Familial Mediterranean Fever Amyloidosis Research Articles

Serum galectin-3 levels were associated with proteinuria in patients with Familial Mediterranean Fever.

The most common and pernicious complication of Familial Mediterranean fever (FMF) is renal amyloidosis, usually affecting the kidneys, leading to end-stage renal failure. FMF-related renal amyloidosis needed to be diagnosed early. Optimal colchicine dose is effective in preventing and reversing renal amyloidosis. Galectin-3, profibrotic mediator, has regulatory functions in inflammation, fibrosis and tumorigenesis. Galectin-3 is a strong prognostic marker for heart failure. Galectin-3 plays role in diabetic nephropathy and chronic kidney disease. The aim of the study is to investigate whether galectin-3 is related to proteinuria and amyloidosis in FMF. Seventy-five FMF patients who have no exclusion criteria and healthy controls (n = 36) were included. Serum galectin-3 was measured and morning spot urine was collected for determination of the protein/creatinine ratio (PCR). Serum Galectin-3 levels were significantly higher in FMF patients than the control group [969.66 (3825) pg/mL vs. 238 (921) pg/mL, respectively; P<0.001]. We classified into two groups: Group1 (n = 48) had FMF patients with proteniuria, Group2 (n = 27) had FMF patients without proteinuria. Group1 had higher levels of galectin-3 than Group2 [1106(3812) pg/mL vs. 867.3(1433) pg/mL, P < 0.001]. Galectin-3 levels were correlated with PCR in whole group and FMF group (r = 0.785, P < 0.001 and r = 0.803, P < 0.001). In ROC curve, best cutoff value = 581.50 pg/mL was used to detect proteinuria (sensitivity = 91.7 %, specificity = 71.4 %, AUC = 0.879) and optimal cutoff value = 1458.00 pg/mL was an indicator of nephrotic-range proteinuric (sensitivity = 100 %, specificity = 92.1 %, AUC = 0.983). Galectin-3 is associated with proteinuria and renal amyloidosis in FMF. Galectin-3 may play role in pathogenesis of amyloidosis.

THU0402 Canakinumab Therapy in Patients with Familial Mediterranean Fever

BackgroundIn a recent pilot study, it was reported that Canakinumab reduced the frequency of attacks in 9 patients with Familial Mediterranean Fever (FMF) resistant to colchicine with no apparent side...

P01-027 – Normal HRV in colchicine-resistant FMF patients

The relationship between autonomic nervous system (ANS) dysfunction and Familial Mediterranean Fever (FMF) is controversial. Heart rate variability (HRV) is a powerful, simple and reliable technique for the evaluation of ANS dysfunction. Recently, we reported on normal HRV parameters, suggestive of normal ANS function, in patients with uncomplicated FMF. Also, we reported on an association between decreased HRV parameters (suggestive of ANS dysfunction), and amyloidosis of FMF, particularly at a progressive stage.

P01-003 – Bleeding disorder in FMF

The most serious complication in Familial Mediterranean fever (FMF) is the development of amyloidosis, which usually determines the prognosis. Amyloid deposition can be systemic or organ-specific. The clinical features of amyloidosis are dependent on the organs involved, type of amyloidosis, rate of amyloid deposition and amount of amyloid fibrils. Organ dysfunction can cause life-threatening bleeding. Amyloid deposition is the main cause of abnormal bleeding but also coagulation factor deficiencies, hyperfibrinolysis, platelet dysfunction and amyloid angiopathy with increased fragility of blood vessels can be regarded as other important pathogenetic factors. Herein a case of FMF amyloidosis with splenomegaly, refractory cytopenia and bleeding disorder is presented.

OP0109 Evaluation of potential risk factors of amyloidosis in familial mediterranean fever

BackgroundFamilial Mediterranean Fever (FMF) is a genetic disease which is frequently seen in Middle East Region. The most common reason of morbidity and mortality is the end stage renal failure...

THU0495 Are Different Disease Subtypes with Distinct Clinical Expression Present in Familial Mediterranean Fever: Results of a Cluster Analysis

BackgroundFamilial Mediterranean fever (FMF) is an auto-inflammatory disorder characterized by self limited attacks of fever and serositis. The disease expression may be different in different ethnic groups and patients with...

Mean platelet volume as a potential predictor of proteinuria and amyloidosis in familial Mediterranean fever

This study aims to compare the mean platelet volume (MPV) levels in children and adults diagnosed with familial Mediterranean fever (FMF) during attack-free periods in order to find out whether it reflects the emergence of microalbuminuria/proteinuria and the development of amyloidosis or not. The study consisted of 63 pediatric patients (group 1), 50 adult patients (group 2), 50 healthy children (group 3), and 43 healthy adults (group 4). Demographic data, age at diagnosis, duration of the disease and colchicine treatment, and FMF gene mutations were recorded, and erythrocyte sedimentation rate, C-reactive protein, fibrinogen, hemoglobin, white blood cell count, platelet count, MPV, blood urea nitrogen, creatine, albumin, and urine microalbumin and protein levels were evaluated. According to the presence of microalbuminuria/proteinuria, patient groups were subgrouped into two by themselves as pediatric and adult groups with and without proteinuria. The most frequent mutation was M694V. MPV was significantly higher in FMF patients than those in the healthy control groups. Microalbuminuria/proteinuria were detected in 18 (28.57 %) of 63 pediatric patients and 26 (52 %) of 50 adult patients. Amyloidosis has been identified in 3 (16.6 %) of 18 pediatric patients and 18 (69.23 %) of 26 adult patients with proteinuria. Subgroup comparisons revealed that MPV levels were significantly higher in patients with proteinuria than patients without proteinuria in both pediatric and adult groups. Moreover, MPV levels were also significantly higher in adult patients with or without proteinuria than in pediatric patients with or without proteinuria. There were significant differences in terms of serum albumin levels between the groups with and without proteinuria as expected. The increase in MPV over the years of the disease, especially in groups with proteinuria, may be an important predictor of continuing increase of subclinical inflammation, the emergence of the microalbuminuria/proteinuria, and the developing of amyloidosis, but further studies are needed in order to support this proposal.

Is Neutrophil/Lymphocyte Ratio Associated with Subclinical Inflammation and Amyloidosis in Patients with Familial Mediterranean Fever?

Background. The purpose of the present study is to determine the association between neutrophil/lymphocyte ratio and both subclinical inflammation and amyloidosis in familial Mediterranean fever. Methods. Ninety-four patients with familial Mediterranean fever and 60 healthy volunteers were included in the study. Of the patients, 12 had familial Mediterranean fever related amyloidosis. The neutrophil/lymphocyte ratio of the patients was obtained from the hematology laboratory archive. Results. The neutrophil/lymphocyte ratio was significantly higher among persons with familial Mediterranean fever compared to healthy individuals (P < 0.0001). Also, neutrophil/lymphocyte ratio was significantly higher in patients with amyloidosis than in amyloidosis-free patients (P < 0.0001). Since NLR was evaluated in nonamyloid and amyloid stages of the same patient population (type 1 phenotype), we obtained significant statistical differences (1.95 ± 0.30 versus 2.64 ± 0.48, P < 0.05, resp.). With the cutoff value of neutrophil/lymphocyte ratio >2.21 and AUC = 0.734 (P = 0.009), it was a reliable marker in predicting the development of amyloidosis. Conclusion. The neutrophil/lymphocyte ratio, an emerging marker of inflammation, is higher in patients with familial Mediterranean fever in attack-free periods. The neutrophil/lymphocyte ratio may be a useful marker in predicting the development of amyloidosis.

Familial Mediterranean Fever in Siblings

Genetic and environmental factors have been implicated in disease severity and development of amyloidosis in familial Mediterranean fever (FMF). We investigated similarities in clinical characteristics, disease severity, and treatment response within siblings with FMF. The study group consisted of 2 or more siblings who were followed in our center with the diagnosis of FMF. Siblings were evaluated for demographic data, clinical and laboratory disease features, genetic analysis of MEFV mutations, and disease severity score. The intraclass correlation coefficient (ICC), which can be interpreted as the expected correlation between 2 siblings, was used to reflect within-family similarity. The study included 67 pediatric patients from 31 different families. When we investigated the similarity of siblings after adjusting for genetic effects, we found very low ICC with p > 0.05 in the majority of clinical features, disease severity, and colchicine dosages. However, age at disease onset, age at onset of therapy, attack-free acute-phase reactant levels, and presence of amyloidosis were found to be similar within siblings (relatively high ICC with p < 0.05). Siblings with FMF had different clinical findings and disease severity. They had similar amyloidogenic potential, proven by both similar presence of amyloid and increased levels of acute-phase reactants between attacks. Our findings strongly support that genetic factors may be more dominant in the development of amyloidosis.

Abnormal heart rate variability in AA amyloidosis of familial mediterranean fever

Background: A scarcity of data exists relating to the effect of amyloidosis of Familial Mediterranean fever (FMF) on the autonomic nervous system. Our aim was to further investigate the presence of dysautonomia in FMF-AA amyloidosis, using a comparative case series design. Material and methods: The study group consisted of 40 patients with FMF: 20 without co-morbidities or amyloidosis and 20 in various stages of renal amyloidosis. Time domain and power spectral analyses of heart rate dynamics were performed according to accepted procedures. Findings were compared with 20 healthy control subjects. Results: No statistically significant differences were found in any of the studied heart rate variability (HRV) parameters between patients with uncomplicated FMF and controls. In contrast, patients with progressive amyloidosis (post renal transplantation or on dialysis) had significantly lower HRV parameters compared to control subjects (i.e. mean low frequency power spectral components 104.30 ms2 vs. 172.09 ms2, p <0.05, mean standard deviation of all normal RR intervals 32.27 ms vs. 51.51 ms, p <0.05, mean HRV triangular index 9.08 vs. 15.82, p <0.05). The adjusted odds ratio was 14.5 (95%CI 1.21–165.03, p = 0.04) for HRV triangular index lower than 12.2 in the progressive amyloidosis group, 41.24 (95%CI 1.81–938.68, p = 0.02) for low frequency power spectral components values lower than 142.35 ms2, and 12.67 (95%CI 1.04–153.96, p = 0.04) for standard deviation of all normal RR intervals values lower than 40.15 ms. Conclusion: Amyloidosis of FMF, particularly at a progressive stage, is associated with HRV abnormalities suggestive of the presence of autonomic nervous system dysfunction.

Recurrent AA Amyloidosis in a Kidney Transplant

Recurrent AA amyloidosis in a kidney transplant is rare, especially when the underlying inflammatory condition is controlled. We present a 59-year-old man who underwent a living donor kidney transplant 17 years ago for kidney failure due to AA amyloid nephropathy in the setting of long-standing Crohn disease. His Crohn disease was quiescent before and after the kidney transplant. Transplant function had been stable until a month before presentation, when he developed worsening proteinuria and decreased kidney function. A transplant biopsy showed recurrent AA amyloidosis despite excellent clinical and histologic control of Crohn disease.

P-wave dispersion in systemic AA amyloidosis of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary disease characterized by attacks of fever and polyserositis. Recent studies differ as to whether FMF is associated with an abnormally high P-wave duration and P-wave dispersion, markers for supraventricular arrhythmogenicity. The aim of our study was to further evaluate atrial dispersion in FMF patients with amyloidosis. The study groups consisted of 16 patients with FMF and amyloidosis, and 16 age- and sex-matched control subjects. All participants underwent 12-lead electrocardiography under strict standards. P-wave length and P-wave dispersion in each individual patient were computed from a randomly selected beat and an averaged beat constructed from 7 to 12 beats, included in a 10-s electrocardiogram. No statistically significant differences were found between the groups for minimal, maximal, and average P-wave duration and P-wave dispersion, calculated either from a random beat or averaged beats. In conclusion, although a small difference cannot be excluded because of the small study groups, FMF patients with amyloidosis appear to have atrial conduction parameters similar to those of healthy controls, and therefore apparently do not have an increased electrocardiographic risk for developing supraventricular arrhythmias.

QT dispersion in amyloidosis due to familial Mediterranean fever

Cardiac amyloid deposition in FMF may cause increased QT dispersion (QTd), a marker for cardiac arrhythmias. The aim of this study was to further evaluate repolarization dispersion in familial Mediterranean fever (FMF) with amyloidosis. Findings on 12-lead electrocardiography were compared between 18 patients with FMF-amyloidosis and 18 age- and sex-matched control subjects. Repolarization and dispersion parameters were computed with designated computer software, and results of the 5 beats were subsequently averaged. There were no statistically significant differences between the groups as to average corrected QT interval length, average QTd interval, average QT corrected dispersion, or QT dispersion ratio. JT dispersion and JT corrected dispersion were also similar in both groups. In conclusion, patients with FMF-amyloidosis seem to have QT and JT dispersion parameters similar to those of healthy subjects. Future research and longer follow-ups should be conducted in order to evaluate the prognostic importance of repolarization dispersion parameters in amyloidosis of FMF.

Successful treatment of renal AA amyloidosis in familial Mediterranean fever with pegylated alpha-2a interferon

Renal AA amyloidosis is a severe consequence of chronic inflammatory diseases such as familial Mediterranean fever (FMF). FMF is caused by mutations in the MEFV gene, resulting in defective control of granulocyte-mediated inflammation. Interferon-alpha is known to induce MEFV expression in monocytes and granulocytes in vitro. We present the first case of colchicine-resistant FMF in which a durable disease remission and regression of renal amyloidosis was induced by chronic treatment with pegylated interferon-alpha.

TLR Polymorphisms in FMF: Association of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly, Thre399Ile) Polymorphisms and Myeloid Cell TLR-2 and TLR-4 Expression with the Development of Secondary Amyloidosis in FMF

Amyloidosis is the major complication of familial Mediterranean fever (FMF). Toll-like receptors (TLR) are involved in the activation of an innate immune system TLR-2 and TLR-4 recognize lipoteichoic acid and lipopolysaccharides (LPS), respectively. While TLR-2 Arg753Gln polymorphism upregulates, TLR-4 Asp299Gly and Thre399Ile polymorphisms downregulate inflammation. We investigated the effect of these polymorphisms on the development of amyloidosis in FMF patients. We also investigated myeloid cell TLR-2 and TLR-4 expressions in these patients. We studied 26 FMF patients and 13 FMF patients with amyloidosis. TLR-2 Arg753Gln and TLR-4 Asp299Gly and Thr399Ile polymorphisms were analyzed with the polymerase chain reaction-restriction fragment length polymorphism method. Myeloid cell baseline TLR-2 and TLR-4 and LPS-induced TLR-4 expressions were evaluated. The TLR-2 and TLR-4 polymorphism rate was compared with the results of 100 healthy subjects in our previous study. In addition, 13 healthy controls were enrolled for leukocyte TLR-2 and TLR-4 expressions. Serum amyloid A (SAA) levels were measured in these 13 control cases and in FMF patients during attack-free periods. The frequency of TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms in healthy controls in our previous study were 1%, 3%, and 2%, respectively. The frequency of these polymorphisms were not different in FMF patients (with or without amyloidosis) compared to the control group. Likewise, myeloid cell TLR-2 and TLR-4 expressions were not different among the controls and FMF patients. However, LPS-induced TLR-4 expression in granulocytes was more prominent in FMF patients. There was no correlation between TLR-2 and TLR-4 expressions and SAA levels. Neither myeloid cell TLR-2 and TLR-4 expressions nor TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms seem to affect the development of secondary amyloidosis in FMF patients in our study population.

Prevention of Amyloidosis in Familial Mediterranean Fever with Colchicine: A Case-Control Study in Armenia

Objective: To determine whether or not the use of colchicine decreases the risk of amyloidosis among Armenian patients with familial Mediterranean fever (FMF). Subjects and Methods: The study included 99 Armenian patients from the Center of Medical Genetics database with genetically ascertained FMF; 33 had renal amyloidosis and 66 were randomly selected control patients without renal amyloidosis. Self- reported colchicine use was assessed by interviewer-based questionnaire. Results: The patients with incident amyloidosis were more likely to be older men, but younger at the time of disease onset, and more likely to have had a family history of amyloidosis and M694F mutation in the MEFV gene compared to patients without amyloidosis. The risk of amyloidosis decreased with adequate colchicine use rather than nonadequate use (adjusted odds ratio, OR, 0.48, 95% confidence interval, CI, 0.16–1.43), continuous colchicine use rather than interrupted use (adjusted OR 0.15, 95% CI 0.04–0.53), earlier rather than later initiation age of colchicine treatment (adjusted OR 0.95, 95% CI 0.90–1.01), current colchicine rather than ever/never colchicine use (adjusted OR 0.20, 95% CI 0.05–0.89). Conclusion: The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2–1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF.

Country as the primary risk factor for renal amyloidosis in familial mediterranean fever

Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis. Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis). Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.

The Effect of Dialytic Modalities on Clinical Outcomes in ESRD Patients with Familial Mediterranean Fever

Background. Familial Mediterranean fever (FMF) is an autosomal recessive disease seen primarily in Sephardic Jews, Turks, and Armenians. The disease manifests as recurrent attacks of fever and serositis. The most important complication of FMF is the development of renal failure due to AA type amyloidosis. There has not been extensive experience with renal replacement therapy in FMF amyloidosis. Nevertheless, there may be a concern about the possibility of higher rates of morbidity and mortality in amyloidotic patients maintained on chronic hemodialysis. Moreover, there is not enough experience regarding patients on chronic peritoneal dialysis. As a result, the best treatment modality of end-stage renal disease (ESRD) in these circumstances still remains unclear. This study aimed to compare the effect of hemodialysis and peritoneal dialysis modalities on clinical outcomes in ESRD patients associated with FMF amyloidosis. Methods. Forty FMF patients with ESRD due to amyloidosis were retrospectively analyzed. All 40 patients were on renal replacement therapy, 20 on hemodialysis (HD), 20 on peritoneal dialysis (PD). Peritoneal solute transport rates, weekly mean creatinine clearance, and daily mean ultrafiltration (UF) of the patients on chronic peritoneal dialysis were evaluated. Weekly dialysis durations, dialysis membrane properties, Kt/V values, interdialytic weight gains, and frequency of hypotension during dialysis were evaluated on hemodialysis patients. All of the patients were examined according to their demographic characteristics, laboratory results, duration time on dialysis, erythropoietin requirements, frequencies of infectious complications requiring hospitalization, and the two renal replacement modalities mentioned above were compared in terms of these parameters. Results. Serum albumin levels of the patients with FMF amyloidosis who were maintained on peritoneal dialysis treatment were lower (2.87 vs 3.45) and the frequency of infections of the same group was higher (4.2 vs 0.5) than the patients with ESRD secondary to other diseases in the CAPD group. Conclusions. This retrospective analysis showed that peritoneal dialysis may have some disadvantages in amyloidotic patients. Due to the high frequency of hypoalbuminemia and infectious complications seen in this group, peritoneal dialysis is widely accepted as an alternative choice of treatment when hemodialysis is not appropriate.

Is the CD14 C159T polymorphism effective in the development of secondary amyloidosis in Familial Mediterranean fever?

The most important complication of FMF is the development of amyloidosis. It is more common in the eastern Mediterranean compared to the US. The individual response to endotoxin may have a significant effect on the development of amyloidosis in FMF patients. To investigate the association between CD14 promotor C-159T polymorphism and development of amyloidosis, one hundred and forty-six patients who had FMF and had not developed amyloidosis; 26 with FMF and secondary amyloidosis and 92 controls were genotyped at the CD14-C159T locus. There was no difference between the genotype distribution of FMF patients (CC 30.0%, CT 50.0%, TT 20.0%) and controls (CC 29.2%, CT 45.8%, TT 25%); or between FMF patients with amyloidosis (CC 30.8%, CT 53.8%, TT 15.4%) or without amyloidosis (CC 29.2%, CT 45.8%, TT 25%). Our study shows that the CD14-C159T polymorphism is not associated with FMF or development of amyloidosis in the population studied. The effect of the genetic variations in the endotoxin signaling pathway under different environmental conditions such as high and low endotoxin exposure remain to be determined.

The value of the levels of acute phase reactants for the prediction of familial Mediterranean fever associated amyloidosis: a case control study

In order to determine the role of levels of acute phase proteins (APPs) for the development of amyloidosis in familial Mediterranean fever (FMF) patients, the levels of serum amyloid A (SAA), C reactive protein (CRP), fibrinogen and erythrocyte sedimentation rate were measured in paired sera of 36 FMF patients during and in between acute attacks, 39 of their healthy parents (obligate heterozgotes), and 15 patients with FMF associated amyloidosis. To compare the levels of APPs, 39 patients with chronic infections or inflammatory diseases who may develop secondary amyloidosis, 20 patients with acute infections who are known to have elevated acute phase response but will never develop amyloidosis and 19 healthy controls were included. The median levels of all APPs are increased in the patients with FMF during attacks and a significant decrease was observed after the attack was over. The level of SAA was above reference range in all FMF patients during the attack free period and the level of at least one other APP was also above normal in 64% of the patients. Both CRP and SAA levels were found to be higher in obligate heterozygotes compared to controls. The levels of SAA in patients with FMF during the attack-free period, obligate heterozygotes and patients with FMF-amyloidosis were found to be similar. The levels in each group were found to be higher than SAA levels found in healthy controls yet lower than the levels measured in the patients with acute infections and patients with chronic inflammation or chronic infections. In conclusion, our results show that SAA level reflects subclinical inflammation with high sensitivity but its value for the prediction of amyloid formation process seems to be low.