Magnetic resonance findings may aid in diagnosis of protracted febrile myalgia syndrome: a retrospective, multicenter study

Background Protracted febrile myalgia syndrome (PFMS) is a rare complication of Familial Mediterranean fever (FMF). The diagnosis is based on clinical symptoms and is often challenging, especially when PFMS is the initial manifestation of FMF. The aim of this report was to describe the magnetic resonance imaging (MRI) findings in pediatric patients with PFMS. Results There were three girls and two boys ranging in age from 6 months to 16 years, all of Mediterranean ancestry. Three had high-grade fever, and all had elevated inflammatory markers. MRI of the extremities yielded findings suggestive of myositis, which together with the clinical picture, normal CPK levels, and supporting family history of FMF, suggested the diagnosis of PFMS. Out of most common MEFV mutations tested, one patient was homozygous for M694V mutation, three were heterozygous for M694V mutation, and one was compound heterozygous for the M694V and V726A mutations. Conclusions MRI may serve as an auxiliary diagnostic tool in PFMS.

An unusual presentation of familial Mediterranean fever with co-existing polyarteritis nodosa and acute post-streptococcal glomerulonephritis

The homozygous M694V mutation in the MEFV gene may cause an augmented response to the streptococcal infection that plays a role in the development of APSGN and PAN. Both clinical manifestations may occur simultaneously after streptococcal infection in a child who is previously healthy but carries a MEFV mutation.

The Assessment of Selected miRNA Profile in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators’ production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment.

Association Between Acute Phase Reactants (High Sensitivity C-Reactive Protein and Erythrocyte Sedimentation Rate) and the Genotype of Familial Mediterranean Fever (FMF) in Patients and Healthy Controls

Background: Familial Mediterranean fever (FMF) is an autosomal recessive disorder mainly common in Arabs, Non-Ashkenazi Jews, Armenians and Turks. The classical clinical features include painful attacks and recurrent acute fever with periods of remission. Results: This study was carried out on 101 clinically diagnosed Syrian FMF patients, in addition to 107 apparently healthy controls. Twelve mutations in the gene locus of MEFV were detected using reverse hybridization and the M694V mutation was found to be the most common in Syrian patients. This study showed that there was a statistically significant difference between the two groups when comparing the levels of the high-sensitivity C-reactive protein (hs-CRP) and the erythrocyte sedimentation rate (ESR) for the two groups of patients and healthy controls. However, this study did not show a relationship between genotype of MEFV mutations and hs-CRP titers and ESR in these patients, as well as the absence of a strong relationship between the M694V mutation and hs-CRP titers and ESR. Conclusion: These data indicate the importance of hs-CRP titers and ESR in patients with familial Mediterranean fever when diagnosing the disease, before starting treatment and in attack-free periods, which may give us an idea about the severity of the disease.

Familial Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA) Syndrome; is it a Separate Disease?

Introduction: PFAPA is the most common periodic fever syndrome in the pediatric population yet pathogenesis is unknown. PFAPA was believed to be sporadic but family clustering has been widely observed.Objective: To identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) compared to those with PFAPA with no family history (FH-).Methods: In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31 (14.3%) of patients were PFAPA FH+. Data from patients with FH+ for PFAPA was compared to data from those with FH- of the disorder. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demography and clinical details. Results: FH+ group had more headaches (32% vs.2%; p= 0.016), myalgia (56% vs. 19%; p= 0.001), higher carrier frequency of M694V mutation (54% vs. 25%; p=0.053), greater family history of FMF (30% vs. 15%; p=0.096) and better outcomes with colchicine (82% vs. 52%; p=0.096) compared to those with FH-. FMs displayed almost identical characteristics to the FH+ group except for greater arthralgia during flares (64% vs. 23%; p=0.008) and compared to the FH- group, more oral aphthae (68% vs. 43%; p=0.002), myalgia/arthralgia (64% vs. 19%/16%; p<0.0001), and higher rates of FH of FMF (45% vs.15%; p=0.003). Conclusions: Our findings suggest that FH+ likely experience a different subset of disease with higher frequency of family history of FMF, arthralgia, myalgia and better response to colchicine compared to FH-. Colchicine prophylaxis for PFAPA should be considered in FH+.

POS1326 FAMILIAL PERIODIC FEVER, APHTHOUS STOMATITIS, PHARYNGITIS AND ADENITIS (PFAPA)SYNDROME; IS IT A SEPARATE DISEASE?

Background:Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in the pediatric population. Unlike other periodic fever syndromes, the pathogenesis and genetics of PFAPA is unknown. Until recently, PFAPA was believed to be a sporadic disease, yet family clustering has been widely observed and current research indicates that heredity is likely.Objectives:To identify demographic and clinical differences between patients with PFAPA who have a positive family history (FH+) compared to those with PFAPA with no family history (FH-) that can reveal if heritable and sporadic subtypes of this disorder exist.Methods:In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31(14.3%) of patients were PFAPA FH+. Data from patients with FH+ for PFAPA was compared to data from those with FH- of the disorder. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demography and clinical details.Results:FH+ group had more headaches (32% vs.2%; p= 0.016), myalgia (56% vs. 19%; p= 0.001), higher carrier frequency of M694V mutation (54% vs. 25%; p=0.053), greater family history of FMF (30% vs. 15%; p=0.096) and better outcomes with colchicine (82% vs. 52%; p=0.096) compared to those with FH-. FMs displayed almost identical characteristics to the FH+ group except for greater arthralgia during flares (64% vs. 23%; p=0.008) and compared to the FH- group, more oral aphthae (68% vs. 43%; p=0.002), myalgia/arthralgia (64% vs. 19%/16%; p<0.0001), and higher rates of FH of FMF (45% vs.15%; p=0.003).Conclusion:Our findings suggest that FH+ had probably different subset of disease with higher frequency of family history of FMF arthralgia, myalgia and better response to colchicine. Colchicine prophylaxis for PFAPA should be considered in FH+.Disclosure of Interests:None declared

POS1302 THE MUSCULOSKELETAL SYSTEM MANIFESTATIONS IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER

Background:Familial Mediterranean fever (FMF) is a monogenic inherited periodic fever syndrome presenting with episodes of self-limiting fever and inflammation of serosal membranes. The attacks emerge with arthritis were defined as one of the major diagnostic criteria besides involvement of serosal membranes. Non-specific musculoskeletal findings such as myalgia, arthralgia, transient synovitis, and more rare manifestations like protracted febrile myalgia can also be seen in FMF patients attacksObjectives:We aim to reveal the frequency and genotype association of musculoskeletal manifestations in children with FMF.Methods:The patients diagnosed with FMF between January 1, 2017 and June 1, 2019, and followed for at least 6 months in our pediatric rheumatology clinic were included in the study. Musculoskeletal manifestations of patients were enrolled. The patients were grouped according to the “Mediterranean Fever” (MEFV) gene variants. Musculoskeletal manifestations of the patients were compared between the groupsResults:The study group included 634 children with FMF (336 female and 298 male, F/M: 1.13/1). The clinical manifestations of patients in attack period were as follows: 99% of the patients had fever, 87.3% had abdominal pain, 20.7% had chest pain, 11.3% had vomiting, 10.7% had erysipelas like erythema, and 9.3% had headache. The musculoskeletal symptoms were accompanied by 58.6% (n: 372) of the patients during the attack period. The most common musculoskeletal manifestation was found as arthralgia (32.6%, n: 206). Also, the other musculosceletal manifestations were found as follows during attacks; arthritis in 23.7% (n: 150), myalgia in 20.5% (n: 130), exertional calf pain in 6.5% (n: 41), and protracted febrile myalgia in 1% (n: 7) of the patients. It was observed that the musculoskeletal manifestations were significantly higher in patients with homozygous M694V variant in exon-10 (p=0.017). Also, it was found that the musculoskeletal manifestations are more common in the attack periods of patients carrying the M694V variant in at least one allele (p = 0.019).Conclusion:It was determined that the musculoskeletal manifestations were seen as an attack symptom in more than half of FMF patients. Also, homozygous and compound heterozygous MEFV mutations including M694V variant found as a risk factor for emerge of musculoskeletal manifestations. In children with unexplained and recurrent musculoskeletal symptoms, especially in ethnicities with the high frequency of FMF, analysis of MEFV gene can help reveal the underlying cause.References:[1]Brik R, Shinawi M, Kasinetz L, Gershoni-Baruch R. The musculoskeletal manifestations of familial Mediterranean fever in children genetically diagnosed with the disease. Arthritis Rheum 2001;44:1416-9.[2]Jarjour RA, Dodaki R. Arthritis patterns in familial Mediterranean fever patients and association with M694V mutation. Mol Biol Rep 2011;38:2033-6.Disclosure of Interests:None declared

Differentiating children with familial Mediterranean fever from other recurrent fever syndromes: The utility of new Eurofever/PRINTO classification criteria

Objectives: In this study, we aimed to investigate the performance of Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria in pediatric patients with familial Mediterranean fever (FMF). Patients and methods:This retrospective, cross-sectional study included a total of 130 pediatric FMF patients (67 males, 63 females; mean age: 12.4±3.6 years; range, 2.5 to 17.7 years) with at least one M694V mutation in MEFV gene between July 2010 and July 2019. Demographic features and disease characteristics were recorded. The control group was consisted of 41 patients (19 males, 22 females; mean age: 7.8±4.0 years; range, 2.1 to 17.8 years) with other hereditary autoinflammatory diseases (AIDs), including periodic fevers with aphthous stomatitis, pharyngitis, and adenitis syndrome (n=30), mevalonate kinase deficiency (n=9), and tumor necrosis factor receptor-associated periodic syndrome (n=2). Sensitivity and specificity of the Eurofever/PRINTO classification criteria were calculated. Results: The sensitivity and specificity were 97.7% and 56.1% for Yalcinkaya-Ozen criteria, respectively and 93.1% and 90.2% for Tel Hashomer criteria, respectively. The Eurofever/PRINTO classification criteria reached a sensitivity and specificity of 94.6% and 82.9% and 93.1% and 80.5%, respectively, when genetic plus clinical criteria and clinical-only criteria were applied. Conclusion: The Eurofever/PRINTO classification criteria have a comparable sensitivity for avoidance of FMF underdiagnosis in childhood. The Yalcinkaya-Ozen criteria have the highest sensitivity without a significant specificity. The Tel Hashomer criteria and Eurofever/PRINTO classification criteria were superior to Yalcinkaya-Ozen criteria to differentiate FMF from other AIDs, thus leading to less complications relevant to underdiagnosis of other AIDs.

Ocular inflammatory diseases in children with familial Mediterranean fever: a true association or a coincidence?

Purpose: To describe the characteristics of patients with familial Mediterranean fever (FMF) concurrent with ocular inflammatory disease (OID) and to criticize possible relations between them.Methods: Clinical data were extracted from electronic medical records. Additionally, the medical literature on OIDs in FMF was reviewed.Results: Among 512 pediatric patients with FMF, five patients were found to have OIDs: bilateral chronic uveitis, recurrent orbital myositis (ROM), recurrent optic neuritis, and acquired Brown’s syndrome. The first cases of ROM and acquired Brown’s syndrome in FMF have been introduced in the literature. All patients presented with early-onset typical FMF attacks carried at least one M694V mutation and experienced OID while on colchicine. Conclusion: Increased frequency of OIDs in FMF as per the pediatric population and relapsing and chronic course of OIDs occasionally with concurrent FMF attacks suggest that this inflammatory syndrome especially those carrying M694V mutations may be a predisposing factor for OIDs.

Analysis of mutations of the MEFV gene in women with infertility and familial Mediterranean fever

Изучение взаимосвязи между мутациями в гене MEFV и бесплодием создает предпосылки для оптимизации диагностики и профилактики репродуктивных нарушений у женщин с семейной средиземноморской лихорадкой (ССЛ). Цель: поиск корреляций между мутациями в гене MEFV и бесплодием в большой когорте армянских пациенток. В период с 1998 по 2018 годы в Центре медицинской генетики и первичной охраны здоровья были обследованы 32 000 человек на наличие мутаций в гене MEFV. Из этой группы выбраны женщины (4577) репродуктивного возраста (18-49 лет), у которых был установлен клинический диагноз ССЛ на основании критериев Тel-Hashomer, подтвержденный генетическим тестированием. Комплексное обследование репродуктивной функции произведено у 373 женщин: 211 пациенток с ССЛ и у 162 женщин с репродуктивными расстройствами без ССЛ. Обнаружено, что гомозиготный генотип M694V/M694V, выявленный у 11,5% женщин с ССЛ, ассоциируется с тяжелым клиническим течением и развитием амилоидоза у 1,5% (р=0,028). Бесплодие чаще встречается у гомозиготных по M694V (90,9%) и M680I (100%) пациенток (р<0,009). Наиболее распространенная у армянских женщин репродуктивного возраста мутация M694V (40,7%) при бесплодии встречается чаще (69,7%), чем у фертильных женщин (30,3%) (p<0,009). Выявлена ассоциация между нерегулярным применением колхицина или использованием низкой дозы препарата и бесплодием у пациенток с ССЛ (88,4%) (р<0,001). Отсроченная диагностика свыше 10 лет наблюдалась у 80,7% бесплодных пациенток с ССЛ по сравнению с 19,3% у фертильных женщин (р<0,007). Таким образом, бесплодие в значительной степени связано с гомозиготными генотипами по мутациям M694V или M680I, которые ассоциируются с более тяжелым течением заболевания. Пациентки с ССЛ имеют сопоставимые репродуктивные показатели с женщинами без ССЛ. Бесплодие формируется под влиянием таких модифицирующих факторов, как социальный статус, нерегулярный прием колхицина, задержка диагностики свыше 10 лет. The study of the relationship between mutations in the MEFV (MEditerranean FeVer) gene and infertility creates opportunity for optimizing the diagnosis and prevention of reproductive disorders in women with familial Mediterranean fever (FMF). Data were collected from the patients registered in 1998- 2018 at the Center for Medical Genetics and Primary Health Care. From the cohort of 32000 patients analyzed for mutations in the MEFV gene, only women (4577) of reproductive age (18-49 years old) were selected, with clinical diagnosis FMF according to the International Tel-Hashomer criteria and confirmed by genetic testing. Comprehensive monitoring of reproductive function was performed in 373 women - 211 FMF patients and 162 non FMF women with reproductive disorders. Homozygous genotype M694V/M694V (11.5%) is associated with severe disease and renal amyloidosis (1.5%) (p=0.028). Infertility was revealed in 90.9% patients homozygous for M694V and 100% for M680I mutations (p<0.009). M694V mutation in population of women of reproductive age was more common in FMF patients with infertility (68.8%) compare to fertile women (31.2%) (p<0.009). A clear correlation between irregular uptakes or a low dose of colchicine and infertility among investigated FMF patients (88.4%) (p <0.001) was revealed. A delayed diagnosis of over 10 years was observed in 80.7% of infertile patients with FMF compared with 19.3% in fertile women (p<0.007). Infertility is largely associated with homozygous M694V or M680I genotypes of MEFV gene. Patients with FMF have a comparable prior-reproductive system with healthy controls. Infertility is formed under the influence of modifying factors such as social status, irregular intake of colchicine, and delayed diagnosis for more than 10 years.