A mathematical model of Familial Mediterranean Fever predicts mechanisms controlling inflammation.

BACKGROUND: Familial Mediterranean Fever (FMF) is a monogenic disease caused by gain-of-function mutations in the MEditerranean FeVer (MEFV) gene. The molecular dysregulations induced by these mutations and the associated causal mechanisms are complex and intricate. OBJECTIVE: We sought to provide a computational model capturing the mechanistic details of biological pathways involved in FMF physiopathology and enabling the study of the patient's immune cell dynamics. METHODS: We carried out a literature survey to identify experimental studies published from January 2000 to December 2020, and integrated its results into a molecular map and a mathematical model. Then, we studied the network of molecular interactions and the dynamic of monocytes to identify key players for inflammation phenotype in FMF patients. RESULTS: We built a molecular map of FMF integrating in a structured manner the current knowledge regarding pathophysiological processes participating in the triggering and perpetuation of the disease flares. The mathematical model derived from the map reproduced patient's monocyte behavior, in particular its proinflammatory role via the Pyrin inflammasome activation. Network analysis and in silico experiments identified NF-κB and JAK1/TYK2 as critical to modulate IL-1ß- and IL-18-mediated inflammation. CONCLUSION: The in silico model of FMF monocyte proved its ability to reproduce in vitro observations. Considering the difficulties related to experimental settings and financial investments to test combinations of stimuli/perturbation in vitro, this model could be used to test complex hypotheses in silico, thus narrowing down the number of in vitro and ex vivo experiments to perform.

The Value of Serum Amyloid A Levels in Familial Mediterranean Fever to Identify Occult Inflammation During Asymptomatic Periods.

OBJECTIVE: The aim of this observational study was to evaluate whether there was any correlation between the acute phase reactants in children with familial Mediterranean fever (FMF) during attack and attack-free periods. METHODS: The study was conducted between June 2016 and January 2018. Clinical features and laboratory parameters of children with FMF during attack and attack-free periods were recorded longitudinally. RESULTS: The cohort consisted of 168 children with FMF (84 boys, 84 girls). Median values of acute phase reactants during FMF attacks were 433.5 mg/L (34.0-1780.0 mg/L) for serum amyloid A (SAA), 56.7 mg/L (7.6-379.0 mg/L) for C-reactive protein (CRP), and 37.5 mm/h (5-100 mm/h) for erythrocyte sedimentation rate (ESR). Median values for the same tests in attack-free periods were 3.2 mg/L (0.1-25.0 mg/L), 1.7 mg/L (0.1-12.7 mg/L), and 8 mm/h (1-30 mm/h), respectively. Correlation analyses showed that SAA and CRP were highly correlated in FMF attack (r = 0.67, p < 0.01), but no correlation was found between SAA and ESR levels. C-reactive protein was elevated in 13.6%, ESR in 20.8%, and SAA in 28.5% of the patients during attack-free period. Age at onset, sex of the patients, and characteristics of attacks were found to be not associated with elevated SAA in attack-free period. On the other hand, having homozygous exon 10 mutation and having elevated CRP were found to be associated with high SAA in attack-free period. CONCLUSIONS: C-reactive protein and SAA correlate well with FMF attacks. Therefore, checking for SAA during a FMF attack is not required. However, SAA seems to be the most sensitive method for demonstrating subclinical inflammation in attack-free period. Thus, checking SAA levels might be a valuable tool in selected FMF patients.

Comorbidities and phenotype-genotype correlation in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting with phenotypic heterogeneity. The phenotype-genotype correlation is not established clearly yet. Furthermore, some comorbidities such as vasculitis and inflammatory arthritis may accompany FMF. Herein, we aimed to define phenotype-genotype correlation and comorbid diseases of children with FMF. The medical records of 1687 children diagnosed and followed up as FMF were reviewed retrospectively. Disease severity was assessed by PRAS score. A total of 1687 children (841 girls, 846 boys) were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 13.1 ± 5.4, 5.4 ± 4, and 8 ± 4.2 years, respectively. Median (min-max) follow-up period was 3 (0.5-18) years. Among them, 118 (7%) patients had at least one concomitant disease and 72% of them were carrying at least one M694V mutation. Patients with a concomitant disease expressed a more severe course of disease when compared to ones without a concomitant disease (23.7% vs 8.8%, p < 0.001). Children carrying homozygous M694V mutation had significantly earlier age of disease onset and severe disease course (p < 0.001). Forty-four patients (2.6%) were colchicine resistant and most of them were carrying homozygous M694V mutation. Sixteen colchicine-resistant patients were treated with anakinra while 28 received canakinumab. Juvenile idiopathic arthritis (JIA) and immunoglobulin A vasculitis were the most commonly seen associated diseases and the patients with a concomitant disease demonstrated more severe course. This is the largest pediatric cohort studied and presented since now. We confirmed that carrying M694V mutation is associated both with a severe disease course and a predisposition to comorbidities.

Altered expression of apoptosis-related, circulating cell-free miRNAs in children with familial Mediterranean fever: a cross-sectional study.

OBJECTIVES: Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disorder characterized by recurrent fever and serositis episodes. Identification of low penetrant or heterozygous MEFV mutations in clinically diagnosed FMF patients did raise a concern on whether epigenetic or environmental factors play an additional role in FMF pathogenesis. We aimed to investigate the expression profile of apoptosis-related miRNAs in FMF and their influence on clinical manifestations in the present study. METHOD: 191 pediatric FMF patients and 31 healthy children included in the study. Expressions of 33 apoptosis-related, circulating cell-free miRNAs were evaluated by a quantitative polymerase chain reaction, statistically calculated within ΔΔCt values and fold changes were evaluated by Welch T test, in which p < 0.05 were considered to be significant. RESULTS: Nineteen miRNAs, including let-7a-5p, let-7c, let-7 g-5p, miR-15b-5p, miR-16-5p, miR-17-5p, miR-23a-3p, miR-24-3p, miR-25-3p, miR-26a-5p, miR-26b-5p, miR-27a-3p, miR-29c-3p, miR-30a-5p, miR-30d-5p, miR-30e-5p, miR-106b-5p, miR-146a-5p, and miR-195-5p, were found down-regulated; miR-15a-5p, miR-29b-3p, miR-181a-5p, miR-181b-5p, miR-181c-5p, miR-214-3p, and miR-365a-3p were up-regulated in FMF patients. In detail, these miRNAs were similar among FMF patients in terms of genotype, colchicine response, and having an inflammatory attack during analysis. CONCLUSION: We found that 26 apoptosis-related circulating miRNAs were deregulated in children with FMF. Thus, we speculate that these miRNAs have a role in FMF pathogenesis via apoptotic mechanisms.

Performance of the new Eurofever/PRINTO classification criteria in Familial Mediterranean fever patients with a single exon 10 mutation in childhood.

The diagnosis of Familial Mediterranean fever (FMF) based on clinical findings supported by genetic mutation. Recently, the new Eurofever/PRINTO classification criteria including genetic analysis were established. The aim of this study is to evaluate the performance of the new criteria in FMF patients with a single exon 10 mutation in childhood. The study group consisted of FMF patients who had a single exon 10 mutation in a referral center in Turkey. Patients with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome were included as a control group. The medical charts of all patients were reviewed retrospectively. A total of 106 FMF patients (59 boys) were enrolled in the study group. The median age at first symptom was 5; the median age at diagnosis was 7 years. The mean follow-up was 33 ± 35.4 months. Majority of the patients (n = 58, 54.7%) had heterozygous M694V, 16 (15%) patients had M694V/E148Q and 13 (13.8%) patients had heterozygous M680I mutation. The sensitivity of the Yalcinkaya-Ozen criteria was 98.1% and it was 97.1% for the Eurofever/PRINTO classification criteria. The specificity of the new Eurofever/PRINTO classification criteria was 96.7% and it was 74.1% for the Yalcinkaya-Ozen criteria. The new Eurofever/PRINTO classification criteria have a good sensitivity as the Yalcinkaya-Ozen criteria in patients with a single exon 10 mutation. Additionaly, the new criteria have better specificity. It should be useful to apply the clinical only criteria where the carrier rate is high.

Twenty-Year Experience of a Single Referral Center on Pediatric Familial Mediterranean Fever: What Has Changed Over the Last Decade?

BACKGROUND/OBJECTIVE: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease and is characterized by recurrent fever and serositis episodes. We aimed to share our 20-year FMF experience, clarify a phenotype-genotype correlation, and compare the characteristics and outcomes of pediatric FMF patients over the last 2 decades in this study. METHODS: This medical record review study included 714 pediatric FMF patients (340 females, 374 males), diagnosed by Tel Hashomer diagnostic criteria between January 2009 and January 2019 and followed up in our department. Demographic and disease characteristics, obtained from medical records of the patients, were compared between patients with M694V homozygosity and other genotypes and showed whether they were diagnosed before (n = 137) or after January 2010 (n = 577). χ2, Student t, and Mann-Whitney U tests were used to compare categorical and continuous variables between these groups. RESULTS: The most common symptoms were abdominal pain (92%), fever (89.5%), and arthralgia (64.5%). Mean ages at symptom onset and diagnosis were 5.16 ± 3.73 and 7.71 ± 3.87 years, respectively. M694V homozygosity was recorded in 111 patients (15.5%). Fever, arthralgia, arthritis, myalgia, erysipela-like erythema, colchicine resistance, and subclinical inflammation were more frequent, and mean disease severity score was higher in patients with M694V homozygosity. Fever, chest pain, and proteinuria were statistically more frequent in patients diagnosed before January 2010. Although M694V homozygosity rate was similar, patients diagnosed in the last decade had lower mean disease severity score. CONCLUSIONS: With this study, we speculate that although genotype and delay in diagnosis were similar, patients diagnosed in the last decade have a milder disease severity.

Amyloid storm: acute kidney injury and massive proteinuria, rapidly progressing to end-stage kidney disease in AA amyloidosis of familial Mediterranean fever.

OBJECTIVE: Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. METHODS: This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. RESULTS: The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. CONCLUSION: Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

OBJECTIVES: Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities. METHODS: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements. RESULTS: Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life. CONCLUSION: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.

Effect of anti-interleukin-1 treatment on quality of life in children with colchicine-resistant familial Mediterranean fever: A single-center experience.

AIM: The aim of this study is to evaluate the clinical parameters, acute-phase reactants, side effects, genetic mutations among colchicine-resistant Familial Mediterranean fever (FMF) patients who received anti-interleukin-1 (anti-IL-1) treatment. We also evaluate the quality of life and school attendance among colchicine-resistant FMF patients, in relation to treatment with anti-IL-1. INTRODUCTION: Familial Mediterranean fever is the most common inherited autoinflammatory disorder. Although the main treatment of FMF is colchicine, a small group of patients are resistant to colchicine treatment. Anti-IL-1 treatment is promising in colchicine-resistant patients due to excessive IL-1ß production in pathogenesis. The aim of this study is to evaluate the quality of life and school attendance rates among colchicine-resistant FMF patients after anti-IL-1 treatment. METHODS: This is a single center retrospective study of 25 pediatric colchicine-resistant FMF patients treated with anti-IL-1 treatment. Autoinflammatory Disease Activity Index (AIDAI) was used for disease activity assessment. School attendance rates were evaluated before and after treatment. RESULTS: There were 25 patients with FMF (11 M/14 F) who were treated with anakinra or canakinumab for various indications (colchicine-resistant recurrent febrile attacks in 20, colchicine-related side effects in 2, subclinical inflammation in 3 patients). Only 3 patients developed side effects with anakinra (2 headache, 1 urticarial rash). There was a significant decrease in the frequency of attacks, acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein), AIDAI and physician's and patient's global assessment scores and improvement in school attendance rates. At the last follow-up, all patients were in remission, and only 3 had subclinical inflammation. CONCLUSION: Anti-IL-1 treatment is quite effective in children with colchicine-resistant FMF patients, proven with improved AIDAI scores and school attendance rates. In the long term by lowering disease activation even development of amyloidosis may be prevented.

Clinical and Genetic Analysis of 22 Japanese Patients with Familial Mediterranean Fever: An Examination of MEFV and 10 Other Genes Related to Autoinflammatory Syndromes.

Objective Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory syndrome, and its frequency is reported to be increasing in Japan. We studied the clinical features and genetic background of patients with FMF in our hospital. Methods We analyzed the clinical features and genomic variants of MEFV, as well as 10 genes related to other autoinflammatory syndromes, in 22 Japanese patients with FMF. A genetic analysis was performed with a next generation sequencer. Results The patients were classified into the typical FMF (n=16) and atypical FMF (n=6) groups. Fever, abdominal pain, thoracic pain, and arthralgia were observed in 22, 12, 8, and 10 patients, respectively. MEFV variants were found in 19 patients (86.4%). Two cases had no MEFV variants and one case only had a variant in the 3' untranslated region (3'-UTR) of MEFV. Genomic variants were found in genes other than MEFV in 7 patients (31.8%); however, none met the diagnostic criteria for autoinflammatory syndromes with disease-related gene variants, and all were classified as typical FMF. Moreover, none of the 6 patients with atypical FMF had any variants among the 10 disease-related genes. All cases in which the onset occurred before 20 years of age were classified as typical FMF. Conclusion The clinical features of FMF recorded in our hospital coincided with those from the Japanese national epidemiological survey of FMF in Japan. More than 30% of the patients with FMF had non-MEFV genes, related to other autoinflammatory syndromes, thereby suggesting that variants of these genes may act as a disease-modifier in FMF.

Autoinflammatory Diseases in Childhood

Autoinflammatory diseases are characterized by recurrent fevers and clinical findings of impaired natural immunity and can involve various organ systems. The concept of autoinflammatory disease emerged after the definition of familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome. This new disease group was considered to differ from the standard concept of autoimmune diseases, which is relatively better known in terms of basic features, such as defects in innate immunity and the absence of antibodies. A better understanding has been achieved regarding the genetic and pathogenetic mechanisms of this relatively new disease group over the past 20 years since they were first diagnosed, which have led to some changes in the concept of autoinflammatory diseases. The recent definition classifies autoinflammatory disease to be a wide range of diseases with different clinical features, mainly accompanied by changes in innate immune and rarely in humoral immunity. The spectrum of autoinflammatory diseases is rapidly expanding owing to recent developments in molecular sciences and genetics. This review article discusses the clinical features, classification criteria, treatment options, and long-term prognosis of periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome, and other common autoinflammatory diseases in the light of current literature.

Evaluation of the structure, autoimmunity, and functions of the thyroid gland in familial Mediterranean fever patients.

Objective Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder that is frequently seen in the eastern Mediterranean region. The thyroid gland can be affected in FMF patients through autoimmunity or amyloidosis. Here, we aimed to evaluate the structure and functions of the thyroid gland in addition to possible autoimmunity in FMF patients. Subjects and methods The study was conducted by the Endocrinology and Metabolism and Internal Medicine Departments. Thirty FMF patients and 30 age and gender-matched healthy controls were enrolled in the study. Free thyroxin (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase (anti-TPO) autoantibodies were investigated. Detailed thyroid grayscale and Doppler Ultrasonography examinations and shear-wave elastosonography (SWE) were performed in the patient and control groups. Results Anti-TPO was detected in 24% (n = 7) of the patients. On the grayscale US, mean thyroid volumes were similar between the FMF and the control groups (p > 0.05). By Doppler US, thyroid vascularity observed was detected in 10.3% (n = 3) of the patients. SWE revealed that the mean velocity value of right vs. left lobe in the patient group was 1.77 ± 0.45 m/s and 1.95 ± 0.51 m/s, respectively. Compared to the control group, the mean velocity values were significantly higher in the right (p = 0.004) and left (p = 0.01) lobes of the patient group. The mean stiffness value in the patient group was also significantly higher in the right and left lobes [10.13 ± 5.65 kPa (p = 0.005) and 12.24 ± 6.17 kPa (p = 0.02), respectively]. Conclusion Recognizing the complications of FMF early in the course of the disease is as important as the early diagnosis of the disorder. Based on this, thyroid functions and changes in its structure should be evaluated carefully for early diagnosis of a possible coexisting thyroid disorder. Arch Endocrinol Metab. 2020;64(1):66-70.

Evaluation of the structure, autoimmunity, and functions of the thyroid gland in familial Mediterranean fever patients

ABSTRACT Objective Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder that is frequently seen in the eastern Mediterranean region. The thyroid gland can be affected in FMF patients through autoimmunity or amyloidosis. Here, we aimed to evaluate the structure and functions of the thyroid gland in addition to possible autoimmunity in FMF patients. Subjects and methods The study was conducted by the Endocrinology and Metabolism and Internal Medicine Departments. Thirty FMF patients and 30 age and gender-matched healthy controls were enrolled in the study. Free thyroxin (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase (anti-TPO) autoantibodies were investigated. Detailed thyroid grayscale and Doppler Ultrasonography examinations and shear-wave elastosonography (SWE) were performed in the patient and control groups. Results Anti-TPO was detected in 24% (n = 7) of the patients. On the grayscale US, mean thyroid volumes were similar between the FMF and the control groups (p > 0.05). By Doppler US, thyroid vascularity observed was detected in 10.3% (n = 3) of the patients. SWE revealed that the mean velocity value of right vs. left lobe in the patient group was 1.77 ± 0.45 m/s and 1.95 ± 0.51 m/s, respectively. Compared to the control group, the mean velocity values were significantly higher in the right (p = 0.004) and left (p = 0.01) lobes of the patient group. The mean stiffness value in the patient group was also significantly higher in the right and left lobes [10.13 ± 5.65 kPa (p = 0.005) and 12.24 ± 6.17 kPa (p = 0.02), respectively]. Conclusion Recognizing the complications of FMF early in the course of the disease is as important as the early diagnosis of the disorder. Based on this, thyroid functions and changes in its structure should be evaluated carefully for early diagnosis of a possible coexisting thyroid disorder. Arch Endocrinol Metab. 2020;64(1):66-70

Familial Mediterranean fever is associated with a wide spectrum of inflammatory disorders: results from a large cohort study.

Familial Mediterranean fever (FMF) is characterized by recurrent short-lived/self-limiting inflammatory attacks. Besides these, a substantial number of patients with FMF present with a variety of other inflammatory diseases; however, this issue has not been systematically studied previously. Hence, we aimed to investigate the frequency of inflammatory comorbid diseases in a large FMF cohort. All patients were recruited from "FMF in Central Anatolia (FiCA) Cohort", comprising 971 (mean age 35.3 ± 12 years, 61.5% female) adult subjects. All patients fulfilled Tel Hashomer criteria. Demographic data, FMF disease characteristics, MEFV gene mutations, and comorbid inflammatory diseases were meticulously questioned, and laboratory features and genotype data were retrieved from hospital records. There were comorbid inflammatory diseases in 205 (21.1%) patients. The most common inflammatory disease was spondyloarthritis (12.9%). Other remarkable inflammatory disorders were psoriasis, immunoglobulin A vasculitis/Henoch-Schönlein purpura, Behçet's disease and inflammatory bowel diseases. Cryptogenic organizing pneumonia is a newly defined entity in our cohort which is seemed to be associated with FMF (0.3%). Number of patients with persistent inflammation was higher in those with comorbid diseases (p < 0.001). Our results suggest that FMF is commonly associated with other inflammatory diseases. Therefore, clinicians should be cautious about comorbid inflammatory diseases in FMF patients, particularly in those with persistent inflammation. Identification of pathogenic pathways linking FMF to these diseases warrants further investigations.

Performance of recently proposed periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria in a region endemic for familial Mediterranean fever.

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an auto-inflammatory condition characterized by recurrent episodes of fever accompanied by aphthosis, cervical adenitis, and pharyngitis. Diagnosis of PFAPA could be challenging due to clinic overlap with familial Mediterranean fever (FMF). An international consensus has been established recently, to define a new set of classification criteria for PFAPA syndrome. We aimed to evaluate the performance of recently proposed PFAPA criteria, to assess their utility in FMF regions. Patients diagnosed with PFAPA syndrome, FMF, and juvenile idiopathic arthritis (JIA) were included. Two investigators blindly evaluated all of patients for the newly proposed PFAPA criteria. A total of 542 patients (322 with PFAPA syndrome, 118 FMF and 102 JIA) were evaluated. Mean age of patients was 6.6 ± 2.81, 12.75 ± 3.9, and 12.42 ± 4.8 years for PFAPA, FMF, and JIA, respectively. We found quite high sensitivity (89.7%) but insufficient specificity of newly proposed PFAPA criteria (69.5%). When applied to control patients separately, specificity was found to be 61% and 79.4% for FMF and JIA patients, respectively. Positive predictive value was 81%, while negative predictive value was 82%. Recently proposed PFAPA criteria have satisfactory sensitivity, but its specificity is still under expectation. There is a need for a distinctive criterion between PFAPA syndrome and FMF, in FMF endemic regions, e.g., cryptic tonsillitis rapidly responsive to single dose of glucocorticoids. Further studies with higher patients' number in different regions are needed.

Familial mediterranean fever: assessment of clinical manifestations, pregnancy, genetic mutational analyses, and disease severity in a national cohort.

The aims of this study were to investigate the main clinical and laboratory features, including pregnancy and genetic analysis, of Turkish Familial Mediterranean Fever (FMF) patients and to analyze the relationships between genotypic features, age of disease onset, clinical findings, and disease severity. A study was planned within a national network of 22 different centers. Demographics, clinical and laboratory findings, attack characteristics, drugs, pregnancy and birth history, disease severity, and gene mutation analyses were evaluated. Disease severity, assessed using a scoring system developed by Pras et al., was evaluated in relation to gene mutations and age of disease onset. A total of 979 patients (643 females and 336 males; mean age: 35.92 ± 11.97 years) with FMF were included in the study. Of a total of 585 pregnancies, 7% of them resulted in preterm birth and 18.1% resulted in abortions. During pregnancy, there was no FMF attack in 61.4% of patients. Of the MEditerranean FeVer (MEFV) mutations, 150 (24.3%) cases were homozygous, 292 (47.3%) cases were heterozygous, and 175 (28.4%) were compound heterozygous. Patients with homozygous gene mutations had more severe disease activity, earlier age of disease onset, higher rates of joint and skin involvement, sacroiliitis, and amyloidosis. Patients with compound heterozygous genotype displayed severe disease activity in close resemblance to patients with homozygous mutation. In addition, patients with compound heterozygous mutations had higher rates of protracted febrile myalgia and elevated fibrinogen levels. In 63.9% of compound heterozygous patients, age of onset was < 20 years, with greater disease severity, and high rates of attack frequency and colchicine resistance. Our results suggest that indicators for disease severity include early onset of disease and homozygous gene mutations. Furthermore, patients with compound heterozygous mutations displayed significant presentations of severe disease activity.

Familial Mediterranean fever and atherosclerosis in childhood and adolescence.

Familial Mediterranean fever is a chronic inflammatory disease characterized by periodic and self-limited episodes of fever and aseptic polyserositis. Although colchicine treatment has altered the course of the disease, it is believed that subclinical inflammation is still present, leading to endothelial dysfunction and atherosclerosis in the course of time. In this review, following the published recommendations, we queried online databases such as MEDLINE Pubmed, Scopus, and Web of science for peer-reviewed studies and reviews written in English language, using the following keywords: familial Mediterranean fever, children, endothelial dysfunction, atherosclerosis, cardiovascular disease. The objective of this review is to highlight the correlation between familial Mediterranean fever and atherosclerosis, and moreover to describe new serum inflammatory markers and non-invasive methods of endothelial dysfunction, to detect the atherosclerosis process early starting from childhood.

Performance of Tel-Hashomer, Livneh, pediatric and new Eurofever/PRINTO classification criteria for familial Mediterranean fever in a referral center.

Until now, the diagnosis of familial Mediterranean fever (FMF) was based on validated subsets of clinical criteria, but recently new Eurofever/PRINTO classification criteria concerning genetic analyses were proposed. The study aimed to compare the performances of three validated diagnostic criteria (Tel-Hashomer, Livneh, pediatric criteria) and new Eurofever/PRINTO classification criteria. The medical charts of study and control groups were reviewed retrospectively. Patients were evaluated for three diagnostic criteria and new Eurofever/PRINTO classification criteria. Control group consists of patients with other autoinflammatory diseases. A total of 1291 patients were classified into three groups according to their mutations: group 1: 447 patients with homozygous mutations; group 2: 429 patients with compound heterozygous mutations; and group 3: 415 patients with one heterozygous mutation. Similar diagnostic utility was found according to Livneh criteria between groups. But, proportion of patients fulfilling Tel-Hashomer and pediatric criteria was higher in groups 1 and 2. According to Eurofever/PRINTO criteria, 98.2% of patients with homozygous mutations, 94.2% of patients with compound heterozygous mutations and 80.2% of patients with heterozygous mutations were classified as FMF. In control group, 99.2% of them fulfilled the Livneh criteria, 66.9% met the pediatric criteria and 0.8% satisfied the Tel-Hashomer criteria, while none of control patients met the Eurofever/PRINTO classification criteria. Performances of three validated diagnostic criteria and new Eurofever/PRINTO classification criteria for FMF were similar and provide high utility in diagnosing/classifying patients with homozygous and compound heterozygous mutations. However, both Eurofever/PRINTO classification criteria and Tel-Hashomer criteria had significantly lower performance in heterozygous patients.

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.

Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inactive by two kinases (PKN1/2). The consequences of MEFV mutations on inflammasome activation are still poorly understood. Here, we demonstrate that PKC superfamily inhibitors trigger inflammasome activation in monocytes from FMF patients while they trigger a delayed apoptosis in monocytes from healthy donors. The expression of the pathogenic p.M694V MEFV allele is necessary and sufficient for PKC inhibitors (or mutations precluding Pyrin phosphorylation) to trigger caspase-1- and gasdermin D-mediated pyroptosis. In line with colchicine efficacy in patients, colchicine fully blocks this response in FMF patients' monocytes. These results indicate that Pyrin inflammasome activation is solely controlled by Pyrin (de)phosphorylation in FMF patients while a second control mechanism restricts its activation in healthy donors/non-FMF patients. This study paves the way toward a functional characterization of MEFV variants and a functional test to diagnose FMF.