Pathogenesis Of Familial Mediterranean Fever Research Articles

Distribution of Killer Cell Immunoglobulin–like Receptor (KIR) Genotypes in Patients with Familial Mediterranean Fever

Genotypic profiles of the natural killer cell immunoglobulin-like receptors (KIR) have been reported to vary among different ethnic groups and variable clinical entities. This study represents the first report on its distribution among patients with familial Mediterranean fever (FMF). We studied 56 unrelated Lebanese FMF patients, had their DNA typed using sequence-specific primer (SSP) technique for the presence of 16 KIR gene and pseudogene loci, and compared them to the general Lebanese population. The AA1 genotype was the most frequent in both the FMF and control groups. Six new KIR profiles were identified. The FMF group showed a higher prevalence of KIR 3DP1*003 (p<0.05) and an increase in the BB genotype compared with controls. The results lead to an interesting future research question of whether or not KIR genotype is involved in the predisposition to or pathogenesis of FMF. This is the first report that describes the KIR genotypic profile in this important clinical disease.

Familial Mediterranean Fever: A review for clinical management

Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive, autoinflammatory disorder characterized by recurrent, self-limiting episodes of short duration (mean 24–72 h) of fever and serositis. FMF is the most frequent periodic febrile syndrome among the autoinflammatory syndromes (AS), a heterogeneous group of recently identified diseases clinically characterized by recurrent febrile attacks, in the absence of autoantibodies and antigen-specific T lymphocytes. In FMF, periodic attacks show inter- and intra-individual variability in terms of frequency and severity. Usually, they are triggered by apparently innocuous stimuli and may be preceded by a prodromal period. The Mediterranean FeVer gene (MEFV) responsible gene maps on chromosome 16 (16p13) encoding the pyrin–marenostrin protein. The precise pathologic mechanism is still to be definitively elucidated; however a new macromolecular complex, called inflammasome, seems to play a major role in the control of inflammation and it might be involved in the pathogenesis of FMF. The most severe long-term complication is type AA amyloidosis, principally affecting the kidney and the cause of chronic renal failure. Two types of risk factors, genetic and non-genetic, have been identified for this complication. Currently, the only effective treatment of Familial Mediterranean Fever is the colchicine. New drugs in a few colchicine resistant patients have been tried, but additional studies on larger series are necessary to draw definitive conclusions.

Circulating adrenomedullin levels in ankylosing spondylitis and Familial Mediterranean Fever

Introduction Adrenomedullin (AM) is a 52-amino acid peptide with vasorelaxant properties. Apart from its roles on vascular tonus, AM can also contribute to inflammatory events. Plasma AM levels were elevated in connective tissue diseases and vasculitic disorders. Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine initiating in the sacroiliac joints. Familial Mediterranean Fever (FMF) is a hereditary disorder characterized by self-limiting acute attacks of fever and the presence of sustained subclinical inflammation in the attack-free periods. In this study, we investigated plasma AM levels in patients with AS and patients with FMF. Methods Twenty AS patients with active disease manifestations (mean age: 41.6 ± 10.9 years, female/male: 7/13), 28 FMF patients with acute attack (mean age: 27.4 ± 10.7 years, female/male: 17/11), and 26 healthy controls (mean age: 39.9 ± 5.5 years, female/male: 16/10) were enrolled in this study. AM levels were also measured in 11 FMF patients 2 months after the cessation of their attacks. AM levels of those 11 patients during their FMF attacks and attack-free periods were also compared. Results Median plasma AM levels were 23.86 (17.24–40.09) pmol/mL, 27.33 (17.24–38.52) pmol/mL, and 26.11 (17.05–37.42) pmol/mL in AS patients, FMF patients with acute attack, and healthy controls, respectively ( p > 0.05). AM levels were also similar in the attack-free periods of FMF patients [26.35 (24.35–34.14) pmol/mL]. There was no correlation between plasma AM levels and C-reactive protein, or between plasma AM levels and erythrocyte sedimentation rate. Conclusions AM does not seem to have any role in the pathogenesis of AS and FMF. Previous reports of elevated levels of AM in connective tissue disorders and vasculitic diseases are probably disease specific, and AM does not seem to be a common component of inflammatory rheumatic disorders.

Serum proinflammatory cytokines directing T helper 1 polarization in patients with familial Mediterranean fever

Th1 type polarization has been implicated in the pathogenesis of familial Mediterranean fever (FMF). Interleukin-12 (IL-12) and IL-10 are proinflammatory cytokines, which play crucial role in Th1 and Th2 type immune response, respectively. IL-18 has a dual effect on T cell response: it was recognized as an IFN-gamma-inducing factor in T cells; acting in synergy with IL-12, leading to the development of Th1 type immune responses. But, in the absence of IL-12, IL-18 can promote the production of Th2 cytokines and take part in allergic inflammation. The aim of this study is to measure serum levels of IL-10, IL-12, and IL-18 in patients with FMF, and to investigate the relationship of their expressions with FMF attacks. Serum IL-10, IL-12, and IL-18 levels from patients with FMF were investigated. Thirty-one FMF patients with attack-free, 24 FMF patients with attack and 20 healthy controls were enrolled in the study. The levels of IL-10, IL-12p70 and IL-18 were measured by ELISA. Serum IL-10 levels were not different in FMF patients with attack and attack-free, and healthy controls. Serum IL-12 levels in FMF patients both with attack and attack-free were significantly higher than healthy controls (P = 0.002 and P = 0.047, respectively). There were no differences between FMF patients with attack and attack-free with regard to serum IL-12 levels. Serum IL-18 levels in FMF patients with attack and attack-free were significantly higher than healthy controls (P < 0.001 for both groups). With respect to serum IL-18 levels, no difference was found between FMF patients with attack and attack-free. Our results suggest that IL-12 and IL-18 contribute to the establishment of Th1 polarization seen in FMF and play a part in its pathogenesis. Detection of increased levels of IL-12 and IL-18 in patients with inactive disease implies that they seem to assist Th1 activation and subclinical inflammation persisting during the attack-free period of the disease.

The expanded clinical spectrum of familial Mediterranean fever

The classical clinical features of familial Mediterranean fever (FMF) are recurrent self-limited attacks of fever and serositis. Amyloidosis of the AA type is the major complication of the disease. The diagnosis of FMF is still based on a history of typical acute attacks, ethnic background, and frequently, notable family history. Together with the discovery of MEFV gene, the clinical criteria for the diagnosis of the disease did not change. Although we have learned a great deal about the clinical features and the pathogenesis of FMF in the past few years, many atypical cases emerge, and caution should be exercised during diagnosis. In this report, we present three FMF patients not fulfilling clinical criteria for the diagnosis, discuss rare and unusual presentations of the disease, and emphasize the role of genetic analysis in these suspicious cases.

Classical pathway complement activity in Familial Mediterranean fever

Objectives: The present study emphasizes the important role of the immune reactions in the pathogenesis of Familial Mediterranean fever. In the present study, the total hemolytic activity of the complement and the activities of individual complement components, C1, C2, C3, and C4, were determined in the blood serum of 32 patients with FMF and 28 healthy subjects. Design and methods: Hemolytic assay was applied, measuring THAC and individual complement components' activities. The patients were divided into 3 groups upon the regularity of colchicine therapy: patients receiving regular, irregular and not receiving colchicine treatment for at least 1 year. Results: No significant changes in the hemolytic activities of the C1, C2, C3, and C4 complement components were found between the healthy subjects and those FMF patients, who were receiving regular colchicine treatment. Conclusions: Our data obtained have raised a number of important questions relevant to FMF pathogenesis and once again confirms the efficiency of regular colchicine treatment.

La maladie périodique au sein des maladies auto-inflammatoires

During the first attacks of familial Mediterranean fever, each of the disease symptoms can suggest a series of disorders. When the disease is older, the recurrence of symptoms may simulate some systemic diseases, but mainly suggests familial Mediterranean fever, one of a group of hereditary autoinflammatory diseases. Before the gene for familial Mediterranean fever was identified, various sets of criteria were used for diagnosis. The presence of MEFV mutations confirms the diagnosis, but the clinical criteria still determine who should undergo this genetic testing. The genotype-phenotype correlations add a prognostic dimension to the mutations identified. Genotyping can also lead to the diagnosis of the other autoinflammatory diseases, which constitute the basis of the differential diagnosis of familial Mediterranean fever. The hyperimmunoglobulinemia D syndrome (HIDS) is very similar to familial Mediterranean fever in its recessive transmission and abdominal and articular symptoms. It can be distinguished by the European origin of the patients, the presence of cervical lymph nodes and the increased IgD levels. Of the diseases with dominant transmission, the TNF receptor-associated periodic syndromes (TRAPS) are suggested by periorbital edema and migrating inflammatory cellulitis. Muckle and Wells syndrome is revealed by episodes of fever with urticaria and arthralgia, complicated by deafness and amyloidosis. Mutations in the same gene are responsible for two disorders, both appearing in childhood: familial cold urticaria syndrome (FCUS) and chronic infantile neurocutaneous articular syndrome (CINC). The pathogenesis of familial Mediterranean fever is still unclear. Pyrin/marenostrin, the protein produced by the MEFV gene, appears to hae a physiological antiinflammatory effect that inhibits proinflammatory cytokines. Mutation of the gene may eliminate this feedback mechanism and expose the patient to flares from any inflammatory stimulus, even minimal. Amyloid is produced by the serum amyloid A protein (SAA), and its occurrence is influenced by the type of MEFV mutation, but also the genotype of the gene producing SAA.

Familial Mediterranean Fever

The pathogenesis of familial Mediterranean fever (FMF) is unknown, and since no specific laboratory test is yet available, the diagnosis of FMF remains clinical. The purpose of this study was to review clinical characteristics of patients with FMF.A total of 96 patients with FMF were evaluated either retrospectively (for those diagnosed before 1997) or prospectively (for those after 1997).The records of 54 male and 42 female patients were studied. All patients were Turks. Family history was positive in 72 patients (75%). Involved site was peritoneum in 73 (76%), joints in 65 (68%), and pleura in 16 (17%). Febrile myalgia occurred in 3 patients (3%), and erysipelas-like skin lesions were observed in 2 (2%). Fever was found in 93 patients (97%). Reactive systemic (AA) amyloidosis was found in 38 patients (40%).Diagnostic problems persist despite increased understanding of the pathogenesis of FMF. Amyloidosis, the most important complication of FMF, is often seen.

Evidence of oxidative stress in erythrocyte phospholipid composition in the pathogenesis of familial Mediterranean fever (periodical disease).

Familial Mediterranean fever (FMF) is a genetically linked disorder common amongst races of the Eastern Mediterranean region. Typical symptoms include episodic pain syndrome extending throughout the chest or abdomen associated with histopathological signs of amyloidosis of the kidney. To investigate possible connections between the aseptic inflammation that occurs during pain crises and cell membrane structural and functional integrity in patients with FMF. Oxidative stress parameters in 42 patients in remission and during a pain crisis were compared with 21 normal subjects. The patient group had significantly greater concentrations of chemiluminescent and thiobarbituric acid-reactive substances in the blood plasma and lower concentrations of alpha-tocopherol than the control group while in remission; these changes were exacerbated during pain crises. Analyses of the phospholipid composition of erythrocyte membranes showed significant increases in amounts of acidic phospholipids (phosphatidic acid, monophosphatidylinositol and cardiolipin) and lysophosphatidylcholine compared with healthy subjects. The pattern of differences in membrane phospholipid composition was consistent with increased oxidative stress in patients with FMF.

A Proposed Mechanism of the Inflammatory Attacks in Familial Mediterranean Fever

To the Editor. — Multiple and varied mechanisms have been proposed to underlie the pathogenesis of the acute febrile attacks of recurrent hereditarypolyserositis, also called familial Mediterranean fever (FMF). However, the pathogenesis of FMF has, thus far, remained enigmatic. 1 We have recently examined whether the lymphokine tumor necrosis factor (TNF), which has many inflammatory activities, 2 may be involved in mediating the acute attacks of FMF. Although plasma TNF was not increased in patients with FMF, we found that the capacity of patients' peripheral blood mononuclear cells to produce TNF in response to an inducer was severely diminished in the acute phase, increasing by about fivefold in asymptomatic patients with FMF, to levels significantly over those of healthy control subjects. 3 This was most probably due to exhaustion of the cells following an already massive release of TNF, which could not be demonstrated due to a short plasma

Tumor necrosis factor in familial mediterranean fever

Purpose The pleiotropic inflammatory effects of tumor necrosis factor (TNF) prompted a study of this cytokine in familial Mediterranean fever (FMF), a recurrent polyserositis of unknown etiology. Patients and Methods Thirty-six asymptomatic and 24 patients with acute FMF were studied and compared with 20 matched healthy subjects. TNF levels were measured by bioassay in the plasma and in supernatants of peripheral blodd mononuclear cells (PBMC) incubated alone or with an inducer (lipopolysaccharide, phytohemagglutinin [PHA], or Sendai virus). Cytotoxicity could be abolished in all cases by preincubation with monoclonal anti-TNF-α antibodies. Results No TNF was found in plasma and non-induced PBMC supernatants. Induced TNF production was markedly decreased in patients with acute FMF and increased in asymptomatic FMF patients to levels over those of control subjects (p <0.05). Thus, PHA-induced TNF levels were 4 U/mL in patients with acute FMF, 25 U/ mL in asymptomatic patients, and 14 U/mL in healthy control subjects (median values), and the other inducers gave similar results. Retesting of patients first studied during an acute episode when their disease was quiescent also revealed a fivefold increase in TNF production. These results were independent of the use of colchicine, which also had no effect on TNF levels when taken by volunteers (1 mg/day) or when added to the PBMC cultures (10−7 M). Conclusions Since TNF has a very short half-life in plasma, the capacity of PBMC to respond to TNF inducers may more accurately reflect its synthesis. A marked decrease in this response in acute FMF suggests “exhaustion” of cells that are already highly activated to produce TNF and the possible participation of TNF in the pathogenesis of FMF. The pleiotropic inflammatory effects of tumor necrosis factor (TNF) prompted a study of this cytokine in familial Mediterranean fever (FMF), a recurrent polyserositis of unknown etiology. Thirty-six asymptomatic and 24 patients with acute FMF were studied and compared with 20 matched healthy subjects. TNF levels were measured by bioassay in the plasma and in supernatants of peripheral blodd mononuclear cells (PBMC) incubated alone or with an inducer (lipopolysaccharide, phytohemagglutinin [PHA], or Sendai virus). Cytotoxicity could be abolished in all cases by preincubation with monoclonal anti-TNF-α antibodies. No TNF was found in plasma and non-induced PBMC supernatants. Induced TNF production was markedly decreased in patients with acute FMF and increased in asymptomatic FMF patients to levels over those of control subjects (p <0.05). Thus, PHA-induced TNF levels were 4 U/mL in patients with acute FMF, 25 U/ mL in asymptomatic patients, and 14 U/mL in healthy control subjects (median values), and the other inducers gave similar results. Retesting of patients first studied during an acute episode when their disease was quiescent also revealed a fivefold increase in TNF production. These results were independent of the use of colchicine, which also had no effect on TNF levels when taken by volunteers (1 mg/day) or when added to the PBMC cultures (10−7 M). Since TNF has a very short half-life in plasma, the capacity of PBMC to respond to TNF inducers may more accurately reflect its synthesis. A marked decrease in this response in acute FMF suggests “exhaustion” of cells that are already highly activated to produce TNF and the possible participation of TNF in the pathogenesis of FMF.

Tumor necrosis factor in familial mediterranean fever

purpose: The pleiotropic inflammatory effects of tumor necrosis factor (TNF) prompted a study of this cytokine in familial Mediterranean fever (FMF), a recurrent polyserositis of unknown etiology. patients and methods: Thirty-six asymptomatic and 24 patients with acute FMF were studied and compared with 20 matched healthy subjects. TNF levels were measured by bioassay in the plasma and in supernatants of peripheral blood mononuclear cells (PBMC) incubated alone or with an inducer (lipopolysaccharide, phytohemagglutinin [PHA], or Sendai virus). Cytotoxicity could be abolished in all cases by preincubation with monoclonal anti-TNF-α antibodies. results: No TNF was found in plasma and non-induced PBMC supernatants. Induced TNF production was markedly decreased in patients with acute FMF and increased in asymptomatic FMF patients to levels over those of control subjects (p <0.05). Thus, PHA-induced TNF levels were 4 U/mL in patients with acute FMF, 25 U/ mL in asymptomatic patients, and 14 U/mL in healthy control subjects (median values), and the other inducers gave similar results. Retesting of patients first studied during an acute episode when their disease was quiescent also revealed a fivefold increase in TNF production. These results were independent of the use of colchicine, which also had no effect on TNF levels when taken by volunteers (1 mg/day) or when added to the PBMC cultures (10 −7 M). conclusions: Since TNF has a very short half-life in plasma, the capacity of PBMC to respond to TNF inducers may more accurately reflect its synthesis. A marked decrease in this response in acute FMF suggests “exhaustion” of cells that are already highly activated to produce TNF and the possible participation of TNF in the pathogenesis of FMF.

Circulating hydroxy fatty acids in familial Mediterranean fever.

Episodes of fever, serositis, and arthritis in familial Mediterranean fever (FMF) suggested circulating mediators of acute inflammation (e.g., neutrophil activation). The mean serum neutrophil-aggregating activity of 51 FMF patients was 2.5 +/- 0.2 cm2/min, compared to 1.0 +/- 0.1 cm2/min in 20 normal controls (P less than 0.0002). Lipid extracts of FMF sera retained neutrophil-aggregating activity and had UV absorbance peaks at 269 and 279 nm, indicating the presence of lipids with a conjugated triene structure. Chromatography of extracts yielded peaks that were coeluted with reference dihydroxyicosatetraenoic acids, had UV absorbance peaks at 259, 269, and 279 nm, and possessed neutrophil-aggregating activity. The presence of leukotriene B4 was excluded by chromatography following methyl-esterification. Monohydroxy compounds identified in FMF extracts by gas chromatography/mass spectrometry included 5-hydroxyicosatetraenoic acid, and 9- and 13-hydroxyoctadecadienoic acids. Hydroxy acids were present in 19 of 31 FMF sera and absent in extracts of sera from 8 patients with active systemic lupus erythematosus, 7 with fever from infection, and 12 normal controls. The finding of circulating mono- and dihydroxy fatty acids in FMF suggests that defects in the formation or elimination of these compounds might play a role in the pathogenesis of FMF.

Monocyte function in familial Mediterranean fever

Monocytes derived from the peripheral blood of patients with familial Mediterranean fever (FMF) demonstrated a consistently lower phagocytic capacity (38-44%) for 125I-labelled Shigella flexneri when compared to monocytes from healthy subjects. Phagocytosis of both viable and killed Staphylococcus albus was similar in patients and controls. However, FMF monocytes had a two- to eight-fold depressed bactericidal capacity against S. albus in comparison to normal monocytes. Acid phosphatase and beta-glucuronidase monocyte activities were similar in patients and controls. It is suggested that the defects in monocyte function may be of importance in the pathogenesis of FMF. Colchicine had no effect on any of the indices studied.

Colchicine in Familial Mediterranean Fever

Letters and Corrections1 September 1977Colchicine in Familial Mediterranean FeverRIDA A. FRAYHA, M.D.RIDA A. FRAYHA, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-87-3-382_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: The cause and pathogenesis of familial Mediterranean fever (FMF) are not clear, hence treatment, by necessity, has been empirical. Prophylactic colchicine therapy has recently been shown to be highly effective in preventing the attacks by suppressing the inflammatory reaction and its symptoms without affecting the basic biorhythm or the underlying excitatory process (1, 2). The mechanism of action of colchicine in FMF remains unclear. Colchicine is known to disrupt the intracellular microtubular structures and to interfere with cellular motility and division. Dinarello and associates (3) have recently shown that patients with FMF on colchicine have significantly fewer...