For Familial Mediterranean Fever Research Articles

Лечение колхицинрезистентной периодической болезни: ретроспективное когортное исследование

Lifelong administration of colchicine is the mainstay of treatment for familial Mediterranean fever (FMF), whereas canakinumab, a monoclonal antibody that blocks the effects of interleukin (IL)-1β, can be used in case of colchicine resistance or its poor tolerability.

Drug metabolism and inflammation related distinct miRNA signature of colchicine resistant familial Mediterranean fever patients

ObjectiveColchicine is the primary treatment for familial Mediterranean fever (FMF). Although colchicine is safe and effective in FMF patients, around 5–10% of patients show resistance to the drug. This study investigates the possibility of a link between colchicine resistance and the distinct miRNA profiles in colchicine resistant FMF patients. MethodsDifferentially expressed miRNAs in colchicine resistant FMF patients were detected by Affymetrix 4.0 miRNA array analysis. These miRNAs were then categorized based on the role of their target genes in drug metabolism and inflammation related pathways. qRT-PCR was used to validate candidate miRNAs selected by Enrichr, a gene enrichment analysis system based on the relevance of possible target genes in drug metabolism pathways. Expression levels of these miRNAs’ potential target genes were investigated by qRT-PCR. Then, a colchicine resistant hepatoblastoma cell line (HEPG2) was established, and the differentially expressed miRNAs and genes identified in patients were also analyzed in this colchicine-resistant cell line. Results25 differentially expressed miRNAs were detected in colchicine resistant FMF patients. miR-183-5p, miR-15b-5p, miR-505-5p, and miR-125a-5p were identified to be associated with drug resistance and inflammatory pathways and thus chosen for further validation. miR-183-5p, miR-15b-5p, miR-505-5p miRNAs showed significantly differential expression in qRT-PCR.NFKB1, NR3C1, PPARα – drug absorption, distribution, metabolism, and excretion (ADME) genes were predicted to be targeted by these miRNAs. Among these targets, NFKB1 and NR3C1 were differentially over expressed in colchicine resistant FMF patients. These findings were validated in the colchicine resistant hepatoblastoma cell line (HEPG2). ConclusionThis is the first study evaluating the role of miRNAs in colchicine resistant patients with FMF. Their differential expression may result in resistance to standard colchicine treatment by affecting the expression of genes that take place in drug absorption, distribution, metabolism, and excretion (ADME) or nuclear receptors that regulate ADME genes, thus potentially playing a role in both drug metabolism and inflammation.

The Effect of Clinical and Genetic Variables of Familial Mediterranean Fever Patients: Real Life Data.

The Eurofever/the Pediatric Rheumatology International Trials Organization (PRINTO) classification criteria for familial Mediterranean fever (FMF) include a combination of clinical symptoms and genotype. The pathogenicity of gene variants associated with FMF is categorized by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification criteria. The aim of this study was to evaluate the real-life impact and usefulness of the Eurofever/PRINTO classification criteria and the INSAID classification criteria in patients with FMF and their impact on treatment management. In this medical records review study, the files of FMF patients who met the Eurofever/PRINTO classification criteria were reviewed. The MEFV (MEditerranean FeVer) variants were grouped according to the INSAID classification criteria. Of the 1062 patients, the female-to-male ratio was 1:1.01. In group 1, there were 150 patients (14.1%) who met the clinical criteria. Group 2 consisted of 912 patients (85.9%) who met the criteria according to genetic variants. The mean ages at symptom onset in groups 1 and 2 were 5.6 ± 3.8 and 1.5 ± 1.2 years, respectively ( p = 0.024). Whereas the mean annual attack frequency was 2.7 ± 3.1/year in group 1, it was 4.1 ± 2.3/year in group 2 ( p = 0.04). The pathogenic variant was higher in the colchicine-resistant group compared with the responders ( p = 0.12). The Eurofever/PRINTO classification criteria may provide a new perspective on the diagnosis and clinical follow-up of FMF patients. Patients with a pathogenic variant who meet the Eurofever/PRINTO classification criteria including genetic variables have earlier onset of disease and more frequent attacks than those who meet the criteria including clinical variables. These patients need regular and closer follow-ups in terms of attack frequency, colchicine dose adjustment, and colchicine resistance.

Possible Association of Mutations in the MEFV Gene with the Intestinal Phenotype of Behçet's Disease and Refractoriness to Treatment.

Mediterranean fever (MEFV) gene mutations are responsible for familial Mediterranean fever (FMF) and associated with other inflammatory diseases. However, the effects of MEFV gene mutations on intestinal Behçet's disease (BD) are unknown. In this study, we investigated these mutations and clinical features in patients with intestinal BD. MEFV gene analysis was performed in 16 patients with intestinal BD, 10 with BD without intestinal lesions, and 50 healthy controls. Clinical features of patients with intestinal BD were retrospectively assessed. The rates of MEFV gene mutations in patients with intestinal BD, BD without intestinal lesions, and healthy controls were 75%, 50%, and 38%, respectively. Only 2 of 12 patients with intestinal BD harboring MEFV gene mutations (17%) were controlled without immunosuppressive treatment, while 8 patients (67%) required therapy with tumor necrosis factor (TNF) inhibitors. Among patients with intestinal BD without MEFV gene mutations (four patients), three (75%) were controlled by the administration of 5-aminosalicylic acid with or without colchicine, and one (25%) required TNF inhibitors. All patients who underwent intestinal resection had MEFV gene mutations. Immunohistochemical analysis and in situ hybridization with interleukin-1β (IL-1β) showed a high expression of IL-1β only in injured areas, suggesting that IL-1β may be involved in the formation of ulcers in patients with intestinal BD carrying MEFV gene mutations. Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.

Importance of hematological markers in familial Mediterranean fever in terms of disease severity and amyloidosis.

There are limited follow-up parameters for familial Mediterranean fever (FMF) related to disease severity and amyloidosis. Some hematological markers are emerging to assess inflammation. In this study, we hypothesized that some hematological parameters could be used to determine disease severity and amyloidosis in FMF. We included 274 adult FMF patients, and evaluated the relationship between neutrophil lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR) and platelet-lymphocyte ratio (PLR), platelet counts and leukocyte counts, mean erythrocyte haemoglobin concentration (MCHC) and mean erythrocyte haemoglobin (MCH) with disease severity and amyloidosis. First, we classified patients according to disease severity and presence of amyloidosis. We then compared the parameters within the groups. In addition, we determined predictive cut-off values with ROC analysis. Finally, we correlated the change in ISSF scores with the change in hematological parameters of 52 patients with follow-up hematological indices after six months. The patients with severe-moderate group had higher CRP levels (p < 0.001), white blood cell (p = 0.002) and neutrophil counts (p = 0.004) and, conversely, lower MCHC levels (p = 0.001) than patients with mild disease severity. FMF patients with amyloidosis had higher neutrophil (p = 0.04) and monocyte count (p = 0.02), increased NLR (p = 0.01) and lower MLR (p = 0.02) levels than those without. In addition, MCHC levels were also lower in the severe-moderate group in the follow-up analyses after sixth months (p = 0.03). MCHC, neutrophil and monocyte counts, NLR, MLR may be associated with poor prognosis in FMF patients. These parameters can be used in conjunction with acute phase reactant and clinical features to assess disease status.

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis.

Several studies have suggested that mutations in MEFV, the gene responsible for familial Mediterranean fever (FMF), are frequently detected in inflammatory bowel disease (IBD) patients. We aimed to provide further evidence regarding a potential correlation between MEFV gene mutations and IBD by identifying all relevant studies and analyzing their results. EMBASE, PubMed/MEDLINE, and Google Scholar were used to identify all studies that published until January 2021 and reported MEFV mutation patterns in patients with ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC) with or without a control group. The Newcastle-Ottawa quality assessment scale was used to appraise the quality of the included studies. Thirteen observational studies, including 937 patients and 977 controls, were analyzed. MEFV mutation rate in IBD patients was 0.238 (95%CI: 0.209-0.270; I 2 =95%); MEFV mutated alleles were more frequent in IBD patients when compared with controls (p=0.03 for UC, p=0.01 for CD and IC). Subgroup analysis indicated that MEFV mutations were increased in patients with IC when compared with UC and CD (I 2 =91%, p<0.001). Patients with extra-intestinal manifestations and pancolitis had 2.57 (95%CI 1.07-6.14; p=0.03) and 2.02 (95%CI: 1.01-4.04, P=0.049) odds ratios to carry MEFV mutant genotypes, respectively. Exon 10 mutations had the most serious impact. No source of heterogeneity was detected. MEFV mutations are common in IBD and are linked with the presence of extra-intestinal manifestations and pancolitis. Further research to assess the clinical significance and evolutionary significance of MEFV mutations in IBD patients is warranted.

The impact of the Eurofever criteria and the new InFevers MEFV classification in real life: Results from a large international FMF cohort

IntroductionNew Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants. ObjectivesTo evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort. MethodsBaseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients. ResultsSince November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC−). The majority of the EPCC− patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC− patients (69%, p < 0.0001), who were treated in a higher proportion with steroid or NSAID on demand (p = 0.003 and 0.008, respectively). Four percent of patients received Anti-IL-1 treatment. ConclusionsThe combination of EPCC and the 2018 INSAID classification of MEFV variants is able to identify two distinct groups of patients, which differ in clinical characteristics, therapeutic approach and response to treatment. EPCC+ patients displayed the typical features of FMF, while EPCC− patients had a more variable phenotype with a lower percentage of response to colchicine.

Discontinuation of Colchicine Therapy in Children With Familial Mediterranean Fever.

Colchicine has been considered a lifelong therapy for familial Mediterranean fever (FMF). Recent studies describe patients who discontinued colchicine, but there is a lack of data pertaining to predictors of success. The aims of our study were to describe a cohort of pediatric patients with FMF who discontinued colchicine therapy, and to identify factors predicting successful termination of colchicine. This study describes a cohort of pediatric patients with FMF who discontinued colchicine therapy following a relatively prolonged attack-free period (> 6 months), and identifies factors predicting successful termination. Data collected included demographic, clinical, and laboratory characteristics of children diagnosed with FMF aged < 16 years who underwent a trial of colchicine discontinuation. Data from patients who successfully ceased colchicine therapy were compared to those of patients who relapsed. Of 571 patients with FMF, 59 (10.3%) discontinued colchicine therapy. The average attack-free period before enrollment was 0.97 ± 1.4 years. Follow-up after ceasing colchicine was 5.0 ± 3.05 years, during which time 11 (20%) patients had an attack. The most common symptoms were fever (100%) and abdominal pain (80%). For those failing discontinuation, colchicine was restarted within 1.3 years (range 0.3-5.0, median 0.7 yrs). A longer attack-free period prior to colchicine discontinuation predicted success. Myalgia and arthritis prior to colchicine cessation were more common among children who required renewal of colchicine. Cessation of colchicine therapy should be considered following prolonged remission in a select group of patients. Patients with arthritis or myalgia are more likely to have an attack after ceasing colchicine therapy.

Clinical features of children with chronic non-bacterial osteomyelitis: A multicenter retrospective case series from Turkey.

Objectives This study aims to evaluate demographic, clinical, and radiological characteristics of Turkish children with chronic non-bacterial osteomyelitis.Patients and methods Between January 2008 and December 2018, a total of 28 patients (10 males, 18 females; median age: 12.5 years; range, 4.5 to 21 years) who were diagnosed with chronic non-bacterial osteomyelitis in three pediatric rheumatology centers were retrospectively analyzed. The demographic, clinical, and laboratory findings of the patients were recorded.Results The median age at the time of diagnosis was 10.2 years. The median time from symptom onset to diagnosis was 6.5 months. The median follow-up was 18.5 months. The most frequent symptom at onset was arthralgia (75.0%). The most frequently involved bone was the femur (67.9%). Eight (63.6%) of 12 patients had at least one Mediterranean fever gene (MEFV) mutation, indicating a significantly higher prevalence than the Turkish population (14.8%). Five of these patients fulfilled the diagnostic criteria for familial Mediterranean fever (FMF). All patients received non-steroidal anti-inflammatory drugs. Other drugs were methotrexate (46.4%), sulfasalazine (39%), corticosteroids (25%), anti-tumor necrosis factor (anti-TNF) agents (32%), pamidronate (25%), and colchicine (21.4%). Six of eight patients with MEFV mutations were administered with colchicine, and all of them responded to treatment.Conclusion Clinical evolution and imaging investigations should be carefully performed to prevent any delay in the diagnosis of patients with chronic non-bacterial osteomyelitis. Based on our study results, FMF coexistence is worth investigating in patients with chronic non-bacterial osteomyelitis, particularly in the Turkish population.

Do all colchicine preparations have the same effectiveness in patients with familial Mediterranean fever?

Aim Colchicine is the primary treatment for familial Mediterranean fever (FMF). Several colchicine preparations are currently using available globally. This study aimed to describe the demographic, clinical, and genetic features of FMF patients treated with multiple colchicine preparations. Materials and methods The records of patients diagnosed as FMF and followed-up by our pediatric rheumatology department were retrospectively evaluated. Patients that were treated with multiple colchicine preparations were included. Patient demographic, clinical, and laboratory data were obtained from the patient files and the hospital patient database. The daily colchicine dose and FMF attack frequency before and after switching from domestically produced (DP)-coated colchicine tablets to foreign produced (FP)-compressed colchicine tablets were compared. Results The study included 35 pediatric FMF patients (22 males and 13 females) with a mean age of 12.85 ± 4.62 years. Mean age at disease onset was 3.66 ± 2.11 years, versus 5.57 ± 4.28 years at diagnosis. The mean attack frequency before and after treatment with FP-compressed colchicine tablets was 9.50 ± 4.46 and 1.85 ± 1.41/year, respectively (p < .001). The mean attack duration significantly decreased in all the patients treated with FP-compressed colchicine tablets (p < .001). The difference in acute phase reactants during the attack-free periods before and after FP-compressed colchicine tablet treatment was significant (p < .001). Conclusion The present findings show that pediatric FMF patients with ongoing attacks and elevated acute phase reactants during attack-free periods while treated with DP-coated colchicine tablets might benefit from switching to FP-compressed colchicine tablets before initiating biologic treatment. Long-term controlled studies are warranted, so as to obtain better evidence of the benefits of multiple colchicine preparations in pediatric FMF patients.

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

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 (2-3mg/day), who were treated with weekly IV injections of 1mg 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 ± 2.85years. 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 ± 1.1days 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.

The etiology and autopsy findings in Colchicine intoxication-related deaths

Colchicine is a drug which has a very narrow therapeutic range. This drug has been commonly used for Familial Mediterranean Fever (FMF), Behcet’s disease, gout arthritis and acute pseudo gout attacks. In this study, the investigation reports and autopsy reports written by the Council of Forensic Medicine of Ankara between the years 2010-2014 were retrospectively analyzed to find out presence in the cases related to colchicine. Six cases were identified as colchicine intoxication, while three of them used colchicine for medical purpose. In four cases, colchicine was found to have been used for suicidal purpose. Among these four cases, two used colchicine for treatment. In all of our cases, colchicine was detected in bile specimen. Alveolar pulmonary edema and petechial hemorrhage were observed in the lung in all cases. Colchicine was detected in blood in four of the cases. In two cases, the concentration was found to be in therapeutic ranges (0,012 mg/L and 0,018 mg/L), while the other two, in lethal levels (0.099 mg/L and 0,264 mg/L). The most frequent histopathological finding is alveolar pulmonary edema in colchicine intoxication autopsies. Colchicine is widely used alkaloid drugs with narrow therapeutic ranges. More than 0.8 mg / kg in the acute high dose has usually fatal effects. The deaths resulted from colchicine intoxication are mainly suicide-oriented. Similar to other suicides with medicines, they are common among women. In our cases, colchicine was used for intention of suicide in four incidents (66, 66%).

Chronic recurrent multifocal osteomyelitis in a patient with Familial Mediterranean Fever

Patients with more than one autoinflammatory disorder are rarely reported in the literature [1]. Additionally, rare reports suggest that MEFV mutations might be associated with atypical manifestations for familial Mediterranean fever (FMF), such as isolated recurrent muscle pain in one patient [2] and chronic recurrent multifocal osteomyelitis (CRMO) responsive to colchicine in another patient heterozygote for E148Q-P369S-R408Q MEFV complex allele [3]. We report a unique case of a patient with classic FMF developing CRMO later in the disease and discuss genetic test results, imaging features, and response to treatment.

Development of the autoinflammatory disease damage index (ADDI)

Autoinflammatory diseases cause systemic inflammation which can result in damage to multiple organs. Organ damage can occur before the start of therapy, or when patients experience ongoing inflammation. A validated instrument to measure damage is essential to quantify damage in individual patients, and to compare disease outcomes in clinical studies. At this moment, there is no such instrument. In the context of the RaDiCEA project, a common damage index for Familial Mediterranean Fever (FMF), Cryopyrin Associated Periodic Syndromes (CAPS), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency (MKD) will be developed.

Comparison of the colchicine concentration between different matrix; plasma, leucocytes, ficoll solution measured by ESI LC-MS/MS

Colchicine is the main therapeutic drug which is used for Familial Mediterranean Fever (FMF) and acute gout attacks. In a limited study, the leucocyte colchicine level has been implicated to be important for monitoring of drug level. It will be important especially in the drug resistant patients. Therefore, we aimed to investigate the usability of different matrix for the monitoring of colchicine level.

Accelerated apoptosis of neutrophils in familial mediterranean Fever.

The causative mutations for familial Mediterranean fever (FMF) are located in the MEFV gene, which encodes pyrin. Pyrin modulates the susceptibility to apoptosis via its PYD domain, but how the mutated versions of pyrin affect apoptotic processes are poorly understood. Spontaneous and induced rates of systemic neutrophil apoptosis as well as the levels of proteins involved in apoptosis were investigated ex vivo in patients with FMF using flow cytometry and RT-qPCR. The freshly collected neutrophils from the patients in FMF remission displayed a significantly larger number of cells spontaneously entering apoptosis compared to control (6.27 ± 2.14 vs. 1.69 ± 0.18%). This elevated ratio was retained after 24 h incubation of neutrophils in the growth medium (32.4 ± 7.41 vs. 7.65 ± 1.32%). Correspondingly, the mRNA level for caspase-3 was also significantly increased under these conditions. In response to the inducing agents, the neutrophils from FMF patients also displayed significantly elevated apoptotic rates compared to control. The elevated rates, however, can be largely explained by the higher basal ratio of apoptotic cells in the former group. Monitoring of several proteins involved in apoptosis has not revealed any conventional mechanisms contributing to the enhanced apoptotic rate of neutrophils in FMF. Although the exact molecular mechanisms of accelerated neutrophil apoptosis in FMF remain unknown, it may provide a protection against excessive inflammation and tissue damage due to a massive infiltration of neutrophils in the acute period of the disease.

FMF50: a score for assessing outcome in familial Mediterranean fever

BackgroundColchicine is the main treatment for familial Mediterranean fever (FMF). However, biological agents and other treatments are available for patients who are unable to receive optimal treatment.ObjectiveTo develop outcome criteria...

A Missing Correlation between the Number and Type of MEFV Mutations and Severity of Clinical Manifestations in Egyptian Pediatric FMF Patients

Aims: Previous researches identified the gene for Familial Mediterranean Fever (FMF) and found several different gene mutations that cause this inherited rheumatic disease. The aim of this work is to investigate the correlation between severity of symptoms of FMF and the number and type of MEFV variants, as well as to shed light on the correlation between the genotype and phenotype of Egyptian pediatric FMF patients. Study Design: Retrospective study. Place and Duration of Study: Department of Pediatrics, Kasr El Aini Hospital, Cairo University Medical School, Cairo, Egypt, between January 2012 and February 2013. Methodology: This study involved 35 childhood cases of Egyptian ethnic origin suspected to suffer from FMF. They include 19 males and 16 females of age range between 1-17 years. MEFV mutations in each patient were determined by performing Research Article British Journal of Medicine & Medical Research, 4(1): 488-500, 2014 489 DNA isolation and purification, in vitro amplification (PCR), and reverse hybridization using an FMF StripAssay. Results: Our results revealed 14% homozygous, 34% single heterozygous, 35% compound heterozygous-bi, and 17% compound heterozygous-tri patients. Twelve MEFV mutations were covered where all mutations were concentrated on exons 10 and 2. Severity of clinical manifestations and severity score did not linearly correlate with the number of variants, nor with the type of variant. Conclusion: Our results question the strength of genotype-phenotype correlation in FMF and indicate that MEFV genotypes express much more variable phenotypes than previously suggested. Our results also revealed no association between the number of mutations and severity of clinical manifestations.

コルヒチンが有効なMollaret髄膜炎で，&lt;i&gt;MEFV&lt;/i&gt;遺伝子変異をみとめた1例

A 66-year-old woman was admitted to our hospital with recurrent meningitis. She presented with 10 episodes of meningitis in 10 months. Examination of cerebrospinal fluid demonstrated pleocytosis, with neutrophils dominant at the early stage, and lymphocytes dominant at the late stage. Mollaret cells were found and the level of IL-6 was increased in cerebrospinal fluid. Several antibiotics and antiviral agents failed to prevent relapse. However, colchicine therapy successfully prevented the recurrence of meningitis. Genetic testing for familial Mediterranean fever (FMF) showed a mutation in the MEFV gene. It is difficult to diagnose the cause of Mollaret's meningitis in some patients. FMF, neuro-Behçet's disease, and neuro-Sweet disease should be included in the differential diagnosis of recurrent meningitis. In addition, colchicine therapy can prevent the relapse of meningitis in such cases.