Case Of Familial Mediterranean Fever Research Articles

Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (β1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (β1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (β1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (β1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (β1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (β1 = 2.089, 95% CI. 0.7-3.5, p=0.002). The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

The possible anti-inflammatory effect of extra virgin olive oil with colchicine in treatment of resistant cases of familial Mediterranean fever in a cohort of pediatric Egyptian patients

BackgroundPeople of Mediterranean descent are primarily affected by the autoinflammatory genetic condition known as familial Mediterranean fever (FMF). The disease is resistant to colchicine therapy in 10–20% of patients. Numerous recent animal studies showed promising results of extra virgin olive oil (EVOO) to control inflammation. The objective of this study was to assess the effectiveness of combining EVOO with colchicine in the treatment of colchicine-resistant familial Mediterranean fever (CRFMF) patients.ResultsBoth the frequency of episodes and inflammatory indicators significantly decreased after a three-month course of daily EVOO treatment with colchicine. The average erythrocyte sedimentation rate (ESR) of patients was 78.6 mm/h before the EVOO administration, and it dropped to 27.8 mm/h, after that. Additionally, after taking EVOO, the mean serum amyloid A (SAA) decreased from 123.82 mg/dl to 59.78 mg/L. Also, the average C-reactive protein (CRP) decreased from 34.22 to 7.84 mg/dl following its administration; the mean nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) level decreased from 134.92 to 64.23 pg/ml. The mean caspase-1 level decreased from 7.8 to 4.98 ng/ml; and the mean levels of cytokines, interleukin 6 (IL-6), interleukin 1 beta (IL-1 β), and tumor necrosis factor-alpha (TNF-α) decreased from 9.8, 18.14, and 52.7 pg/ml, respectively, to 5.95, 12.51, and 29.39 pg/ml. Finally following the administration of EVOO, there was a notable overall improvement in the quality of life of (CRFMF) patients.ConclusionEVOO demonstrated a significant positive impact when paired with the tolerated dosage of colchicine in the management of CRFMF. Improvements were observed in both clinical and laboratory settings, including a reduction in the attack frequency and serum levels of inflammatory markers, such as NLRP3, caspase-1, ESR, CRP, IL-1β, IL-6, and TNF-α without any negative side effects.

Co-Occurrence of Familial Mediterranean Fever and Hematologic Malignancies: Case Report Series

Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder primarily found among individuals of Mediterranean descent, including Armenians, Italians, Greeks, Arabs, Turks and Jews. In the Armenian population, approximately 90% of FMF cases are associated with three main mutations (M694V, V726A, and M680I) in two alleles of MEFV gene, while more than 300 MEFV variants have been reported worldwide. The homozygous M694V genotype is associated with frequent renal failure due to amyloidosis. Clinical manifestations of FMF include periodic attacks of diffuse serositis with pain and fever that are treated with colchicine or biologic therapy. There is a scarcity of data on patients with FMF and hematologic malignancies. Limited data makes it difficult to generate evidence-based recommendations for the management of these patients, which is mostly based on expert opinions or few case reports. Here we report the case series of patients from Armenia with simultaneous presence of FMF and hematologic malignancies (FMFHM) and evaluate their management challenges. Methods: Data was collected from the Armenian National Registry of Blood Disorders, at the Hematology Center after Prof. R. Yeolyan, and through personal interviews conducted with each patient. Hematology Center is the only institution in Armenia managing hematologic malignancies. We have analyzed 8 patients diagnosed with both FMFHM during 2000-2020, treated in the pediatric (1 patient) and adult (7 patients) hematology departments. Results: 8 patients with FMFHM were identified, from which 4 were diagnosed with myeloproliferative neoplasms (MPN), 2 with acute leukemia (AL), and 2 with non-Hodgkin lymphoma (NHL). The median age of patients was 46, range 20-60 years. Only 5 (62.5%) of patients were regularly taking colchicine for FMF, while the rest refused it. Four MPN patients received treatment only with oral medications (tyrosine kinase inhibitors, hydroxyurea). Autologous hemopoietic stem cell transplantation (auto-HSCT) was performed in 1 NHL patient after indicated 1 st and 2 nd line immuno-chemotherapy. Another 2 AL patients and one NHL patient received protocol-based respective chemotherapy regimens. Moderate gastrointestinal (GI) complications (e.g., epigastric pain, nausea, vomiting, intestinal discomfort) was experienced by 7 (87.5%) patients. Allergic reactions (e.g., moderate skin rash, itching) were seen in 5 patient (62.5%), of which one developed severe anaphylactic shock. A patient with FMF and PMF had ischemic stroke caused by thrombi. Arterial hypertension occurred in 3 (37.5%). Only in one patient reduction of colchicine dosage was performed (1mg/day was reduced to 0.6mg/d), because of interaction with imatinib. The rest of patients received chemotherapy and colchicine treatment as indicated. All 8 patients are alive, 5 of them are in hematologic or molecular remission, two of which received concurrent colchicine treatment. One patient in remission developed renal failure due to FMF (colchicine was refused). Two patients with MPN treated with colchicine experienced disease stabilization. Conclusion: In conclusion, the concurrent appearance of FMFHM may potentially increase the risk of GI side effects, allergic complications, and arterial hypertension, however definitive conclusions require further investigations in larger patient cohorts. While the overall treatment responses were largely positive, the association between MEFV and HM mutations warrants deeper exploration to provide more precise drug administration recommendations for colchicine and cancer medications. Future studies in this area will contribute to a better understanding of the interplay between these conditions and guide optimal treatment strategies.

A case of familial mediterranean fever in an elderly patient experiencing recurrent fever and weigh loss

Familial Mediterranean Fever (FMF) is a rare hereditary autoinflammatory disease. In particular, the onset is rare in the elderly, and the symptoms are atypical, making diagnosis difficult.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

Amyloid goiter secondary to familial Mediterranean fever with E148Q mutation: A unique case.

A case of Familial Mediterranean Fever presented with recurrent infection.

The periodic fever syndrome Familial Mediterranean Fever (FMF) is caused by mutations in MEFV, which promote inflammation and present with uncontrolled systemic and organ-specific inflammation that can resemble infectious conditions. It is diagnosed based on clinical criteria, including frequent symptoms such as abdominal and thoracic pain, family history, and response to treatment with colchicine, which is confirmed by genetic assessment. Herein, we present a case of FMF with a relatively uncommon presentation. A 22-month-old female was referred to the allergy and clinical immunology clinic with eczematoid skin rashes. She was admitted to the hospital several times since the 2nd day of life with different complaints like fever, seizure, and restlessness, and treated with the diagnosis of septicemia. Endoscopy and colonoscopy were done at the age of 6 months due to poor weight gain and bloody diarrhea, which revealed active crypt-destructive colitis with foci of erosion in favor of infectious or allergic colitis. The colon biopsy was negative for Cytomegalovirus (CMV). Regarding family history, she was the second child of the first cousins parents and had a healthy 12-year-old sister. There was a history of death for unknown reasons of her cousin, whose parents were related. The immunologic evaluation was done, which showed a relatively normal immunoglobulin level, antibody response, flow cytometry, and lymphocyte transformation test. Nonetheless, a genetic study was done, which showed a homozygote mutation in exon 10 of the MEFV gene in the patient and a heterozygote mutation in both her parents. The periodic fever syndrome Familial Mediterranean Fever (FMF) is caused by mutations in MEFV, which promote inflammation and present with uncontrolled systemic and organ-specific inflammation that can resemble infectious conditions. The patient was diagnosed with FMF, and treatment was started using colchicine, which successfully controlled the patient's symptoms and prevented the recurrence of fever and other inflammatory manifestations.

Acute stroke in familial Mediterranean fever: An analysis of 23 new cases and systematic review of the literature.

The nature of neurovascular involvement in cases of familial Mediterranean fever (FMF) has not been adequately clarified. Clinical features, infarct topography, vascular status, and stroke etiology were prospectively determined in 35 acute neurovascular events that occurred in 23 FMF patients. Clinicoradiological features were compared with an age- and gender-matched control group of 115 acute stroke patients. Characteristics of additional FMF and acute stroke cases (6 episodes in 6 patients) identified from a systematic literature review (PROSPERO registration no: CRD420212264820) were also analyzed. There were 27 acute ischemic stroke episodes in 19 patients, 7 transient ischemic attack episodes in 3 patients, and 1 patient with a single episode of parietal hematoma in our cohort. Twenty (74%) ischemic stroke episodes in 12 patients were cryptogenic. Ten of these 12 cases had a previous FMF diagnosis and were taking colchicine. There was no significant difference in the FMF group in terms of the presence of vascular risk factors and angiography-documented disease in comparison to controls. Cerebral distal artery involvement was significantly prevalent in FMF (78% vs 45%, P= .002). Especially, midbrain central deep perforating territory involvement was higher (30% vs 1%, P< .001). The long-term prognosis (median 8.5 years) under antiplatelet agents and colchicine is favorable. The acute stroke phenotype in FMF cases is herein described for the first time. Several clinicoradiological features such as thrombotic lacunar infarcts located in the central mesencephalon seem so typical that we recommend searching for FMF mutations in geographic regions where FMF is common.

A Typical Case of Familial Mediterranean fever in a War Survivor with Post-Traumatic Stress Disorder of Caucasian Descent Treated with Standard Colchicine Therapy

Objective: A rare case of FMF with atypical presentation of fever attacks lasting 7 days predominantly evident after the war has been described. Usually, the FMF bouts last for 3-4 days but the unusual presentation of our patient led to the initial misdiagnosis of PTSD (Post traumatic stress disorder). Patient and Method: A case of a 38-year-old former Armenian soldier who participated in a 44-day long war with Azerbaijan showing symptoms of recurrent fever, thoracic and abdominal pain predominant only on the left hypochondriac, lumbar and inguinal region. The changes in the laboratory examination were not significant. A wide range of diagnostic tests like X-Ray, CT, and MRI performed all of which were inconclusive. Result: The diagnosis was confirmed after 5 years by positive molecular genetic testing for the MEFV gene. The patient was given colchicine 1 mg/kg/day which reduced the severity and frequency of attacks. Conclusion: The atypical presentation of FMF with prolonged fever lasting up to 7 days, no familial history, post-war trauma, and pain only on the left side led to the differential diagnosis excluding FMF.FMF was suspected when his blood analysis showed acute phase reactants returned to normal after the 7-day attack period. He was started on colchicine therapy and showed a positive response which led to the diagnosis of FMF. The positive MEFV genetic testing confirmed the diagnosis. Clinicians should not exclude the possibility of FMF in patients who do not show the classic fever attack period of 3 to 4 days.

Investigation of different genomic variants in familial Mediterranean fever cases with monoallelic MEFV mutation.

Familial Mediterranean Fever (FMF) is an inflammatory disease characterised by periodic fever and concurrent episodes of serous membrane inflammation. FMF is considered to be inherited in autosomal recessive manner and biallelic mutations in the MEFV gene are associated with the disease. However, approximately 20-25% of patients only have a single mutation in MEFV gene, which creates confusion in differential diagnosis of many patients. This study aimed to reveal rare variants that may act in conjunction with the single pathogenic MEFV variant in the pathogenesis of FMF. We performed whole exome sequencing in 17 individuals from 5 different families who were diagnosed according to the clinical criteria, responded positively to colchicine treatment, but had no biallelic MEFV mutation. A disease-causing variant or a common affected cellular pathway that was shared in all index cases was not detected. When cases were examined individually, two de novo variants were identified in the BIRC2 and BCL10 genes, both of which play a role in inflammatory pathways. Functional studies are needed to confirm the physiopathological relationship of these genes with FMF. This study is one of the most extensive aetiological researches in FMF cases with monoallelic MEFV mutation. We have shown that genotype-phenotype correlation in these cases may not be established by rare genetic variants and discussed underlying causes. Clinical criteria with emphasis on colchicine response and family history should be the main tool and genetic results should only be used for support in FMF diagnosis.

S2473 A Case of Familial Mediterranean Fever Diagnosed by Abdominal CT Scan in a Patient Previously Diagnosed With Functional Abdominal Pain

Introduction: Familial Mediterranean fever (FMF) is a hereditary autoimmune disease in which patients present with periodic, self-limited episodes of fever and serositis. It is prevalent in individuals of Middle Eastern origin. Since no definitive diagnostic test is available, FMF is suspected based on clinical symptoms; there are major and minor criteria to aid in making the diagnosis. Imaging modalities are not included in these criteria. We present a patient whose only symptom was recurrent abdominal with no family history of FMF. At the time he was diagnosed with Functional Abdominal Pain. FMF was suspected based on unexplained focal peritonitis on computerized tomography (CT). Case Description/Methods: A 45-year-old male of Middle Eastern descent was seen in clinic complaining of episodic right upper quadrant (RUQ) abdominal pain since he was 17 years old. The pain occurred once or twice per month. Over the years he had multiple visits to the emergency department and extensive work up including endoscopic evaluation and imaging studies. He underwent cholecystectomy, and bilateral inguinal hernia repair without benefit. He was diagnosed with Functional Abdominal Pain then. When evaluated in our clinic, lab work showed mild iron deficiency anemia; otherwise, unremarkable. Upper endoscopy, colonoscopy, small bowel series and capsule endoscopy were normal. 3 months later he presented to our ER with an acute episode of severe RUQ pain. He was afebrile; abdominal exam was remarkable for localized tenderness in the RUQ. Lab work was remarkable for an elevated erythrocyte sedimentation rate of 31. Abdominal CT was only remarkable for fat stranding around the hepatic flexure and the proximal half of the transverse colon. Colonoscopy was normal with no evidence for segmental colitis to explain the inflammatory changes. Given the history of recurrent abdominal pain, ethnicity, and focal unexplained peritonitis on CT scan, FMF was suspected, and treatment with colchicine was initiated without recurrence of symptoms for now several years since the diagnosis, meeting diagnostic criteria for FMF. Discussion: If not considered, FMF can remain misdiagnosed for many years leading to unnecessary procedures and surgeries. This was an unusual presentation with afebrile episodes of intermittent RUQ pain with the diagnosis ultimately suspected by CT imaging and confirmed by response to colchicine. Clinicians should consider FMF in patients of high-risk ethnic origin presenting with unexplained focal peritonitis on CT scan.

Early predictors of colchicine resistance in familial Mediterranean fever.

To explore early features that can predict colchicine resistance in familial Mediterranean fever (FMF) patients. It included FMF cases who fulfilled the Yalcinkaya-Ozen criterion and were on colchicine for at least 6 months. Data were collected from medical files and interpreted with respect to clinical parameters, incluing the auto-inflammatory diseases activity index (AIDAI) and FMF severity score. FMF50 score assessed the treatment response. Laboratory findings and genetic analysis of Mediterranean fever (MEFV) mutations were evaluated according to the standard technique. Patients were classified into two groups according to their response to colchicine. Both groups were compared, and significant variables were entered into a logistic regression model to detect independent predictors. The diagnostic accuracy of these predictors was assessed using the receiver operating characteristic curve. In all, 120 FMF children were included. After the exclusion of 16 non-compliant patients (13.3%), colchicine responders were 66 (63.4%) (group I) and colchicine-resistant cases (group II) were 38 (36.5%). The fever duration after colchicine, number of attacks before/after colchicine, skin rash/erysipelas-like erythema, myalgia/protracted febrile myalgia, AIDAI before/after treatment, FMF severity score, and the maximum colchicine dose were higher in group II. Furthermore, high C-reactive protein and neutropenia were frequent in group II. However, different MEFV mutations, including M694V were similar between the two groups. Eight variables were detected in the regression analysis model, and independent predictors were utilized to generate a scoring model. This study constructed a prediction model for colchicine nonresponse based on clinical and laboratory profiles. This model will be valuable for the treatment decisions of FMF children.

A patient with familial Mediterranean fever mimicking diarrhea-dominant irritable bowel syndrome who successfully responded to treatment with colchicine: a case report

BackgroundIrritable bowel syndrome is a functional gastrointestinal disease. Visceral hypersensitivity is the most important pathophysiology in irritable bowel syndrome. Currently, diagnosis of irritable bowel syndrome is based on symptoms and exclusion of other organic diseases. Although the diagnosis of irritable bowel syndrome can be made based on the Rome IV criteria, one may speculate that complete exclusion of other organic diseases is not so easy, especially in cases uncontrolled with standard therapies.Case presentationWe present herein a case of familial Mediterranean fever in a young Japanese patient who had been suffering from an irritable bowel syndrome-like clinical course. A 25-year-old Japanese male had been diagnosed as having diarrhea-predominant irritable bowel syndrome 5 years earlier. Unfortunately, standard therapies failed to improve irritable bowel syndrome symptoms. After careful medical history-taking, we understood that he had also experienced periodic fever since 10 years ago. Although no mutation was identified in the Mediterranean fever gene, not only periodic fever but abdominal symptoms improved completely after colchicine administration. He was therefore diagnosed as having familial Mediterranean fever and that the abdominal symptoms may be related to the disease.ConclusionsFamilial Mediterranean fever should be considered as a cause of irritable bowel syndrome-like symptoms.

Health Related Quality of Life of Children Aged 2-18 Years With Familial Mediterranean Fever

Objective: We aimed to evaluate both child-self reported and parents proxy reported health related quality of life of children with familial Mediterranean fever (FMF) aged between 2-18 years old and to compare the scores with their healthy peers. Material and Methods: Fifty -one patients with FMF and fifty one gender and age matched controls were enrolled in the study. Children aged 8-18 years completed the PedsQL4.0 child form questionnaires. Parents of all cases completed the PedsQL4.0 parent form. Results: Lower scores in the FMF group, with no statistical significance, was found between the FMF cases and healthy volunteers aged 8-18 years for the physical health, social health, school functioning, psychosocial total and scale total score of PEDsQL4.0 child self-report. The parent proxy report PedsQL4.0 scores of all patients with FMF were lower than the healthy group for physical, emotional, social, psycho-social, school functioning scores and scale total score but the difference was not statistically significant. A significant correlation was present between PedsQL4.0 child self-report and parent PedsQL4.0 report in all subscales except for social health total score. There was not a significant correlation between the demographic variables and clinical features of the patients and the child subscales of PedsQL4.0. Conclusion: The scores of FMF cases from the scales were lower than those of the healthy volunteers from the questionnaires but this difference was not statistically significant. Considering the relatively small sample size of the study it is obvious that more comprehensive prospective studies are required on this subject.

Ultrasonographic evaluation of femoral cartilage thickness in patients with familial Mediterranean fever.

Objectives This study aims to determine femoral cartilage thickness using ultrasonography in familial Mediterranean fever (FMF). Patients and methods A total of 45 patients (16 males, 29 females; mean age: 38.5±9.1 years; range, 24 to 49 years) with the diagnosis of FMF and 31 healthy individuals (6 males, 25 females; mean age: 37.0±8.7 years; range, 25 to 47 years) between January 2016 and July 2016 were included in this study. Clinical data and demographic characteristics of the patients were recorded. All FMF cases in the study were in remission with colchicine treatment. The thickness of femoral cartilage in both knees were evaluated using ultrasonography. Three measurements (mid-point) were taken from both knees (at the medial/lateral femoral condyles and intercondylar area). Results Ultrasonographical measurements revealed that cartilage measurements of FMF patients were significantly thinner at both the medial/lateral femoral condyles and intercondylar area on the right knee and at the medial/lateral femoral condyles on the left knee (p<0.001). The cartilage measurements in FMF patients were significantly thinner at the intercondylar area on left knee, compared to those in controls (p=0.023). Conclusion Our study showed decreased femoral cartilage thickness in FMF patients. These findings indicate that even if these patients do not have an attack, they may have subacute and chronic arthritis in their joints, and their femoral cartilage thickness can be affected.

Challenges and insights raised by comorbidity with FMF and selective IgA deficiency

: Familial Mediterranean Fever (FMF) is the most common form of genetic autoinflammatory disease worldwide. In turn, selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency, yet most patients remain asymptomatic. Case Presentation: A Jewish Brazilian female came to our attention due to recurrent inflammatory febrile episodes since very early in life, initially attributed to unexplained infections linked to SIgAD. At the age of 15 years, disabling buttock pain prompted a sacroiliac MRI, which demonstrated sacroiliitis. Direct genetic sequencing of the MEFV gene confirmed the diagnosis of FMF. After severe gastrointestinal intolerance to colchicine was observed, canakinumab achieved clinical and radiological control, enabling the reinstatement of colchicine. Conclusion: Here we report the first case of concomitant FMF and SIgAD in a Brazilian patient, highlighting the relevance of these comorbidities in the patient's diagnosis and follow-up. This coincidental association also provides insight into interactions between serum and mucosal IgA and the pyrin inflammasome in the control of inflammation and gut dysbiosis.

Late onset familial Mediterranian fever: a clinical case

Familial Mediterranean fever (FMF) is a rare genetic autosomal recessive disease typical for special ethnic groups, such as Arabs, Greeks, Armenians, Jews, Turks and other ethnicities inhabiting the Mediterranean coast. The characteristic clinical signs and symptoms of the disease are recurrent episodes of fever, associated with polyserositis, in particular, with benign (aseptic) peritonitis. The disease is caused by mutation in the MEFV gene encoding the synthesis of the protein pyrine, which leads to an uncontrolled release of pro-inflammatory cytokines by granulocytes. The criterion for the severe course of the disease is AA-renal amyloidosis associated with an unfavorable prognosis. Here we present a clinical case of classic FMF with high fever and abdominal pain syndrome. A 26-year-old Armenian patient had a sudden attack of fever and severe pain in the right iliac area several months before his first hospital admission. Non-steroid anti-inflammatory drugs and antispasmodics were unable to relieve the symptoms, with the attack ceasing spontaneously after 3 days from the beginning. Thereafter, the attacks recurred 1 to 2 times per month within a year. During hospital stay at the peak of the attack, peritoneal symptoms at abdominal palpation, together with neutrophilic leukocytosis and a significant increase in acute phase parameters of inflammation (C-reactive protein, fibrinogen, erythrocyte sedimentation rate) were found. Based on the characteristics of the complaints, past history, laboratory and instrumental results, we excluded infections, autoimmune and surgical disorders and made a decision to perform genetic testing to detect the MEFV gene mutation. Confirmation of the mutation has led to the definitive diagnosis of FMF. This clinical case is remarkable for its late onset, which is not typical for FMF. As a result, the patient was prescribed continuous therapy with сolchicine. Six months of the follow up have demonstrated a positive trend with no attacks during this period.

Increased Frequency of Mutations in the Gene Responsible for Familial Mediterranean Fever (MEFV) in a Cohort of Patients with Chronic Idiopathic Neutropenia

▪Introduction-Aim: Chronic idiopathic neutropenia (CIN) is a neutrophil disorder characterized by the prolonged and unexplained reduction in the number of peripheral blood (PB) absolute neutrophil counts (ANC). The underlying pathogenesis in CIN implicates the production of proinflammatory cytokines by activated lymphocytes and monocytes that induce excessive apoptotic death of the bone marrow (BM) granulocytic progenitor cells. Clonal hematopoiesis identified by next generation sequencing (NGS) of myeloid genes is found in 11% of CIN patients conferring an increased risk for MDS/AML transformation whereas the non-clonal patients display usually a benign course. The basis for the immune cell activation and proinflammatory cytokine production in CIN remains obscure. Based on previously reported data showing increased frequency of mutations of the MEFV gene encoding pyrin in patients with idiopathic inflammatory conditions other than typical Familial Mediterranean Fever (FMF), we sought to investigate the common MEFV mutations in a cohort of well characterized CIN patients.Patients-Methods: We have studied 50 patients fulfilling the previously reported diagnostic criteria of CIN (median ANC 1.5x10 9/L, range 0.2-1.7 x10 9/L), 44 females and 6 males with a median age of 56 years (range 25-87 years) and a long-follow-up (median 132 months, range 8-336 months) in the Department of Hematology of the University Hospital of Heraklion, Crete, Greece. Nonisotopic RNase cleavage assay (NIRCA) analysis was used as first screening method to detect MEFV exons 10 and 2 mutations in DNA extracted from PB or BM samples from CIN patients, confirmed by direct NGS analysis. These sequences contain the main disease-related mutations and polymorphisms.Results: Genetics alterations of MEFV were detected in 22 out of 50 CIN patients (44%). Pathogenic mutations (variants associated with typical or “atypical” FMF phenotype in Greek population) were identified in 10/50 CIN patients (20%). The 20% frequency of MEFV mutations in exon 10 and/or exon 2 in CIN patients is significantly higher compared to the carrier rate of common MEFV mutations in the healthy Greek population (0.7%) according to our previously reported data (P<0.0001, Fisher's exact test). NGS analysis confirmed the mutational pattern of NIRCA and specifically showed: (a) one patient with heterozygous I720M (ATC>ATG; Ile>Met), two patients with heterozygous A744S (GCC>TCC; Ala>Ser) and one with homozygosity, one patient with heterozygous M694V (ATG>GTG; Met>Val), one with heterozygous K695R (AAG>AGG; Lys>Arg) and one with heterozygous M680I (ATG>ATC; Met>Ile), all in exon 10, and (b) four patients with homozygous R202Q mutation in exon 2 (one patient with homozygous A744S co-mutation in exon 10) and two patients with R202Q heterozygosity combined with heterozygosity of I720M and A744S of exons 10, respectively. None of the patients displayed any symptoms/signs of FMF or other systemic inflammatory disease. No statistically significant differences were identified between MEFV mutated and non-mutated CIN patients in the severity of neutropenia or in lymphocyte, monocyte, hemoglobin and platelet counts. A significant difference was identified between the two patient groups in serum IgG (1440±264 vs 1133±245 mg/dl; P = 0.0023, Mann-Whitney test) but not IgA or IgM levels.Discussion: This study reports for the first time that 20% of unselected, consecutive patients with CIN carry mutations of the MEFV gene without clinical manifestations of FMF. Whether these patients represent atypical cases of FMF or the identified MEFV genetic alterations have a pathogenetic/modifying effect in the inflammatory responses associated with CIN is an open/novel field of research. As a first step we are currently investigating the neutrophil autophagic status, IL-1β production and the neutrophil extracellular trap (NET) formation in CIN patients with mutations in MEFV to clarify their potential effect in the immune deregulation known to characterize CIN. DisclosuresNo relevant conflicts of interest to declare.

Haemophagocytic lymphohistiocytosis in a patient with familial Mediterranean fever and miliary tuberculosis: a case report

Haemophagocytic lymphohistiocytosis (HLH) is a lethal complication of several infections, especially viral origin. Mycobacterium tuberculosis infection can also lead to HLH, yet it is an uncommon trigger. Considering the role of increased cytokines in HLH, autoinflammatory conditions, such as familial Mediterranean fever (FMF), might contribute to its development. Nevertheless, the possible relationship between FMF and HLH has been suggested only in some case reports. We present a case of FMF who admitted to the hospital with consitutional symptoms and chest pain regarding to recurrent pericarditis. On a blood test, pancytopenia and elevated acute phase reactants were seen. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography demonstrated positive FDG uptake sites on both the right and left surrenal glands, the visceral layer of pericard, and reactive lymphadenomegalies at multiple mediastinal regions. Bone marrow biopsy revealed haemophagocytosis. Methylprednisolone treatment was initiated. Despite immunosuppressive treatment, clinical and biochemical parameters deteriorated; thus, a thorax computed tomography was executed. Findings were consistent with miliary tuberculosis infection. M. tuberculosis was detected in blood culture and bronchoalveolar lavage culture material. Also, bone marrow and surrenal biopsy material revealed necrotising caseating granuloma.

Fibrinogen-to-Albumin Ratio in Familial Mediterranean Fever: Association with Subclinical Inflammation.

Familial Mediterranean fever (FMF) is the most seen monogenic periodic fever syndrome characterised by bouts of fever and serositis. It is known that subclinical inflammation (SI) can persist in the symptom-free period and lead to amyloidosis even under colchicine treatment. This study aimed to evaluate the role of the fibrinogen-to-albumin ratio (FAR) in FMF and its correlation with SI. A total of 112 patients with FMF and 78 controls were enrolled in this retrospective study. Demographic, laboratory and genetic data were obtained from the hospital records. The FAR values of the FMF cases were significantly higher than the control group (p<0.001). In the FMF group, the patients with SI had higher FAR values than those without SI (p<0.001). FAR was positively correlated with SI (r=0.413, p<0.001). The receiver operating characteristic curve analysis showed that FAR had a higher area under the curve value than albumin and fibrinogen. Detecting SI in patients with FMF is crucial in preventing amyloidosis, the most devastating complication of FMF. FAR is a simple, inexpensive, easily obtained indicator which can be used for reflecting SI in FMF. Familiäres Mittelmeerfieber (FMF) ist das am häufigsten auftretende monogene periodische Fiebersyndrom, das durch Fieberschübe und Serositis gekennzeichnet wird. Die subklinische Entzündung (SI) kann bekanntlich auch in der symptomfreien Phase fortbestehen und zu Amyloidose führen, selbst unter Behandlung mit Colchicin. Ziel dieser Studie ist es, die Beziehung zwischen Fibrinogen und Albumin (AFR) bei FMF und deren Korrelation mit SI zu untersuchen. Insgesamt wurden für diese retrospektive Studie 112 Patienten mit FMF und 78 Kontrollpatienten eingeschlossen. Die demographischen, labortechnischen und genetischen Daten wurden aus den Krankenhausunterlagen entnommen. Die Werte von AFR bei Patienten mit FMF waren signifikant höher als die der Kontrollgruppe (<0,001). Patienten mit FMF mit SI zeigten höhere AFR-Werte als FMF-Patienten ohne SI (<0,001). AFR korrelierte positiv mit SI (r=0,413, p<0,001). Die Analyse der ROC-Kurve (Receiver Operating Characteristic) zeigte, dass AFR einen höheren Wert der Fläche unter der Kurve (AUC) hatte als Albumin und Fibrinogen. Die Erkennung von SI bei FMF-Patienten ist entscheidend für die Vermeidung von Amyloidose, der schlimmsten Komplikation von FMF. AFR ist ein einfacher, kostengünstiger, leicht durchzuführender Indikator, der in FMF zur Spiegelung von SI verwendet werden kann.

POS1298 COMPARISON OF FMF CLINICAL FEATURES BETWEEN TURKISH AND CRIMEAN TATAR CHILDREN

Background:Crimean Tatars is an ethnic group in Russia. The presence of familial Mediterranean fever (FMF) has been recognized since 2016.Objectives:The study aimed to evaluate the prevalence and clinical features as well as genetic aspects of FMF in children of Crimean Tatar (CT) origin and compare them with a cohort from Turkey.Methods:This retrospective study included all FMF cases in patients of CT origin (n=18) diagnosed in Children’s Regional Hospital in Simferopol since 2016. We included 40 consecutive FMF cases between February-March 2020, diagnosed and followed at Hacettepe University, Ankara, Turkey. All children were less than 18 years old at the time of inclusion. The diagnosis of FMF was based on the EULAR criteria (2019). We excluded other autoinflammatory diseases and any doubtful cases. For assessment of MEFV alleles prevalence 127 healthy unrelated CT adults from different parts of Crimea peninsula were included. Sanger sequencing of MEFV exons 2 and 10 was performed in all the patients and controls.Results:FMF in CT was diagnosed with nearly 5 year-delay, despite the earlier age at onset. CT children had more frequent and prolonged fever, joint involvement (arthritis and arthralgia) and erysipeloid rash compared to Turkish, who had more attacks with chest pain and abdominal pain which last longer. (Table 1) CT had higher white blood cell count, C-reactive protein, erythrocyte sedimentation rate and lower hemoglobin. It might be explained by the fact that the majority of Crimean Tatars were admitted to the clinic during an attack, which was not always the case with Turkish children. Distribution of MEFV pathogenic alleles p.M694V, p.M680I, p.V726A in CT children was 81%, 9.5% and 9.5%, respectively, while in Turks it was 68.6%, 14.3% and 12.9%. Among the CT patients, proportion of homozygotes, compound-heterozygotes and heterozygotes were 11%, 6% and 83%, and among Turkish patients were 45%; 30%; and 25%, respectively. MEFV pathogenic variants were detected in 10.2% of healthy CT donors: 7.1% individuals had p.M694V, 1.6% - p.M680I, 1.6% - p.V726A. Comorbid diseases including IgA vasculitis, sacroiliitis, JIA, autoimmune hepatitis and inflammatory bowel disease were reported in 5.6% of CT and 10% of Turks. The colchicine treatment rate and regimen were similar, but CT received biologics more frequently (44%) than Turks (22.5%).Conclusion:CT is an ethnic group with a significant number of MEFV mutation carriers assuming the expected prevalence of FMF to be as high as 1:385. Thus, any periodic fever in CT patients should be considered as a sign of possible FMF. The clinical course of FMF has some peculiarities in CT patients.This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001).Table 1.Comparative data of FMF patients with Turkish and Crimean Tatar originFMF featuresTurkish (n=40)Crimean Tatars (n=18)рFamily history of FMF, n (%)16 (40)9 (50)0.477Consanguinity, n (%)8 (20)6 (33)0.272Onset age, years3.3 (2; 5)1.3 (0; 4)0.040Age at FMF diagnosis, years4.7 (3; 8)9.6 (4; 14)0.005Diagnosis delay, years0.9 (0; 2)5.5 (2; 10)0.00001Fever, n (%)33 (83)18 (100)0.058Episode duration, days2.0 (2; 3)3.0 (3; 6)0.000003Fever duration, hours48.0 (48; 72)72.0 (72; 120)0.000002Chest pain, n (%)12 (30)1 (6)0.039Chest pain duration, hours48.0 (24; 72)0.0 (0; 0)0.000001Abdominal pain, n (%)30 (75)9 (50)0.061Abdominal pain duration, hours48.0 (24; 48)24.0 (24; 24)0.043Arthritis, n (%)10 (25)16 (89)0.000006Arthralgia, n (%)19 (48)17 (94)0.0007Erysipeloid rash, n (%)0 (0)9 (50)0.000001Disclosure of Interests:None declared