Familial Mediterranean Fever Patients Research Articles

Preliminary Evaluation for the Development of a Scoring System to Predict Homozygous M694V Genotype in Familial Mediterranean Fever Patients

Objective The aim of this study was to identify key parameters of a scoring system to be developed to predict the homozygous M694V genotype in patients clinically diagnosed with familial Mediterranean fever. Methods This study was a cross-sectional analysis of 472 pediatric familial Mediterranean fever patients with a homozygous genotype on exon 10, followed at our tertiary pediatric rheumatology clinic between June 2016 and June 2023. The patients were categorized into 2 groups based on their genotypes: group 1 comprised 402 patients (85.2%) with the homozygous M694V genotype, whereas group 2 consisted of 70 patients (14.8%) with other homozygous genotypes. Demographic information, clinical manifestations, MEFV (Mediterranean fever) gene variant analysis, and treatment responses were recorded from the patients' medical charts. Results The odds ratios for age at disease onset, arthritis, and chest pain were 0.892 (95% confidence interval [CI]: 0.832–0.958, p = 0.002), 2.565 (95% CI: 1.109–5.934, p = 0.028), and 2.351 (95% CI: 1.123–4.922, p = 0.023), respectively. A total of 60.7% of patients in group 1 had arthralgia, and 25% had erysipelas-like erythema, with these percentages were higher in group 1 compared with group 2 (p = 0.002, p = 0.001, respectively). Protracted febrile myalgia syndrome was detected in 1.5% of patients, all of whom had homozygous M694V genotype. Colchicine resistance was detected in 13.3% of patients, and all had homozygous M694V genotype. Conclusions This preliminary evaluation identified key parameters for a scoring system designed to predict the homozygous M694V genotype. A multicenter national study will further refine these parameters and develop the scoring system, which will aid clinicians in disease prognosis and therapeutic decision-making.

Fabry disease in familial Mediterranean fever according to the severity of the disease

ObjectivesMutations in the α-galactosidase A (GLA) gene result in Fabry disease (FD), a rare metabolic condition. FD patients present with heterogeneous clinical manifestations, which may overlap with systemic diseases including familial Mediterranean fever (FMF). The aim of this study was to determine the frequency of FD in patients with mild and severe FMF and to prevent misdiagnosis by increasing clinicians’ awareness. MethodsBased on Tel-Hashomer criteria, the study included a total of 91 FMF patients. Patients were divided into two groups according to the number of recurrent clinical episodes or failure to respond to maximum therapy: those with mild and severe forms of the disease. GLA gene mutations and α-GLA enzyme activity were assessed. Records of MEFV mutations, therapies and demographic characteristics were kept. ResultsFD testing was performed on a cohort of 91 FMF patients, 54.9% had mild FMF, 45.1% had severe FMF, and only one patient in the mild FMF subgroup tested positive for FD. The patient was a 39-year-old woman with a history of recurrent abdominal pain, distal limb pain and fever. She had low GLA enzyme activity and a heterozygous GLA gene mutation. ConclusionsOur findings suggest that FD should be considered in the differential diagnosis of FMF, especially in individuals with unusual symptoms.

Familial Mediterranean fever in children from central-southern Italy: a multicentric retrospective cohort study.

Although familial Mediterranean fever (FMF) is a relevant disease in countries surrounding the Mediterranean Sea, there are still few reports from Italy. We retrospectively evaluated patients with FMF diagnosed according to the EuroFever/PRINTO classification criteria in three pediatric rheumatology referral centers in central-southern Italy. Logistic regression analysis assessed the associations between age at disease onset and symptoms. Overall, 48 patients were enrolled (28 females, 20 males), with a median age at onset of 3.3 [3.1] years, and a median follow-up period of 5.1 [10.8] years. The most common MEFV genotype was M694V/- (11 patients, 22.9%), followed by M694V/M694V (6 patients, 12.5%). At onset, recurrent fever was observed in 47 patients (97.9%), with a median time between attacks of 18 [11] days. Overall, recurrent fever was observed in all patients, abdominal pain in 44 (91.7%), and chest pain in 18 (37.5%). At the last follow-up visit, 24 patients were on colchicine (50%), 2 on biologic (4.2%), and 6 on both (12.5%). Canakinumab was the most used biologic drug, in 6 (12.5%) patients. MEFV genotype was associated with disease severity (p = 0.007) and the use of a biological drug (p = 0.01). FMF prevalence in the Abruzzo region was found highly than expected (at least 1:45,000). Differently, we found a relevant gap among FMF patients expected and observed in the Apulia and Sicily regions. FMF is a relevant issue in central-southern Italy. A large epidemiologic study should be performed to better define its prevalence in the country. Key Points • Italian children with familial Mediterranean fever tend to have an early age of onset, primarily manifesting with recurrent fever and characteristic associated symptoms. • Many MEFV gene variants are present in Italian children with familial Mediterranean fever, and these patients are most often heterozygous, exhibiting a mild to moderate phenotype. • The prevalence of familial Mediterranean fever in Italy is still unknown but recently estimated to be around 1:60,000, probably higher in central and southern Italy. • According to our cohort, the prevalence of FMF in the Abruzzo region is at least 1:45,000, higher than expected. Differently, we found lower prevalence rates of the disease in Apulia and Sicily.

Investigating the impact of tocilizumab on serum cytokines concentrations in Japanese FMF patients: a sub-analysis of the NUH01FMF study

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease, characterized by recurrent fever, arthritis, rash, and serositis, and is caused by mutations in the MEFV gene coding for the pyrin protein. The primary treatment goal is to prevent acute attacks and minimize subclinical inflammation to avoid secondary amyloidosis with colchicine as the first-line treatment. However, 10-20% of patients are colchicine-resistant or intolerant. While the therapeutic potential of IL-6 inhibitors such as tocilizumab (TCZ) has been suggested, the detailed serum cytokine profiles after TCZ treatment in patients with FMF remain largely unexplored. This study focused on a sub-analysis of a clinical trial evaluating TCZ in patients with colchicine-resistant FMF (crFMF). We analyzed the serum cytokine profiles at 0, 2, 4, 8, 12, 16, 20, and 24 weeks in the TCZ and placebo groups. Our findings revealed a decrease in serum C-X-C motif chemokine ligand 1 and vascular endothelial growth factor levels in the TCZ group at week 4 compared to baseline, which persisted until week 24, indicating the potential of TCZ to manage crFMF by modulating specific inflammatory cytokines. Further research is required to confirm these findings and optimize the treatment strategies for FMF.

Cost-saving approach with screening of selected variants in genetic diagnosis in Turkish pediatric familial Mediterranean fever patients: a single center longitudinal study.

The aim of this study was to investigate whether a short exon screening consisting of selected variants could confirm the diagnosis in patients with a preliminary diagnosis of familial Mediterranean fever (FMF), thus providing a cost-saving alternative to a comprehensive MEditerranean FeVer (MEFV) gene sequence analysis test. This observational study on pediatric patients focused on clinically suspected FMF cases without prior genetic analysis. Participants met the Turkish pediatric FMF criteria. They underwent short exon screening for M694V, M680I, V726A, and E148Q variants. Those who were heterozygous or negative on short exon screening received further MEFV gene sequence analysis. The study involved 1557 patients. Pathogenic variants in both alleles of the MEFV gene were found in 611 patients (39.2%), and a high-penetrance variant in heterozygosity or an E148Q variant on the other allele was found in 643 patients (41.3%). A further 189 patients (12.1%) had one or two E148Q variants. Short-exon screening was negative in 114 patients (7.6%). Of the 876 patients who underwent MEFV gene sequence analysis, additional variants were found in 72 of the 762 initially heterozygous patients. Of the 114 initially negative patients, 34 had homozygous or compound heterozygous variants, and 74 had heterozygous variants. Ultimately, only 6 patients yielded negative results in the MEFV gene sequence analysis. The short exon screening for common MEFV mutations offers a practical and cost-saving alternative to comprehensive MEFV gene sequence analysis in populations with a high prevalence of FMF.

Diagnostic delays in familial Mediterranean fever: a Juvenile Inflammatory Rheumatism (JIR) cohort study.

Several studies reported that Familial Mediterranean Fever (FMF) diagnosis may be missed or delayed even in countries with a high FMF prevalence. Our aim was to study on a large cohort of European FMF patients the frequency and associated factors of diagnosis delay. Clinical data were extracted from the Juvenile Inflammatory Rheumatism (JIR)-cohort. All FMF patients fulfilled Livneh Criteria and had been sequenced for MEFV exon 10. FMF-diagnostic delay (d-FMF) was defined as the duration between the onset of the symptoms and the diagnosis of more than 10years. 960 FMF patients were enrolled: delayed diagnosis (d-FMF) was noted in 200 patients (20%). d-FMF patients were significantly older compared to non d-FMF with a median age of 46.4years old vs. 15.5 (p < 0.0001). Women displayed more d-FMF compared to men (56 vs. 47%, p = 0.03). Clinical presentation during attacks was not statistically significant except for erysipelas-like erythema, which was higher among d-FMF patients (33 vs. 22%, p = 0.0003). The presence of one or two pathogenic MEFV mutation was not different between patients. Compared to other FMF, d-FMF patients displayed significantly more AA amyloidosis (10 vs. 2.6%, p < 0.0001) and received more biotherapy (18 vs. 3.8%, p < 0.0001). Twenty percent of FMF patients had a diagnostic delay >10years, including more women. The differential diagnosis of abdominal attacks with menstrual pain may be an explanation, and erysipelas-like erythema may not be recognized as FMF by all practitioners.

Protracted Febrile Myalgia Syndrome: A Rare and Difficult Manifestation of Familial Mediterranean Fever.

Protracted febrile myalgia syndrome (PFMS) is characterized by severe myalgia, fever, abdominal pain, and arthralgia/arthritis episodes lasting for several weeks in patients with familial Mediterranean fever. Treatment options include nonsteroidal anti-inflammatory drugs, corticosteroids, and anti-interleukin-1 therapy. This study aimed to share our experiences of PFMS so as to shed light on this rare and elusive condition. This cross-sectional analysis included 17 patients diagnosed with PFMS at our pediatric rheumatology clinic between January 2018 and September 2023. In our clinic, 17 (1%) of 1663 familial Mediterranean fever patients presented with PFMS, and it was the initial manifestation in 10 patients (58.8%) in the cohort. Eight of the 17 patients had an M694V homozygous mutation in the MEFV gene. A magnetic resonance imaging showed myositis and fasciitis in just 1 patient, and myositis alone was evident in 5 others. Symptoms improved in 2 patients with nonsteroidal anti-inflammatory drugs, whereas prednisolone improved symptoms in 12 patients and anakinra was required in 3 patients. Patients who received anakinra had another severe attack and required long-term anakinra or canakinumab. Syndrome for PFMS is difficult to recognize as it can sometimes be the first manifestation of familial Mediterranean fever. The syndrome is not accompanied by fever in some patients, even though the word febrile is part of its name. Most patients respond dramatically to nonsteroidal anti-inflammatory drugs or corticosteroids. In some patients with PFMS, long-term anakinra or canakinumab treatment may be more useful in preventing severe attacks of PFMS than short-term (5 to 7 days) anakinra treatment.

Factors Associated With Successful Withdrawal of Biologic Agents in Children With Colchicine-Resistant Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease, and colchicine is the mainstay of treatment. Approximately 5%-10% of patients may respond inadequately to colchicine, and anti-interleukin-1 (anti-IL-1) agents are important treatment options in these patients. The aim of this study was to see whether there is any factor associated with the withdrawal of these anti-IL-1 agents and to investigate the characteristics of colchicine-resistant FMF patients who needed biological therapy. Demographic, clinical characteristics, and disease severity of patients, at 2 referral centers, between 2012 and 2022, in whom anti-IL-1 treatment was continued and discontinued, were compared in this study. The international severity scoring system for FMF (ISSF) was used for disease severity assessment. In 64 colchicine-resistant FMF patients, the median (interquartile range) duration of biological treatment was 39 (45) months. Treatment of 26 patients (40.6%) was started with anakinra and 38 (59.4%) with canakinumab. During follow-up, anti-IL-1 treatment was discontinued in 23 patients (35.9%). High ISSF scores before biological treatment, presence of exertional leg pain, subclinical inflammation, and comorbidity were found to be statistically more frequent in the group whose biological therapy could not be discontinued (p = 0.009, p = 0.006, p = 0.026, p = 0.001, respectively). Low ISSF scores before biological treatment with no accompanying exertional leg pain, subclinical inflammation, and comorbidities may be stated as an associated factors in terms of the discontinuation of biological agents in colchicine-resistant pediatric FMF patients.

Clinical significance of mean platelet volume, platelet distribution width, and neutrophil-lymphocyte ratio in children with familial mediterranean fever

Objective: Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by recurrent fever and polyserositis. Studies conducted in recent years emphasize the importance of platelet parameters in chronic diseases. This study examined changes in attack and attack-free periods in children with FMF, focusing on Mean Platelet Volume (MPV), an indicator of disease severity. Method: 150 FMF patients (90 girls, 60 boys) and 50 healthy individuals (29 men, 21 women) were included in the study. Data were analyzed according to colchicine treatment, attack, and attack-free periods. The severity of the disease was classified as mild, moderate, and severe. Results: MPV levels of patients with FMF were higher than the healthy group. In particular, MPV levels decreased significantly during attacks, with a more pronounced decrease in severe cases. Conclusion: As a result, MPV measurement is a cost-effective and rapid method that can support the evaluation of disease severity and attack periods in FMF patients.

The Phenotype-Genotype Correlations of FMF Patients: A Single Center Study

Purpose: Familial Mediterranean Fever (FMF) is an autosomal recessive, auto-inflammatory disease that is characterized by recurrent fever and polyserositis episodes like peritonitis, arthritis, and pleuritis. The disease occurs most commonly in populations of Jewish, Turkish, Armenian, and Arabian origin. We aimed to show the genotype-phenotype relationship in FMF patients in our centre. Materials and Methods: We conducted a retrospective analysis of the medical registries of 200 FMF pediatric patients from Sisli Hamidiye Etfal Education and Research Hospital, Department of Pediatrics, Pediatric Nephrology Policlinic between 2011 and 2017. The diagnosis was based on the Tel-Hashomer clinical diagnostic criteria. We used the severity score recommended by Pras in 1998. Clinical data and baseline investigations were collected. Mutation analysis was performed by the amplification-refractory mutation system (ARMS)-PCR method. Findings: Females represented 54% and ages ranged from 40-210 months. The most frequent symptoms were abdominal pain, fever, and arthralgia.Among the 200 patients, 41 (20,5%) were homozygous, 63 (31,5%) were compound heterozygous, and 96 (48%) were heterozygous for MEFV mutations. The first 3 most common mutations were heterozygotus R202Q, M694V/R202Q and heterozygotus E148Q respectively., which was statistically significant. M694V mutation was positive in at least one allele in 72 patients studied. The symptom of fever and arthralgia were found to be significantly higher in patients with M694V mutation. Also, the number of episodes in one year before treatment, PRAS score and the values of fibrinogen during episodes were higher in M694V patients as a result, the age at diagnosis was found to be earlier in patients with homozygotus M694V mutation. The ratio of female gender and myalgia was significantly higher in patinets with the mutation of R202Q homozygotus. The number of episodes in one year before treatment was lower in R202Q patients when compared to the M694V carriers, therefore the initiation age to colchicine was later in the R202Q group which was statistically significant. İmplications to Theory, Practice and Policy: Our results support the notion that the genotype influences the phenotype as regards clinical manifestations, disease severity, and colchicine response.

Novel use of interleukin-1 antagonists in male familial Mediterranean fever patients with infertility: Case series.

Novel use of interleukin-1 antagonists in male familial Mediterranean fever patients with infertility: Case series.

E148Q variant: a familial Mediterranean fever-causing mutation or a sequence variant?

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, linked to mutations in the MEFV gene. The p.E148Q variant, found on exon 2, has an uncertain role in FMF, with debates on whether it is a benign polymorphism or a pathogenic mutation. This study aimed to assess the clinical characteristics and severity of FMF in patients homozygous for the p.E148Q variant and to evaluate the impact of the p.V726A variant in these patients. This retrospective cohort study analyzed data from electronic medical records at Carmel Medical Center, Israel. Patients who underwent genetic testing for FMF from November 2004 to December 2019 and had p.E148Q/p.E148Q or p.E148Q/p.E148Q + p.V726A variants were included. Disease severity was assessed using the Tel Hashomer Key to Severity Score. Statistical analyses compared clinical characteristics and severity between genotype groups. The study included 61 FMF patients, with 24 (39%) having p.E148Q/p.E148Q and 37 (61%) having p.E148Q/p.E148Q + p.V726A variants. The majority (72%) were Druze. Most patients (65.5%) exhibited mild disease, while 31.1% had moderate disease, with no cases of severe disease. Colchicine treatment significantly reduced CRP levels in all patients.Conclusion: These findings suggest that the p.E148Q variant, whether alone or with p.V726A, generally results in mild to moderate FMF severity, supporting its pathogenic role in particular ethnicity. These results contribute to understanding the clinical significance of the p.E148Q variant and considering the patient’s need for Colchicine treatment.What is Known:• The role of the p.E148Q variant in FMF is debated, with questions about whether it is a benign polymorphism or a pathogenic mutation.• The prevalence of MEFV variants can vary significantly among different ethnic groups.What is New:• The p.E148Q variant has clinical significance in particular ethnicities, as supported by a significant reduction in CRP levels following colchicine treatment.• The p.E148Q variant, whether alone or with p.V726A, generally results in mild to moderate FMF severity.

The Impact of Different MEFV Genotypes on Clinical Phenotype of Patients with Familial Mediterranean Fever: Special Emphasis on Joint Involvement

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In this retrospective cohort study, we aimed to assess the effects of various MEFV genotypes on the clinical characteristics of the patients, with a special focus on the joint involvement. In total, 782 patients with FMF were categorized into 3 groups according to the MEFV mutation; Group 1: Patients homozygous for M694V; Group 2: Patients carrying other pathogenic MEFV variants in exon 10 in homozygous or compound heterozygous states; and Group 3: FMF patients with other variants or without mutations. Clinical and demographic findings were compared between groups. Among the 782 FMF patients, total frequency of arthritis was 237 (30.3%): 207 (26.4%) were acute monoarthritis and 67 (8.5%) were chronic arthritis. Both the frequency of arthritis (acute and/or chronic) (40.4% vs. 24.8% vs. 26.7%; p:0.001) and acute monoarthritis (35.4% vs. 20% vs. 23.7%; p:0.001) were significantly higher in Group 1 than in the other groups. FMF patients with chronic arthritis showed a distinct juvenile idiopathic arthritis (JIA) distribution pattern with a more frequent enthesitis-related arthritis (ERA) subtype (43.2%). HLA-B27 was positive in 24% of the ERA patients.Conclusion: Homozygous M694V mutation is associated with a more frequent and longer acute monoarthritis comparing to other MEFV genotypes. In addition, the risk of chronic arthritis seems not related to the MEFV mutations. However, FMF patients with chronic arthritis show a distinct ILAR JIA distribution pattern with a more frequent ERA and undifferentiated arthritis subtype.What is known:• Homozygous M694V mutation is associated with a more frequent and longer acute monoarthritisWhat is new:• FMF patients with chronic arthritis show a distinct ILAR JIA distribution pattern with a more frequent ERA subtype• ERA patients with negative HLA-B27 antigen should also be assessed for polyserositis episodes of FMF, especially in countries with high FMF carrier frequency

The Quality of Life in Patients with Familial Mediterranean Fever and Their Parents Perception.

Familial Mediterranean fever (FMF) is a chronic disease characterized by recurrent episodes of fever and polyserositis. This study aimed to assess children's quality of life (QoL), as reported by children and their parents, and to compare the results according to clinical variables. The study examined 107 children with FMF, evaluating their demographic and genetic data, utilizing the Pediatric Quality of Life Inventory (PedsQL) to assess QoL, and comparing scores based on disease severity. The severity of FMF is inversely correlated with QoL scores, with mild cases having the highest scores (97±4), followed by moderate (76±11) and severe cases (52±10.3) (p<0,001). Disease severity, treatment adherence, healthcare utilization, genetic mutations, family income, and maternal age at birth all significantly impact perceived quality of life in FMF patients (p<0,001). Additionally, parents reported lower QoL for children with FMF who experienced various adverse factors such as low family income, household smoking, frequent attacks, hospitalizations, irregular medication use, and low maternal education levels (p<0,001). Children's daily activities, academic performance, and family functioning are all significantly impacted by FMF. Physicians caring for patients with FMF should be aware of the QoL changes in the management of these patients. As a result, medical therapy, patient education, and indicators of psychological and social support can all be offered more effectively.

Clinical Associations of E148Q Heterozygosity: What to Expect From E148Q?

The exact effects of MEFV variants on inflammation are still under investigation, and reports on variants of unknown significance, particularly the E148Q variant, have been conflicting. Therefore, this study aims to investigate patients exhibiting E148Q heterozygosity, focusing on diagnoses and disease courses to assist physicians in interpreting the variant. Data of pediatric patients presenting to the Pediatric Rheumatology clinic between November 2016 and September 2023, exhibiting only E148Q heterozygosity in MEFV gene analysis, were extracted. Patients who were lost before 9 months of follow-up have been excluded to ensure the completion of initial diagnostic tests and evaluations. Among the 119 patients with E148Q variant, the diagnoses were as follows: healthy, 51.3%; IgA vasculitis, 10.1%; Familial Mediterranean Fever (FMF), 7.6%; Periodic fever, Aphtous stomatitis, Pharyngitis, Adenitis (PFAPA), 6.7%; and other diagnoses, 19.3%. IgA vasculitis patients experienced articular, gastrointestinal, and renal involvement at rates of 91.7%, 58.3%, and 16.7%, respectively. Complete response, partial response, and no response to colchicine were 37.5%, 12.5%, and 50%, respectively, in PFAPA patients. All FMF patients responded to colchicine treatment resulting in reduced mean FMF episode counts in 6 months from 3.22 ± 0.92 to 0.56 ± 0.52. The E148Q variant may amplify inflammation and modify disease courses. Patients with the E148Q variant experiencing typical FMF episodes should receive colchicine, but clinicians should exercise caution regarding alternative diagnoses. Additionally, the E148Q variant may increase acute phase reactants and disease severity in IgA vasculitis. However, to reach definitive conclusions on its treatment-modifying role in PFAPA, universal diagnosis and treatment response criteria should be adopted.

Role of serum calprotectin in identifying familial Mediterranean fever attacks.

The aim of the study was to evaluate serum calprotectin (CLP) levels in familial Mediterranean fever (FMF) patients and to investigate the utility of CLP in distinguishing patients with attack from patients without attack. FMF patients, rheumatoid arthritis (RA) patients, and healthy controls were included. Serum calprotectin levels were quantified utilizing the enzyme-linked immunosorbent assay (ELISA) method. Receiver operating characteristic (ROC) curve analysis was used to identify the cut-off value of serum CLP level to differentiate FMF patients with attack from those without. Logistic regression analysis was performed to identify predictors. Significant differences were observed among the three groups concerning white blood cell (WBC), neutrophil, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum CLP levels (p = 0.003, p = 0.004, p < 0.001, p < 0.001, and p = 0.002, respectively). Higher ESR, CRP, and serum CLP levels were observed in FMF patients with attacks than those without (all, p < 0.001). Serum CLP was significantly higher in RA patients than in FMF patients in remission (p < 0.001). ROC analysis identified a threshold CLP concentration in FMF with an attack to be 47.1pg/mL (83.3% sensitivity, 60.6% specificity, AUC = 0.74, 95% CI = 0.63-0.85, p < 0.001). In univariate logistic regression analysis, CLP (β = 1.045, 95% CI = 1.017-1.073, p = 0.001) was predictive of FMF patients experiencing an attack. Serum CLP proves to be as productive as ESR in illustrating inflammation and demonstrating the existence of attacks in FMF patients.

The increased chromosomal DNA damage in patients with Familial Mediterranean Fever

ABSTRACT Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease. In this study, we aimed to assess chromosomal DNA damage and cell proliferation by using cytokinesis-block micronucleus cytome (CBMN-cyt) assay in the peripheral blood lymphocytes of untreated FMF patients carrying M694V and R202Q mutations, which are the most common MEFV gene mutations in Turkish society. The study included 20 untreated FMF patients with M694V and R202Q mutations and 20 healthy individuals of similar age and sex as the control group. Micronucleus (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) were scored in the obtained bi-nucleated (BN) cells. Additionally, the nuclear division index (NDI) was calculated using the scores of mononuclear, binuclear, and multinuclear cells. We found that MN and NPBs frequencies in FMF patients were significantly higher than in controls, and number of metaphases was significantly lower (respectively, p < 0.05, p < 0.01, and p < 0.01). However, there was no significant difference in NBUDs frequencies and NDI values between FMF patients and controls (p > 0.05). Our study is the first to evaluate FMF patients’ lymphocytes using the CBMN-cyt assay, as no previous research has been found in this respect. Increased MN and NPB frequencies may be useful as biomarkers for chromosomal DNA damage, and may indicate a potential for elevated cancer risk in untreated FMF patients.

Sacroiliitis in familial Mediterranean fever: A rare joint involvement of the disease.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease characterised by recurrent episodes of fever and polyserositis. Sacroiliac joint involvement is rare in FMF patients. The purpose of this study was to evaluate the demographic, clinical, laboratory and imaging findings of patients with FMF who developed sacroiliitis. The files of paediatric patients aged 0-18 years who were followed up with a diagnosis of FMF were retrospectively reviewed. FMF patients with evidence of sacroiliitis on magnetic resonance imaging (MRI) were included in the study. Among 1062 FMF patients, 22 (12 males; median age 8.5) (2.1%) of them were found to have sacroiliitis. FMF was diagnosed before sacroiliitis in nine (40.9%) patients and after in 13 (59.1%) patients. The most common symptom in patients with sacroiliitis was low back pain (n = 21, 95.5%). In MEFV gene analysis, M694V was found in 16 (72.7%) patients and was the most common mutation. MRI showed evidence of sacroiliitis in all patients. All patients were using colchicine. Patients with FMF-associated sacroiliitis, remission was achieved with non-steroidal anti-inflammatory drugs in 12 (54.5%), conventional disease-modifying antirheumatic drugs in six (27.3%) and tumour necrosis factor inhibitor treatment in four (31.8%). Four (31.8%) patients experienced sacroiliitis when colchicine incompatible and four (31.8%) patients experienced sacroiliitis while using biologic agents for colchicine-resistant FMF. FMF-associated sacroiliitis should be considered especially in patients with M694V mutation if they have symptoms such as low back pain. Colchicine-resistant FMF patients should be evaluated for sacroiliitis symptoms at each visit.

Molecular analyses of MEFV gene mutation variants in Turkish population.

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease primarily affecting individuals of Turkish, Armenian, Arab, and non-Ashkenazi Jewish descent, caused by mutations in the MEFV gene. The aim of this study was to review the common genotype distributions of MEFV variants and mutations in the Turkish population and evaluate rare mutations. The study included 2984 patients who applied to Ankara University Ibni Sina Hospital Immunology Laboratory with clinical suspicion of FMF between 2004 and 2014. The data of patients from different regions of the country who were followed up in the immunology-rheumatology clinic with clinical suspicion and presumptive diagnosis of FMF were evaluated retrospectively. Patients were tested for all mutations in Exon 2 and Exon 10, including M694V, M680I, M694I, V726A, E148Q and R202Q. There were 2504 patients with FMF variant. According to genotyping, R202Q (n = 1567, 39.2%) was the most common mutation. The most common co-variant was the R202Q/M694V genotype (n = 507, 16.98%). Allele frequencies for MEFV mutations were as follows: R202Q (n = 1567, 39.2%), M694V (n = 1004, 25.1%), E148Q (n = 463, 11.5%), M680I (n = 354, 8.8%), V726A (n = 319, 7.9%), A744S (n = 51, 1.2%), R761H (N = 41, 1.0%), P706P (N = 25, 0.6%), E167D (N = 23, 0.5%), M694I (N = 23, 0.5%), and K695R (N = 20, 0.5%). This research revealed the prevalence of both common and rare MEFV gene mutations in Turkish FMF patients in various age groups. R202Q was the most prevalent mutation.

The Role of Tenascin-C in the Physiopathology of Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disease common in the Mediterranean basin. It has been determined that tenascin-C level is increased in rheumatic inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus, and systemic sclerosis. However, the role of tenascin-C has not been investigated in FMF. This study aimed to investigate serum tenascin-C levels in FMF patients and to investigate possible relationships between them. About 38 patients diagnosed with FMF and 40 healthy controls were included in the study. The patient's sex, age, clinical symptoms, physical examination, and laboratory results were recorded. Serum tenascin-C levels were determined by the enzyme-linked immunosorbent assay (ELISA) method. The serum tenascin-C levels were significantly lower in the FMF patients (10297 ± 8107 pg/ml) compared to the healthy control group (29461 ± 13252 pg/ml) (p < 0.001). In receiver operating characteristic(ROC) analysis, when the cut-off point was chosen as 11076 pg/ml, sensitivity was 77.1%and specificity was 91.9%. When the cut-off point was chosen as 19974 pg/ml, sensitivity was 91.4%and specificity was 75.7%. It was determined that the serum tenascin-C levels did not correlate with age, gender, and laboratory parameters in the healthy control group and FMF patients (p > 0.05). This is the first study investigating tenascin-C levels in FMF. Tenascin-C levels in FMF patients were lower than in healthy controls. Low tenascin-C levels in FMF, which are high in other chronic rheumatic diseases, may be a valuable indicator. Therefore, serum tenascin-C level seems to be a useful marker in distinguishing FMF patients from healthy individuals.