Acute Familial Mediterranean Fever Research Articles

Are thiol-disulfide homeostasis & neutrophil-to-lymphocyte ratio useful in the differential diagnosis of acute familial Mediterranean fever attacks & acute appendicitis?

Continuous subclinical inflammation can be seen in patients with familial Mediterranean fever (FMF) during the attack-free period. The importance of oxidative stress parameters in acute appendicitis (AA) progression has also been shown in previous studies. So, oxidative stress and the oxidant/antioxidant balance may play a role in this persistent subclinical inflammation. With this background the main objective of this study was to investigate the usefulness of combining the thiol-disulfide homeostasis parameters and the neutrophil-to-lymphocyte ratio (NLR) in the differential diagnosis of AA and an acute FMF attack. The present study was conducted prospectively with 84 patients who were admitted to the emergency department between May 1, and December 31, 2018. Another 40 healthy individuals were assigned as the control group. The homeostasis parameters of thiol-disulfide were measured by a spectrophotometric method and NLR was measured in the patient and control groups. Native thiol and total thiol values were lower, while disulfide values were insignificantly higher in patients with AA than in patients with FMF. The white blood cell (WBC), neutrophil and NLR values were significantly higher in the AA group (P<0.001, P<0.001, P<0.001, respectively). When the neutrophil cut-off value for AA was set at 8.55, the calculated sensitivity was 80 per cent, the specificity was 72.2 per cent, and the area under the curve was 0.837. The results of this study suggest that neutrophil, WBC and NLR values can be useful in the differentiation of AA from an acute FMF attack.

Evaluation of S100A12 protein levels in children with familial Mediterranean fever

Background/aim Familial Mediterranean fever (FMF), the most common autoinflammatory disease in children, is characterized by recurrent febrile episodes. FMF is known to progress with chronic inflammation, particularly during attack periods. This study aimed to investigate the relationship of S100A12, an inflammatory marker, with attacks and inflammatory events in FMF patients. Materials and methods The study included 57 patients diagnosed with FMF, 43 in an attack-free period and 14 in an attack period, and 31 healthy children as the control group. Only white blood cell (WBC) count, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and S100A12 level were analyzed in the control group. In addition, serum amyloid A (SAA), and fibrinogen levels were measured, and a mutation analysis was performed in the patient group. The results were compared among the attack-free period, acute attack FMF and control groups.Results The mean age of patients and control group was 10 (2.5–18) and 9.5 (2.5–16) years, respectively. The CRP (p = 0.001), S100A12 (p = 0.003) and ESR (p= 0.001) values differed significantly between the FMF and control groups. S100A12 level (p = 0.027), WBC count (p = 0.003), CRP level (p = 0.0001), ESR (p = 0.004), and fibrinogen level (p = 0.001) differed significantly between the acute attack and attack-free period groups. SAA level (p = 0.05), ESR (p = 0.001), fibrinogen level (p = 0.001), WBC count (p = 0.001), and S100A12 level (p = 0.027) were higher in M694V homozygous FMF patients than in other FMF patients. Conclusion Patients with FMF had higher S100A12 levels than the control group, while the mean S100A12 concentration was higher in acute attack period patients than in attack-free period patients. S100A12 level might be an important indicator in the monitoring of chronic inflammation in patients with FMF.

The role of neutrophil lymphocyte ratio to leverage the differential diagnosis of familial Mediterranean fever attack and acute appendicitis

Background/Aims:Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by attacks of fever and diffuse abdominal pain. The primary concern with this presentation is to distinguish it from acute appendicitis promptly. Thus, we aimed to evaluate the role of neutrophil lymphocyte ratio (NLR) to leverage the differential diagnosis of acute FMF attack with histologically proven appendicitis.Methods:Twenty-three patients with histologically confirmed acute appendicitis and 88 patients with acute attack of FMF were included in the study. NLR, C-reactive protein and other hematologic parameters were compared between the groups.Results:Neutrophil to lymphocyte ratio was significantly higher in patients with acute appendicitis compared to the FMF attack group (8.24 ± 6.31 vs. 4.16 ± 2.44, p = 0.007). The performance of NLR in diagnosing acute appendicitis with receiver operating characteristic analysis with a cut-off value of 4.03 were; 78% sensitivity, 62% specificity, and area under the curve 0.760 (95% confidence interval, 0.655 to 0.8655; p < 0.001).Conclusions:This study showed that NLR, the simple and readily available inflammatory marker may have a useful role in distinguishing acute FMF attack from acute appendicitis.

Familial Mediterranean fever attacks do not alter functıonal and morphologıc tissue Doppler echocardıographıc parameters

The aim of this study is to investigate the tissue Doppler echocardiographic (TDE) characteristics of acute familial Mediterranean fever (FMF) attack on young Turkish males. Thirty-four young males with FMF were investigated utilizing echocardiography both before and after FMF attacks. Echocardiographic findings were assessed by two cardiologist utilizing Vingmed system V echocardiography machine and a 2.5 MHz probe by two-dimensional and color Doppler examination, as well as tissue Doppler parameters. The incidence of pericardial effusion was found to be 23.3% during acute FMF attack. There was no significant difference between the patients in attack-free period and attack period with respect to TDE measurements. TDE measurements did not differ between the patients with and without pericardial effusion. There was no correlation between pericardial effusion and disease duration, family history, and physical findings. In conclusion, our results suggest preserved systolic and diastolic ventricular functions in attack period. Pericardial effusion is not associated with impaired TDE parameters.

Serum adenosine deaminase activities during acute attacks and attack-free periods of familial Mediterranean fever

Background Familial Mediterranean Fever (FMF) is a systemic relapsing autoinflammatory disorder. Adenosine deaminase (ADA) is an enzyme widely distribute in tissues and body fluids. Circulating levels of ADA have been shown to increase in several inflammatory conditions. This study was designed to evaluate the serum ADA in patients with FMF during acute attacks and attack-free periods. Methods The study groups comprised 23 FMF patients in attack-free period (male/female: 11/12), 30 FMF patients in attack period (male/female: 11/19) and 20 healthy control (male/female:10/10). The groups were similar for age, gender and disease duration. Results The mean age of FMF patients in attack-free period, patient with acute attack were 34.3 ± 11.7 and 29.4 ± 11.1 respectively. The disease durations were 13.1 ± 10.2 and 8.2 ± 7.6 years for patients in attack-free periods and patients with acute FMF attack, respectively. Patients with acute attack had significantly higher ADA levels than both patients with attack-free periods and healthy controls (for each, p < 0.001). Conclusion In this study we demonstrated that FMF patients with acute attacks had higher serum ADA levels than attack-free periods and healthy controls. It is likely that ADA may have a role in the cytokine network of the inflammatory cascade of FMF. Also, elevated ADA levels may be a part of the activated Th1 response in the disease. ADA may be used as a supportive marker to differentiate FMF attacks from attack-free periods. Further larger-scale studies are needed to support this result.

Plasma levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) in familial Mediterranean fever

Aims To assess the levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) in patients with familial Mediterranean fever (FMF). Methods Plasma levels of sVEGFR-1 were investigated in 33 FMF patients in an attack-free period (mean age 30.8 years; males/females 10/23), in 15 patients with acute FMF attack (mean age 32.7 years; males/females 7/8), and 19 healthy controls (mean age 32 years; males/females 11/8). Levels of sVEGFR-1 were also compared among patients who were receiving colchicine and those who were not. Results Plasma sVEGFR-1 levels were 3.49 ± 1.10, 3.53 ± 1.02, and 0.37 ± 0.28 ng/ml for FMF patients in the attack-free period, FMF patients with acute attack, and healthy controls, respectively. Plasma sVEGFR-1 levels were significantly higher in FMF patients with and without acute attack compared to the control group ( p < 0.05). sVEGFR-1 levels were not statistically significant between patients with acute attack and attack-free FMF patients ( p > 0.05). The plasma levels of sVEGFR-1 were also comparable in colchicine treated and untreated patients. Conclusion Our data suggest that sVEGFR-1 may have a role in the ongoing inflammatory cascade in FMF.

Taux d'interféron gamma au cours de la maladie périodique

Aims. – To evaluate the levels of endogenous interferon-gamma (IFN-γ) in patients with familial Mediterranean fever (FMF). Materials and methods. – Plasma levels of IFN-γ were assayed in 29 FMF patients in attack-free period (mean age: 32, min–max: 17–48; male/female: 10:19), 18 FMF patients with acute FMF attack (mean age: 32, min–max: 19–50; male/female: 8:10), and 19 healthy controls (mean age: 31.94 ± 1.50, min–max: 23–42; male/female: 11:8). IFN-γ levels were also compared among colchicine treated and untreated groups. Results. – Median plasma IFN-γ levels were significantly higher in patients both with and without FMF attack than the control group ( P < 0.05). Moreover, plasma IFN-γ levels were higher in patients with acute FMF attack compared to patients in attack-free periods ( P < 0.05). Plasma levels of IFN-γ were comparable in colchicine treated and untreated groups. Conclusion. – Our results suggest that IFN-γ may contribute to the inflammatory cascade of FMF.

Leukotriene b4, acute abdominal familial mediterranean fever and acute abdominal pain from other etiologies

Study objectives: Familial Mediterranean fever (FMF) or familial paroxysmal polyserositis, an autosomal recessive disease, is a frequent etiology for acute abdominal pain in febrile patients arriving at emergency departments (EDs) attending areas with a high rate of population from Mediterranean extraction. Diagnosing acute peritonitis as a peritoneal FMF attack is extremely important because its nature is benign and its treatment medical, whereas other etiologies may be life threatening and require a different medical approach and, frequently, surgical intervention. An accurate and feasible test that corroborates acute abdominal FMF may prevent unnecessary abdominal surgery. Lipoxygenase products are present in the serum and synovial fluid of FMF patients (6), and attacks may be prevented or reduced in frequency by dietary fat restriction (7-11) or by colchicine therapy (12, 13); lipocortin defect has been suggested as a potential cause of phospholipase A2 release of arachidonic acid and its subsequent cyclooxygenase- and lipoxygenase-mediated eicanoside derivatives. Eicanoside generation, especially prostaglandin E2, prostacyclin, and leukotriene B4, has a potent proinflammatory effect that could be responsible for symptoms occurring during an acute attack. Methods: Urine samples were collected from consecutive patients arriving at the ED for right lower quadrant abdominal pain and tested for leukotriene B4 (LTB4). Clinical follow-up, computed tomography, and ultrasonographic examinations, as well as pathology results, were analyzed, and patients were classified into 4 groups: acute appendicitis, urinary conditions, nonspecific abdominal pain, and acute FMF. Results: Urine samples from 17 healthy individuals and from 36 patients with right lower quadrant abdominal pain and presenting to the ED were examined for LTB4 concentrations. Mean LTB4 concentrations were as follows: acute FMF 328±237 pg/mg chromium, nonspecific abdominal pain 297±173 pg/mg chromium, acute appendicitis 261±105 pg/mg chromium, urologic conditions 244±64 pg/mg chromium, controls 210±62 pg/mg chromium. Conclusion: LTB4 level is high in acute abdominal conditions, especially in acute FMF (<i>P</i><.032). Although significant differences in urine LTB4 levels were found between acute FMF and the control group, urine LTB4 levels were also high in right lower quadrant abdominal pain from other etiologies, the differences being insignificant. Our findings suggest a role of the lipocortin pathway in acute FMF but suggest that urine LTB4 is not specific enough to differentiate acute FMF from other conditions presenting with right lower quadrant abdominal pain, and especially acute appendicitis.

Interferon-gamma levels in familial Mediterranean fever

Aims. – To evaluate the levels of endogenous interferon-gamma (IFN-γ) in patients with familial Mediterranean fever (FMF). Methods. – Plasma levels of IFN-γ were assayed in 29 FMF patients in attack-free period (mean age: 32, min–max: 17–48; male/female: 10/19), 18 FMF patients with acute FMF attack (mean age: 32, min–max: 19–50; male/female: 8/10), and 19 healthy controls (mean age: 31.94 ± 1.50, min–max: 23–42; male/female: 11/8). IFN-γ levels were also compared among colchicine treated and untreated groups. Results. – Median plasma IFN-γ levels were significantly higher in patients both with and without FMF attack than the control group ( P < 0.05). Moreover, plasma IFN-γ levels were higher in patients with acute FMF attack compared to patients in attack-free periods ( P < 0.05). Plasma levels of IFN-γ were comparable in colchicine treated and untreated groups. Conclusion. – Our results suggest that IFN-γ may contribute to the inflammatory cascade of FMF.

Neutrophil Adhesion Molecule Expression in Familial Mediterranean Fever: Discordance between the Intravascular Regulation of β2 Integrin and L-Selectin Expression in Acute Attack

Background To determine the surface expression of neutrophil β2 integrin (CD11b/CD18) and L-selectin (LS) adhesion molecules in patients with familial Mediterranean fever (FMF) and to investigate the in vitro regulation of their expression in response to chemoattractant stimuli. Methods Neutrophil surface expression of CD11b and LS molecules was analyzed by flow cytometry in anticoagulated whole blood drawn from FMF patients and normal controls, and the in vitro regulation of these molecules induced by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP) was assayed. Results Patients during acute FMF attacks showed a statistically significant increased neutrophil surface CD11b compared with normal controls (mean fluorescence intensity: 22.8 ± 13.7 vs 12.8 ± 10.41, respectively; p = .03). There was no difference in LS expression between the groups. Neutrophils of FMF patients regulate CD11b and LS expression induced by chemoattractant (FMLP) stimulation to a degree similar to that in controls. Conclusions: β2 Integrin is up-regulated during an acute attack of FMF in dissociation with LS expression, suggesting a unique nonchemoattractant-mediated neutrophil activation.

Neutrophil Adhesion Molecule Expression in Familial Mediterranean Fever: Discordance between the Intravascular Regulation of β2 Integrin and L-Selectin Expression in Acute Attack

BackgroundTo determine the surface expression of neutrophil β2 integrin (CD11b/CD18) and L-selectin (LS) adhesion molecules in patients with familial Mediterranean fever (FMF) and to investigate the in vitro regulation of...

Colchicine derivatives inhibit neopterin production in human peripheral blood mononuclear cells (PBMC).

Colchicine is a microtubule disrupting agent, mostly used as treatment in various kinds of inflammatory diseases such as acute familial Mediterranean fever and Behcet's disease, as well as gout. In patients with familial Mediterranean fever treatment with colchicine induces a decline of urinary neopterin concentrations which indicates a decrease of cell-mediated immune activation. In this study, we investigated a potential effect of colchicine on the T cell/macrophage system in vitro. The human myelomonocytic cell line THP-1 and PBMC were treated with colchicine or the colchicine derivative, colcemide, in the presence or absence of 250 U/ml interferon-gamma (IFN-gamma) or 10 microg/ml lipopolysaccharide (LPS) for 48 h or 96 h. Colchicine and colcemide increased neopterin/protein production in unstimulated THP-1 cells, but no such effect was apparent in cells stimulated with IFN-gamma. By contrast, when PBMC were treated with colchicine or colcemide a significant reduction in neopterin formation was evident in cells without and with prestimulation by IFN-gamma or LPS. In parallel, reduced production of IFN-gamma was observed in PBMC. These data suggest that colchicine and colcemide are able to inhibit T cell activation within the cellular immune response.

Serum soluble interleukin-2 receptor levels in familial Mediterranean fever.

To investigate serum soluble interleukin-2 receptor (sIL-2R) in familial Mediterranean fever (FMF) and assess its role in acute FMF crisis. Serum sIL-2R concentrations were measured in patients with FMF during acute crises and during inactive periods of the disease, using an immunoenzymatic assay kit. Twenty four FMF patients during acute crisis (active FMF), 17 patients with inactive FMF, 24 healthy controls, and 20 active patients with rheumatoid arthritis (as a disease control group) were studied. Serum sIL-2R concentrations were increased during an acute FMF crisis compared with the values in inactive FMF patients and healthy controls (P = 0.0105 and P = 0.0012 respectively), while there was no significant difference between the mean values in active FMF and rheumatoid arthritis patients (P = 0.7325). In 14 of the FMF group whose blood samples were available in both active and inactive phases, sIL-2R concentrations were significantly higher in an acute attack than in an attack-free period (P = 0.027). An increase in sIL-2R may be a result of hyperreactivity of IL-2R-expressing cells during an acute inflammatory attack 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 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.

Colchicine prophylaxis in familial Mediterranean fever: Reappraisal after 15 years

As determined in this study of 45 patients, the prolonged use of colchicine therapy in familial Mediterranean fever (FMF) is safe and effective in preventing flares of FMF and amyloidosis. It has an acceptable adverse effect profile and can be used in children and pregnant women. Its discontinuation predisposes patients to acute FMF attacks and the development of amyloidosis. Articular involvement is less responsive to colchicine and may require therapy with nonsteroidal antiinflammatory drugs.

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.