Severe tortuosity but not altered retinal vessel diameters in children and young adults with Familial Mediterranean Fever: a case-control study.

Concomitant fibromyalgia syndrome (FMS) has been known to be more frequent in patients with several rheumatic diseases. In this study, our aim was to investigate the prevalence of FMS in patients with familial Mediterranean fever (FMF), to analyze the possible factors related to this frequency, and to evaluate the impact of FMS on the functionality and quality of life (QoL) of the patients with FMF. One hundred cases with FMF and 100 controls were included to this case-control study. FMS coincidence was investigated in all participants according to revised 2016 classification criteria. Demographic features, FMF disease duration, FMF gene mutations, drugs used, attack frequency per year, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum fibrinogen levels were recorded. FMF disease severity was assessed by International Severity Scoring System for Familial Mediterranean Fever (ISSF). For the assessments of QoL and functioning, FMF-QoL, Short form 36 (SF-36), and Health Assessment Questionnaire-Disability Index (HAQ-DI) were used, and for the assessment of FMS impact, the fibromyalgia impact questionnaire (FIQ) were used. We found an FMS frequency of 33% in patients with FMF in our study using the current FMS classification criteria. This result was significantly higher than in age- and gender-similar controls (6% FMS frequency; P < 0.05). The number of woman patients and FMF disease duration were significantly higher in patients with FMF + FMS than in patients with only FMF (P < 0.001). There was no significant difference in ISSF scores, ESR, CRP, and fibrinogen levels, management regimens, and FMF gene mutation distributions between FMF + FMS and FMF groups. FMF attack frequency was reported as significantly higher in FMF + FMS patients than in others (P < 0.000). In spite of similar FMF-QoL scores, there were significant differences in HAQ-DI and SF-36 scores between groups (P < 0.05). Higher impact of FMS presented negative correlation with functioning and general health, and positive correlation with QoL in FMF + FMS (P < 0.05). Concomitant FMS was a common clinical problem in patients with FMF regardless of the severity and characteristics of FMF. The FMS impact may affect function and QoL in patients of FMF. Considerations of the FMS component in the management of FMF may contribute to the holistic approach to FMF.

BackgroundAlthough familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10–20% of FMF patients do not carry any FMF gene (MEFV) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called “FMF without MEFV mutations”. In this study we clinically and demographically characterize this subset.MethodsMEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation.ResultsForty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV-mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset.ConclusionsMEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.

The plasminogen (PLG) activation system plays an essential role in severe inflammation based diseases such as periodontitis, destructive membranous periodontal disease (ligneous periodontitis), familial Mediterranean fever (FMF), and amyloidosis. We have aimed to evaluate variations in PLG and the associations between PLG and MEFV genotypes in patients with FMF/ FMF-related secondary amyloidosis and periodontitis. A total of 247 individuals who were either diagnosed with FMF or systemically healthy were recruited to this human observational study with a cross-sectional design. All individuals were also diagnosed with periodontitis or periodontally healthy. Blood samples were obtained from patients with FMF and systemically healthy controls. Clinical periodontal indicators were recorded. All polymorphisms located in exons 6 and 8 of PLG and mutations located on exons 2 and 10 of the MEFV gene were analyzed by DNA Sanger Sequencing. Genotypes and allele frequencies of PLG and MEFV were detected and tested by the Hardy-Weinberg equilibrium. Serum levels of amyloid A (SAA), high-sensitive C-reactive protein (hs-CRP), PLG, and salivary PLG levels were determined by using enzyme-linked immunosorbent assay (ELISA). Two polymorphisms were identified in PLG: G to A polymorphism on the 14th nucleotide of intron 8 and C to T polymorphism on the 924th nucleotide of the coding region (IVS 8+14 G>A and c.924C>T, respectively). In IVS 8+14 G>A polymorphisms, wild-type genotype: GG, heterozygote genotype: GA and homozygote genotype: AA. In c.924C>T polymorphism, wild-type genotype: CC, heterozygote genotype: CT and homozygote genotype: TT. The frequency of the heterozygous polymorphisms of PLG was significantly increased (17.6%) in FMF patients with periodontitis (p = .027). A large proportion of the test group that was heterozygous for MEFV-R202Q also had heterozygous PLG polymorphisms. Remarkable exacerbation in periodontal parameters was observed in patients with FMF and amyloidosis. SAA and hs-CRP levels were significantly correlated with salivary PLG levels in patients with periodontitis and heterozygous PLG. The current study describes IVS 8+14 G>A (rs2295368) and c.924C>T (rs1380916375) polymorphisms for the first time in the periodontal literature, which might play an important role in the pathogenesis of periodontitis, FMF, or amyloidosis. The elucidation of PLG polymorphisms is beneficial from a public health perspective by increasing the quality of life in these patients and reducing the mortality and morbidity associated with inflammatory diseases such as periodontal disease, FMF, and FMF-related amyloidosis.

Background: Several autoimmune diseases have been associated with schizophrenia and epilepsy, however little is known about putative links with the auto-inflammatory conditions. Objectives: We investigated the association between familial Mediterranean fever (FMF), a paradigmatic auto-inflammatory disease, schizophrenia and epilepsy, and assessed the impact of the latter disorders on the survival of FMF patients utilizing a large sample database. Methods: A case-control study was performed by utilizing the database of Clalit Health Services. FMF patients were compared to age- and sex- matched counterparts in terms of prevalence of schizophrenia and epilepsy. The chi-squared test was used to assess the distribution of categorical variables, while the t-test were applied for continuous variables. Analysis regarding survival were performed using Kaplan-Meier curves, log rank test and multivariate Cox proportional-hazards method. Results: The study included 7,747 FMF patients, and 10,080 age- and sex- matched controls. At the univariate analysis, schizophrenia and epilepsy as co-morbidities, 50 FMF patients (0.6%) and 89 controls (0.9%) had schizophrenia, respectively. On multiple logistic regression model, FMF was inversely associated with schizophrenia (OR 0.64 [95%CI 0.43-0.90], p=0.0173), while there was no association between FMF and epilepsy. Subjects having either FMF (HR 1.43 [95%CI 1.23-1.66]), schizophrenia (HR 3.97 [95%CI 1.47- 10.70]) or epilepsy (HR 2.54 [95%CI 1.72-3.75]) were independently associated with all-cause mortality. However, schizophrenia as co-morbidity in FMF subjects did not worsen their prognosis (HR 2.17 [95%CI 0.60-7.86]). Conclusion: FMF patients have a significantly lower proportion of schizophrenia than controls. Patients with either FMF, schizophrenia or epilepsy are at higher risk of all-cause mortality, a finding that calls for assessment of better medical management on mortality outcome. Acknowledgement: None Disclosure of Interests: Kassem Sharif: None declared, Nicola Luigi Bragazzi: None declared, Abdulla Watad: None declared, Doron Comanesther: None declared, Arnon Cohen Grant/research support from: Prof. Arnon Cohen received research grants from Janssen, Novartis and AbbVie and Sanofi, Consultant for: Prof. Arnon Cohen served as a consultant, advisor for AbbVie; Amgen; Boehringer Ingelheim; Dexcel pharma; Janssen, Lilly; Neopharm; Novartis, Perrigo; Pfizer; Rafa; Sanofi , Speakers bureau: Prof. Arnon Cohen served as speaker for AbbVie; Amgen; Boehringer Ingelheim; Dexcel pharma; Janssen, Lilly; Neopharm; Novartis, Perrigo; Pfizer; Rafa; Sanofi , Dennis McGonagle Consultant for: Lilly, Novartis UCB, Speakers bureau: Lilly, Novartis UCB, Howard Amital Grant/research support from: Pfizer, AbbVie, Janssen, Grant/research support from: Pfizer, AbbVie, Janssen, Consultant for: Pfizer, Merck Sharp & Dohme, Consultant for: Pfizer, Merck Sharp & Dohme, Speakers bureau: Pfizer, Merck Sharp & Dohme, Janssen, Sanofi, Bristol-Myers Squibb, Abbvie, Neopharm, Speakers bureau: Pfizer, Merck Sharp & Dohme, Janssen, Sanofi, Bristol-Myers Squibb, Abbvie, Neopharm

HighlightsWhat are the main findings?The Willems method provided the most accurate estimates, while Demirjian consistently overestimated chronological age.Similar dental ages were observed between children with familial Mediterranean fever (FMF) and healthy peers.What are the implications of the main findings?FMF, under regular colchicine treatment, does not negatively affect dental maturation.Willems and Cameriere methods provide reliable dental age estimation in Turkish pediatric populations, including children with FMF.Background and objectives: This study aimed to investigate the effects of familial Mediterranean fever (FMF)—a chronic inflammatory disease—on dental maturation regarding dental development using three dental age estimation methods. Methods: The orthopantomograms of 78 children diagnosed with FMF were compared with those of 78 systemically healthy control children. Demirjian, Willems, and Cameriere’s methods were used to estimate the dental age from seven teeth in the left mandible on the orthopantomograms. The data were analyzed using R statistical software. Results: The mean difference between dental age (DA) and chronological age (CA) using the Demirjian method was 0.646 in the control group and 0.753 in the FMF group (p = 0.595). For the Willems method, the mean DA versus CA difference was 0.283 in the control group and 0.322 in the FMF group (p = 0.835). Regarding the Cameriere method, the mean difference between DA and CA was −0.399 for the control group and −0.435 for the FMF group (p = 0.863), indicating no significant differences. At the ±1-year threshold, the Willems method showed the highest accuracy (69.87%), followed by the Cameriere method (66.67%), whereas the Demirjian method had the lowest accuracy (54.49%). These results suggest that the Willems method provides a more reliable estimate of chronological age within a ±1-year margin compared with the other two methods. Conclusions: Of the dental age estimators, the Willems method gave the closest age estimates. The Demirjian method overestimated the chronological age in both healthy children and children with FMF. For Turkish children receiving regular colchicine therapy, dental maturation was unaffected by FMF, suggesting that effective inflammatory control might preserve odontogenesis.

Familial Mediterranean fever is the most common auto-inflammatory disease in childhood. The aim of present study is to assess whether familial Mediterranean fever increases the risk of premature atherosclerosis. It is a case-control prospective study. The study included 32 patients in attack-free period and 22 healthy children who did not have any chronic disease. Demographic features, clinical findings, response to colchicine therapy, Mediterranean Fever gene mutations were recorded in familial Mediterranean fever group. Mean platelet volume and intima-media thickness were evaluated as a possible marker of early onset atherosclerosis. Intima media thickness of abdominal aorta and common carotid arteries with color Doppler ultrasound, mean platelet volume and acute phase reactants were measured in both groups. No significant difference was documented between the patient and control groups regarding the intima-media thickness (p>0, 05). Familial Mediterranean fever patients had significantly higher mean platelet volume values compared with the controls (8.35±1.0 vs. 7.79±0.78 fl, p=0.026). Intima media thickness and mean platelet volume values of familial Mediterranean fever patients were not correlated with lipid profiles, inflammatory markers. The present study found out no evidence that intima media thickness of abdominal aorta and common carotid arteries in familial Mediterranean fever patients could predict early atherosclerosis. However, mean platelet volume value was found higher in children with familial Mediterranean fever. Mean platelet volume may be useful marker to show premature atherosclerosis in familial Mediterranean fever.

BackgroundThe transition from pediatric to adult health care often challenging for young adults with rheumatic diseases. During the transition period, disruptions, diagnostic changes, and treatment differences may occur. The successful...

Perimenstrual attacks have been reported in up to 15% of patients with FMF, suggesting that menstruation may be a trigger for FMF attacks. The aim of this study was to investigate menstrual period patterns and dysmenorrhea in adolescents with FMF in comparison to their healthy peers. This cross-sectional case–control study included 73 FMF patients and 70 age- and body mass index-matched controls. A structured questionnaire was designed to assess menstrual history, the frequency and severity of dysmenorrhea, symptoms related to dysmenorrhea, and the clinical features of FMF attacks. Dysmenorrhea was present in 90.4% of patients and 95.7% of controls (p = 0.32). Pain was reported during every cycle or every two cycles by 83.3% of patients versus 65.6% of controls (p = 0.02). Fever (27.4% vs. 10.3%, p = 0.01) was significantly more frequent in patients, while musculoskeletal symptoms (46.6% vs. 66.2%, p = 0.02), fatigue (53.4% vs. 83.8%, p < 0.001), and sleep disturbances (19.2% vs. 50.7%, p < 0.001) were more common in controls. Notably, FMF patients reported heavier bleeding episodes with higher number of sanitary pads used during menstruation (p = 0.001). Menstruation-associated FMF attacks were reported by 37% of patients, with 14.8% experiencing them every cycle. Exon 10 variants were present in 86.3% of cases, with 23.3% being homozygous. The frequency and character of dysmenorrhea did not differ significantly according to genetic profiles. Conclusions: This study is the first to investigate menstrual patterns and dysmenorrhea symptoms in adolescent FMF patients compared to their healthy peers. Dysmenorrhea is prevalent in FMF patients with distinct menstrual characteristics, including more frequent fever and heavier bleeding.What is Known:• Menstruation may trigger Familial Mediterranean Fever (FMF) attacks in a subset of patients, but the relationship between FMF and dysmenorrhea remains unclear.• Some studies suggest that inflammation associated with FMF could contribute to menstrual pain and abnormalities, but comprehensive data in adolescents are limited.What is New:• This study is the first to compare menstrual patterns and dysmenorrhea characteristics between adolescent FMF patients and healthy controls, highlighting distinct menstrual symptoms in FMF patients.• FMF patients experience more frequent febrile episodes and heavier menstrual bleeding compared to their healthy peers, but dysmenorrhea characteristics are not influenced by specific MEFV gene mutations.

Introduction: Technological advances have made high-altitude ski slopes easily accessible to skiers of all ages. However, research on the effects of hypoxia experienced during excursions to such altitudes on physiological systems, including the ocular system, in children is scarce. Retinal vessels are embryologically of the same origin as vessels in the brain, and have similar anatomical and physiological characteristics. Thus, any hypoxia-related changes in the morphology of the former may reflect the status of the latter. Objective: To compare the effect of one-day hypoxic exposure, equivalent to the elevation of high-altitude ski resorts in North America and Europe (∼3,000m), on retinal vessel diameter between adults and children. Methods: 11 adults (age: 40.1 ± 4.1years) and 8 children (age: 9.3 ± 1.3years) took part in the study. They spent 3days at the Olympic Sports Centre Planica (Slovenia; altitude: 940m). During days 1 and 2 they were exposed to normoxia (FiO2 = 0.209), and day 3 to normobaric hypoxia (FiO2 = 0.162 ± 0.03). Digital high-resolution retinal fundus photographs were obtained in normoxia (Day 2) and hypoxia (Day 3). Central retinal arteriolar equivalent (CRAE) and venular equivalents (CRVE) were determined using an Automated Retinal Image Analyser. Results: Central retinal arteriolar and venular equivalents increased with hypoxia in children (central retinal arteriolar equivalent: 105.32 ± 7.72µm, hypoxia: 110.13 ± 7.16µm, central retinal venular equivalent: normoxia: 123.39 ± 8.34µm, hypoxia: 130.11 ± 8.54µm) and adults (central retinal arteriolar equivalent: normoxia: 105.35 ± 10.67µm, hypoxia: 110.77 ± 8.36µm; central retinal venular equivalent: normoxia: 126.89 ± 7.24µm, hypoxia: 132.03 ± 9.72µm), with no main effect of group or group*condition interaction. A main effect of condition on central retinal arteriolar and venular equivalents was observed (central retinal arteriolar equivalent:normoxia: 105.34 ± 9.30µm, hypoxia: 110.50 ± 7.67µm, p < 0.001; central retinal venular equivalent: normoxia: 125.41 ± 7.70µm, hypoxia: 131.22 ± 9.05µm, p < 0.001). Conclusion: A 20-hour hypoxic exposure significantly increased central retinal arteriolar and venular equivalents in adults and children. These hypoxia-induced increases were not significantly different between the age groups, confirming that vasomotor sensitivity of the retinal vessels to acute hypoxia is comparable between adults and prepubertal children.

Background:Autoinflammatory diseases are diseases associated with excessive activation of innate immunity. Most continue into adulthood if they begin in childhood. The transition from pediatric to adult care is a complex...

IntroductionVarious types of vasculitides have been identified in patients with familial Mediterranean fever (FMF); however, FMF characteristic in patients who experience vasculitis during the disease course have not been described. This study aimed to describe the types of vasculitides in FMF and characterize the patients.MethodsThis nested case-control study compared 27 patients with FMF (12 male) diagnosed with vasculitis with 100 patients (49 men) who did not develop vasculitis.ResultsMost patients (25/27) developed vasculitis after FMF diagnosis. Four types of vasculitides were observed: cutaneous small vessel vasculitis (10 patients, 37%), Henoch–Schonlein purpura/immunoglobulin A vasculitis (8 patients, 30%), periarteritis nodosa (three patients, 11%), and Behçet disease (six patients, 22%). The vasculitis group was younger at FMF onset (6.6 [± 5.9] years vs. 16.2 [± 13.7] years, p < 0.002) and diagnosis (13.1 [± 13.1] years vs. 25.1 [± 17.92] years, p < 0.001). This group showed a higher frequency of homozygosity for the M694V mutation (73.9% vs. 29.4%, p < 0.001), had a more severe FMF (mean Pras severity score: 10.4 [± 2.6] vs. 7.3 [± 3.1], p < 0.001), required higher colchicine doses (1.96 [± 0.61] mg/d vs. 1.66 [± 0.65] mg/d, p < 0.025), and tended to show higher rates of colchicine resistance (29.6% vs. 12%, p = 0.053). However, vasculitis was not an independent factor influencing FMF severity.ConclusionPatients with FMF and vasculitis are characterized by a more severe disease, likely due to factors other than vasculitis itself. Yet, its presence can serve as a clinical clue to disease severity.

To evaluate the utility of the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic immune-response index (SIRI) in the prediction of adverse pregnancy outcomes in pregnant women with Familial Mediterranean fever (FMF) MATERIAL AND METHODS: This retrospective case-control study was conducted between 2019-2023. First-trimester NLR, SII (NLR X platelet count), and SIRI (NLR X monocyte count) values were compared between pregnant women with FMF (n=85) and without FMF (n=105). Thereafter, pregnant women with FMF were divided into two groups: 1) FMF with perinatal complications (n=30), and 2) FMF without perinatal complications (n=55). NLR, SII, and SIRI values were compared between the two subgroups. Finally, an ROC analysis was performed to determine optimal cut-off values for NLR, SII, and SIRI in the prediction of composite adverse pregnancy outcomes. The FMF group had significantly higher first-trimester NLR, SII, and SIRI values compared to the controls. The FMF with perinatal complications group had significantly higher NLR, SII, and SIRI values than the FMF group without perinatal complications (p<0.05). Optimal cut-off values were 4.89 (80% sensitivity, 78.2% specificity), 1180.6 (76.7% sensitivity, 72.7% specificity), and 1.9 (83.3% sensitivity,72.7% specificity) for NLR, SII, and SIRI, respectively. SII, SIRI, and NLR may be used to predict adverse pregnancy outcomes in pregnant women with FMF.

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.

Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was...

The spectrum of periodic fever syndromes (PFS)/autoinflammation diseases is continuously expanding. This review provides an overview of the primary research and an update on the main clinical developments in these disorders published in the past 12-18 months. IL-1β is pivotal to the pathogenesis of most of the PFS. In familial Mediterranean fever (FMF) MEFV mutations lead to gain of pyrin function, resulting in inappropriate IL-1β release that is dependent on ASC but not the NLRP3 inflammasome. Anti-IL-1 therapy is effective in tumour necrosis factor receptor-associated periodic syndrome (TRAPS), whilst both spontaneous and pathogen-associated molecular patterns (PAMPs) induced IL-1β release have been demonstrated in NLRP12-associated periodic syndrome (NAPS12). Somatic NLRP3/CIAS1 mosaicism is a significant cause of cryopyrin-associated periodic syndromes (CAPS). Close connections have also been established between metabolic and inflammatory pathways. In TRAPS increased reactive oxygen species (ROS) of mitochondrial origin leads to production of pro-inflammatory cytokines, whilst NLRP3 inflammasome activation in type 2 diabetes (T2D) is induced by oligomers of islet amyloid polypeptides (IAPP). Caspase 1 activation and IL-1β release is central to the pathogenesis of many autoinflammatory syndromes. This is supported by the effectiveness of anti-IL-1 biologics in treatment of these disorders.