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.

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. Disclosures No relevant conflicts of interest to declare.

Successful Treatment of Hidradenitis Suppurative With Secukinumab in a Patient with Ankylosing Spondylitis and Familial Mediterranean Fever

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterised by pain, inflamed nodules, abscess, sinus tract, and fistula. HS is more common in patients with axial spondyloarthritis (SpA) and Familial Mediterranean Fever (FMF) compared to the normal population. Mediterranean fever gene (MEFV) mutations are thought to be responsible for the relationship between these three diseases. Case reports of secukinumab treatment in HS have been reported. In this article, a case of successful treatment of HS with secukinumab in a patient with ankylosing spondylitis (AS) and FMF is presented.

AB0782 MONOARTHRITIS: PROBABLE OUTCOMES

Background:Numerous joint disorders initially produce swelling in a single joint and new onset monoartritis will probably further lead to the involvement of other joint groups and development of extraarticular manifestations. It is essential to take a proper diagnostic approach for organizing appropriate treatment and lowering possibility of disease progression.Objectives:The aim of this study was to investigate joint distribution, determine rheumatological diseases of patients with acute monoarthritis and reveal the development of further systemic manifestations.Methods:100 patients (age 18-75 years) with clinically apparent monoarthritis of less than 6 weeks duration were included in the study. Criteria of exclusion were infection, trauma and crystal induced arthritis. Joint distribution, presence of systemic manifestations and development of chronic inflammatory rheumatic disease were evaluated. Presence of arthritis was proved with help of ultrasound examination. Complete blood count, ESR, CRP, RF, anti-CCP; HLAB27; MEFV mutations and X-ray of swollen joint were performed for all patients. Temperature was also measured.Results:Mean age of patients with acute monoarthritis was 46±13 years. Female predominance was noted (61%). 71% of patients had elevated ESR, 69%- CRP. In 24% of cases homozygous or heterozygous mutations of MEFV gene were revealed. 21% of patients had positive RF and 18% - anti-CCP. 11% patients carried HLA-B27 antigen. 28% of examined patients had subfebril fever. Hepatosplenomegaly was determined in 16%, uveitis in 5%, psoriatic plaque in 4%, interstitial pneumonia in 2% of casesAt the baseline 82 patients were diagnosed with rheumatologically disease. Baseline data is shown in the Table 1 bellow.Table 1.Baseline dataDiagnosis Number of patientsFMF23Osteoarthritis (reactive synovitis)16Rheumatoid arthritis15Reactive arthritis10Ankylosing spondylitis6Psoriatic arthritis4SLE3Schonleyn-Henoch purpura2Sarcoidosis2Behcet diseases1Conclusion:In this study monoarhtritis in majority of cases underlies FMF. Though FMF is not considered as a frequent cause of acute monoarthritis, more attention should be paid on this pathology in focus of monoarthritis, especially in specific for FMF region. Further follow up of acute monoarthritis progression is needed.References:[1]A. Becker, J. Daily, K. Pohlgeers. Acute Monoarthritis: Diagnosis in Adults.Am Fam Physician 2016; 94(10): 810-816[2]S. Camacho-Lovillo, A. García-Martínez. Arthritis as presentation of familial Mediterranean fever. An Pediatr (Barc). 2015; 83(2):130. DOI: 10.1016/j.anpede.2015.07.007[3]J. Ellis. Acute monoarthritis. JAAPA. 2019, 32(3):25-31. doi: 0.1097/01.JAA.0000553379.52389.ebDisclosure of Interests:None declared

A HYPOTHETICAL ROLE FOR PLAGUE IN THE SELECTION OF MEFV MUTATION CARRIERS IN THE MEDITERRANEAN AREA

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease associated with mutations in the MEFV gene encoding Pyrin. MEFV mutations are frequent in the Mediterranean region. Increased resistance to an infection endemic to this area could have caused a selective advantage for individuals with MEFV mutations. Recent studies have shown that Pyrin is a part of host defense against microorganisms and it gets activated after sensing Rho GTPase inactivation by bacteria such as Clostridium difficile or Yersinia pestis. However, Yersinia species have another effector molecule, YopM which inhibits Pyrin in addition to RhoA modifiers YopE and YopT. Continuously overactive Pyrin in individuals with MEFV mutations could be a good host defense against Yersinia infections. Y. pestis causes plague, which led to a devastating pandemic in the Mediterranean basin. Thus, plague could be the infection which caused a selective biologic advantage for MEFV mutation carriers in this area.

Recurrent Synovitis of Hip and MEFV Gene Related Arthritis in Children

Background : Recurrent and relapsing arthritis has been proposed to describe a group of arthritis with recurring and periodic nature, in which the joints are intermittently involved. This study reports three non-FMF patients with heterozygous MEFV gene mutations and an extraordinary arthritis as a recurrent synovitis of hip (RSH) Methods : During 16-years from 2003 to 2019 at pediatric rheumatologic clinic among 195 recorded files with chronic oligoarthritis, 3 patients with diagnosis of recurrent synovitis of hip (RSH) were reviewed thoroughly. Peripheral blood was collected from patients and the samples were screened for the 12 common MEFV gene pathogenic variants. Results: This study included three patients, two female and one male with relapsing idiopathic arthritis that has been located on hip joints as a sole manifestation and pathologic findings of MEFV mutations as follow: A744S, V726A, and R761H. Conclusion : On the basis of possible role of MEFV gene in different rheumatic disease, MEFV gene related arthritis may be considered as a background of RSH particularly in Mediterranean area.

P733 The influence of concomitant familial Mediterranean fewer on Crohn’s disease course: Data from an FMF endemic area

Background Crohn’s disease (CD) and Familial Mediterranean fever (FMF) are both inflammatory disorders characterised by recurrent abdominal pain and fever attacks. Mutations of Mediterranean (MEFV) gene appear to be associated with stricturing behaviour and extraintestinal manifestations of CD. Further clinical studies regarding progression of CD in coexistence with FMF is still required. The aim of this study was to evaluate the influence of concomitant FMF in CD patients on the course of the CD in FMF endemic area. Methods Total 210 adult patients who had diagnosed with CD with or without FMF between November 2006 and April 2019 were respectively examined. FMF diagnoses were based on Tel-Hashomer criteria. The Montreal classification was used to define location and behaviour of CD. CD patients were divided into two groups FMF positive and FMF negative. Severity of CD was assessed by the need for hospitalisation related to CD, whether biological therapy was received and/or whether surgery was undergone due to CD. All demographic features, MEFV mutations, location/behaviour of disease, and extraintestinal manifestations were analysed retrospectively. Results In the present study, 8 (3.8%) of the total 210 CD patients have concomitant FMF. Mean follow-up time in CD-FMF was 59.55 months and CD-non-FMF was 60.98 months. CD patients with or without FMF showed similar demographic features including age, sex, smoking behaviour, disease location, behaviour, and treatment regimen in maintenance of the remission. Regarding extraintestinal manifestations, only peripheral arthritis was found significantly higher in CD-FMF patients (n = 3, 37.5%) compared CD-non-FMF patients (n = 21, 10.4%). In the CD-FMF patients, a result of MEFV mutation gene analysis was found in medical records 6 patients. Of those, 2 had homozygote MEFV mutation, 2 had heterozygote MEFV mutation and 2 without any MEFV mutations. In CD-FMF group, percentage of patients on biological therapy (n = 4, 50%) was significantly higher than CD-non FMF group (n = 24, 11.9%) (p = 0.012). Steroid dependence and hospitalisation in CD-FMF (n = 3, 37.5% and n = 5, 62.5%) group were relatively higher than CD-non-FMF (n = 83, 41.1%) group, but not statistically significant. The percentage of CD-FMF patients who underwent intestinal surgery (n = 1, 12.5%) was similar to that of CD-non-FMF (n = 33, 16.3%). Conclusion In the current study, the prevalence of FMF in CD patients was detected 3.8% in FMF endemic area. The group of patients on biological therapy in CD-FMF patients was significantly higher than CD-non-FMF patients. Frequency of hospitalisation in CD-FMF patients was relatively higher than CD-non-FMF patients. Our findings indicate that concomitant FMF in CD patients may have a negative effect on the course of CD.

Recurrent Synovitis of Hip and MEFV Gene Related Arthritis in Children

Background: Familial Mediterranean fever (FMF) is an autosomal recessive inherited auto inflammatory disorder. Arthritis is the presenting finding of FMF in some patients, and sometimes it remains as the major manifestation of the disorder. This study reports three non-FMF patients with heterozygous MEFV gene mutations and an extraordinary arthritis as a recurrent synovitis of hip (RSH) Methods: During 16-years from 2003 to 2019 at pediatric rheumatologic clinic among 195 recorded files, 3 patients with diagnosis of recurrent synovitis of hip (RSH) were reviewed thoroughly. Peripheral blood was collected from patients and the samples were screened for the 12 common MEFV gene pathogenic variants. Results: This study included three patients, two female and one male with relapsing arthritis that has been located on hip joints as a sole manifestation and pathologic findings of MEFV mutations as follow: A744S, V726A, and R761H. Conclusion: On the basis of possible role of MEFV gene in different rheumatic disease RSH could be considered as a MEFV gene related arthritis. Key words: FMF, MEFV gene, Recurrent synovitis of hip in children