Efficacy and safety of long-term treatment with intravenous colchicine for familial Mediterranean fever (FMF) refractory to oral colchicine.

Colchicine is the mainstay of treatment for familial Mediterranean fever (FMF). Intravenous (IV) colchicine, administered over several months, has been shown to be effective for FMF patients unresponsive to oral colchicine. The objective of this study was to evaluate the efficacy and safety of long-term IV colchicine treatment in oral colchicine-resistant FMF. We analyzed data of 15 patients with frequent FMF attacks, despite a maximal tolerated dose of oral colchicine (2-3 mg/day), who were treated with weekly IV injections of 1 mg of colchicine for at least 12 months. Treatment efficacy was determined by changes in frequency, duration and severity of FMF attacks. Safety was assessed according to adverse events. The mean duration of IV colchicine treatment was 5.16 ± 2.85 years. Decreases were observed from pre-treatment period in the monthly mean rates of abdominal attacks (from 5.6 ± 3.7 to 1.9 ± 3.3, p = 0.0009), joint attacks (from 6.5 ± 5.1 to 1.6 ± 1.6, p = 0.01) and overall attacks (from 22.3 ± 16.2 to 7.4 ± 5.7, p = 0.002) as well as in the mean duration (from 3.8 ± 1.5 to 2.4 ± 1.1 days per attack, p = 0.008) and severity of attacks (from 9.9 ± 0.3 to 5.7 ± 2.6, on a scale of 0-10, p < 0.05). The rate of adverse events was low, and they were mainly gastrointestinal. No severe or serious adverse events were recorded. Long-term treatment with IV colchicine in patients unresponsive to oral colchicine therapy is effective and safe.

Toll-like receptor 2 is overexpressed in Familial Mediterranean fever patients and is inhibited by colchicine treatment.

AIM: To study the role of Toll-like receptor (TLR) 2 in Familial Mediterranean fever (FMF) inflammatory process. METHODS: TLR2 expression on monocytes of FMF attack-free patients (n = 20) and the effect of sera of FMF patients with an acute attack (n = 9) on TLR2 expression on monocytes of healthy donors were studied by flow cytometry (FACS). TLR2 expression was also studied in THP-1 cells, and TLR2 downstream signaling was studied by ELISA for the secretion of IL-1ß and pro-inflammatory cytokines or by western blotting to measure nuclear factor (NF)-κB. RESULTS: FMF attack-free patients had increased CD14 + TLR2+ cell count as compared to healthy donors. High-dose colchicine treatment (≥2 mg/d) inhibited this increased expression in FMF patients. Colchicine in vitro also inhibited TLR2 expression on THP-1 cells. Sera from FMF patients with an acute attack induced TLR2 expression by both monocytes of healthy donors and THP-1 cells as well as pro-inflammatory cytokine secretion by healthy monocytes, while colchicine inhibited this induction. Pam2CSK4 increased interleukin-1ß (IL-1ß) secretion by peripheral blood mononuclear cells (PBMCs) of healthy donors, and this activation was inhibited by colchicine. THP-1 cells presented elevated NF-κB expression when cultured with Pam2CSK4, whereas colchicine inhibited this elevation. CONCLUSIONS: TLR2 activation was upregulated in monocytes of FMF patients, and colchicine inhibited this upregulation both in -vitro and in -vivo. This indicates that elevated expression of TLR2 promotes the production of pro-inflammatory cytokines, which may contribute to uncontrolled inflammation in FMF.

Normal arterial stiffness in familial Mediterranean fever. Evidence for a possible cardiovascular protective role of colchicine.

OBJECTIVES: Familial Mediterranean fever (FMF) is an autoinflammatory disorder with episodic and persistent inflammation, which is only partially suppressed by continuous colchicine treatment. While chronic inflammation is considered an important cardiovascular risk factor in many inflammatory disorders, its impact in FMF is still disputed. We measured arterial stiffness, a marker of atherosclerotic cardiovascular disease, in a group of FMF patients, in order to evaluate the cardiovascular consequences of inflammation in FMF and the role of colchicine in their development. METHODS: Eighty colchicine treated FMF patients, without known traditional cardiovascular risk factors, were randomly enrolled in the study. Demographic, genetic, clinical and laboratory data were retrieved from patient files and examinations. Arterial stiffness was measured using pulse wave velocity (PWV). The recorded values of PWV were compared with those of an age and blood pressure adjusted normal population, using internationally endorsed values. RESULTS: FMF patients displayed normal PWV values, with an even smaller than expected proportion of patients deviating from the 90th percentile of the reference population (5% vs. 10%, p=0.02). The lowest PWV values were recorded in patients receiving the highest dose of colchicine (≥2 mg vs. 0-1 mg, p=0.038), and in patients of North African Jewish origin, whose disease was typically more severe than that of patients of other ethnicities; both observations supporting an ameliorating colchicine effect (p=0.043). CONCLUSIONS: Though subjected to chronic inflammation, colchicine treated FMF patients have normal PWV. Our findings provide direct evidence for a cardiovascular protective role of colchicine in FMF.

Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Familial Mediterranean fever (FMF) is refractory to colchicine prophylaxis in 10-20% of patients. In a number of patient series, treatment with anakinra, an interleukin-1-blocking agent, prevented FMF attacks in those with colchicine-resistant FMF. This study was undertaken to evaluate the efficacy and safety of anakinra in the treatment of colchicine-resistant FMF, using a randomized controlled trial. METHODS: Patients with colchicine-resistant FMF receiving colchicine (dosage ≥1.5 to ≤3 mg/day) were recruited and randomly assigned to receive anakinra or placebo (vehicle). The treatment duration was 4 months. Primary efficacy outcomes were the number of attacks per month, and the number of patients with a mean of <1 attack per month. Quality of life was assessed using a 0-10-grade visual analog scale (VAS), and safety was assessed according to the number and severity of adverse events. RESULTS: Twenty-five patients with colchicine-resistant FMF (14 women) were enrolled, of whom 12 were randomized to receive anakinra and 13 to receive placebo. The mean ± SD number of attacks per patient per month was 1.7 ± 1.7 in those receiving anakinra and 3.5 ± 1.9 in those receiving placebo (P = 0.037). Six patients in the anakinra group, compared to none in the placebo group, had <1 attack per month (P = 0.005). A beneficial effect of anakinra was noted in the number of attacks in the joints per month in patients receiving anakinra (mean ± SD 0.8 ± 1.6 versus 2.1 ± 1.1 in the placebo group; P = 0.019) and in quality of life (mean ± SD VAS score 7.7 ± 2.3 in the anakinra group versus 4.2 ± 2.9 in the placebo group; P = 0.045). The number of adverse events per patient per month was comparable between the anakinra group and the placebo group (mean ± SD 2.03 ± 1.75 versus 3.34 ± 2.5; P = 0.22). There were no severe adverse events. CONCLUSION: In this randomized controlled trial, anakinra appears to be an effective and safe treatment for colchicine-resistant FMF.

[POST COLONOSCOPY AND POLYPECTOMY ENDOCARDITIS - A CASE CHALLENGING THE CURRENT AMERICAN GUIDELINES FOR ANTIMICROBIAL PROPHYLAXIS].

INTRODUCTION: Short text: Click here for article written by Naama Rappoport, Neta Gotlieb, Olga Feld, Avi Livneh HAREFUAH 2016: 155: November: 637-641.

Colchicine-free remission in familial Mediterranean fever: featuring a unique subset of the disease-a case control study.

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.

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.

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.

Normal autonomic nervous system responses in uncomplicated familial Mediterranean fever: a comparative case-control study.

There is a paucity of knowledge regarding the autonomic nervous system function in patients with familial Mediterranean fever (FMF). Therefore, our aim was to evaluate autonomic responses in patients with FMF using complementary tests. The study groups included 33 patients with uncomplicated FMF and 39 control subjects. Autonomic function was evaluated by measuring responses to metronomic breathing, the Valsalva maneuver, and the Ewing maneuver. Autonomic parameters were computed from electrocardiograms with designated computer software. There were no statistically significant differences in any of the measured parameters of autonomic function between the patient and control group. The measured autonomic parameters of both groups were similar to those previously reported in healthy individuals. In conclusion, patients with FMF who did not develop amyloidosis due to continuous colchicine treatment appeared to have normal autonomic function, as reflected by the normal response to physiological autonomic stimuli.

Heart rate variability in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a hereditary disease, characterized by recurrent episodes of fever and polyserositis. Heart rate variability (HRV) is a powerful, simple and reliable technique to evaluate autonomic nervous system function. Previous studies of physiologic parameters during tilt-test have suggested that patients with FMF have abnormal cardiovascular reactivity and occult dysautonomia. Prompted by these findings, the present study sought to evaluate HRV in patients with FMF, at rest and in the standing position. The study sample included 34 patients with FMF and 34 sex- and age-matched control subjects. All underwent electrocardiography according to strict criteria. HRV parameters were computed with custom-made software. There was no significant difference in HRV parameters, in either the supine or standing position, between the FMF and control groups. In both groups, the upright position was associated with a significant decrease, when compared with the supine position, in maximal RR interval, minimal RR, average RR, root square of successive differences in RR interval, number of intervals differing by >50 ms from preceding interval (NN50), NN50 divided by total number of intervals (pNN50) and high-frequency components as well as a significant increase in average heart rate, very low frequency or low-frequency components, low-frequency/high-frequency components ratio and total power. In conclusion, patients with FMF who are continuously treated with low-dose colchicine have not developed amyloidosis and have normal HRV parameters in the supine and upright position. Further investigation of occult dysautonomia in FMF is needed.

QT dispersion in uncomplicated familial Mediterranean fever.

The aim of the study was to further evaluate repolarization dispersion in familial Mediterranean fever (FMF). Findings on 12-lead electrocardiography were compared with 32 patients with uncomplicated FMF and age- and sex-matched control subjects. All procedures followed stringent standards. Repolarization and dispersion parameters were computed with designated computer software, and results of the five beats were subsequently averaged. There were no statistically significant differences between the groups in average QT and average corrected QT interval length, average QT interval dispersion, average QT corrected dispersion, or QT dispersion ratio. During 6 months of follow-up, no cases of sudden death or arrhythmia were documented in either group. Patients with FMF who are continuously treated with low-dose colchicine and have not developed amyloidosis seem to have QT dispersion parameters similar to those of healthy subjects and therefore apparently have no increased risk of adverse cardiac events associated with abnormal repolarization.

Familial Mediterranean fever in children presenting with attacks of fever alone.

OBJECTIVE: Familial Mediterranean fever (FMF) is an inherited disease characterized by attacks of febrile polyserositis. In children, attacks of fever alone, or with headache and malaise, may precede other forms of attacks. Our objective was clinical and genetic characterization of FMF and its development in pediatric patients who first presented with attacks of fever alone. METHODS: Clinical characterization and MEFV genotype of all FMF patients < 16 years of age at disease onset and first presenting with attacks of fever alone were analyzed and compared for age, sex, and disease duration with matched FMF patients presenting with serositis at the onset of the disease. RESULTS: There were 814 patients with FMF in our registry. Fifty patients formed the study group and 234 patients the control group. In the study group, the first (febrile) attacks appeared at a younger age than in the control group (1.7 +/- 1.6 yrs vs 5.0 +/- 4.1 yrs, respectively; p < 0.0001), diagnosis was made earlier (4.2 +/- 2.7 yrs vs 6.7 +/- 4.1 yrs; p < 0.0001), despite a trend for a longer delay in diagnosis. In the study group, attacks were shorter (1.6 +/- 0.8 days vs 2.1 +/- 1.0 days; p = 0.023) and homozygosity to the M694V mutation was more prevalent (46% vs 31%; p = 0.03). Attack rate, colchicine dose, and the MEFV mutation carrier rates were comparable between the groups. In 40/50 (80%) of the patients with fever alone, serositis had developed over a course of 2.9 +/- 2.2 years after disease onset. CONCLUSION: FMF in young children may begin with attacks of fever alone, but it progresses to typical FMF disease over the next 2.9 +/- 2.2 years. Our study demonstrates that clinical heterogeneity at presentation is more likely to indicate a feature of a disease in development, rather than to mark distinct phenotypes of FMF.

Familial Mediterranean Fever in the first two years of life: a unique phenotype of disease in evolution.

OBJECTIVE: To characterize the clinical and genetic features of familial Mediterranean fever (FMF). STUDY DESIGN: Clinical presentation and MEditerranean FeVer mutation type of all patients with FMF, who first manifested the disease at < or =2 years of age were analyzed and compared with patients who first presented with FMF between 2 and 16 years. RESULTS: Of 814 patients with FMF, in 254 patients (31.2%) the first FMF attack was at < or =2 years of age, with a mean age at onset of 1.1 +/- 0.8 years. They were compared with 242 patients who presented with their first manifestation of FMF at 2 to 16 years. The clinical manifestations of FMF were comparable in the 2 patient groups, but the delay of diagnosis was longer in patients with early presentation (3.2 +/- 3.2 years vs.1.9 +/- 2.7 years in the group with onset at 2-16 years, P < .001). A subgroup of patients (60/254), who were diagnosed at < or =2 years had the highest rate of attacks of fever alone as their sole manifestation (40.0% vs 8.4%, P < .05), and less peritonitis (45% vs 86.1%, P < .05) and pleuritis (3.4% vs 32.9%, P < .05). Most of these patients were homozygous for the M694V mutation and were of North African (Sephardic Jewish) extraction. CONCLUSION: In early life, FMF often begins with an atypical presentation, characterized by attacks of fever alone, and its diagnosis and initiation of treatment is therefore significantly delayed.

MEFV mutation carriage in Israeli Jewish individuals from ethnicities with low risk for familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a disease caused by mutations in the MEditerranean FeVer gene (MEFV), and in Israel it most commonly affects Jews of North African extraction, in whom the mutation carrier rate is as high as 1 in 5. To assess the protective as well as the modulating affect of MEFV mutation carriage on various inflammatory disease states, we sought to define the frequency of MEFV mutations in Israeli Jewish individuals of various ethnicities, including those with low frequency of FMF, which were not in the focus of our attention hitherto. A total of 163 adults of Bucharian, Turkish, Georgian, Yemenite and Bulgarian origin comprised the study group. The prevalence of the most frequent MEFV mutations in the Israeli Jewish population, namely: M694V, V726A and E148Q, was assessed. The association of mutation carriage with a personal history of FMF-like phenomena, as well as various inflammatory and non-inflammatory diseases, was evaluated. A high MEFV mutation frequency was found among Jews of Bucharian, Georgian and Bulgarian origin (20%), whereas intermediate and low rates were detected in Jews of Turkish and Yemenite extraction (14 and 8%, respectively). FMF-like manifestations and related diseases were observed more often in MEFV mutation carriers than in their counterparts. MEFV mutation frequency, directly assessed by DNA analysis, exceeds the rate calculated from disease prevalence in Israeli Jewish individuals originated from ethnicities with a low prevalence of FMF. MEFV mutation carriage in this subgroup is associated with various inflammatory disorders.

A case of murine typhus associated with large vessel infarct of the spleen.

We present a case of Rickettsia typhi infection (the causative agent of endemic typhus) associated with an isolated splenic infarction. Large vessel infarction is a rare complication of murine typhus, unlike infections caused by Rickettsia rickettsii and Rickettsia conorii (the spotted fever group rickettsias) which are known to cause hemostatic changes that lead to coagulopathies and thrombotic events. This case adds to the scarce data in the literature on the association between large vessels infarction and endemic typhus and also highlights the importance of considering rickettsial infection in the differential diagnosis in the appropriate clinical settings.