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Epigenetic modifications play a pivotal role in autoimmune/inflammatory disorders and could establish a bridge between personalized medicine and disease epidemiological contexts. We sought to investigate the role of epigenetic modifications beside genetic alterations in the MEFV gene in familial Mediterranean fever (FMF). The study comprised 63 FMF patients diagnosed according to the Tel Hashomer criteria: 37 (58.7%) colchicine-responders, 26 (41.3%) non-responders, and 19 matched healthy controls. MEFV mutations were detected using a CE/IVD-labeled 4-230 FMF strip assay. DNA methylation of MEFV gene exon 2 was measured using bisulfite modification and related to pyrin level, phenotypic picture, MEFV mutations, disease severity, serum amyloid A (SAA), CRP, ESR, disease severity, and colchicine response. Our results showed that FMF patients exhibited significantly higher methylation percentage (p < 0.001) and lower pyrin levels (p < 0.001) compared to the control. The MEFV gene M694I mutation was the most commonly reported mutation (p < 0.004). High methylation percentage of the MEFV exon 2 and low pyrin concentration were correlated with disease severity, high SAA, ESR levels, H-pylori, and renal calculi. In conclusion, this study highlights the relation between high methylation percentage, reduced pyrin level, and different biomarkers in FMF, which underscores their role in the pathogenesis of FMF and could be considered as potential therapeutic targets.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by polyserositis and arthritis attacks, which are mediated by increased plasma levels of cytokines. Our hypothesis was that the increase in specific cytokines can also lead to portal hypertension, even in the absence of overt hepatic steatosis.We designed a comparative cross-sectional study with 41 patients and 30 healthy individuals to show if there is a relationship between portal hypertension and FMF. B mode ultrasound and Doppler ultrasound were utilized to evaluate liver echogenicity, portal vein diameter, peak portal blood flow velocity, and portal vein flow direction, which are important diagnostic criteria for portal hypertension.Spleen and liver sizes and portal vein diameters of the FMF patients and the healthy controls were not significantly different. Imaging of 4 patients revealed periportal cuffing and one patient with periportal cuffing also had a fine granular appearance of the liver. The peak portal blood flow velocity of the FMF patients was lower than that of the control group (p0.007).The FMF group had significantly lower peak portal blood flow velocity than the control group, indicating the existence of portal hypertension. However, the differences between the other findings that correlate with portal hypertension were not significant.

Netrins are primarily defined as being of guidance in axonal cell migration in the embryonic period. Cell migration has an important role in the occurrence of organogenesis and inflammation. In the etiopathogenesis of autoimmune diseases, there is said to be tissue destruction associated with uncontrolled activation of the immune system and uncontrolled migration of inflammatory cells to tissues. We aimed to determine whether netrin-1 has a role in the etiopathogenesis of the FMF disease. This study included 42 patients with Familial Mediterranean Fever (FMF) and 44 healthy control subjects. The plasma netrin 1 levels were measured, and relationships were examined between the netrin levels and demographic data, clinical findings and laboratory test results in both groups. No significant difference was determined between the groups in respect of the plasma netrin levels. The lack of difference between the two groups in this study in respect of plasma netrin levels could suggest that netrin-1 does not have an important role in the etiopathogenesis of FMF. There is a need for further in vivo and in vitro studies to examine netrin-1 and receptors in inflammation tissue samples and in normal tissue.

This study aimed to investigate the disease characteristics of familial Mediterranean fever (FMF) patients undergoing dose optimisation and discontinuation of canakinumab therapy. A total of 61 patients diagnosed with FMF and using canakinumab for the resistant disease were enrolled on this retrospective study. Patients' characteristics, disease activity, treatment response, dose optimisation, dose intervals, attack-free periods, drug-free periods and side effects were noted. Dose intervals were extended in patients who achieved remission without being bound by any protocol at the discretion of the rheumatology physician who followed up with the patients in the outpatient clinic. The drug was discontinued in some patients whose dose intervals were 2 months or longer and remained in remission for 6 months or longer. A total of 57 patients (56% female, median age 32.4 years) were included. The mean attack frequency before canakinumab was 3.4/6 months, while it was 1.2 at the last post-treatment visit (p 0.001). The median duration of canakinumab use was 46 months. After the first 6 months, the dosing interval was extended in 22 patients, and then treatment was discontinued in 12 of them who did not have an attack in the last 6 months. Three of the 12 patients whose treatment was discontinued started monthly treatment again after their attacks recurred. In the remaining ten patients, dose intervals were extended to 8-12 weeks after 6 months of monthly treatment. Nine patients are still being followed up without attacks and receive only colchicine therapy. Canakinumab is a safe and effective treatment, dose intervals may be extended, and follow-up without medication may be possible for eligible patients. However, there is a need for a consensus on dose optimisation or tapering.

Aim: Familial Mediterranean Fever (FMF), is a chronic auto-inflammatory disease characterized with recurrent attacks. In between attacks, subclinical inflammation persists which results in increased risk of atherosclerosis. Epicardial adipose tissue is a novel cardiometabolic risk factor which predicts the risk of atherosclerosis. The aim of this study was to measure the epicardial adipose tissue thickness (EATT) and to evaluate the risk of subclinical atherosclerosis in patients with FMF.Materials and Methods: 18 years old and older FMF patients diagnosed according to Tel-Hashomer criteria and age and sex matched healthy individuals were recruited for this cross-sectional study. Disease characteristics, gene mutations, erythrocyte sedimentation rate, C-reactive protein, serum amyloid-A, fibrinogen, lipid levels and complete blood counts were recorded at the time of inclusion. EATT was measured by a two-dimensional transthoracic echocardiography. A p value, Amaç: Ailevi Akdeniz Ateşi (FMF), ataklar halinde giden kronik otoinflamatuvar bir hastalıktır. Ataklar arası dönemde subklinik düzeyde inflamasyonun devam etmesi nedeniyle bu hastalarda artmış ateroskleroz riski mevcuttur. Epikardiyal yağ doku yeni bir kardiyometabolik risk faktörü olup aterosklerotik riskin belirlenmesinde kullanılmaktadır.Bu çalışmanın amacı FMF tanısı ile takip edilen erişkin hastalarda epikardiyal yağ doku kalınlığının ölçülmesi ve subklinik aterosklerotik hastalık riskinin değerlendirilmesidir.Gereç ve yöntemler: Tel-Hashomer kriterlerine göre tanı almış 18 yaş ve üzeri FMF hastası ile yaş ve cinsiyet uyumlu sağlıklı kontrol bu kesitsel çalışmaya dahil edilmiştir. Hastalık özellikleri, FMF gen mutasyonları ve eritrosit sedimentasyon hızı, C-reaktif protein, serum amiloid-A, fibrinojen, lipid düzeyleri ve tam kan sayımları çalışmaya dahil edilme esnasında kaydedilmiştir. Epikardiyal yağ doku kalınlığı, iki boyutlu transtorasik ekokardiyografi ile ölçülmüştür. P değeri

Patients with undefined systemic autoinflammatory diseases (uSAIDs) are challenging to manage, as there are no guidelines or recommendations for targeted therapy. We aimed to evaluate the efficacy of empiric treatment with colchicine in our single-center uSAID population in the United States, as well as the patient characteristics associated with the most robust colchicine response.Children with uSAID 18 years old at initial evaluation during 2000-2019 were included if they received 3 months of colchicine therapy. Data on demographics, clinical features, laboratory/ genetic studies, and treatment responses were collected. Most statistics were based on chi-square analyses for categorical data. Complete response to colchicine was defined as resolution of episodes or the presence of minor residual symptoms that did not require any further therapy. A partial response was defined as a decrease in the frequency, severity, or length of episodes but still necessitating additional therapy. Patients were considered nonresponders if they did not experience any improvement with colchicine at target therapeutic dosing.We identified 133 children diagnosed with uSAID who met our inclusion criteria. The median time to starting empiric colchicine was 5 months from the diagnosis of autoinflammatory disease. 92.5% (n = 123) of patients had a beneficial response to colchicine, including 46.6% (n = 62) partial responders and 45.9% (n = 61) complete responders. The presence of a nonurticarial rash was associated with an incomplete colchicine response (29.2% (n = 21) vs 13.1% (n = 8), P = .025). The presence of a heterozygous MEFV mutation in patients who did not fit Familial Mediterranean Fever diagnostic criteria (n = 25) appeared to be associated with a greater likelihood of complete colchicine response, although this was not statistically significant (62.5% (n = 14) vs 42.6% (n =11), P = .08). In MEFV mutation-negative patients, a nonurticarial rash was even more strongly associated with incomplete colchicine response, with an OR of 27.53 (CI [1.59-477], P = .023). The presence of oral ulcers also corresponded to incomplete colchicine response, although this did not reach clinical significance (38.9% (n = 28) vs 24.6% (n = 15), P = .08). There was no significant association between episode duration or frequency and colchicine response.Colchicine leads to clinical benefits in most children with uSAID. We, thus, recommend an early trial of colchicine in newly diagnosed patients with uSAID.

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.

Acute appendicitis is the most common surgical emergency in children. Diagnosis and management are often straightforward. However, familial Mediterranean fever is an important condition to consider in the assessment of children with acute abdominal pain, particularly in children with an origin in eastern Mediterranean basin where the disease is common. The key feature of familial Mediterranean fever is relapsing episodes of fever and serositis including peritonitis, pleurisy, or arthritis. The disease is treated with colchicine that prevents acute attacks, control subclinical inflammation between the attacks and the long-term complication of amyloidosis. The acute attacks may be a challenge to identify and distinguish from other causes of acute abdomen, including acute appendicitis, but also small bowel obstruction. Ultrasound and CT scan findings are nonspecific during acute attacks of familial Mediterranean fever, but imaging is useful to identify acute appendicitis and small bowel obstruction. The purpose of this article was to increase the awareness and knowledge of familial Mediterranean fever and provide support for the paediatric surgeon in the clinical care of these children in parts of the world where familial Mediterranean fever is rare.

Aim of the work: To evaluate the value of three hematological indices to determine subclinical inflammation in Familial Mediterranean Fever (FMF) patients during attack-free period. Patients and methods: This study included 60 FMF patients without FMF-related symptoms or signs in the preceding month and 50 age and sex matched healthy control. Subclinical inflammation was defined as the presence of elevated C-reactive protein (CRP) > 5 mg/dL and/or serum amyloid A (SAA) levels > 6.4 mg/L in the absence of any FMF related clinical signs and symptoms. The neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR) and mean platelet volume (MPV) were evaluated. Results: The median age of the patients was 32 and 80% were females. They were 12 (80%) with subclinical inflammation and 48 (80%) without. Mutations of MEFV gene were analyzed in 43 (56.6%) patients and were homozygous in 21, heterozygous in 12 and compound heterozygous in 10. The most common mutation was of M694V. The NLR and PLR were significantly higher and MPV lower in patients with inflammation (p = 0.002, p = 0.02, p = 0.03, respectively) but was comparable to the values in the control. Only NLR was significantly higher in those with inflammation compared to those without (p = 0.009) whereas MPV and PLR were similar (p = 0.45 and p = 0.22, respectively). The best cut-off value for NLR in predicting subclinical inflammation in patients was 2.94 (sensitivity 66.7%, specificity 94.9%;p = 0.009). Conclusions: Only NLR increased in FMF patients with subclinical inflammation which may be used as a marker in determining early activity or flare in addition to other markers.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by a pyrin dysfunction, leading to uncontrolled interleukin-1 production that triggers the attacks. Here we report a case of a 36-year-old female patient repeatedly admitted to the cardiology ward with recurrent episodes of pericarditis, with intervals of 1 and 2 months between the episodes. During the attacks, chest pain and fever were the only symptoms. Following the administration of steroids and non-steroidal anti-inflammatory drugs, the patient became afebrile. She also had lymphoma and thyroid carcinoma in anamnesis essential for differential diagnosis. Laboratory tests for infection and autoimmune disease were all negative, and the positron emission tomography–CT scan did not reveal lymphoma relapse. Genetic testing revealed a mutation in the MEFV gene. It is very rare for pericarditis to be the first and only manifestation of FMF.

Co-existence of Familial Mediterranean Fever(FMF) and Paget’s disease (PD)is very rare. In this paper, we aimed to present a case of FMF patient presenting with PD. A 62-year old male patient admitted with complaint of chronic low back pain and weight loss. An increased uptake at pelvis which was reported as paget metabolic bone disease was identified in bone scintigraphy. An infusion of 5 mg of zoledronic acid, calcium and Vitamin D treatments were administered. Paget’s disease (PD)is a rare condition in patients with FMF. The co-existence of FMF and PD should not be forgotten.

Familial Mediterranean fever (FMF) is a hereditary auto-inflammatory disease resulting from mutations of the MEFV gene. The disease is characterised by recurrent attacks of abdominal pain and fever. Most FMF patients develop arthritis at some point in their life usually manifesting as self-limiting monoarthritis. On very rare occasions, arthritis in FMF can mimic septic arthritis (pseudo-septic arthritis) with very similar clinical and laboratory findings. We report a case of a young male patient who presented with recurrent attacks of prolonged monoarthritis. For 2 years, he had undergone multiple admissions and operations for drainage of suspected septic joints. The synovial aspiration showed culture-negative pus with very high synovial white blood cell counts highly suggestive of septic arthritis. The patient was later found to have FMF based on homozygous M694V mutation of the MEFV gene. He was treated with colchicine monotherapy with a quick improvement of arthritis and later good control of his disease. The literature review showed very few case reports with similar presentations, most of which responded well to colchicine. FMF can mimic septic arthritis resulting in unnecessary expensive and invasive interventions and prolonged courses of antibiotics. Pseudo-septic arthritis is usually associated with M694V homozygous mutation and can complicate FMF at any time throughout the disease course. It is important to consider FMF in the differential diagnosis of septic arthritis, particularly with a family history of FMF and in patients from communities with a high prevalence of MEFV gene mutation.

This study aimed to evaluate ocular blood flow and, retinal, choroidal and retinal nerve fiber layer thickness in children with familial Mediterranean fever (FMF) with patients who had at least five attacks.Fifty-six patients with FMF and 56 healthy subjects were enrolled in the study. Each participant's choroidal thickness (CT) and retinal thickness (RT) measurements were performed in the foveola and at horizontal nasal and temporal quadrants within 500-μm intervals up to 1.500 μm from the foveola using spectral-domain optical coherence tomography as well as the retinal nerve fiber layer thickness (RNFLT). Disc boundaries were determined manually by identifying seven points on the inner edge of the scleral ring. Following complete ophthalmological evaluation, peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistivity index (RI) values in the central retinal artery (CRA), ophthalmic artery (OA), and nasal posterior ciliary artery (NPCA) were measured using color Doppler ultrasonography (CDU) in the left eyes of the patients diagnosed with FMF and the controls. The results were subsequently compared.No statistically significant differences were observed between the groups in terms of all RNFLT quadrant and RT measurements. All CT measurements were thinner in patients with FMF than in the controls (For Central and Temporal_1500 p = 0.01; For Temporal_500, Nasal 500 and Nasal_1000 p 0.001; Temporal_1000 p = 0.002) except than the Nasal_1500 point. For nasal_1500 p = 0.121). The PSV and EDV values in the OA, CRA, and NPCA were significantly lower in patients with FMF compared to healthy controls (p 0.001 for all). In contrast, the RI values of all arteries were significantly higher than in the control group (Regarding OA, CRA and NPCA RI, p = 0.003, p = 0.039, and p = 0.039, respectively).The results of this study support the idea that chronic inflammation and frequent attacks in FMF may have an effect on decreased ocular blood flow and choroidal thinning.

Introduction Exertional leg pain (ELP) and enthesitis are musculoskeletal findings in familial Mediterranean fever (FMF). They are not accepted as principal treatment targets. In this study, we assessed the effectiveness of treatments on ELP and enthesitis. Material and methods We have included 218 FMF patients to the study. We retrospectively compared the FMF attacks’ frequency, duration and intensity (FMF attack VAS score) and levels of ELP VAS and enthesitis VAS scores between pre-treatment stage and while patients were on treatment at the last visit. Results Forty-nine (22.5%) and 52 (23.9%) of the patients had enthesitis and ELP respectively. All patients were on colchicine treatment. Serositis attacks respond the treatments significantly. Moreover, both ELP VAS scores (p = 0.002) and enthesis VAS scores (p = 0.17) were improved with treatment. But only improvement in ELP VAS scores was significant. Conclusion FMF treatments had favourable effect on ELP and enthesitis in FMF patients. However, the response rates would be inadequate. Therefore, there would be unmet need for treatment of both conditions.

We aimed to evaluate and compare fetal cardiac morphology and functions of pregnant women with familial Mediterranean fever (FMF) and healthy pregnant women.The study included 34 pregnant women with FMF and 68 healthy pregnant women matched with maternal age, gravidity, parity, gestational age, and pre-pregnancy body mass index (BMI) in 34th-37th gestational weeks. Fetal echocardiographic evaluation was performed with two-dimensional (2D) imaging, M-mode imaging, pulsed wave (PW) Doppler, and tissue Doppler imaging (TDI).Fetal cardiac morphological measures, including cardiothoracic ratio, cardiac axis angle, right and left ventricular area, sphericity index, and ventricular septal thickness was similar in both groups. Compared with the control group, myocardial performance index (MPI), which indicates global myocardial performance, was significantly higher, and ejection time (ET) was significantly shortened in the FMF group. In addition, which shows the diastolic functional parameters such as, tricuspid E wave, E/A, E/E' ratio, and mitral E wave, E/A, E/E' ratio, were significantly higher; tricuspid A and mitral A waves were significantly lower. We found that mitral and tricuspid annular plane systolic excursion (MAPSE and TAPSE) were significantly lower in those with FMF duration over eight years than those with FMF duration less than 8 years.There is no fetal cardiac morphological change in pregnant women with FMF. However, there may be changes in diastolic function. As the maternal FMF duration increases, systolic functions may also change.

Objective: We aimed to evaluate both child-self reported and parents proxy reported health related quality of life of children with familial Mediterranean fever (FMF) aged between 2-18 years old and to compare the scores with their healthy peers.Material and Methods: Fifty -one patients with FMF and fifty one gender and age matched controls were enrolled in the study. Children aged 8-18 years completed the PedsQL4.0 child form questionnaires. Parents of all cases completed the PedsQL4.0 parent form. Results: Lower scores in the FMF group, with no statistical significance, was found between the FMF cases and healthy volunteers aged 8-18 years for the physical health, social health, school functioning, psychosocial total and scale total score of PEDsQL4.0 child self-report. The parent proxy report PedsQL4.0 scores of all patients with FMF were lower than the healthy group for physical, emotional, social, psycho-social, school functioning scores and scale total score but the difference was not statistically significant. A significant correlation was present between PedsQL4.0 child self-report and parent PedsQL4.0 report in all subscales except for social health total score. There was not a significant correlation between the demographic variables and clinical features of the patients and the child subscales of PedsQL4.0.Conclusion: The scores of FMF cases from the scales were lower than those of the healthy volunteers from the questionnaires but this difference was not statistically significant. Considering the relatively small sample size of the study it is obvious that more comprehensive prospective studies are required on this subject., Amaç: Bu çalışmada ailevi Akdeniz ateşi (AAA) olan 2-18 yaş arası çocuk hastaların ve ebeveynlerinin sağlıkla ilgili yaşam kalitesini değerlendirmek ve aynı yaş grubundaki sağlıklı çocuklar ile karşılaştırmak amaçlandı.Gereç ve Yöntemler: Ailevi Akdeniz ateşi olan 51 çocuk ile yaş ve cins olarak eşleştirilmiş 51 sağlıklı gönüllü çalışmaya dahil edildi. Sekiz-18 yaş arası çocuklar PedsQL4.0 çocuk formunu doldururken, tüm yaş gruplarında ebeveynler PedsQL4.0 ebeveyn formunu doldurdu. Bulgular: Sekiz-18 yaş grubu çocuk formlarının değerlendirilmesinde, istatistiksel anlamlı olmamakla birlikte, fiziksel sağlık, sosyal sağlık, okul işlevselliği, psikososyal total skor ve ölçek toplam skoru açısından AAA olan çocukların puanlarının daha düşük olduğu saptandı.Ebeveyn PedsQL4.0 değerlendirildiğinde ise tüm yaş gruplarında AAA olan çocukların ebeveynlerinde fiziksel, duygusal, sosyal, psikososyal, okul işlevselliği skorları ve ölçek toplam skorlarının sağlıklı çocukların aileleri ile karşılaştırıldığında daha düşük olduğu ancak istatistiksel anlamlı düzeye ulaşmadığı saptandı. Sosyal sağlık toplam skoru hariç tüm ölçeklerde AAA olan çocuklar ve ebeveynlerinin PedsQL4.0 değerlendirmeleri arasında anlamlı korelasyon olduğu saptandı. Demografik değişkenler ve klinik bulgular ile çocuk PedsQL4.0 arasında anlamlı ilişki saptanmadı.Sonuç: Ailevi Akdeniz ateşi olan olgularda ölçek skorları istatistiksel anlamlı olmasa da sağlıklı kontrollere göre daha düşüktür. Çalışmamızda göreceli olarak az sayıda hasta olduğu göz önünde bulundurulduğunda bu alanda daha kapsamlı ve fazla sayıda hasta içeren çalışmalara ihtiyaç olduğu sonucuna varılmıştır.

Background Familial Mediterranean Fever (FMF) is a periodic auto-inflammatory disease with multiple systemic manifestations. This study aims to describe the various musculoskeletal and neurological manifestations in a cohort of Egyptian FMF patients and to evaluate their relation to the different Mediterranean fever gene (MEFV) mutations. Results This study involved 145 FMF patients, of them 62.1% were females and 31.7% were of the pediatric age. All involved patients had homozygous MEFV gene mutation. The presenting manifestation in 71.9% of these patients was abdominal pain followed by musculoskeletal manifestations in 35.2% of them. 38.6 % of the involved patients had arthritis during the period of follow-up. Monoarthritis was the most frequent pattern of arthritis. Arthralgia was present in 96.6% of the studied patients. Myalgia was present in 19.3% of the studied patients especially involving the lower limb muscles with one case of protracted febrile myalgia. Neurological manifestations were present in about 86.9 % of patients with vertigo, paresthesia, and seizures as the most common. Five major MEFV gene mutations were found in most of the studied patients (135 patients): M694V, M680I, E148Q, V726A, and M694I. When a comparative study was done between these five major mutations according to the age of onset of the symptoms, different musculoskeletal and neurological manifestations, ESR, serum amyloid level and dose of colchicine, no statistical difference was found. Conclusion Musculoskeletal manifestation is the second most common presenting symptom in a cohort of Egyptian FMF patients after abdominal pain. Arthralgia is the most frequent musculoskeletal manifestation while monoarthritis of the knee or ankle joint is the most common pattern of arthritis in FMF patients. Vertigo, paresthesia, and seizures are the most frequent neurological manifestations. Musculoskeletal manifestations, neurological manifestations, serum amyloid level, and dose of colchicine are not related to the type of the genetic mutation in this cohort.

Colchicine is an old, inexpensive, and relatively safe anti-inflammatory drug traditionally used in gout and over the last 50 years in familial Mediterranean fever. A search of all high-hierarchy studies (randomized controlled trials [RCTs], systematic reviews and meta-analysis of RCTs) over the last 20 years revealed myriad other evidence-based applications. Colchicine seems efficacious in the treatment of acute pericarditis and prevention of recurrences and in the prevention of postcardiac injury syndrome and atrial fibrillation following cardiac surgery or percutaneous interventions. In patients already fully treated with statins and antiplatelet agents following acute coronary syndromes or stable coronary disease, adding low-dose colchicine achieved secondary prevention of major cardiovascular events (myocardial infarction, stroke, or cardiovascular death) with pooled risk reduction 0.75. Colchicine may also be useful in Behcet's syndrome and most recently, in improving outcomes of COVID-19 infection. Colchicine in the low doses used in most trials (≤ 1 mg/d) was generally safe and well-tolerated, excepting diarrhea (approximately 10%) which sometimes led to drug discontinuation. Further RCTs are required to confirm these results, and will likely lead to expanding indications for low-dose colchicine. Increasing numbers of patients will be treated with colchicine in the near future, with improved health outcomes, as long as basic caveats are heeded.

Background: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease affecting mainly the ethnic groups of the Mediterranean basin. It has been reported that it can coexist with various systemic inflammatory diseases. This study aimed to obtain information on rheumatic diseases that accompany FMF and evaluate the relation between FMF and such diseases. Methods: Eighty-four patients diagnosed with FMF and have rheumatic disease comorbidity in the rheumatology clinic between January 2018 - March 2020 were included in this study. Results: The most common accompanying rheumatic disease was spondyloarthritis with 36 patients. Vasculitides was the second common disease accompanying FMF with 22, followed by connective tissue disease in 13, rheumatoid arthritis in 5, juvenile idiopathic arthritis in 4, gout in 3, and hidradenitis suppurativa in 1 patients. The most common MEFV mutation observed was M694V. There was no significant difference in demographic characteristics and clinical manifestations between M694V mutation types. Conclusions: In this study, the relation between FMF and various rheumatic diseases was determined. Two new conditions, eosinophilic granulomatous polyangiitis, and scleroderma were detected. The associations may be just coincidental or an extension of the common underlying pathology. To be aware of this association is important to early diagnosis and appropriate treatment.

Familial Mediterranean fever (FMF) is a hereditary, autoinflammatory disease characterized by recurrent fever and serositis attacks. The disease onset occurs before 20 years of age in 90% of patients and rarely after the 4th decade. The aim of this study is to screen our FMF patient pool for patients with disease onset after age of 40 and to compare them to patients with early onset with regard to clinical and genetic features. The charts of 2020 patients registered in our FMF center in the years 2008-2017 were screened with regard to age of disease onset. Patients with disease onset after the age of 40 were considered as late-onset group (Group 1). The control group (Group 2) consisted of patients with a disease onset before the age of 20 who were randomly selected from the patient pool with twice the number of probands. Demographic, clinical and genetic data were recorded. Out of 2020 patients, the attacks of FMF had started after the fourth decade in 41 patients (2.02%), (Group 1). The male to female ratio was 1:1.7 in both groups. The delay of diagnosis was 5.6 ± 5.75 years in group 1, 10.7 ± 12.3 years in group 2. The only significant difference with regard to clinical features between two groups was the frequency of fever, which was present in 26 (63.4%) patients in group 1 and 67 (81.7%) in group 2 (p = 0.026). M694V mutation was more prevalent among early-onset group whereas exon 2 variants were more frequent in patients with late onset. The mean colchicine dose in the last 6 months was 1.38 ± 0.64 mg in group 1, and 1.61 ± 0.47 mg in group 2. FMF may start after 40 years of age in approximately 2% of the patients. Lower frequency of fever, lower daily colchicine dose and lower prevalence of exon 10 mutations point out that FMF patients with a disease onset after 40 years of age experience a milder disease compared to those with an onset before the second decade of life.

Objective We aimed to find out the asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence among pediatric patients with rheumatic diseases and healthy children and to compare them with each other. Methods Patients with familial Mediterranean fever (FMF), juvenile idiopathic arthritis (JIA), and juvenile systemic lupus erythematosus (jSLE) and healthy children as healthy control (HC) group who remained asymptomatic during the pandemic are examined by ELISA immunoglobulin (Ig) A and IgG tests in this cross-sectional study. Results Overall, 149 subjects (90 females) were included in the study. While IgA was positive in 15 subjects (10%) (HC: 8, jSLE: 3, FMF: 2, JIA: 2; p = 0.196), IgG was positive in 14 subjects (9.4%) (HC: 7, JIA: 5, FMF: 1, jSLE: 1; p = 0.156). Nineteen subjects (12.75%) were IgA or IgG positive (HC: 8, JIA: 5, jSLE: 3, FMF: 3; p = 0.644). Although not significant, seropositivity was more often in HC group. Both IgA and IgG positivity were not found to be related to age, sex, underlying rheumatic diseases, and received treatments of the patients. Conclusion We revealed that patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication such as biologic or conventional disease-modifying anti-rheumatic drugs, might have an asymptomatic SARS-CoV-2 infection, similarly to their healthy peers. Key points• Although it has been already known that children are most likely to have asymptomatic SARS-CoV-2 infection, there is a lack of data on the disease course of children with rheumatic disease.• There was no significant difference regarding the asymptomatic SARS-CoV-2 seropositivity rates between healthy children and the patients with childhood-onset rheumatic diseases.• Patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication, might have asymptomatic SARS-CoV-2 infection, similarly to their healthy peers.

The emerging group of autoinflammatory diseases (AIDs) is caused by a dysregulation of the innate immune system while lacking the typical footprint of adaptive immunity. A prominent subgroup of AIDs are inflammasomopathies, which are characterised by periodic flares of cutaneous signs as well as systemic organ involvement and fever. The range of possible skin lesions is vast, ranging from urticarial, erysipelas-like and pustular rashes to erythematous patches, violaceous plaques and eventual necrosis and ulceration. This review provides a structured overview of the pathogenesis and the clinical picture with a focus on dermatological aspects of inflammasomopathies. Current treatment options for these conditions are also discussed.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever and serositis. Diagnosis is made according to clinical findings and supported by genetic analysis. The most commonly used adult diagnostic criteria are the Tel-Hashomer criteria. Pediatric criteria for FMF diagnosis were described in 2009, but their reliability should be supported by additional reports. In this study, we aimed to compare the pediatric criteria and the Tel-Hashomer and 2019 Eurofever/PRINTO classification criteria using our FMF cohort. A total of 113 patients diagnosed with FMF were included. Demographic features and laboratory findings were retrospectively collected from the patients' files. The patients were evaluated with the Tel-Hashomer, pediatric and Eurofever/PRINTO classification criteria. At least two of five new pediatric criteria were as sensitive (89%) and specific (85%) as the Tel-Hashomer criteria (sensitivity 70%, specificity 96%). We also evaluated the Eurofever/PRINTO classification criteria using our cohort and found a sensitivity of 94% and specificity of 91%. Conclusion: Using pediatric criteria for the diagnosis of FMF in children is a feasible and simple approach that can diagnose the disease based on at least two criteria. Therefore, our study supports the use of pediatric criteria in FMF diagnosis of children. Our results also confirm that the Eurofever/PRINTO classification criteria can be successfully applied for the diagnosis of FMF due to their high sensitivity (94%) and specificity (91%). What is Known: • The FMF diagnosis is made according clinical findings and supported by genetic analysis. • The use of adult diagnostic criteria in pediatric FMF patients is controversial since classical clinical presentation is often absent in children. What is New: • Our study supports both the use of pediatric criteria and Eurofever/PRINTO classification criteria in clinical practice.

Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, caused by recessively inherited MEFV gene mutations. The most frequent MEFV mutations differ in penetrance and disease severity. We investigated the genotype-phenotype associations of the three most frequent MEFV gene mutations (M680I, M694V, and V726A) in Egyptian FMF children, regarding clinical features, severity, and colchicine response.We conducted a retrospective analysis of the medical registries of 500 FMF pediatric patients from Metropolitan Cairo between 2010 and 2015. The diagnosis was based on the Tel-Hashomer clinical diagnostic criteria. Clinical data and baseline investigations were collected. Mutation analysis was performed by the amplification-refractory mutation system (ARMS)-PCR method.Males represented 54% and ages ranged from 2 to 18 years. The most frequent symptoms were abdominal pain, fever, and arthralgia. Clinical features mostly associated with M694V mutation either homozygous or heterozygous whether simple, double, or triple. Of the patients, 94.6% completely responded to colchicine. Among patients benefiting from colchicine, 42.5% had M694V/V726A, 21.6% had M694V/V726A/M680I, and 21.1% had M694V genotype. Simple heterozygous M694V or V726A mutations conveyed a moderate phenotype in 57.1% and 50% of cases, respectively. Homozygous M694V mutation showed moderate and severe phenotypes in 21.7% and 65.2% of cases, respectively. Compound M694V/V726A mutation associated with moderate or severe disease in 48.3% and 33.8% of cases, respectively.This study encompasses the largest group of Egyptian pediatric FMF up to date to explore their genotype-phenotype associations. Our results support the notion that the genotype influences the phenotype as regards clinical manifestations, disease severity, and colchicine response.• This study encompasses the largest group of Egyptian pediatric patients affected by FMF up to date to explore their genotype-phenotype associations. • Our results support the notion that the genotype influences the phenotype as regards the clinical manifestations, the disease severity, and the response to colchicine treatment.

Fever is a common symptom of infection in children. Periodic fever syndromes are less common but more complex. One of these Periodic fever syndromes is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome which is known as the most benign syndromes. The cause of this disease is unknown. Various factors, including environmental and genetic factors, are involved in the development of this disease. In this study, the association of rs13075270 and rs13092160 polymorphisms were investigated in CCR1 and CCR3 genes with susceptibility to this syndrome in the Chinese population. In this regard, 38 patients with PFAPA syndrome and 100 healthy individuals were selected. After DNA sampling and extraction, polymorphisms of CCR1 and CCR3 receptor genes were examined by the PCR-RFLP method. Findings were analyzed using SPSS software version 22 with a significant level of P

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever and serositis. Periodic febrile attack can be managed with biologic medication in colchicine-resistant FMF patients, however, no reports or guidelines exist regarding the postoperative management of elective joint surgery in these patients. Although it is not clear how FMF attacks are triggered, they may be precipitated by stress including anesthesia or surgery. This study reports the case of a 51-year-old FMF patient who received total hip replacement under canakinumab (a specific interleukin-1β monoclonal antibody) treatment. He had highly active FMF, which was resistant to colchicine; however, his recurrent febrile attack with serositis was successfully controlled with canakinumab. Four months later from the start of canakinumab treatment, his hip osteoarthritis was required for total hip replacement (THR) because of the traumatic fracture. THR was successfully done and FMF attack was not occurred after this elective surgery. Discontinuation of canakinumab 3 weeks before surgery and resumption 6 weeks after led to favorable outcome without complications. This case addresses the differential management concerning stopping and restating of canakinumab in the perioperative setting in contrast to the other biologics such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) blocking agents. This case report suggests that canakinumab may represent a safe and effective therapy for the colchicine-resistant FMF, even in the patients requiring THR therapy.

Familial Mediterranean Fever (FMF) is a rare, hereditary, auto-inflammatory disease. The aims of this study were to explore the time trend and geographical distribution of hospitalizations in Spain from 2008 to 2015. We identified hospitalizations of FMF from the Spanish Minimum Basic Data Set at hospital discharge, using ICD-9-CM code 277.31. Age-specific and age-adjusted hospitalization rates were calculated. The time trend and the average percentage change were analyzed using Joinpoint regression. Standardized morbidity ratios were calculated and mapped by province. A total of 960 FMF-related hospitalizations (52% men) were identified across the period 2008–2015, with an increase in hospitalizations of 4.9% per year being detected (p < 0.05). The risk of hospitalization was higher than expected for the national total (SMR > 1) in 13 provinces (5 in the Mediterranean area), and lower (SMR < 1) in 14 provinces (3 in the Mediterranean area). There was an increase in hospitalizations of patients with FMF in Spain throughout the study period, with a risk of hospitalization that was higher, though not exclusively so, in provinces along the Mediterranean coast. These findings contribute to the visibility of FMF and provide useful information for health planning. Further research should take into account new population-based information, in order to continue monitoring this disease.

Amaç: Ailevi Akdeniz ateşi inflamasyon atakları ile karakterize otoinflamatuar bir hastalıktır. Tedaviye rağmen, normal laboratuvar değerleri ile subklinik inflamasyonun devam ettiğine dair kanıtlar vardır. Bu çalışma, çocuklarda devam eden subklinik inflamasyonun kardiyak etkilerini ve ailesel Akdeniz ateşinde aritmiye yatkınlığı araştırmak için yapılmıştır.Gereç ve Yöntem: Yaş ve cinsiyet açısından eşleştirilmiş ailevi Akdeniz ateşi hastaları ve sağlıklı kontroller demografik, laboratuvar, ekokardiyografik ve elektrokardiyografik veriler açısından karşılaştırıldı. Ailevi Akdeniz ateşi hastaları hastalık şiddeti skorlarına göre gruplandırıldı ve aritmogenezi gösterebilecek elektrokardiyografik veriler açısından karşılaştırıldı. Elektrokardiyografik ölçümler ile klinik ve laboratuvar verileri arasındaki ilişkiyi incelemek için korelasyon analizi kullanıldı. Bulgular: İki grup karşılaştırıldığında, ekokardiyografik ölçümlerde sol ventrikül sistolik ve diyastolik fonksiyonları açısından anlamlı bir fark bulunmadı. Bu verilere göre QT ve Tp-e intervalleri ailesel Akdeniz ateşi olanlarda anlamlı olarak daha uzundu (sırasıyla p=0.002, p=0.046). Hastalar 3 ayrı hastalık şiddeti skoruna göre sınıflandırıldığında, orta-şiddetli hastalık grubunda QT dispersiyonu hafif hastalık grubuna göre anlamlı olarak daha uzundu (sırasıyla p, Aim: Familial Mediterranean fever is an autoinflammatory disease characterized by attacks of inflammation. Despite treatment, there is evidence of subclinical persistence of inflammation with normal laboratory values. This study was conducted to investigate the cardiac effects of continued subclinical inflammation in children and the predisposition towards arrhythmia in familial Mediterranean fever.Materials and Methods: Age and sex-matched familial Mediterranean fever patients and healthy controls were compared in terms of demographic, laboratory, echocardiographic and electrocardiographic data. The patients with familial Mediterranean fever were grouped according to disease severity scores and compared in terms of electrocardiographic data that could indicate arrhythmogenesis. Correlation analysis was used to examine the relationship between the electrocardiographic measurements and the clinical and laboratory data. Results: In the comparison of the two groups, no significant difference was found in the echocardiographic measurements in terms of left ventricular systolic and diastolic functions. According to these data, QT and Tp-e intervals were significantly longer in those with familial Mediterranean fever (p=0.002, p=0.046, respectively). When the patients were classified according to the 3 separate disease severity scores, QT dispersion in the moderate-severe disease group was significantly longer than in the mild disease group (p

Objectives Familial Mediterranean Fever (FMF) patients are required to adhere to a life-long treatment with colchicine, primarily for preventing amyloidosis. As some patients may be asymptomatic for long periods of time, it remains unclear whether it is possible to discontinue colchicine treatment in a selective group of patients. We aimed to identify predictive characteristics for a successful cessation of colchicine therapy. Methods Out of 646 FMF pediatric patients followed in our referral FMF clinic, colchicine treatment was discontinued in 51 patients. In this study we compared the genetic, demographic, and clinical characteristics between patients for whom a successful cessation of therapy was made (Group 1; n = 21) and patients for whom cessation of therapy was deemed a failure (Group 2; n = 30) and consequently had to resume colchicine therapy. Results Patients for whom a successful cessation of therapy was achieved had no biallelic pathogenic MEFV mutations, were less likely to have “severe attacks” (two or more FMF characteristic symptoms) (24% vs 80%; P = 0.000067) and did not require higher than 1 mg/day of colchicine, prior to the drug cessation. Remission duration under colchicine treatment was significantly higher in group 1 compared with group 2 (4.36 years ±2.12 vs 2.53 years ±2; P = 0.0036). Conclusion This study supports the concept of colchicine free remission in a minority of FMF patients (3%). Holding treatment, under close monitoring, may be reasonable when selecting the appropriate patients.

Purpose: The primary aim of our study was to compare the changes in physical activity, sleep, fatigue, pain, and quality of life levels before and during confinement in patients with Behçet’s Disease (BD) and Familial Mediterranean Fever (FMF) disease (FMFD). The secondary aim of the present study was to determine the exercise behavior of patients with BD and FMF during the Covid 19 Pandemic. Methods: A total of 21 patients with BD (mean age was 42 years, 57.1% were female) and 21 patients with FMF (Mean age was 39 years, 71.4% were female) were included in this cross sectional study. Internal Physical Activity Questionnaire- Short Form, Short Form 36 and Exercise Stages of Change Questionnaire were administered to all participants. Sleep satisfaction, fatigue and pain was assessed with the Numeric Rating Scale. Results: There were no significant differences in sociodemographic data and all outcome scores except sleep duration between the groups at baseline (p>0.05). Physical activity, pain, fatigue, sleep, and quality of life were compared with pre-confinement in both BD and FMF patients. It was found that the level of pain and fatigue increased in BD patients, and physical activity and quality of life decreased in both BD and FMF patients (p0,05). Fiziksel aktivite, ağrı, yorgunluk, uyku ve yaşam kalitesi hem Behçet hem de AAA hastalarında karantina öncesi ile karşılaştırıldı. Behçet hastalarında ağrı ve yorgunluk düzeyinin arttığı hem Behçet hem de AAA hastalarında ise fiziksel aktivite ve yaşam kalitesinin azaldığı bulundu (p

Objective Kinesiophobia is a common problem in patients with rheumatic diseases and can cause physical inactivity, social isolation, disability, and poor quality of life. This study aimed to evaluate kinesiophobia and associated factors in patients with familial Mediterranean fever (FMF). Methods A total of 38 patients diagnosed with FMF volunteered to participate in the study. All patients were assessed using the Tampa Kinesiophobia Scale (TKS), the International Physical Activity Questionnaire (IPAQ), the Fatigue Severity Scale (FSS), and the Hospital Anxiety and Depression Scale (HADS). Results Thirty-three (86.8%) of the patients had TKS scores over 37, indicating high levels of kinesiophobia. The TKS score was positively correlated with the HADS depression score (r=0.530; p=0.001) and the FSS score (r=0.340; p=0.035) but was not significantly associated with age (r=0.102; p=0.543), disease duration (r=–0.110; p=0.511), body mass index (r=0.283; p=0.085), the HADS anxiety score (r=0.306; p=0.061), or the IPAQ score (r=–0.097; p=0.563). Conclusions Our sample of adult FMF patients showed high levels of kinesiophobia associated with fatigue and depression. Treatments focusing on kinesiophobia in FMF patients could help to increase the effectiveness of rehabilitation.

Στην παρούσα διδακτορική διατριβή, έγινε μελέτη της πιθανής μικρο- και μακροαγγειοπάθειας σε διαφορετικά αγγειακά πεδία που δύναται να παρατηρηθεί στους ασθενείς με Οικογενή Μεσογειακό Πυρετό (ΟΜΠ) από την παιδική ακόμα ηλικία. Κύριος σκοπός της μελέτης αυτής, αποτελεί η προσπάθεια αξιολόγησης του καρδιαγγειακού συστήματος σε ασθενείς που πάσχουν από ΟΜΠ εκτιμώντας πιθανές μορφολογικές και λειτουργικές διαταραχές των μικρών και μεγάλων αγγείων τους. Δευτερεύοντα στόχο της μελέτης αποτελεί η αναζήτηση πιθανών συσχετίσεων των αγγειακών βλαβών με εργαστηριακά ευρήματα σχετιζόμενα με αυξημένο καρδιαγγειακό κίνδυνο σε ασθενείς με ΟΜΠ. Σε ασθενείς πάσχοντες από ΟΜΠ με χαμηλά επίπεδα συστηματικής φλεγμονής όπως οι ασθενείς που συμπεριλήφθησαν στη μελέτη, η προσβολή των μεγάλων αγγείων, όπως αξιολογείται με την αορτική σκληρία (PWV και AIx), την υποκλινική αθηροσκλήρωση των καρωτίδων (cIMT) και το υπερηχογράφημα της καρδιάς δεν ήταν εμφανής. Οι ασθενείς μας είναι ιδιαίτερα συμμορφωμένοι στην αγωγή τους με κολχικίνη και η συντριπτική πλειοψηφία τους εμφανίζει κλινικά χαμηλή προς μέτρια ενεργότητα της νόσου. Επιπλέον, το νεαρό της ηλικίας στην πλειονότητα του πληθυσμού της μελέτης μας, συνέβαλε στην απουσία εύρεσης παθολογικών ευρημάτων στους δείκτες εκτίμησης των μεγάλων αγγείων σε σχέση με τον υγιή πληθυσμό. Παρόλα αυτά, στην παρούσα μελέτη ανιχνεύθηκαν αλλοιώσεις των μικρών αγγείων στους ασθενείς με ΟΜΠ (σοβαρή ελίκωση αγγείων του αμφιβληστροειδούς στο βυθό του οφθαλμού) αλλά και σημαντικές διαφορές σε εργαστηριακούς παραμέτρους (ΑΙΡ, δείκτες φλεγμονής, παράγοντες που προάγουν τη θρόμβωση) που προδιαθέτουν σε καρδιαγγειακή νόσο σε σχέση με τον υγιή πληθυσμό. Καταλήγουμε στο συμπέρασμα ότι η υποκλινική συστηματική φλεγμονή συνεχίζει να υφίσταται στην νόσο του ΟΜΠ ακόμα και σε ασθενείς παιδικής και νεανικής ηλικίας με ικανοποιητική ρύθμιση της νόσου. Αποτελεί λοιπόν επιτακτική ανάγκη η συστηματική παρακολούθηση αυτών των ασθενών και η συμμόρφωσή τους στην αγωγή με κολχικίνη, έτσι ώστε να επιβραδυνθούν οι πιθανότητες εμφάνισης καρδιαγγειακών επιπλοκών που εμφανίζουν σε σχέση με τον υγιή πληθυσμό., In this doctoral thesis, we studied the possible micro- and macrovascular alterations in different vascular fields that can be observed from a pediatric age, in patients with Familial Mediterranean Fever (FMF). The main objective of this study is to evaluate the cardiovascular system in patients with FMF by assessing possible morphological and functional disorders of small and large vessels. A secondary objective of the study is to search for possible correlations of vascular damage utilizing laboratory findings related to inflammation and other disease parameters related to increased cardiovascular danger in FMF patients. Ιn FMF patients with low levels of systemic inflammation, such as the patients included in the study, the involvement of large vessels, as assessed by aortic stiffness (PWV and AIx), subclinical carotid atherosclerosis (cIMT) and cardiac ultrasound, was not evident. Our patients are particularly compliant towards their colchicine treatment, and the majority of them exhibit clinically low to moderate disease activity. Furthermore, it is possible that the young age of the majority of our FMF study population contributed to the absence of pathological findings in the indices assessing large vessels compared to healthy controls. However, in the present study, distortions of small vessels were detected in FMF patients (severe tortuosity of the ocular fundus) as well as significant differences in laboratory parameters (AIP, inflammatory markers, prothrombotic factors) that predispose to cardiovascular disease compared to healthy controls. We conclude that subclinical systemic inflammation continues to exist in FMF disease even in pediatric and young adult patients with satisfactory disease control. It is therefore imperative to systematically monitor these patients and ensure their compliance with colchicine treatment to avoid the likelihood of cardiovascular complications compared to healthy population.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long-term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin-1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence-based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF.

Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by an autosomal recessive transition, self-limiting, recurrent fever and serositis attacks. Neurological symptoms of FMF are rare. Ischemic stroke, posterior reversible encephalopathy syndrome and demyelinating lesions are shown in FMF patients. A 17-year-old male patient was admitted due to left side weakness for two days. In cranial magnetic resonance diffusion-weighted (MRI-DWI) imaging, an appearance compatible with acute ischemia was detected in mesencephalon right crus cerebri and central localizations. All the young stroke examinations performed for the etiology of the patient who was in remission in terms of FMF were found to be normal. It was thought that the underlying mechanism of young stroke etiology may be the possible subclinical inflammation that causes endothelial dysfunction commonly seen in FMF. A stroke case with this rare complication was found worth presenting.

Aim:Familial Mediterranean Fever (FMF) is one of the most frequent genetic diseases with a frequency of 1/1,000 in our country. We aimed to assess awareness of FMF among caregivers of patients with and without FMF.Materials and Methods:Caregivers of FMF patients (group 1) and other caregivers who were in hospital for other reasons (group 2) were given a questionnaire regarding FMF and the results were compared between the 2 groups.Results:The mean ages were similar between group 1 (n=142) and group 2 (n=207). Female gender and lower educational status were more frequent in group 1. Group 1 was more aware that recurrent fever, joint pain, abdominal pain, and its occurrence in attacks are seen in FMF; and also that the disease is inherited rather than contagious; that a specific treatment exists; that the risk of kidney and heart failure increases when not treated; that attacks are triggered by sleeplessness, tiredness or emotional stress; that colchicine does not provide complete recovery; and that diarrhea is the most common side effect of colchicine (p0.05). Interestingly, group 2 was more aware that different treatment options exist (p=0.04). The total score was higher in group 1 and in participants who only graduated from secondary school or less (p

In the last 20 years the clarification of monogenic periodic febrile diseases has led to the independent concept of autoinflammation. In this heterogeneous group polygenic complex diseases are also now included. The spectrum of symptoms is continuously growing. The main difference to autoimmunity is an excessive activation of the innate immune system without formation of autoantibodies or antigen-specific T‑cells. The cardinal symptom is recurrent fever episodes accompanied by signs of inflammation, which in the periodic manifestations alternate with intervals of general well-being. The classical monogenic diseases are also known as hereditary recurrent fever (HRF). Examples are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor 1‑associated periodic syndrome (TRAPS), adenosine deaminase 2 (ADA2) deficiency and mevalonate kinase deficiency (MKD, hyper-IgD syndrome). The polygenic diseases are also known as nonhereditary fever syndromes. These include adult-onset Still's disease (AoSD), Adamantiades-Behçet disease, the PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and gouty arthritis. All autoinflammatory fever syndromes are accompanied by a long-term risk of development of amyloid A amyloidosis, depending on the individual severity and treatment success. In some diseases severe complications can sometimes occur.In den letzten 20 Jahren hat die Aufklärung von monogenetisch verursachten periodischen Fiebererkrankungen zum eigenständigen Konzept der Autoinflammation geführt. In diese heterogene Gruppe werden inzwischen auch polygenetisch verursachte, komplexe Erkrankungen eingruppiert. Das Spektrum der Krankheitsbilder wächst kontinuierlich. Hauptunterschied zur Autoimmunität ist eine übermäßige Aktivierung des angeborenen Immunsystems ohne Autoantikörperbildung oder antigenspezifische T‑Zellen. Als Kardinalsymptom treten rezidivierende Fieberschübe, begleitet von Entzündungszeichen, auf; diese wechseln sich bei den periodischen Krankheitsbildern mit Intervallen allgemeinen Wohlbefindens ab. Die klassischen monogenetischen Erkrankungen werden auch als hereditäres rezidivierendes Fieber (HRF) bezeichnet. Beispiele sind das familiäre Mittelmeerfieber (FMF), das Cryopyrin-assoziierte periodische Syndrom (CAPS), das Tumor-Nekrose-Faktor-Rezeptor-1-assoziierte periodische Syndrom (TRAPS), die Adenosindesaminase(ADA2)-Defizienz und die Mevalonatkinasedefizienz (MKD; Hyper-IgD-Syndrom). Die polygenetischen Erkrankungen werden auch als nichthereditäre Fiebersyndrome bezeichnet. Hierzu zählen die adulte Form der Still-Erkrankung („adult-onset Still’s disease“, AoSD), die Adamantiades-Behçet-Erkrankung, das PFAPA-Syndrom (periodisches Fieber, aphthöse Stomatitis, Pharyngitis und zervikale Adenitis) und die Gichtarthritis. Alle autoinflammatorischen Fiebersyndrome gehen mit einem von individuellem Schweregrad und Therapieerfolg abhängigen Langzeitrisiko für die Entwicklung einer Amyloid-A-Amyloidose einher. Bei einigen Erkrankungen können z. T. schwere Komplikationen auftreten.

Amaç: Ailesel Akdeniz ateşine (FMF) neden olan Mediterranean FeVer (MEFV) genindeki mutasyonlarbaşka spesifik romatizmal hastalıkların da ortaya çıkmasına neden olabilir. Bu çalışmanın amacı pediatrikFMF hastalarında diğer romatizmal hastalıkların sıklığını belirlemek, eşlik eden romatizmal hastalığı olan veolmayanlar arasında klinik ve genetik farklılık olup olmadığını değerlendirmek ve verileri önceki çalışmalarlakarşılaştırmaktır.Gereç ve yöntem: Çocuk romatoloji bölümünde takip edilen FMF hastalarının dosyaları retrospektif olarakincelendi. Dosyalardan demografik veriler, MEFV mutasyonları, tedavi, hastalık şiddet skorları ve eşlik edenromatizmal hastalıkları kaydedildi.Bulgular: 303 FMF hastası (154 kadın/149 erkek) vardı. Ortalama tanı yaşı 7,04±3,9 idi. Ortalama hastalıksüresi 5,33±3,13 yıldı. Kohortta 41 FMF hastasına (%13,5) başka bir romatizma hastalığı teşhisi kondu. 22juvenil idiyopatik artrit (%53,6), yedi vaskülit (%17), altı periyodik ateş aftöz stomatit ve adenit sendromu(%14,6), üç Behçet hastalığı (%7,3), iki akut romatizmal ateş (%4,8) ve bir sistemik lupus eritematozus (%2,4)olgusu vardı. Bu 41 FMF hastasının 32'sinde (%78) M694V mutasyonu vardı (11’i homozigot, 21’i heterozigot).Hastalık şiddet skorları Pras ve ISSF skorları romatizmal hastalığı olan FMF hastalarında daha yüksekti(sırasıyla p=0.002 ve p, Purpose: Mutations in the Mediterranean FeVer (MEFV) gene, which causes familial Mediterranean fever(FMF), may also cause the emergence of other specific rheumatic diseases. This study aims to determine thefrequency of other rheumatologic diseases in paediatric FMF patients, evaluate whether there are clinical andgenetic differences between those with and without concomitant rheumatologic diseases, and compare the datawith previous studies.Materials and methods: The files of FMF patients who were followed up at the paediatric rheumatologydepartment were reviewed retrospectively. Demographic data, MEFV mutations, treatment, disease severityscores, and concomitant rheumatic diseases were recorded from the files.Results: There were 303 FMF patients (154 female/149 male). The mean age at diagnosis was 7.04±3.9 years.The mean disease duration was 5.33±3.13 years. In the cohort, 41 FMF patients (13.5%) were diagnosed withanother rheumatic disease. There were 22 cases of juvenile idiopathic arthritis (53.6%), seven cases of vasculitis(17%), six cases of periodic fever aphthous stomatitis and adenitis syndrome (14.6%), three cases of Behçet’sdisease (7.3%), two cases of acute rheumatic fever (4.8%), and one case of systemic lupus erythematosus(2.4%). Thirty-two of these of these 41 FMF patients (78%) had the M694V mutation (homozygous in 11,heterozygous in 21). Disease activity scores Pras and ISSF scores were higher in FMF patients with rheumaticdiseases (p=0.002 and p

We read with great interest the article “Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial” by Ozen et al .1 This article makes a remarkable contribution to treatment in patients with colchicine-resistant familial Mediterranean fever (FMF), which shows a great remission rate with minimal side effects. However, there are some aspects that need to …

Familial Mediterranean fever (FMF) patients may have hepatic cytolysis, although its origin is not formally elucidated. We aimed to evaluate liver involvement in familial Mediterranean fever (FMF) using non-invasive methods. All adult FMF patients harboring two non-ambiguous mutations of the MEFV gene with hepatic cytolysis were identified in a French tertiary adult center for FMF. Liver impairment was explored with FibroMax (a non-invasive method to estimate hepatic steatosis, necrosis, inflammation and fibrosis) and liver ultrasound. Among 520 FMF adult patients, 43 had persistent hepatic cytolysis and 20 patients were included (11 women, median age at inclusion: 49.5 years). According to the FibroMax results, patients were classified as having steatosis, fibrosis, and possible or definite nonalcoholic steato-hepatitis in 10 (50%), 9 (45%) and 7 (35%) of cases, respectively. The score of steatosis did not seem associated with the usual metabolic risk factors. No significant association was found between the cumulated dose of colchicine and any of the scores included in FibroMax. In adult FMF patients with persistent hepatic cytolysis, steatosis is the first cause to consider even in the absence of usual metabolic risk factors, suggesting other mechanisms. Colchicine did not seem to be involved in this toxicity.

Background Autoinflammatory diseases are rare disorders of the innate immune system characterized by fever and other signs of inflammation. A feared complication of autoinflammatory diseases is the development of AA amyloidosis. AA amyloidosis is caused by extracellular deposition of soluble serum amyloid A (SAA) proteins as insoluble amyloid fibrils leading to organ damage. Prolonged high levels of SAA are a prerequisite to develop AA amyloidosis. Since measurement of SAA is relatively expensive and sometimes unavailable, C-reactive protein (CRP) is often used as a surrogacy marker to test for inflammation. Objective The aim of this research is to evaluate the possible relation between CRP and SAA. Methods A retrospective cohort of patients with autoinflammatory diseases (n = 99) where SAA and CRP blood testing was performed in the period between 2015 and 2021 in the University Medical Centre in Groningen was used to investigate the correlation between CRP and SAA. Results CRP and SAA have a high correlation (rho = 0.755, p 10SAA. Conclusion There was a significant correlation between CRP and SAA in our retrospective cohort. CRP levels below 5 mg/L proved to be highly predictive of SAA levels below 4 mg/L. This may not be true for patients on steroids.

Objectives No studies examined the lower extremity–related anaerobic exercise capacity or functional status in adult patients with FMF. Methods Twenty-four patients with FMF (12 males) and 24 age–sex-matched healthy controls (13 males) were included in the study. Lower extremity–related anaerobic exercise capacity was assessed by using Wingate Anaerobic Test. Lower extremity–related functional status was examined by using 9-Step Stair Climb Test, 10-Repetition Chair Stand Test, and Six-Minute Walking Distance. Muscle strength of hip flexors, hip extensors, knee flexors, and knee extensors were evaluated by using a hand-held dynamometer. Results Patients with FMF had significantly poorer results in all anaerobic exercise capacity parameters and functional status assessments (P 0.05). Both average and peak anaerobic exercise capacities correlated significantly with all muscle strength measurements, 9-Step Stair Climb Test, 10-Repetition Chair Stand Test times, and Six-Minute Walk Distances (P Conclusion Lower extremity–related anaerobic exercise capacity and functional status seem to be diminished in adult patients with FMF. Evaluating these parameters may be beneficial for planning more appropriate and individualized treatment regimens such as patient education and exercise counselling for patients with FMF.

INTRODUCTION Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease with an increased risk for secondary amyloidosis. Since lifelong colchicine has been the treatment of choice that prevents renal amyloidosis, non-amyloid kidney diseases are more frequently considered in the differential diagnosis of proteinuria. Nutcracker syndrome (NCS) can be one of the confounding causes. This long-term retrospective study aimed to evaluate the causes of proteinuria in a pediatric cohort of patients with FMF and discuss changing trends in recent years . METHODS Demographic, clinic, and laboratory data were extracted from electronic medical records of patients with FMF. All urine tests of the study population were reviewed. Patients were evaluated for persistent proteinuria and grouped according to the etiology of proteinuria. RESULTS A total of 576 patients with FMF were identified with a mean follow-up of 6.3 years in the last 10 years; 8% had persistent proteinuria. The etiology was NCS in 67.5% of the patients with proteinuria, and renal amyloidosis was less commonly encountered (15%) without any new diagnosis for the last 8 years. Non-amyloid kidney diseases were also diagnosed in 17.5% of the patients. Patients with NCS had significantly lower BMI than other patients in the cohort and less subclinical inflammation, higher hemoglobin concentration, and milder levels of proteinuria with normal serum albumin and eGFR than other patients with proteinuria. CONCLUSION Nutcracker syndrome is the leading cause of proteinuria in children with FMF nowadays, and it should be kept in mind during the evaluation of proteinuria in these patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Autoinflammatory diseases present as multisystemic inflammation and often manifest in early childhood. In contrast, in a few diseases, e.g., the recently described VEXAS (vacuoles, E1 enzyme, X‑linked, autoinflammatory, somatic) syndrome, the first symptoms occur exclusively in adulthood. This article describes how the phenotypic expression and severity of individual autoinflammatory diseases differ depending on age. Furthermore, differences in the development of organ damage in children and adults are pointed out. In addition to the hereditary periodic fever syndromes, the clinical picture of deficiency of adenosine deaminase 2, the interferonopathies, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome as well as VEXAS and Schnitzler syndromes are highlighted.

Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory disease. This study aimed to evaluate the risk of subclinical vascular damage in FMF children, and young adults, using both imaging and laboratory tests. Forty-five FMF patients (mean age 14.3 ± 9.5 years, 33 children) and 44 healthy controls(mean age 13.3 ± 8.6 years, 36 children) were included in the study. The patients were diagnosed according to Tel-Hashomer criteria, were positive for MEFV gene mutation, were treated with colchicine and were evaluated during an attack free-period. The arterial stiffness parameters studied were carotid-femoral pulse wave velocity (PWV), Augmentation Index (Aix), subendocardial viability ratio (SEVR) and carotid intima-media thickness (cIMT). Laboratory parameters, inflammation markers and lipid profile were also evaluated for all participants. There were no significant differences between patients and healthy individuals, as well as in our children population regarding PWV, SEVR, Aix and cIMT. However, significantly higher ESR, CRP and fibrinogen levels were detected in the total population of FMF patients and higher amyloid levels in FMF children, compared to controls. Atherogenic Index of Plasma was significantly higher both in the total patient population and in the subgroup of children, compared to controls. Furthermore, a significant positive correlation between Aix and CRP and a negative correlation between SEVR and ESR became apparent in the pediatric subgroup. Our study demonstrated no significant differences in vascular measurements between FMF patients and controls. The above could be attributed to the regular colchicine treatment, which seems to have a cardioprotective role against vascular damage.

We here report on a 60-year-old woman with familial Mediterranean fever (FMF) who developed cognitive impairment 16 years after initial diagnosis. On MRI, a new extensive white matter lesion in the right frontal lobe with mild local mass effect but without contrast enhancement was detectable and classified as a tumefactive lesion. Additional MR spectroscopy showed markedly increased choline levels accompanied by a significant lactate peak, highly suggestive of a low-florid demyelinating process. Although diffuse central nervous system (CNS) lesions have been described in single FMF cases, tumefactive lesions have not been observed in FMF patients without concomitant multiple sclerosis. In summary, this case highlights rare differential diagnoses of atypical, inflammatory CNS lesions and the clinical utility of MR spectroscopy.Die Autoren berichten in dem vorgestellten Fall von einer 60-jährigen Frau mit vorbekanntem familiärem Mittelmeerfieber (FMF), die 16 Jahre nach Diagnosestellung subakut kognitive Defizite entwickelt hatte. In der Bildgebung mittels Magnetresonanztomographie (MRT) zeigte sich als mögliche Erklärung dafür eine neue, frontal rechts gelegene Läsion mit leichtem Masseneffekt, aber ohne Kontrastmittelaufnahme, die als tumefaktive Läsion eingestuft wurde. Eine ergänzende MR-Spektroskopie zeigte einen deutlich erhöhten Cholin-Peak zusammen mit einem Laktat-Peak, was einen niedrigfloriden demyelinisierenden Prozess nahelegte. Auch wenn diffuse Läsionen des zentralen Nervensystems (ZNS) bei FMF vorbekannt sind, so wurden bislang tumefaktive Läsionen bei FMF ohne begleitende Multiple Sklerose nicht beschrieben. Zusammenfassend werden anhand dieses Falls seltene Differenzialdiagnosen von atypischen ZNS-Läsionen und der klinische Nutzen der MR-Spektroskopie hervorgehoben.

The impact of the COVID-19 pandemic, and implemented restrictions on the frequency of pediatric rheumatic diseases remain unknown, while they have probably prevented common infections in children. We present the effects of the COVID-19 on our pediatric rheumatology practice in a main referral center. We retrospectively reviewed the medical records of patients presenting to pediatric rheumatology department in 4 years before March 2020 and compared it to the pandemic year (March 2020–March 2021). Since there was an overall decrease in patient numbers, we calculated the percentage according to the total number of that year. A total of 32,333 patients were evaluated. The mean annual number of patients decreased by 42% during the COVID-19 pandemic. When follow-up visits (25,156) were excluded, there were 2818 new diagnoses of rheumatic diseases. In the pre-pandemic period, familial Mediterranean fever (FMF) (n = 695, 28.1%) was the most frequent, whereas in the pandemic period multisystem inflammatory syndrome in children (MIS-C) (n = 68, 19.2%) was the most common diagnosis. There were no significant differences in the percentages of juvenile idiopathic arthritis, autoimmune diseases, rare autoinflammatory diseases, and other vasculitides. However, there was a significant decrease in patients diagnosed with FMF, IgA vasculitis (IgAV), acute rheumatic fever (ARF), classic Kawasaki disease (KD), and macrophage activation syndrome (MAS) (all p

Objectives The aims of this study were to describe the clinical features, comorbidities and outcome of systemic childhood polyarteritis nodosa (PAN) and to evaluate PAN-like diseases in differential diagnosis. Methods The study group consisted of patients who were diagnosed as PAN in a referral center in Turkey. The files of all patients were reviewed retrospectively. Disease activity was evaluated with pediatric vasculitis activity score (PVAS). Results A total of 19 (13 boys/six girls) patients were enrolled in the study. The mean age of patients was 10.37 ± 3.6 years. The mean duration of follow-up was 5.73 ± 3.74 years. Eight patients (42.1%) were also diagnosed with familial Mediterranean fever (FMF). The cutaneous involvement was higher in patients with PAN than those with FMF-associated PAN (p = .03). The median (min–max) PVAS at diagnosis was 5 (3–7). There was no correlation between PVAS scores at the time of diagnosis and age, clinical findings and relapse. CECR1 mutation was detected in one patient leading to deficiency of adenosine deaminase 2. Conclusion The clinical presentation is variable in children with PAN. PAN-like diseases characterized by necrotizing vasculitis should be considered. The possibility of FMF should be kept in mind if inflammation cannot be controlled.

Objective To investigate the genetic characteristics of one of the MEFV gene variants, p.Glu148Gln (E148Q), in patients with familial Mediterranean fever (FMF) and examine its significance in Japanese patients with recurrent fever. Methods The clinical phenotype and genomic variants of systemic autoinflammatory diseases (SAIDs), including MEFV, were analyzed in 211 Japanese patients with recurrent fever. Genetic analysis was performed via next-generation sequencing of exons, including exon-intron boundaries. Results Twelve patients met the diagnostic criteria for SAIDs other than FMF. Considering 199 patients with recurrent fever, 137 cases (68.8%) were clinically diagnosed with FMF. Although Bonferroni-adjusted p-value did not reach significance level, the group containing heterozygous E148Q and other variants tended to be at higher risk of developing the FMF phenotype (nominal p = .036) than the group with heterozygous E148Q only. Comparison between the group with heterozygous E148Q and other variants and the heterozygous group containing non-E148Q showed no statistically significant difference in FMF phenotype expression (nominal p = 1.00). Conclusion Patients with heterozygous E148Q and other variants exhibited higher expression of FMF phenotype than those with heterozygous E148Q only, and suggested that other variants than E148Q as well as exon 10 variants might contribute to the FMF phenotype.