Familial Mediterranean Fever Disease Research Articles

Hereditary periodic fevers in children

Fevers in children is a pressing challenge in paediatrics, as they are one of the most common symptoms people seek medical help. Autoinflammatory diseases (AIDs) constitute a group of diseases, where fever is one of the main symptoms, and fever attacks have a certain frequency and duration. Autoinflammatory diseases are rooted in the systemic aseptic inflammation associated with activation of the innate immune system, without elevated levels of autoantibodies. The most common autoinflammatory diseases include hereditary periodic fevers, among which are familial Mediterranean fever (FMF), HIDS/MKD, CAPS-, TRAPS-syndromes and rarer diseases (deficiency of natural interleukin receptor antagonists). The pathogenesis of this group of diseases is based on the process of accelerated formation of a supramolecular protein complex (inflammasome), which subsequently leads to the transition of the inactive form of IL1β into its active form. The clinical presentations of these diseases may be similar and include episodes of fever, abdominal pain, arthralgia, various rashes, etc., as well as an increase in acute phase parameters. These diseases are characterized by symptoms at certain intervals; they usually have intervals without showing any symptoms. Familial Mediterranean fever is characterized by a certain ethnic background (Armenians, Turks, Arabs, Jews). Today, molecular genetic testing is the most accurate method for diagnosing familial Mediterranean fever. Current therapy aims to prevent attacks of the disease, but it is also important to use symptomatic therapy to relieve the child’s condition when an attack has already developed. Modern treatment strategies include both drugs that have long been used in paediatric practice (colchicine, non-steroidal anti-inflammatory drugs (ibuprofen), glucocorticosteroids) and novel genetically engineered biological drugs (interleukin antagonists and tumour necrosis factor inhibitors, etc.).

Epigenetic insights into Familial Mediterranean Fever: Increased RGS10 expression and histone modifications accompanies inflammation in familial Mediterranean fever disease

BackgroundFamilial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurring fever, erythema, joint pain, and abdominal discomfort during acute episodes. While FMF patients typically share MEFV gene mutations, they display varying clinical manifestations, suggesting the involvement of modifying genes, epigenetic mechanisms, or environmental factors. G protein regulator signal 10 (RGS10), a member of the RGS protein family, exhibits anti-inflammatory effects in autoinflammatory diseases. There are no studies on the role of plays in FMF pathogenesis or histone modification in FMF. AimsThis study aimed to shed light on the epigenetic regulation of FMF from several perspectives. The relationship between RGS10 DNA hypermethylation in FMF clinical parameters and the regulation of 22 histone modifications were examined in FMF attack patients and the control group. MethodsSixty FMF (remission/attack) and thirty healthy individuals were included in the study. First, RNA was isolated from the blood of patients/controls, and the expression of RGS10 was examined. Then, DNA was isolated from the patients, and gene-specific hypermethylation was investigated using the bisulfite conversion method. Finally, histone extraction was performed for FMF patients and controls and 22 histone H3 modifications were determined. In addition, using ADEX bioinformatics tools, RGS10 expression and methylation profiles were detected in different autoinflammatory diseases. ResultsThis study indicate that RGS10 expression decreased in attack-free/attack patients than control, attributed to DNA methylation. In addition, there were a positive correlation between FMF patients and attack, WBC, neutrophil, MCHC and MPV. Moreover, higher H3K4 me3, H3K9 me2, and H3K14ac levels were observed in patients with FMF attacks. This research also showed a consistent decrease in RGS10 expression in patients with SjS, SSc, and T1D compared with controls. I also obtained five prognosis-related CpGs (cg17527393, cg19653161, cg20445950, cg18938673 and cg13975098) of RGS10 in patients with SjS, RA, SSc, SLE and T1D. ConclusionThe present study provides insights into the complex relationship between RGS10, epigenetic modifications, and immune responses in FMF. While RGS10 may initially enhance immune responses, genetic mutations and epigenetic changes associated with FMF acute episode may override this regulatory effect, resulting in increased inflammation and clinical symptoms. Moreover, our study revealed elevated levels of specific histone modifications in the context of FMF, suggesting significant epigenetic changes that could contribute to the disease pathogenesis. Understanding these associations opens new avenues for research and potential therapeutic interventions, potentially involving epigenetic therapies targeting histone modifications.

Course of COVID-19 in patients carrying different MEFV mutations of familial Mediterranean fever

Familial Mediterranean Fever (FMF) is a genetic auto-inflammatory disease. Mutations in the Mediterranean fever (MEFV) gene cause inappropriate immune system triggering, leading to inflammatory episodes in the peritoneum, pleura, and joints. In the severe Coronavirus disease-19 (COVID-19) picture, the hyperimmune response and inflammatory process develop with exacerbation of the clinical condition. FMF disease, the drugs used in its treatment, and the possible effects of different genetic MEFV mutations on the course of COVID-19 arouse interest. In this study, 158 FMF patients with different MEFV gene mutations were evaluated using an online survey method in terms of COVID-19 course, hospitalization, additional comorbidities, and COVID-19 vaccination status. Participants were asked 21 questions and the data provided were compared between FMF MEFV gene mutations. 104 out of 158 cases did not get COVID-19. 9 of 54 cases who got COVID-19 were hospitalized. No statistically significant difference was found between MEFV gene mutations when evaluated and compared in terms of susceptibility to COVID-19, vaccination status, and presence of additional chronic diseases and comorbidities. The present study provides guidance on the role of FMF genetic mutations in the course of COVID-19. Our study may suggest that FMF MEFV gene mutations do not have a protective role against COVID-19. The results also may suggest that, as an inverse effect, MEFV gene mutations do not increase the risk of hyper-immune response and severe acute respiratory syndrome (SARS), which play a role in the severe course of COVID-19.

Abstract 26 — Clinical Characteristics of Familial Mediterranean: Fever in Hemodialysis Patients

Introduction Familial Mediterranean fever (FMF) is an inherited genetic disorder characterized by recurrent episodes of fever, serositis, arthritis, and skin rash. Uncontrolled disease can lead to amyloid A disposition, nephrotic syndrome and progressive renal failure. Recurrence of AA amyloidosis post kidney transplantation has been reported. Long-term colchicine therapy will reduce the FMF attacks and risk of AA amyloidosis. Although there is high prevalence of FMF in MENA region, the data of end stage renal disease (ESRD) in FMF is limited. We report our center experience. Method A retrospective chart review study was conducted at Tawam Hospital over 12 years (January 2010 to January 2023). We included adult ESRD on hemodialysis with FMF disease and studied their management outcomes. Descriptive analysis was used. Results 1900 ESRD patients were on hemodialysis during study period, and only two patients were diagnosed with FMF and renal amyloidosis. Case 1: A 60-year-old male patient from Syria who is known to have FMF and polycystic kidney disease leading to ESRD. He underwent successful LRD kidney transplantation in 2009. He was on mycophenolic acid: 540 mg, BID, prednisolone: 5 mg, tacrolimus: 1 mg am, 0.5 mg and colchicine 0.5 mg BID. He developed progressive renal allograft dysfunction with evidence of nephrotic syndrome. The renal biopsy revealed recurrence of AA amyloidosis due to FMF in kidney allograft in 2018. He had decline in renal function over years was initiated on hemodialysis on 2022. He developed two attacks of FMF peritonitis while on hemodialysis that responded well to steroid/colchicine therapy. Case 2: 48 years old male, from Egypt, known to have irritable bowel syndrome. He presented to our hospital with bilateral lower limb edema, and progressive shortness of breath for one month. Investigations revealed heavy proteinuria (8.98 g/g Creat) and acute kidney injury. Serology and autoimmune workup were negative. Kidney biopsy showed renal amyloidosis, and chronic tubulointerstitial nephritis with severe interstitial fibrosis (60%). History taken again and was positive for FMF in his uncle. Genetic study and clinical confirmed the diagnosis of FMF. He was started on colchicine, but developed ESRD within 8 months and initiated on hemodialysis. He had attacks of FMF. Conclusion Renal amyloidosis in FMF patient leads to progressive renal failure despite colchicine therapy. In our dialysis cohort over 12 years, only two FMF patients were identified. Colchicine therapy is required in ESRD-FMF in order to managed FMF attacks and prevent other organ AA amyloidosis.

The effects of working conditions on work life in Familial Mediterranean Fever (FMF) patients

Introduction: Familial Mediterranean Fever (FMF) is a common autoinflammatory disease, especially in Mediterranean populations. FMF typically occurs with fever and serositis attacks and can negatively affect the individual's life. In our study, we aimed to investigate the effects of working conditions and the disease course on the work life of FMF patients.
 Methods: The adult patients with pathogenic or likely pathogenic mutations in the MEFV gene who applied to our medical genetic outpatient clinic of the Faculty of Medicine, Çanakkale Onsekiz Mart University between 01.01.2010 and 01.08.2020 were included in our study. We created a questionnaire of 34 questions, which included sociodemographic data, information about the FMF course of the patients, and the effects of work conditions and FMF on the work life of these patients. The questionnaire link, created over Google Drive, was sent to the patient's current mobile phone numbers via text message, and the answers received until 31.12.2020 were evaluated.
 Results: A total of 154 survey responses were obtained, and 113 were eligible for our study. Twenty-four of 104 (23.1%) participants who have worked in any job so far stated that they have changed or quit their jobs because of increased or worsening FMF attacks. Of 72 participants who have been working actively for the last year, 4 (5.6%) of them we are reported that they have a health problem in the workplace due to FMF disease. The statistically significant relationships were found between the FMF-induced changing or quitting job and the attack number in the last year regardless of attack severity, work-related adverse psychological effects, the mode of transportation to work, and the physical conditions in the working environment.
 Conclusion: We suggest that the regulation of work environments, considering the factors that trigger attacks in FMF patients, will contribute to the increase in quality of life and work performance in these patients.

Peripheral T Cell Populations are Differentially Affected in Familial Mediterranean Fever, Chronic Granulomatous Disease, and Gout

Both innate errors of immunity, such as familial Mediterranean fever (FMF) and chronic granulomatous disease (CGD), and the common inflammatory disease gout are characterized by episodes of sterile inflammatory attacks in the absence of an infection. While these disorders encompass distinct pathologies due to differentially affected metabolic pathways and inflammasome activation mechanisms, their common features are the excessive production of interleukin (IL)-1ß and innate immune cell hyperreactivity. On the other hand, the role of T cells and innate-like lymphocytes such as gamma delta (γδ) T cells in these pathologies is ill-defined. In order to widen our understanding of T cell involvement in CGD, FMF and gout pathology, we developed multicolour immunophenotyping panels for flow cytometry to characterize γδ T cells as well as CD4 and CD8 T cell populations in terms of their cytokine production, activation status, memory or naive phenotypes, exhaustion status, homing receptor expression, and cytotoxic activity. Our study is the first deep immunophenotyping analysis of T cell populations in CGD, FMF, and gout patients. We found that CGD affects the frequencies and activation status of T cells, while gout impairs the cytokine production capacity of Vδ2 T cells. FMF was characterized by decreased percentages of regulatory T cells in circulation and attenuated IFN-γ production capacity by Vδ2 T cells. Autoinflammatory syndromes and congenital defects of phagocyte differentially affect T cell compartments. Future studies are warranted to assess whether these phenotypical changes are relevant for disease pathology.

Hyperinflammatory Immune Response in COVID-19: Host Genetic Factors in Pyrin Inflammasome and Immunity to Virus in a Spanish Population from Majorca Island.

The hyperinflammatory response caused by SARS-CoV-2 infection contributes to its severity, and many critically ill patients show features of cytokine storm (CS) syndrome. We investigated, by next-generation sequencing, 24 causative genes of primary immunodeficiencies whose defect predisposes to CS. We studied two cohorts with extreme phenotypes of SARS-CoV-2 infection: critical/severe hyperinflammatory patients (H-P) and asymptomatic patients (AM-risk-P) with a high risk (older age) to severe COVID-19. To explore inborn errors of the immunity, we investigated the presence of pathogenic or rare variants, and to identify COVID-19 severity-associated markers, we compared the allele frequencies of common genetic polymorphisms between our two cohorts. We found: 1 H-P carries the likely pathogenic variant c.887-2 A>C in the IRF7 gene and 5 H-P carries variants in the MEFV gene, whose role in the pathogenicity of the familial Mediterranean fever (FMF) disease is controversial. The common polymorphism analysis showed three potential risk biomarkers for developing the hyperinflammatory response: the homozygous haplotype rs1231123A/A-rs1231122A/A in MEFV gene, the IFNAR2 p.Phe8Ser variant, and the CARMIL2 p.Val181Met variant. The combined analysis showed an increased risk of developing severe COVID-19 in patients that had at least one of our genetic risk markers (odds ratio (OR) = 6.2 (95% CI) (2.430-16.20)).

Familial Mediterranean fever: perspective on female fertility and disease course in pregnancy from a multicenter nationwide network.

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.

Diagnostic Efficacy of Renal 2-D Shear Wave Elastography in Familial Mediterranean Fever Disease.

The aims of this study were to evaluate the kidneys of patients with familial Mediterranean fever (FMF) noninvasively and quantitatively using 2-D shear wave elastography (SWE) and to reveal the diagnostic efficacy of SWE in FMF-induced renal involvement. Healthy controls, FMF patients, and FMF patients with proteinuria were included in the study, and differences in renal stiffness values between the groups were examined. In addition, a relationship between age, sex, height, weight, body mass index, serum erythrocyte sedimentation rate, C-reactive protein, glomerular filtration rate, and renal stiffness values was evaluated. A total of 120 subjects, including 60 controls, 41 FMF patients without proteinuria, and 19 FMF patients with proteinuria, were enrolled in the study. Renal stiffness values were found to be significantly higher in the group with FMF compared with the control group. In addition, the values in the proteinuria group were higher than both the control group and FMF patients without proteinuria ( P < 0.001). A significant positive correlation was found between the renal stiffness value and C-reactive protein. According to receiver operating characteristic analysis, the mean renal stiffness value was 7.905 kPa or greater to determine FMF-induced proteinuria. The current study shows that renal stiffness values were higher in FMF patients compared with the normal population and the values showed further increase in the presence of proteinuria, which indicates a more advanced stage of renal involvement of the disease. These findings reveal that SWE can be used as a noninvasive diagnostic tool in the diagnosis, follow-up, and evaluating the severity of FMF.

The Clinical Characteristics and Prognosis of Exon 2 Mutations in Familial Mediterranean Fever

Objective: It is unclear whether exon 2 mutations are variations or a mutations that causes the disease. This study aimed to evaluate the clinical features and prognosis exon 2 mutations in Familial Mediterranean Fever. Methods: The clinical features, disease severity and prognosis of all patients with at least one exon 2 mutations were evaluated retrospectively. These data were compared seperately for homozygous (Group 1), heterozygous (Group 2), compound heterozygous (Group 3), and complex alleles (Group 4), and the data were compared by grouping patients into those with and without exon 10 mutations. Results: There were a total of 119 patients with exon 2 mutations, including 11.7% in Group 1, 36.1% in Group 2, 21.8% in Group 3, and 30.2% in Group 4 were similar in terms of demographic data, clinical characteristics, and disease course. When compared patients with exon 10 mutations (+) to those with exon 10 mutations (-), the exon 10 mutations (+) group had a higher presence of chest pain (100%, p=0.02) and a significantly higher mean Pras severity score (6.66±1.87, 6.01±1.40; p=0.02). Additionally, a higher number of patients with exon 10 mutation (-) achieved remission with treatment (76 (67.9%), 36 (32.1%); p=0.03). Conclusion: Exon 2 mutations have a milder course and higher remission rates but they should be considered as Familial Mediterranean Fever disease because of their similar clinical presentation and response to colchicine treatment with exon 10 mutations. Early treatment and close follow-up should be performed.

Fractal dimension analysis of different mandibular regions in familial Mediterranean fever patients: A cross-sectional retrospective study.

Familial Mediterranean fever (FMF) is a genetic condition that may cause loss of bone mineral density (BMD) due to chronic inflammation. Previously, fractal dimension (FD) analysis values of mandibular cortical bone were shown to be lower in osteoporosis. Therefore, FD might be considered as an auxiliary tool to refer patients for dual-energy x-ray absorptiometry (DXA), which is the gold standard for BMD measurement. The purpose of this cross-sectional retrospective study was to evaluate trabecular and cortical microarchitecture of the mandible with FD analysis on panoramic radiographs in a subpopulation of FMF. Also, the effect of colchicine use was investigated. Forty-three FMF patients, aged between 10.8 and 71.2 years, and age- and gender-matched control group consisting of patients, who had no systemic diseases, were included. Demographic information such as age and gender, and colchicine use were recorded. In terms of age, the patients were classified as <30 and 30< years. On each panoramic radiographs five regions of interest were selected on the mandible as: 1- premolar, 2- molar, 3- angular, 4- condylar, and 5- basal cortical bone regions on right (R) and left (L) sides. Statistical significance was accepted at p<0.05 level. Intra- and inter-observer agreements demonstrated good to excellent consistency. In FMF patients, L3 and L4 values were higher, whereas L5 values were lower (p<0.05) than the control group. In terms of age, the difference between groups was insignificant in FMF patients (p>0.05), whereas in control group R3 and L4 values were higher in the 30< age group (p<0.05). Regarding gender and colchicine use, the difference between groups was insignificant (p>0.05). FMF disease might be a candidate for referral to DXA examination based on decreased bone density in the mandibular cortex detected by FD measurements on routine panoramic radiographs. Further studies are warranted to ascertain this relationship.

Molecular and in Silico Analysis of &lt;i&gt;MEFV&lt;/i&gt; Variants in Familial Mediterranean Fever Patients in Southwest Iran

Familial Mediterranean Fever (FMF) is classified as an autoinflammatory genetic disease inherited by mutations in &lt;em&gt;MEFV&lt;/em&gt;. These mutations can affect the dysregulation of inflammatory processes in the human body and lead to fever and pain in the chest and abdomen. Many known missense mutations in &lt;em&gt;MEFV&lt;/em&gt; are linked to FMF disease. Mutations in &lt;em&gt;MEFV&lt;/em&gt; in most cases are located on the short arm of chromosome 16 and can impair the function of the pyrin protein. In this research, we aimed to examine the entire exons of &lt;em&gt;MEFV&lt;/em&gt; for 13 cases (8 females and 5 males) with FMF diagnosis from Southwest Iran. Hence, we amplified and sequenced the exons of &lt;em&gt;MEFV&lt;/em&gt; and then, in-silico analysis of detected changes was applied to estimate the probability of pathogenicity for the identified variants. Finally, we found five single nucleotide substitutions, including M694V (c.2080A&gt;G), R202Q (c.605G&gt;A), E447G (c.1430A&gt;G), E148Q (c.442G&gt;C), and V726A (c.2177T&gt;C), in the under-represented patients. The most frequent mutations in our study were R202Q (38.46%) within exon 2 and M694V (30.7%) within exon 10. Other mutations accounted for a further 23% of the alleles, including E477G (7.6%), E148Q (7.6%), and V726A (7.6%). According to the &lt;em&gt;in-silico&lt;/em&gt; analyses, including variation pathogenicity, protein structure, and allele frequency assessments, we concluded that all these variants could be considered in FMF molecular profiling in southwest Iran.

Covid 19 Pandemi’sinde Behçet hastalığı ve Ailesel Akdeniz Ateşi hastalığında fiziksel aktivite düzeyi, uyku, yorgunluk ve yaşam kalitesi

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&amp;gt;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 (p&amp;lt;0.05). We found a significant relationship between physical activity and mental health subscale of quality of life in BD patients (p&amp;lt;0.05). In addition, only 9.5% of BD patients and only 14.3% of FMFD patients in our study stated that they had been exercising for more than 6 months. Conclusion: The patients in both groups were physically inactive and the majority of them did not exercise. This situation increased during the confinement period. In order to have a positive effect on these symptoms, personalized exercise therapy can be planned and physical activity levels can be increased in BD and FMF patients.

Host genetics and gut microbiota composition: Baseline gut microbiota composition as a possible prognostic factor for the severity of COVID-19 in patients with familial Mediterranean fever disease.

It is known that the gut microbiome of a healthy person affects the process of COVID-19 after getting infected with SARS-CoV-2 virus. It is also believed that colchicine can alleviate the severity of COVID-19. Current investigations aimed to evaluate the associations between the baseline gut microbiota composition of healthy and Familial Mediterranean fever (FMF) - carrier Armenian men populations, and the severity of the COVID-19 disease after their infection with the SARS-CoV-2. The study has a purpose of answering three core questions: i. Do the characteristics of gut microbiome of Armenians affect the course of COVID-19 severity? ii. How does the COVID-19 disease course on go for FMF patients who have been taking colchicine as a medication over the years after getting infected with SARS-CoV-2? iii. Is there an initial gut micribiota structure pattern for non-FMF and FMF patients in the cases when COVID-19 appears in mild form? The gut microbiota composition in non-FMF and FMF patients before the first infection (mild and moderate course of COVID-19) was considered. COVID-19 was diagnosed by SARS-CoV-2 nucleic acid RT-PCR in nasopharyngeal swab and/or sputum. The number of patients with male FMF with mild COVID-19 was approximately two times higher than that of non-FMF male subjects with COVID-19. In addition, an association of COVID-19 disease severity with the baseline gut Prevotella, Clostridium hiranonis, Eubacterium biforme, Veillonellaceae, Coprococcus, and Blautia diversities in the non-FMF and FMF populations were revealed by us, which can be used as risk/prognostic factor for the severity of COVID-19.

Similarities and differences between familial Mediterranean fever (FMF) and multisystem inflammatory syndrome (MIS-C) in children

Aim: We aimed to reveal the similarities and differences between the rare and severe multisystem inflammatory syndrome (MIS-C) and active familial Mediterranean fever (FMF) disease in children. Our study may help in the early recognition of MIS-C syndrome in children and distinguish it from other diseases with similar symptoms.Methods: We evaluated the demographic and clinical characteristics, laboratory findings, treatments and outcomes of patients with MIS-C syndrome and active FMF.Results: The clinical and laboratory findings of a total of 66 patients hospitalized in our pediatric clinic with the diagnosis of active FMF (n: 42) and MIS-C syndrome (n: 24) were reviewed retrospectively. The reason for pediatric emergency admission was determined as resistant fever in all patients. When the clinical findings of the patients were compared, it was determined that joint and abdominal pain in the FMF group and vomiting, rash, cough, Lenfadenopati (LAP) and myalgia findings in the MIS-C group were statistically significantly higher (p

Colchicine may cause elevated serum levels of CA72-4: Case Series

Colchicine is used in the treatment of Behçet's disease, familial Mediterranean fever, gout arthritis, pericarditis, some inflammatory and fibrotic diseases by extracting it as an alkaloid from the plant named Autumn Crocus, which is from the lily family. CA 72-4, which has a glycoprotein structure, is especially useful in the diagnosis and follow-up of gastrointestinal adenocarcinomas as well as it's serum level can be increased in pancreatic, ovarian, endometrial, and breast cancers. No drugs that cause CA 72-4 rise have been reported to date. In this article, four patients who were referred to our clinic because of CA 72-4 serum elevation and who used colchicine for various reasons are presented.

Clues for inflammatory diseases in the differential diagnosis of a child with sacroiliitis.

The purpose of this study was to compare the demographic, clinical and laboratory characteristics of patients with enthesitis-related arthritis (ERA), familial Mediterranean fever (FMF) and inflammatory bowel disease (IBD), which are inflammatory diseases that may develop sacroiliitis. Thus, it was aimed to reveal various findings that may indicate primary disease in patients with sacroiliitis. Pediatric patients aged 6-18 years, who were being followed with a diagnosis of ERA (n= 62), FMF (n= 590), and IBD (n= 56) over the period 2013-2021 were included in the study. Sacroiliitis (n= 55) was diagnosed by magnetic resonance imaging of the sacroiliac joint, obtained from clinically suspected patients. Sacroiliitis was detected in 54.8% of ERA patients, 2.3% of FMF patients, and 12.5% of IBD patients. The mean follow-up period was 4.1± 2.8 years (10 months-8 years) for the entire study group. The most common MRI finding for sacroiliitis was bone marrow edema. Peripheral joint involvement (73.5%) and HLA B27 positivity (64.7%) was significantly higher in ERA patients, and ERA was diagnosed more frequently in patients presenting with sacroiliitis. Non-steroidal anti-inflammatory drugs (NSAIDs) were the first choice of treatment agent when sacroiliitis developed in all three patient groups. The clinical and laboratory findings of ERA, FMF and IBD can sometimes be intertwined or can even coexist. Treatment may differ depending on the disease associated with sacroiliitis, although NSAIDs may be used in the first-line treatment of all three diseases. Sacroiliitis patients with HLA B27 positivity and peripheral arthritis may need to be addressed as ERA.

NLRP13 inflammasome complex is hypermethylated in familial Mediterranean fever and global methylation correlates with the disease severity.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by variations in the MEFV gene, which encodes the pyrin protein, a member of the inflammasomes. Despite the complex pathogenesis of FMF, epigenetic changes also play roles in the disease progression. In our previous study, we observed a relationship between NLRP13, which is one of the members of the inflammasome complex and has a pyrin domain in its structure, and the MEFV gene using the STRING database. In this study, we examined NLRP13 expression and methylation status in 40 patients with FMF attack and 20 healthy individuals. We then investigated the global DNA methylation status of patients with FMF in the attack period and control groups. We further examined the relationship between the clinical manifestation and global methylation as well as NLRP13 gene expression of patients with FMF and healthy individuals. As a result, we showed that hypomethylation in patients with FMF leads to different clinical outcomes in terms of disease severity. In addition, the data indicated that NLRP13 inflammasome is epigenetically controlled in patients with FMF and the presence of amyloidosis may affect the hypermethylation of this gene. Moreover, NLRP13 was silenced because of the hypermethylation of the promoter. The increase of methylation level at the promoter region participated in the inactivation of NLRP13. In the current study, we not only found a new gene that plays a role in the pathogenesis of FMF disease, but also new evidence for the epigenetic regulation of the disease.

Galantamine attenuates autoinflammation in a mouse model of familial mediterranean fever.

Autoinflammatory diseases, a diverse group of inherited conditionscharacterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine. We tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Multiple chronic disease markers were evaluated in animals that received long-term galantamine treatment compared to vehicle. Long-term treatment with galantamine attenuated the associated splenomegaly and anemia which are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch. These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.

Investigation of Neutrophil Extracellular Trap (NET) Induction in Patients with Chronic Idiopathic Neutropenia Bearing Mutations in the Mediterranean Fever (MEFV) Gene

Introduction: Chronic idiopathic neutropenia (CIN) is a disorder characterized by the prolonged and unexplained reduction in the number of circulating neutrophils. The pathophysiology of CIN has been associated with an inflammatory bone marrow microenvironment consisting of activated T-cells with an oligoclonal/monoclonal profile and intermediate CD14bright/CD16+ monocytes that induce the apoptotic death of the granulocytic progenitor cells. To probe further the basis of immune cell activation in CIN we have recently investigated by next generation sequencing (NGS) the frequency of mutations in the MEFV gene encoding pyrin, in a cohort of 50 CIN patients without any signs/symptoms of Familial Mediterranean Fever (FMF). We have found that 9/50 patients displayed variants associated with typical or atypical FMF phenotype in the Greek population implicating exon 10 and/or exon 2 (Skendros P et al. Blood, 138, Sup.1, p3124;2021). Aim:MEFV mutations have been associated with increased neutrophil activation in FMF and other inflammatory diseases, neutrophil entry in autophagy and extrusion of Neutrophil Extracellular Traps (NETs) decorated with the pro-inflammatory cytokine IL-1β. The aim of the current study is to investigate the association between MEFV mutations and NET formation in neutrophils of CIN patients. Patients-Methods: We studied 20 CIN patients (17 females and 3 males) aged 27 to 78 years. Six CIN patients harbored at least one MEFV mutation with potential clinical significance (A744S homo/R202Q homo, I720M hetero, R202Q homo, K965R hetero, A744S hetero, M694V hetero) and 14 were negative for MEFV pathogenic mutations. The MEFV R202Q mutation is located in exon 2 whereas all the rest mutations are located in exon 10. We isolated neutrophils from healthy subjects (n=5), age- and sex- matched with the patients, and co-cultured them with serum from CIN patients. We used the supernatants of the cultures to quantify NETs with Sytox green staining for extracellular DNA and/or ELISA for dsDNA/MPO complexes. We also used the serum-treated neutrophils for the evaluation of NETosis by immunostaining using confocal microscopy. In addition, neutrophils isolated from CIN patients were used to detect their direct response to spontaneous NETosis induction. Statistical analysis was performed with one-way ANOVA adjusting for multiple comparisons. Results: By co-culturing patients' sera with healthy neutrophils obtained from five different healthy donors, we did not identify statistically significant differences in NETosis evaluation between the three study groups i.e. CIN patients with MEFV mutations, CIN patients negative for pathogenic MEFV mutations, and healthy individuals. On an individual basis, the patient harboring the double homozygous MEFV mutations (A744S/R202Q) displayed increased NETosis in immunostaining, Sytox and ELISA evaluation, as compared to MEFV unmutated CIN patients and healthy individuals. In addition, ex vivo culture of patients' neutrophils and microscopic observation gave us the indication that CIN patients, regardless of their MEFV gene variants, present increased NETosis compared to healthy individuals, suggesting an overactivation status of neutrophils in CIN. Conclusions: The neutrophils of CIN patients display increased NETosis irrespectively of the MEFV mutation status and may thus contribute to the inflammatory processes associated with the disease, a field that has not been investigated so far. Although in our study MEFV mutations did not appear to contribute significantly to inflammatory processes through the NETosis mechanism in CIN patients, their involvement in other aspects of immune deregulation such as through the mTOR/autophagy pathway remains to be further explored.