The treatment was safe and well tolerated, without side effects.
CONCLUSION: Treatment with weekly IV colchicine injections in addition to oral colchicine therapy is effective and safe in patients with FMF refractory to oral colchicine.

Semin Arthritis Rheum. 2004 Feb;33(4):273-82.
Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization.
Lidar M, Scherrmann JM, Shinar Y, Chetrit A, Niel E, Gershoni-Baruch R, Langevitz P, Livneh A.

Abstract
OBJECTIVES: To identify the ethnic, clinical, genetic, and pharmacokinetic correlates of colchicine treatment failure in patients with familial Mediterranean fever (FMF). 
METHODS: Fifty-nine FMF patients, unresponsive to a daily dose of > or =2 mg colchicine, were compared with 51 colchicine-responsive patients by clinical, demographic, and socioeconomic assessment, FMF gene (MEditerranean FeVer [MEFV) mutation and serum amyloid A1 (SAA1) gene polymorphism analysis, and plasma and white blood cell colchicine level determination.
RESULTS: Colchicine responders and nonresponders were comparable with respect to gender, age, duration and onset of the disease, and various demographic parameters. The 2 cohorts were found to carry mainly the M694V MEFV mutation and had a similar number of homozygotes or compound heterozygotes. Predominance of the alpha/beta alleles of SAA1 and comparable plasma and polymorphonuclear colchicine concentrations characterized both groups. Nonresponders were from lower socioeconomic backgrounds, had less education, and a more severe form of disease. A statistically significant 2-fold elevation of colchicine concentration in the mononuclear cells (MNC) of responders was found.
CONCLUSIONS: Colchicine treatment failure in FMF is associated with inadequate colchicine MNC concentration, probably resulting from a genetic defect unrelated to the underlying FMF.

Semin Arthritis Rheum. 2005 Aug;35(1):57-64.
Evaluation of disease severity in familial Mediterranean fever.
Mor A, Shinar Y, Zaks N, Langevitz P, Chetrit A, Shtrasburg S, Rabinovitz E, Livneh A.

Abstract
OBJECTIVE: To establish a new, objective, statistically based severity score for familial Mediterranean fever (FMF).
METHODS: One hundred consecutive FMF patients were evaluated independently by 2 FMF experts for severity of their disease and were assigned to 1 of 3 severity levels: mild, intermediate, or severe. Nine candidate criteria, reflecting objective suffering and disability, were analyzed to determine their weight for patient placement in the 3 predefined severity groups.
RESULTS: Candidate criteria best differentiating between the 3 patient categories were the frequency of attacks, the number of sites affected during an attack and during the course of the disease, and the duration of the attacks. These criteria were applied in a classification-tree model to establish a new FMF-severity score (F-SS). The first set of F-SS (F-SS-1) was highly sensitive and specific. Integrating F-SS-1 with clinical parameters strongly associated with disease severity resulted in a simplified score, the second set of F-SS (F-SS-2).
CONCLUSIONS: New, useful, objective, and valid severity scores were established and found to distinguish between patients with mild, intermediate, and severe diseases with high sensitivity and specificity. RELEVANCE: The F-SS established may be important for treatment decisions, prognosis evaluation, and comparative analysis of patient populations.

Medicine (Baltimore). 2007 Nov;86(6):355-62.
Familial Mediterranean fever and cryptogenic cirrhosis.
Tweezer-Zaks N, Doron-Libner A, Weiss P, Ben-Horin S, Barshack I, Lidar M, Livneh A.

Abstract
Familial Mediterranean fever (FMF) is a febrile disease characterized by acute, spontaneously resolving episodes of fever and pain caused by serosal inflammation and associated with mutations in the FMF gene, MEFV. Prophylaxis is maintained with colchicine. To our knowledge, no study has yet shown an association between FMF and cirrhosis of the liver. We conducted the current study to describe cryptogenic cirrhosis in FMF and to examine the possible relationship between the 2 entities. Patients with chronic liver disease were retrospectively identified through a computer search of a registry of 6000 patients with FMF followed in the clinics of the National Center for FMF. Data pertaining to FMF phenotype and
genotype and characteristics of the liver disease were abstracted from patients' charts. Cryptogenic cause of cirrhosis was determined by exclusion of known causes of liver disease. Nine patients with cryptogenic cirrhosis were identified, comprising 0.15% of the FMF patient population, a rate significantly higher than the rate of 0.015% of cirrhosis of all types expected in the total population of Israel (p < 0.000). Most patients had typical FMF, with a normal severity score distribution. The mean daily dose of colchicine was 1.4 +/- 0.4 mg, not different from the usual dose. All 7 patients who underwent mutation analysis had 2 mutations. Five of them were homozygous for M694V. Child-Pugh classification was determined in 6 patients at the time of cirrhosis diagnosis, and was classified as A in 4 of them. These findings suggest that MEFV may serve as a modifier gene in cryptogenic cirrhosis. Genetic analysis in patients with cryptogenic cirrhosis unrelated to FMF, particularly patients of a Mediterranean origin, may be warranted in future studies.

J Rheumatol. 2013 Dec;40(12):2083-7. 
Familial Mediterranean fever (FMF) with proteinuria: clinical features, histology, predictors, and prognosis in a cohort of 25 patients.
Kukuy O, Livneh A, Ben-David A, Kopolovic J, Volkov A, Shinar Y, Holtzman E, Dinour D, Ben-Zvi I.

Abstract    
OBJECTIVE: Reactive (AA) amyloidosis may complicate familial Mediterranean fever (FMF), the prototype of autoinflammatory diseases. Thus, proteinuria in FMF is commonly viewed as resulting from amyloidosis, and kidney biopsy is deemed superfluous. However, nephropathy other than amyloidosis has been described in FMF, but its rate and distinctive characteristics are unknown. Our aim was to determine the rate and underlying pathology of FMF-related nonamyloidotic proteinuria and compare its clinical course, demographic, and genetic features to those of FMF-amyloid nephropathy.
METHODS: This study is a retrospective analysis of data from patients with FMF undergoing kidney biopsy for proteinuria above 0.5 g/24 h, over 10 years (2001-2011). Clinical, laboratory, genetic, and pathology data were abstracted from patient files. Biopsies were viewed by an experienced pathologist, as necessary.
RESULTS: Of the 25 patients referred for kidney biopsy, only 15 (60%) were diagnosed with amyloid kidney disease (AKD), and 10 were diagnosed with another nephropathy. The AKD and nonamyloid kidney disease (NAKD) groups were comparable on most variables, but showed distinct characteristics with regard to the degree of proteinuria (6.45 ± 4.3 g vs 2.14 ± 1.6 g, p = 0.006), rate of severe FMF (14 vs 5 patients, p = 0.022), and rate of development of end stage renal disease (73.3% vs 20%, p = 0.015), respectively.

CONCLUSION: NAKD is common in FMF and, compared to amyloidosis, it is featured with milder course and better prognosis. Contrary to common practice, it is highly recommended to obtain a kidney biopsy from patients with FMF and proteinuria more than 0.5 g/24 h.

Orphanet J Rare Dis. 2014 Jan 9;9:3. 
Colchicine-free remission in familial Mediterranean fever: featuring a unique subset of the disease-a case control study.
Ben-Zvi I, Krichely-Vachdi T, Feld O, Lidar M, Kivity S, Livneh A.

Abstract
BACKGROUND: To demonstrate and clinically, genetically and demographically characterize familial Mediterranean fever (FMF) patients, maintaining remission despite colchicine abstinence.
METHODS: FMF patients were screened for an endurance of prolonged remission (≥ 3 
years), despite refraining from colchicine. Clinical, demographic and genetic parameters were collected. Data were compared with those of consecutive control FMF subjects, coming to the clinic for their periodic follow up examination.
RESULTS: Of 1000 patients screened over 5 years, 33 manifested colchicine-free remission. The mean duration of the remission period was 12.6 ± 8.1 years. Patients in the remission group had milder severity of FMF, compared to the control group (22 vs. 11 patients with mild disease, respectively, p=0.003) and a longer diagnosis delay (21 ± 15.7 vs. 13.4 ± 13.5 years, respectively, p=0.04). Patients experiencing remission suffered mostly of abdominal attacks, low rate of attacks in other sites and low rate of chronic and non-attack manifestations. When the disease resumed activity, it responded well to colchicine, despite using a lower dose, as compared to the control subjects (p<0.001). None of the patients
in this group was homozygous for the M694V mutation (p=0.0008). 
CONCLUSIONS: Prolonged colchicine-free remission defines a rare and milder form of FMF with unique clinical, demographic, and molecular characteristics.

Orphanet J Rare Dis. 2015 Mar 25;10:34. 
Familial Mediterranean fever without MEFV mutations: a case-control study.
Ben-Zvi I, Herskovizh C, Kukuy O, Kassel Y, Grossman C, Livneh A.

Abstract
BACKGROUND: Although familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10-20% of FMF patients do not carry any FMF gene (MEFV) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called "FMF without MEFV mutations". In this study we clinically and demographically characterize this subset.
METHODS: MEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation.
RESULTS: Forty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV-mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset.
CONCLUSIONS: MEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.

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