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INTRODUCTION: Despite numerous investigations into the impact of drugs/probiotics on the gut microbiota composition in Familial Mediterranean Fever (FMF) patients, the question as to whether there exists a significant bacterial diversity(ies) independent of the placebo effect that can be reliably considered in clinical and nutritional trials remains unresolved. METHODS: This study represents the in augural analysis of the placebos influence on the gut microbiota of both healthy individuals and FMF afflicted men, utilizing previously collected data from PhyloChip™ DNA microarray experiments. A total of 15 healthy and 15 FMF male volunteers, aged 18 to 50, participated in this partially randomized placebo trial, which is accessible through the GEO Series accession number GSE111835. RESULTS AND DISCUSSION: Key findings from current investigations include i. the anticipated divergence in gut bacteria resistance to placebo between healthy and FMF individuals, ii. the minor impact of placebo on gut bacterial diversities in healthy individuals, with Enterobacteriaceae diversities identified as placebo-resistant among healthy gut bacteria, and iii. the comprehensive influence of placebo on all bacterial phyla in the gut microbiome of FMF patients, extending to nearly all bacterial genera, except for the resilience of gut Akkermansia muciniphila spp. to placebo in FMF patients. This study underscores the susceptibility of Faecalibacterium, Blautia, and Clostridium genera to placebo. Consequently, this investigation holds significance for the proper design of placebo-controlled trials and establishes a foundation for further exploration of the gut-brain axis. Furthermore, it contributes valuable insights to discussions regarding proposals for probiotic therapies, particularly focusing on Faecalibacterium spp., Blautia spp., and Clostridium spp.

Background: Many of the familial Mediterranean fever (FMF) patients present with arthritis during attacks, which may vary in its characteristics. Aims: In this study, we aimed to describe and characterise arthritis in FMF patients. Methods: We used our hospital's record system to retrospectively identify FMF patients with arthritis who presented to our clinic between 2005 and 2020. The prevalence, laboratory results of attack, remission periods, genetic mutations, demographic data, characteristics of attacks, characteristics of arthritis, comorbidities, treatments and treatment responses were recorded. Results: Nine hundred fifty‐four patients from a cohort of 2350 FMF patients had arthritis (40%). The male/female ratio was 0.49 in patients with arthritis. The frequency of at least one exon 10 mutation was high. The age of onset of symptoms was earlier for patients with arthritis. Monoarticular pattern was more frequent compared to oligo‐ and polyarticular patterns. Colchicine resistance was higher; the required colchicine dose for disease control and the frequency of use of biological agents were higher compared to general FMF population. Conclusion: Since M694V mutation is common and the colchicine dose required for disease control is high, we can conclude that the disease activity is high in FMF patients with arthritis. The frequency of sacroiliitis and spondyloarthropathy is significantly increased, especially in individuals with M694V mutation, suggesting that there may be a common pathway in their pathogenesis. FMF should be included in the differential diagnosis in patients presenting with arthritis in FMF endemic regions. [ABSTRACT FROM AUTHOR]

Mutations 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. Based 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. FD 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. Our findings suggest that FD should be considered in the differential diagnosis of FMF, especially in individuals with unusual symptoms. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the rare manifestation of retinal vasculitis in Familial Mediterranean fever (FMF) and its correlation with specific gene mutations, particularly the MEFV gene, with a focus on the severity of phenotypes and systemic vasculitis. Methods: A case report of a 45-year-old Armenian patient with FMF history and dual mutations (M680I and M694V) was analyzed. Clinical assessments, including ocular examinations, were conducted at various stages of the disease. Treatment modalities, including prednisone, Anakinra, and Canakinumab, were administered and their effectiveness was assessed. Results: The patient presented with bilateral ocular pain and decreased vision, exhibiting acute anterior uveitis, perivascular hemorrhages resembling Roth spots, and subsequent features of persistent vascular sheathing and cotton-wool spots. Dual mutations, especially M694V, were associated with a severe phenotype and systemic vasculitis. Treatment with prednisone induced remission, and IL-1 pathway inhibition with Anakinra and Canakinumab successfully managed relapses. Conclusion: This case underscores the rarity of retinal vasculitis in FMF, particularly involving arteries, and highlights the correlation between specific gene mutations (M680I, M694V) and disease severity. The successful management with IL-1 pathway inhibitors suggests a potential therapeutic approach. Increased clinical awareness, further research, and reporting are crucial for optimizing the understanding and treatment of FMF-related ocular manifestations. [ABSTRACT FROM AUTHOR]

There is little and conflicting data on the role of the plasminogen activator inhibitor-1 (PAI-1, SERPINE1) 4G/5G polymorphism in familial Mediterranean fever (FMF). Therefore this study aimed at evaluating the impact of this polymorphism on the disease course in a cohort of 303 Armenian FMF patients. Genotyping for 12 Mediterranean fever (MEFV) gene mutations and the PAI-1 4G/5G (rs1799762) polymorphism were performed by PCR/reverse-hybridization (StripAssay) and real-time PCR, respectively. PAI-1 genotypes 4G/4G, 4G/5G, and 5G/5G could be identified in 4 (5.88%), 30 (18.63%) and 9 (12.16%) patients with erysipelas-like erythema (ELE), while this was the case for 64 (94.12%), 131 (81.37%), and 65 (87.84%) patients without ELE, respectively (P < 0.033). We have identified a significant relationship between the PAI-1 4G/5G genotype and the occurence of ELE in a relatively large cohort of Armenian FMF patients. Because of conflicting results concerning the impact of this polymorphism on the clinical course of FMF in different populations, further studies are desirable to substantiate the findings reported here. [ABSTRACT FROM AUTHOR]

Introduction: Familial Mediterranean fever (FMF) is the most frequent monogenic auto-inflammatory disease worldwide responsible for episodes of fever, serositis and musculoskeletal symptoms. Inflammatory attacks are responsible for sedentary behavior and FMF patients may be at increased cardiovascular risk. Cardiorespiratory Fitness (CRF) and physical capacities during adolescence are associated with cardiovascular mortality in adulthood. In this study, we aimed to describe the physical fitness of FMF adolescents. Methods: A monocentric retrospective study at the Versailles Hospital between January 2020 and June 2023. All FMF patients over 14-year-old who had completed a routine physical test were included. Clinical and physical data including results of the 6-minute walking test, timed unipedal stance test, Ruffier-Dickson index, 30-seconds chair-stand test and sit-and-reach test were extracted from medical records. Results were compared with previously published normative reference values and criterion-referenced standards for healthy subjects. Results: Eighteen FMF patients (12 girls, 6 boys) were included. The median age was 16 years old [14–18]. Clinical history included joint symptoms (n = 11), chest pleuritis (n = 8), and leg pain (n = 11). Estimated VO2max was below the recommended thresholds in 13 patients, which predicts cardiovascular risk. Cardiovascular adaptation was poor in 11 patients. Low VO2max was associated with CRP > 5 mg/l on test day and history of joint symptoms. Conclusion: FMF patients displayed altered physical capacities compared to normative values of healthy subjects. History of musculoskeletal pain, systemic inflammation and sedentary behavior may participate in impaired physical abilities and promote cardiovascular diseases in adulthood. Specific exercise programs could benefit patients for disease control and cardiovascular risk reduction. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study is to evaluate the efficacy of a single-dose anakinra during familial Mediterranean fever (FMF) attacks and its effect on the duration, severity, and frequency of attacks. The patients with FMF who had disease episode and received a single-dose anakinra during disease episode between December 2020 and May 2022 were included. Demographic characteristics, MEFV gene variants detected, concomitant medical conditions, demographics of recent and previous episodes, laboratory findings and length of hospital stay were recorded. A retrospective analysis of medical records revealed 79 attacks from 68 patients who met inclusion criteria. The patients had a median age of 13 (2.5–25) years. All patients reported that the average duration of their previous episodes lasted longer than 24 h. When the recovery time of attacks after subcutaneous anakinra application at the disease attack was examined, it was observed that 4 attacks (5.1%) ended in 10 min; 10 attacks (12.7%) in 10–30 min; 29 attacks (36.7%) in 30–60 min; 28 attacks (35.4%) in 1–4 h; 4 attacks (5.1%) in 24 h; and 4 attacks (5.1%) ended in more than 24 h. There was no patient who did not recover from their attack after a single dose of anakinra. Although the efficacy of a single-dose anakinra administration during FMF attacks in children needs to be confirmed by prospective studies, our results suggest that use of a single-dose anakinra during FMF attacks is effective in reduction of severity and duration of disease attacks. [ABSTRACT FROM AUTHOR]

Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAE-nC1-INH) is a rare disease that presents with laryngeal edema due to oral surgical procedures. Familial Mediterranean fever (FMF) is a disorder commonly characterized by an autosomal recessive inflammatory process, and manifests in the oral cavity and facial structures. A 50-year-old woman with HAE-nC1-INH and FMF was referred to our department for bone augmentation in the right maxillary molar region. We performed lateral window sinus augmentation under the backup support of an anesthesiologist. A hematologist used intravenous Berinert® and oral Orladeyo® to prevent perioperative angioedema attacks. The postoperative course was uneventful. Regarding surgical intervention in patients with HAE, interdepartmental cooperation is crucial to prevent angioedema attacks and prepare for life-threatening complications. Oral hygiene and occlusion should be considered in the dental implant treatment of patients with FMF. Every oral and maxillofacial surgeon and dental practitioner should familiarize themselves with HAE and FMF. [ABSTRACT FROM AUTHOR]

VEXAS syndrome is a newly described autoinflammatory entity characterized by somatic mutations in the UBA1 X-linked gene in hematopoietic progenitor cells. Several studies have demonstrated that the presence of vacuoles in progenitor cells from bone marrow aspirates is a hallmark finding for this syndrome. Therefore, this study aimed to characterize leukocytes from VEXAS patients versus patients with ANCA-associated vasculitis (AAV), familial Mediterranean fever (FMF), and healthy donors (HD) to define a specific cytological pattern that can support VEXAS diagnosis. Twelve VEXAS patients were included in the study. Blood samples from FMF (n = 16), AAV (n = 16) and HDs (n = 20) acted as controls. May-Grünwald Giemsa (MGG) staining was used for studying cellular morphology, including cytoplasm, granules, and vacuoles and to performa cytogenic evaluation of leucocytes. Plasma IL-1b, IL-1a, TNFa, IL-18 and IL-8 were measured using ELISA assay. The cytological analysis fromblood smears confirmed the presence of immature neutrophils in VEXAS patients. We found a greater number of vacuoles in VEXAS patients vs. FMF, AAV and HD. Micronuclei (MNi) and cell death rate were higher in VEXAS patients vs. HD. Cell death correlated with IL-1b and IL-8 levels. MNi were positively associated with IL-8 and IL-1b levels, and with the percentage of immature neutrophils and vacuoles. In conclusion, our findings suggested that cytological testmay be supportive for VEXAS diagnosis, despite genetical analysis is mandatory for confirming the disease. Finally, we identified several cytological hallmarks that may distinguish the VEXAS "cytotype" not only from HD but also from other inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: the role of the R202Q (c.605G>A, p.Arg202Gln) missense variant of the MEFV gene has been debated as either a benign polymorphism or a potentially pathogenic mutation. We report and discuss here the case of a young female with corticosteroid-dependent recurrent pericarditis carrying the homozygous R202Q variant, exhibiting distinctive clinical features possibly influenced by this genetic variant. Methods: a 30-year-old woman with a previous diagnosis of cancer and recent respiratory infection presented with severe pleuritic chest pain, hypotension, tachycardia, and fever. Initial diagnostic evaluation indicated cardiac tamponade, and emergent pericardiocentesis was performed. Despite initial treatment with NSAIDs, colchicine, and corticosteroids, the patient experienced multiple recurrences. Genetic testing identified homozygous R202Q variant in the MEFV gene. Given the corticosteroid dependency and recurrent nature of her condition, IL-1 inhibitor anakinra was introduced, leading to significant improvement, although tapering below 150 mg per week failed to prevent recurrences. Results: the introduction of anakinra resulted in rapid symptom relief and resolution of pericardial effusion. However, attempts to taper or discontinue anakinra led to pericarditis recurrences. Ultimately, a maintenance dose of 50 mg every three days was established, which maintained remission for 18 months without recurrence. Despite multiple tapering attempts, further reduction in anakinra dosage was unsuccessful without triggering relapses. Conclusions: the R202Q variant, although typically considered benign, may contribute to an autoinflammatory phenotype resembling familial Mediterranean fever. This case underscores the potential pathogenicity of the homozygous R202Q variant in recurrent pericarditis and its responsiveness to IL-1 inhibition. In patients with corticosteroid-dependent recurrent pericarditis, genetic testing for the R202Q variant should be considered when anti-IL-1 drugs cannot be withdrawn. Further studies are warranted to elucidate the variant's role in pericardial inflammation and guide personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Aim: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is characterized by inflammatory attacks due to overactivation of pyrin inflammasome. This study aimed to investigate the reliability of S100A8/A9, neopterin, and matrix metalloproteinase 3 (MMP3) at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. Blood samples (n = 75), comprising from FMF patients during an attack (n = 20), the same FMF patients during the attack-free period (n = 14), patients with appendicitis (n = 24), and healthy volunteers (n = 17) were obtained. Duplicate determinations of S100A8/A9, neopterin, and MMP-3 levels were conducted using the enzyme-linked immunosorbent assay (ELISA). FMF patients with and without attack and patients with appendicitis had significantly elevated S100A8/A9 levels compared to healthy volunteers (P-values: < 0.001, 0.036, 0.002, respectively). Patients with appendicitis and FMF patients with and without attack had significantly increased serum neopterin levels compared to healthy volunteers (P-value: < 0.001). MMP3 levels were significantly higher among patients with appendicitis and FMF patients during attack compared to healthy controls (P-values: < 0.001, 0.001). Serum levels of S100A8/A9, neopterin, and MMP3 were increased significantly during attacks compared to attack-free periods among FMF patients (P-values: 0.03, 0.047, 0.007). S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging. S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging. Graphical Abstract [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is an autoinflammatory disease which may cause endothelial dysfunction and arterial stiffness. In this study, we evaluated patients with FMF in terms of arterial stiffness indicators and investigated whether there was any difference according to colchicine response. This is a single-center, prospective, case-control study conducted on pediatric patients with FMF. Patients were categorized into 2 groups: patients on colchicine monotherapy (group 1) and patients who used anti-interleukin-1 (IL-1) plus colchicine (group 2). Patient age, mutations in the MEFV gene, overall duration of treatments, and general characteristics of symptoms were recorded. Laboratory values in an attack-free period were noted. Pulse wave velocity (PWV) was measured in all patients. Erythrocyte sedimentation rate and C-reactive protein, nocturnal hypertension, and PWV were higher in group 2. Arterial stiffness develops due to subclinical inflammation in patients with FMF. It is more pronounced in colchicine-resistant patients. [ABSTRACT FROM AUTHOR]

Background: Although it is known that consumed nutrition affects inflammatory load, and total antioxidant capacity (TAC) is affected by inflammatory diseases and consumed nutrients, these conditions have not been adequately investigated in adolescents with familial Mediterranean fever (FMF). Therefore, this study aimed to compare the dietary inflammatory index (DII), TAC and total oxidant capacity (TOC) of adolescents with FMF and healthy adolescents. Methods: This case‐controlled study consisted of 180 adolescents (aged 10–19) divided into FMF (n = 135) and control (n = 45 healthy) groups. Study data were collected face‐to‐face using a survey on demographic characteristics, anthropometric measurements, biochemical biomarkers and 3‐day dietary recall to calculate DII scores. Results: FMF group had lower DII score than controls (2.12 ± 0.78 vs. 2.33 ± 1.06, p < 0.05). In addition, they had higher C‐reactive protein (CRP), TOC (p < 0.05) and oxidative stress index (OSI) (p = 0.51) than the control group. On the contrary, the control group had significantly higher tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) values (p < 0.05). There was a positive correlation between DII scores and TNF‐α in the FMF group (p < 0.05). The control group had significantly higher energy, protein, medium‐chain fatty acids (MCT) and saturated fatty acids (SFA) intake than FMF (p < 0.05). On the contrary, the FMF group had significantly higher vitamin A and D, niacin and zinc intake (p < 0.05). Conclusion: The results showed that adolescents with FMF had lower DII and higher OSI than healthy adolescents. It may be beneficial for adolescents with FMF to consume a diet containing anti‐inflammatory nutrients to maintain normal growth and development and to prevent symptoms and complications of the disease. Key points: It is important for adolescents with familial Mediterranean fever (FMF) to grow and develop normally like their healthy peers.A diet high in antioxidants may affect inflammation.The results of this study show that adolescents with FMF have higher oxidative stress and have a more anti‐inflammatory diet than healthy adolescents.Instead of parents'/adolescents' own efforts to eat healthy, a diet with high anti‐inflammatory content planned by a dietitian may be more helpful in reducing the inflammatory burden of adolescents with FMF. [ABSTRACT FROM AUTHOR]

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 monoarthritis What 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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the pregnancy process, especially the Familial Mediterranean fever (FMF) disease course and attack types during pregnancy, and to examine the relationship between disease-related factors and female infertility in FMF patients. The study, which was planned in a multicenter national network, included 643 female patients. 435 female patients who had regular sexual intercourse were questioned in terms of infertility. Pregnancy and delivery history, FMF disease severity and course during pregnancy were evaluated. The relationship between demographic and clinical findings, disease severity, genetic analysis results and infertility was investigated. 401 patients had at least 1 pregnancy and 34 patients were diagnosed with infertility. 154 patients had an attack during pregnancy. 61.6% of them reported that attacks during pregnancy were similar to those when they were not pregnant. The most common attack symptoms were fever, fatigue and abdominal pain-peritonitis (96%, 87%, and 83%, respectively) in the pregnancy period. The disease-onset age, disease activity score, gene mutation analyses, and regular colchicine use (> 90%) were similar between the fertile and infertile groups, while the frequency of previous appendectomy and alcohol consumption rates were higher in individuals with infertility. Our results indicated no significant change in the frequency and severity of attacks during pregnancy. The low rate of infertility (7.8%) in our patients was noted. It has been suggested that the risk of FMF-related infertility may not be as high as thought in patients who are followed up regularly and received colchicine. [ABSTRACT FROM AUTHOR]

Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder, primarily observed in populations around the Mediterranean Sea, linked to MEFV gene mutations. These mutations disrupt inflammatory responses, increasing pyrin-protein production. Traditional diagnosis relies on clinical symptoms, family history, acute phase reactants, and excluding similar syndromes with MEFV testing, which is expensive and often inconclusive due to heterozygous mutations. Here, we present a biosensor platform that detects differences in pyrin-protein levels between healthy and affected individuals, offering a cost-effective alternative to genetic testing. Our platform uses gold nanoparticle-based plasmonic chips enhanced with anti-pyrin antibodies, achieving a detection limit of 0.24 ng/mL with high specificity. The system integrates an optofluidic system and visible light spectroscopy for real-time analysis, with signal stability maintained for up to six months. Our technology will enhance FMF diagnosis accuracy, enabling early treatment initiation and providing a cost-effective alternative to genetic testing, thus improving patient care. There are currently no laboratory tests available for definitive diagnosis of Familial Mediterranean Fever (FMF). Here, the authors develop cost-effective and accurate plasmonic biosensor platform which detects pyrin-protein levels to aid diagnosis of FMF. [ABSTRACT FROM AUTHOR]

Background: FMF is the most common autoinflammatory disease. The activation of the pyrin inflammasome is the mainstay of the pathogenesis, which might lead to a specific cell-death mechanism, pyroptosis. Pyroptosis is a programmed inflammatory cell death mediated by gasdermin proteins, featuring cell swelling, membrane rupture, and release of inflammatory contents Aim: In this study we aimed to analyze the cell-death mechanisms in the pathogenesis of FMF attacks. Methods: Twenty-five FMF patients were included, and PFAPA patients (n = 10) and healthy controls (HC, n = 10) served as controls. We collected plasma samples from FMF and PFAPA patients during the attack and the attack-free period. We measured the soluble plasma levels of sFas, sFasL, granzyme A, granzyme B, perforin, granulysin, IL-2, IL-4, IL-10, IL-6, IL-17A, TNF-α, and IFN-γ by commercial pre-defined cytometric bead array kits. Results: There was no significant difference between groups in terms of sex and age between FMF patients and HCs, but PFAPA patients were younger than other groups due to the nature of the disease. We then analyzed the components of apoptosis and pyroptosis. The levels of sFasL (p = 0.035) and granzyme A (p = 0.038) in FMF patients were significantly increased during the attack period and decreased to levels comparable to HCs during the attack-free period. This increase was not seen in the PFAPA patients, with comparable levels with the HC group both during attack period and attack-free period. During the attack period of FMF patients, granzyme B (p = 0.145) and perforin (p = 0.203) levels were also increased; however, the differences were not statistically significant. The levels of sFasL, granzyme A, granzyme B, and perforin were closely correlated with each other during the attack period of FMF patients. Conclusions: Our study on death pathways during an FMF attack, suggests an upregulation in both pyroptosis through the granzyme-gasdermin pathway and apoptosis with the increased FasL and perforin levels, which was different from PFAPA patients. These findings might shed light on the reason for the nature of self-limited attacks, but further studies are needed to prove this hypothesis. [ABSTRACT FROM AUTHOR]

In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients' cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples. [ABSTRACT FROM AUTHOR]

Introduction: Protracted febrile myalgia syndrome (PFMS) is a rare manifestation of familial Mediterranean fever (FMF), characterized by myalgia, fever and elevated inflammatory markers lasting several weeks. As the hallmark of FMF are short episodes of disease symptoms, the long duration of PFMS may lead to a delayed diagnosis and treatment. Objectives: 1. To perform a review of literature and rheumatology textbooks focused on clinical features and treatment of PFMS in children. 2. To present our own case. Methods: All articles in Pub Med generated using the keywords "protracted febrile myalgia" and information on PFMS in seven rheumatology textbooks were collected. The systematic review was supplemented with our own case presentation. Results: In total, 18 articles with 78 pediatric patients (including our own) were retrieved. More than half of the patients presented with PFMS as the first manifestation of FMF. All complained of myalgia, 65% of abdominal pain and 26% had a rash. Corticosteroids (CS) were effective in 77%. In all CS-refractory cases, anakinra was shown efficient. MRI was used in 5 patients and showed myositis in all of them. The scrutiny of seven rheumatology textbooks showed that PFMS presenting with myalgia was mentioned in six. Possible accompanying symptoms were described only once, the long duration of symptoms twice, the efficacy of corticosteroids three times and anakinra only once. The presented 6 year old patient manifested with fever, myalgia, abdominal pain and petechial rash lasting 6 weeks. She had undergone multiple diagnostic procedures before her parents mentioned a positive family history for FMF. The subsequent genetic testing confirmed a homozygosity for M694V pathogenic variant in the MEFV gene. Conclusion: The long duration of PFMS may be misleading to clinicians especially if PFMS occurs at manifestation of FMF. The fact that more than half of the reported patients experienced PFMS as the presenting symptom of FMF is one of the key findings of our study. Our case presentation demonstrates the importance of genetic testing early in suspected autoinflammatory diseases. Furthermore, MRI may be an important diagnostic tool showing myositis in PFMS. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to evaluate the frequency of juvenile fibromyalgia syndrome (JFMS) in patients diagnosed with juvenile idiopathic arthritis (JIA) and familial Mediterranean fever (FMF) with joint symptoms and compare them with a healthy control group. Patients and methods: This retrospective study was conducted with 181 participants between January and April 2023. One hundred twenty-one patients with JIA or FMF diagnoses (71 females, 50 males; mean age: 15.6±2.1 years; range, 12 to 23 years) and 60 healthy individuals (36 females, 24 males; mean age: 14.5±1.6 years; range, 12 to 17 years) were included in the patient group and the control group, respectively. The pain and symptom assessment scale was applied for the JFMS diagnosis, and the output data were analyzed with the widespread pain index and symptom severity scale. Results: Of the patient group, 57% (n=69) were diagnosed with FMF, and 43% (n=52) were diagnosed with JIA. When the two groups were compared with those diagnosed with JFMS, statistical significance was detected (p<0.05). Thirteen (87%) of those diagnosed with JFMS were female, and two (13%) were male, with a statistically significant difference. Conclusion: In patients with JIA and FMF who complain of chronic musculoskeletal pain, tiredness, and weakness, JFMS diagnosis should always be considered in the clinical evaluation. [ABSTRACT FROM AUTHOR]

Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations. [ABSTRACT FROM AUTHOR]

Drug repurposing, also known as drug repositioning or drug reprofiling, is gaining momentum as a strategy to identify novel therapeutic uses for existing drugs outside their original medical indications. This approach leverages the known safety profiles and mechanisms of action of approved medications to expedite the development of treatments for various diseases. Colchicine, an ancient herbal medicine with established anti-inflammatory properties and recognized efficacy in conditions like gout and Familial Mediterranean fever, has garnered interest in its potential applications beyond traditional uses. The discovery of colchicine's binding capacity to microtubules, essential for cellular structure and mitosis, has sparked exploration into its role in cancer therapy. Histone deacetylase inhibitors (HDACs) have also shown promise in cancer research by modulating gene expression through histone and non-histone protein acetylation. While colchicine is not conventionally classified as an HDAC inhibitor, studies suggest its potential impact on HDAC activity. This study aims to investigate the similarities in enzyme binding energies between colchicine and HDAC inhibitors, exploring the potential utility of colchicine as an HDAC inhibitor and introducing a new avenue for cancer treatment. By elucidating the potential therapeutic overlap between colchicine and HDAC inhibitors, this research seeks to advance the field of drug repurposing and provide novel insights into the treatment of cancer and other diseases. [ABSTRACT FROM AUTHOR]

Purpose: To investigate perinatal outcomes and long-term infectious morbidity in children of mothers with familial Mediterranean fever (FMF). Methods: A population-based cohort study comparing perinatal outcomes and long-term infectious morbidity of offspring of mothers with and without FMF was conducted. All singleton deliveries between the years 1991–2021 in a tertiary medical center were included. The study groups were followed until 18 years of age for long-term infectious morbidity. A Kaplan–Meier survival curve was used to compare the cumulative incidence of long-term infectious morbidity, and generalized estimation equation (GEE) models as well as Cox proportional hazards models were constructed to control for confounders. Results: During the study period, 356,356 deliveries met the inclusion criteria. 411 of them were women with FMF. The mean follow-up period interval was 9.7 years (SD = 6.2) in both study groups. Using GEE models, preterm delivery, cesarean delivery, and low birth weight were independently associated with maternal FMF. The total infectious-related hospitalization rate was significantly higher in offspring born to mothers with FMF compared to the comparison group (Kaplan–Meier survival curve, log-rank p < 0.001). Using a Cox proportional hazards model, controlling for gestational age, maternal age, diabetes mellitus, cesarean delivery, and hypertensive disorders, being born to a mother with FMF was found to be an independent risk factor for long-term infection-related hospitalization of the offspring. Conclusion: Maternal FMF was found to be independently associated with long-term infection-related hospitalization of the offspring. This positive correlation may reflect an intra-uterine pro-inflammatory environment which may result in the offspring's long-term susceptibility to infection. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever, serositis (peritonitis, pleuritis, or synovitis), and erysipelas‐like erythema. Genetic variants in the MEFV gene are associated with this disease. Familial Mediterranean fever is considered an autosomal recessive disease. However, in Middle Eastern countries, a third of the patients expressing FMF manifestations, carry a single mutation only. Moreover, some cases of pure dominant inheritance linked to specific single MEFV variants have also been described. This complex inheritance of MEFV‐associated inflammatory diseases poses a serious challenge when interpreting the results of genetic testing in patients having recurrent fever syndromes. In addition, in certain situations, asymptomatic individuals may be incidentally found to carry MEFV variants. These cases pose the question of their exact diagnosis and whether they should be treated. Previous studies have focused on genetic results interpretations among symptomatic patients. In the current article, we would like to elaborate on the genetic interpretation in cases of symptomatic individuals suspected to have FMF and on asymptomatic individuals carrying MEFV variants. We aim to assist physicians unfamiliar with FMF to cope with genetic results interpretation when facing symptomatic and asymptomatic individuals carrying MEFV variants and suggest a management plan accordingly. [ABSTRACT FROM AUTHOR]

• CRP and SAA are good biomarkers to discriminate crises in FMF and USAID patients. • Serum calprotectin is not a suitable biomarker to discriminate crises in SAID. • Contrary to SAA, CRP diagnostic performances were not affected by the BMI. • CRP is a suitable, not expensive and easily available biomarker to monitor SAID. With their broad presentations and no global biomarker to discriminate crises and attack-free periods, Systemic Auto-Inflammatory Diseases (SAID) are difficult to manage. This study assessed Serum Amyloid A (SAA), C-reactive protein (CRP) and serum calprotectin as potential biomarkers to monitor patients with SAID. SAA (already studied in Familial Mediterranean Fever (FMF)), CRP and serum calprotectin were measured on SAID adult patients from Juvenile Inflammatory Rheumatism (JIR) cohort during their follow-up visits between 2020 and 2022. Crises and attack-free periods were clinically determined. 96 measures, mainly from FMF (43 %) and Unclassified SAID (USAID) (37 %) patients were included. Using ROC curves, a threshold with sensitivity and specificity of/over 75 % was determined for SAA (9 mg/L) and CRP (9 mg/L) but not for serum calprotectin, not investigated further. With this threshold, the results were similar in FMF and USAID patients' subgroups. SAA and CRP showed a positive correlation with crises and attack-free periods in SAID patients (r = 0.4796, p < 0.001 and r = 0.5525, p < 0.001, respectively) as in FMF and USAID patients, with no significant difference between both markers in diagnosis value and ROC curves Area Under Curve (AUC) (p = 0.32). Only the CRP results were not influenced by obesity. SAA and CRP can discriminate crisis and attack-free periods in our cohort of SAID patients mainly composed of FMF and USAID patients. However, only CRP can be used regardless of body mass index. It is the first report of common biomarkers for all SAID, including USAID patients, with CRP widely accessible in routine worldwide. [ABSTRACT FROM AUTHOR]

The past 25 years have seen major novel developments in the field of paediatric rheumatology. The concept of autoinflammation was introduced to this field, and medicine more broadly, with studies of familial Mediterranean fever, the most common autoinflammatory disease globally. New data on the positive evolutionary selection of familial Mediterranean fever-associated genetic variants might be pertinent to mild gain-of-function variants reported in other disease-associated genes. Genetic studies have unveiled the complexity of human heritability to inflammation and flourishing data from rare monogenic disorders have contributed to a better understanding of general disease mechanisms in paediatric rheumatic conditions. Beyond genomics, the application of other 'omics' technologies, including transcriptomics, proteomics and metabolomics, has generated an enormous dataset that can be applied to the development of new therapies and in the practice of precision medicine. Novel biomarkers for monitoring disease activity and progression have also emerged. A surge in the development of targeted biologic therapies has led to durable remission and improved prognosis for many diseases that in the past caused major complications. Last but not least, the COVID-19 pandemic has affected paediatric rheumatology practice and has sparked new investigations into the link between viral infections and unregulated inflammatory responses in children. Paediatric rheumatology has seen many notable developments in the past 25 years, including the introduction of the concept of autoinflammation and a greater understanding of the genetics and pathogenesis of inflammatory diseases. In this Perspective, Ozen and Aksentijevich discuss how these and other discoveries have transformed the field and herald improvements in patient care. [ABSTRACT FROM AUTHOR]

A recent study published in the Journal of Internal Medicine explores the use of IL-1β/DNA complex levels as a diagnostic tool for distinguishing autoinflammatory disorders from autoimmune and infectious diseases. The researchers developed a novel ELISA assay to measure the amount of IL-1β bound to extracellular DNA in plasma samples. They found that circulating IL-1β/DNA complex levels were significantly higher in patients with autoinflammatory disorders compared to those with autoimmune rheumatic diseases, acute infections, and healthy individuals. The assay also showed promise in evaluating treatment response in patients receiving IL-1 inhibitors. Further studies are needed to validate the diagnostic and prognostic utility of this assay in diverse inflammatory disorders. [Extracted from the article]

Autoinflammatory disease (AID) is a vast spectrum of disorders characterized by recurrent attacks of sterile inflammation. Since the first cloning of the familial Mediterranean fever gene in 1997, there has been a rapid rate of discovery of new AIDs. As of 2022, there have been 485 inborn errors of immunity documented by the International Union of Immunological Societies, for which many display aspects of autoinflammation. The pathophysiology of AIDs is complex. Although many are caused by rare mutations in genes that govern innate immunity, others are polygenic, where disease expression is thought to be triggered by environmental factors in genetically predisposed hosts. AIDs range in prevalence from common entities like gout to ultrarare monogenic diseases. Whereas AIDs were initially studied in pediatric populations, it is now apparent that they can present in adulthood and even in the elderly. AIDs can be clinically challenging given their rarity, as well as the heterogeneity in presentation and underlying etiology. Although the care of AIDs can span medical disciplines, the rheumatologist often plays a central role given the inflammatory nature of these illnesses. In this review, we explore the current understanding of the pathophysiology of these complex conditions and propose a classification system for AIDs. We place an emphasis on AIDs that present to the adult rheumatologist and discuss important AIDs that can mimic more classic rheumatic diseases such as systemic lupus erythematosus and inflammatory arthritis. Finally, we offer an approach to the clinical assessment, diagnosis, and management of AIDs. [ABSTRACT FROM AUTHOR]

Objectives We describe the clinical pictures of an index case with dystonia and his family resulting from VPS16 and MEFV genetic variations based on previously published data and discuss the mechanisms that may have brought out the clinical findings. Methods A 17-year-old male had generalized dystonia that started at age 6 years, non-febrile abdominal pain attacks and was diagnosed with type 1 diabetes at age 14 years. Meanwhile, his 13-year-old sister had the same clinical presentation. His father was diabetic and his mother was asymptomatic. There was no consanguinity between the parents. Genetic variations were detected with whole exome sequencing. Results VPS16 c.1513C>T/p.Arg505* (likely pathogenic), MEFV c.2080A>G p.Met694val (pathogenic) and MEFV c.1772T>C p.Ile591Thr (unknown significance) heterozygous variants were detected in his siblings. The father had VPS16 c.1513C>T/p.Arg505* and MEFV c.2080A>G p Met694val variations and the mother had MEFV c.1772T>C p.Ile591Thr variations. Conclusions The occurrence of these diseases in siblings but their absence in the parents suggests the idea that the coexistence of two separate variations in the VPS16 and MEFV genes determines the phenotype. In addition, the increase in MEFV variation load in this family and the fact that DM occurs at an earlier age suggest that inflammation may cause an early diabetic clinical presentation. [ABSTRACT FROM AUTHOR]

The detection of variants of unknown significance (VUS) in familial Mediterranean fever (FMF) is common; however, their diagnostic value remains elusive, and the interpretation of multiple VUS remains difficult. Therefore, we examined FMF diagnosis-associated factors 1-year post-genetic testing in patients with only VUS and assessed the impact of multiple VUS on diagnosis and clinical features. A 1-year follow-up was conducted on patients clinically suspected of having FMF without confirmatory diagnosis owing to the presence of only VUS. Clinical features were compared between patients with a single VUS and those with multiple VUS among patients diagnosed with FMF. Among 261 patients followed up, 202 were diagnosed with FMF based on clinical judgment. No specific clinical symptoms or variant patterns at genetic testing were associated with diagnosis at 1 year. Multiple VUS was significantly and independently associated with a lower response to colchicine than single VUS among patients diagnosed with FMF. However, clinical symptoms showed no correlation with the number of VUS. In conclusion, predicting FMF diagnosis 1-year post-genetic testing in patients with only VUS remains challenging. Moreover, the impact of multiple VUS on FMF may be limited owing to the lack of correlation with clinical features, except colchicine response. [ABSTRACT FROM AUTHOR]

Objectives: Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease affecting both genders in reproductive age. In this study, we aimed to investigate the relation between FMF and pregnancy on both maternal and fetal aspects. Material and methods: In this retrospective, single-center, descriptive study we analysed total of 95 pregnancies of 40 FMF patients. Clinical and demographic data were obtained from patients’ records. To prevent recall bias, only the last pregnancy of each patient was evaluated for disease activity and use or revision of medications during pregnancy. Results: The median age of the patients at diagnosis was 22 and the first pregnancy age was 26 years. The median duration of FMF at last pregnancy was 8 (0–23) years. Eight (20%) patients had at least 1 pregnancy via assisted reproductive techniques (IVF), while 34 (85%) patients had at least 1 spontaneous pregnancy. While 32 patients were in remission (80%) before pregnancy, 8 were clinically active (20%). Improvement in clinical course and attack frequency during pregnancy was observed in 23 patients (57.5%), stable course in 10 (25.0%), and worsening in 7 (17.5%). The rate of live birth was 70.0%, abortus was 28.9%, preterm labor was 8.1%, pre-eclampsia was 5.0%, and only 1 achondroplasia as congenital fetal abnormality was observed. Conclusion: FMF did not constitute a contraindication for pregnancy. The most important obstetric problems, complications, and negative fetal outcomes in the course of pregnancy are increased IVF requirement, abortion, and cesarean rates. There is no increase in the risk of congenital malformations due to FMF itself or use of colchicine.

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.

Abstract In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients’ cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples.

Abstract Background Artificial intelligence (AI) has become a popular tool for clinical and research use in the medical field. The aim of this study was to evaluate the accuracy and reliability of a generative AI tool on pediatric familial Mediterranean fever (FMF). Methods Fifteen questions repeated thrice on pediatric FMF were prompted to the popular generative AI tool Microsoft Copilot with Chat-GPT 4.0. Nine pediatric rheumatology experts rated response accuracy with a blinded mechanism using a Likert-like scale with values from 1 to 5. Results Median values for overall responses at the initial assessment ranged from 2.00 to 5.00. During the second assessment, median values spanned from 2.00 to 4.00, while for the third assessment, they ranged from 3.00 to 4.00. Intra-rater variability showed poor to moderate agreement (intraclass correlation coefficient range: -0.151 to 0.534). A diminishing level of agreement among experts over time was documented, as highlighted by Krippendorff’s alpha coefficient values, ranging from 0.136 (at the first response) to 0.132 (at the second response) to 0.089 (at the third response). Lastly, experts displayed varying levels of trust in AI pre- and post-survey. Conclusions AI has promising implications in pediatric rheumatology, including early diagnosis and management optimization, but challenges persist due to uncertain information reliability and the lack of expert validation. Our survey revealed considerable inaccuracies and incompleteness in AI-generated responses regarding FMF, with poor intra- and extra-rater reliability. Human validation remains crucial in managing AI-generated medical information.

Abstract Background Familial Mediterranean fever (FMF) is the most prevalent inherited autoinflammatory disease globally. Metabolic syndrome (MetS) is a cluster of interrelated risk factors; insulin resistance, obesity, dyslipidemia, and hypertension are the main constituents of MetS. Aim This study aimed to investigate components of metabolic syndrome among Egyptian children with FMF during the attack-free period. Patients and methods This is a case–control study that was conducted in the Pediatric Rheumatology Outpatient Clinic and Pediatric Endocrinology Clinic, Children’s Hospital, Faculty of Medicine, Cairo University. It was conducted on 40 patients with FMF. The patients included were of both sexes and aged 10 years or older, during the FMF attack-free period; they were compared to 40 apparently healthy age- and sex-matched children as controls. All subjects in this study were subjected to detailed history taking, anthropometric measurements, general and systemic examinations. Laboratory evaluation (at the time of the study) was done at time of study, in the form of CBC with differential, BUN, creatinine, ESR, serum amyloid A, urine analysis, serum insulin, fasting blood glucose, and lipid profile. FMF gene mutations were collected from patients’ files. Results The mean ± SD age of FMF patients was 12.65 ± 1.82 (10–17) years, while the mean ± SD age of the control group was 12.6 ± 1.82 (10–16) years. Among FMF patients, 50% were males, and 50% were females (F:M = 1:1), while in the control group, 47.5% were females, and 52.5% were males. All FMF patients were during the attack-free period. There was a statistically significant difference between both groups regarding insulin resistance, being more frequent among the FMF patients’ group, with a p-value of 0.025. Conclusion None of our FMF patients met the criteria for the definition of metabolic syndrome, but there was a significant difference between cases and control regarding insulin resistance with higher frequency among FMF patients, probably due to the ongoing subclinical inflammation. This indicates that children with FMF may be at a higher risk of getting metabolic syndrome later on in life.

Abstract Background FMF (Familial Mediterranean Fever) is the most prevalent autoinflammatory disease. It arises due to mutations in the pyrin-encoding MEFV gene. Prolidase, an enzyme culpable of splitting the bonds of proline-containing dipeptides, is essential for matrix remodeling, collagen turnover, and cell proliferation. It has a crucial role in inflammation. Aim To compare serum levels of prolidase between FMF children during the attack-free periods and healthy children and to correlate it with different FMF disease criteria and inflammatory marker, also to investigate if it can serve as a marker for subclinical inflammation. Results Forty-one children diagnosed with FMF and 41 sex and age-matched apparently healthy children as a control group were included in this study, serum prolidase was measured by ELISA. The mean ± SD serum level of prolidase among FMF patients was 0.6 ± 0.2 mU/ml × 104, while among the control group, it was 1.3 ± 1.4 mU/ml × 104, a statistically significant difference existed between both groups, p value = 0.001. The level of serum prolidase was not correlated with FMF severity score, inflammatory markers, and other FMF disease criteria. Conclusion Serum prolidase level was lower among FMF patients during the attack-free period than in the healthy control group, it was not correlated with disease severity and was not predictive of the presence of subclinical inflammation. Further studies are needed to highlight the role of serum prolidase in FMF children.