Publications by authors named "Eldad Ben-Chetrit"

73 Publications

Incidence and course of COVID-19 hospitalizations among patients with familial Mediterranean fever.

Rheumatology (Oxford) 2021 Jul 22. Epub 2021 Jul 22.

Rheumatology Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel.

Objectives: To evaluate the incidence of hospitalization for COVID-19 in patients with familial Mediterranean fever (FMF), as compared with the general population, and to compare the disease course between FMF inpatients, and age, sex, ethnicity, and comorbidity-matched non-FMF COVID-19 inpatients.

Methods: We used electronic medical records (EMR) to obtain data about the total number of the insured population and the number of FMF patients in the two largest health management organizations (HMOs) in Jerusalem, Clalit and Meuhedet. The total number of COVID-19 inpatients at the Hadassah Medical Center, including those with FMF, for the period between the 1 February 2020, and the 10 March 2021 was retrieved from the EMR of Hadassah. COVID-19 course was compared between the FMF inpatient group and age, sex, ethnicity, and comorbidity-matched non-FMF COVID-19 inpatients. Each FMF inpatient was matched with 2 non-FMF controls.

Results: We found no statistically significant difference in the odds of hospitalization for COVID-19 between FMF patients and the non-FMF population (0.46% vs 0.41%; p= 0.73). Furthermore, we found similar disease severity and therapeutic approach in FMF COVID-19 inpatients and matched non-FMF COVID-19 inpatients.

Conclusions: Neither FMF, nor baseline colchicine therapy appear to affect the incidence of hospitalization for COVID-19 or the disease course, in terms of severity and therapeutic approach.
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http://dx.doi.org/10.1093/rheumatology/keab577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344485PMC
July 2021

Serological and hematological characteristics of Sjogren's syndrome and dry eye syndrome patients using a novel immune serology technique.

PLoS One 2020 31;15(12):e0244712. Epub 2020 Dec 31.

Department of Ophthalmology Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Objectives: To compare hematologic and serological parameters among patients with Sjogren's syndrome (SS), dry eye syndrome (DES) and controls, and validate a novel multiplex-serology method for identifying auto-antibodies in these populations.

Methods: In a clinic-based case-control study a total of 422 participants were recruited, including 91 with SS, 120 DES, and 211 controls (age and sex frequency-matched). We measured blood counts, anti-nuclear-antibodies (ANA), anti-SSA/SSB, anti-ribonucleoprotein (RNP), anti-double-stranded-DNA (DS-DNA), and rheumatoid factor (RF) using the "Immunodot" qualitative-ELISA assay. Immunoglobulins, C3 and C4 were measured by immune-fluorescence. Autoantibodies were also quantified with a newly-developed method using glutathione-S-transferase fusion proteins of SSA/Ro 52 and 60kD and SSB/La (multiplex-serology), measuring median fluorescence intensity (MFI).

Results: Among DES patients, only 2% (95%CI: 0.36-6.3) had positive immune serology. SS patients had lower lymphocyte, hemoglobin and C3 levels but higher prevalence of RF, ANA, anti-SSA/B and higher IgG and MFI levels, compared to DES and controls (P<0.001). Presence of anti-SSA/Ro-52kD was associated with SS [odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.46-2.88]. Anti-SSB/La was inversely associated with DES (OR = 0.81, 95%CI: 0.65-1.00) compared to controls. Positivity to RF (adjusted for age, gender and ethnicity OR = 5.03, 95%CI: 1.78-14.21), ANA (OR = 14.75, 95%CI: 4.09-53.17), or combination of anti-SSA/B (OR = 20.97, 95%CI: 4.60-95.54) were more likely in SS compared to DES. The novel multiplex-serology method correctly identified anti-SSA/B autoantibodies by ELISA among SS, DES patients and controls (sensitivity = 1.0, negative-predictive-value = 1.0).

Conclusions: Serologic parameters distinguish SS from DES patients and controls. A newly-developed multiplex-serology technique may be useful to detect autoantibodies in large epidemiologic studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244712PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774976PMC
March 2021

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

Rheumatology (Oxford) 2021 08;60(8):3799-3808

Division of Paediatric Rheumatology, Department of Paediatrics and Autoinflammation Reference Center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany.

Objectives: Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities.

Methods: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements.

Results: Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life.

Conclusion: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.
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http://dx.doi.org/10.1093/rheumatology/keaa863DOI Listing
August 2021

Is the country of living important in the phenotypic expression of E148Q mutation? The Armenian experience.

Clin Exp Rheumatol 2020 Sep-Oct;38 Suppl 127(5):124-125. Epub 2020 Dec 1.

Centre of Medical Genetics and Primary Health Care and the Yerevan State Medical University, Armenia.

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February 2021

Caught Red Handed.

Arthritis Care Res (Hoboken) 2020 Dec 5. Epub 2020 Dec 5.

Infectious Disease Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

A 54-year-old female patient admitted April 2020 for diarrhea, skin rash and shock. The patient presented to the Emergency Room with mild headache, nausea, vomiting, and diarrhea that began several days earlier. She also complained of diffuse arthralgia affecting knees, elbows and shoulders, and reported a skin rash over her face, phalanges of both hands and calves that worsened on the day of admission.
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http://dx.doi.org/10.1002/acr.24532DOI Listing
December 2020

Infertility Causes and Pregnancy Outcome in Patients With Familial Mediterranean Fever and Controls.

J Rheumatol 2021 04 1;48(4):608-614. Epub 2020 Oct 1.

O.L. Sotskaya, MD, PhD, H.S. Hayrapetyan, MD, PhD, T.F. Sarkisian, MD, PhD, Center of Medical Genetics and Primary Health Care, and Yerevan State Medical University after Mkhitar Heratsi, Yerevan, 0025, Armenia;

Objective: Recurrent attacks of peritonitis due to familial Mediterranean fever (FMF) may lead to peritoneal adhesions and fallopian tube obstruction. Colchicine, which is the treatment of choice for FMF, may disturb cell division. Secondary amyloidosis, a complication of untreated FMF, may involve the testes and ovaries. Thus, FMF and colchicine may potentially affect fertility and pregnancy in patients with FMF. The aims of the study are to evaluate the causes of infertility and pregnancy outcome in FMF patients and to compare them with 2 groups: non-FMF patients with peritoneal female genital tuberculosis (FGTB) and normal healthy controls.

Methods: This is a retrospective study in which FMF patients with reproductive disorders were recruited from the National Center of Medical Genetics and Primary Health Care in Yerevan, Armenia. The patients with FGTB and the healthy controls with reproductive problems were recruited successively from a large gynecology clinic in Yerevan. Genetic analyses for FMF were performed using ViennaLab StripAssay.

Results: The FMF group (211 patients) resembles the FGTB group (127 patients) regarding etiologies of infertility. However, fertilization (IVF) success rate and pregnancy outcome were comparable between the FMF patients and the control group (162 patients). Infertility in patients with FMF was clearly associated with a more severe disease and a lack of adequate colchicine treatment.

Conclusions: Colchicine medication and controlled FMF disease do not adversely affect the reproductive system and pregnancy outcome. However, a lack of an appropriate colchicine treatment may cause infertility and poor pregnancy outcome.
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http://dx.doi.org/10.3899/jrheum.200574DOI Listing
April 2021

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

Clin Chem 2020 04;66(4):525-536

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.

Background: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.

Methods: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.

Results: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.

Conclusions: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
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http://dx.doi.org/10.1093/clinchem/hvaa024DOI Listing
April 2020

Familial Mediterranean fever: different faces around the world.

Clin Exp Rheumatol 2019 Nov-Dec;37 Suppl 121(6):18-22. Epub 2019 Oct 17.

Academic Hospital, Istanbul, Turkey.

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January 2020

SNP variations in IL10, TNFα and TNFAIP3 genes in patients with dry eye syndrome and Sjogren's syndrome.

J Inflamm (Lond) 2019 18;16. Epub 2019 Mar 18.

2Department of Ophthalmology, Hadassah-Hebrew University Medical Center, POB 12000, 91120 Jerusalem, Israel.

Background: Cytokines are known to be key players in dry eye syndrome (DES) and Sjogren's syndrome (SS) pathogenesis. In this study we compared single nucleotide polymorphism (SNP) variations in genes encoding cytokine levels among SS and DES patients in Israel.

Methods: We recruited 180 subjects, 82 with SS and 98 with DES. Using a candidate gene approach and allele-specific PCR technique for genotyping, proportions of risk alleles in Tumor Necrosis Factor α (TNFα) (rs1800629), IinterLeukin-10 (IL-10) (rs1800896) and TNFAIP3 (rs2230926) SNPs were compared between study groups.

Results: Allelic distribution was found very similar to Caucasian (CEU - Utah residents with Northern and Western European roots) population distributions in these SNPs. While none of the SNPs' variants were significantly associated with SS or DES in a recessive model, in an additive model the TNFα G risk allele was found higher among SS patients compared to DES (Homozygote-G: 84.2% vs. 70.8%; Heterozygote: 26.9% vs. 11.2%, respectively,  = 0.02). After adjustment for age, gender and ethnicity, these variants weren't associated with SS. Genetic scoring reveals that SS patients are more likely to present variants of all three SNPs than DES subjects.

Conclusions: This is the first study evaluating these SNP variations among both patients with DES and patients with SS. We found the allelic distribution in each SNP to be very similar to that found in healthy Caucasian populations presented in the HapMap project. We found the TNFα allele significantly associated with DES for homozygotes, and associated with SS for heterozygotes in the additive model.
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http://dx.doi.org/10.1186/s12950-019-0209-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421669PMC
March 2019

Shared Medical and Environmental Risk Factors in Dry Eye Syndrome, Sjogren's Syndrome, and B-Cell Non-Hodgkin Lymphoma: A Case-Control Study.

J Immunol Res 2019 21;2019:9060842. Epub 2019 Jan 21.

Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Objectives: To assess whether there are shared exposures associated with Sjogren's syndrome (SS), dry eye syndrome (DES), and B-cell non-Hodgkin lymphoma (B-NHL), in order to determine whether they are etiologically related.

Methods: In a clinic-based case-control study, 702 participants (91 SS, 120 DES, 211 (age and sex frequency-matched) controls, and 280 B-NHL cases) were recruited and interviewed regarding exposures, medical history, and family history.

Results: Female predominance was noted in SS (ratio 9.2 : 1). Eye dryness was severest in SS compared to DES and controls ( < 0.001). Compared to controls, alcohol consumption was inversely associated with NHL, DES, and SS (odds ratio (OR) = 0.47, 95% confidence interval (CI): 0.31-0.71; OR = 0.54, 95% CI: 0.33-0.88; and OR = 0.26, 95% CI: 0.14-0.49, respectively), while a previous history of infection requiring hospitalization was positively associated with all three conditions: NHL (OR = 1.92; 95% CI: 1.23-2.99), DES (OR = 3.29; 95% CI: 1.97-5.47), and SS (OR = 4.74; 95% CI: 2.66-8.44). NHL patients were more likely to report first-degree relatives with hematologic cancer, while having first-degree relatives with an autoimmune disease (AID) was associated with SS (OR = 5.25; 95% CI: 2.59-10.63) and DES (OR = 3.55; 95% CI: 1.83-6.91) compared to controls.

Conclusions: Some exposures are associated with all three conditions (such as an inverse association with alcohol consumption and a positive association with serious past infection), while a family history of AID appears to be shared by DES and SS, but not NHL subjects. Shared risk factors for all three conditions indicate possible mutual etiological pathways.
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http://dx.doi.org/10.1155/2019/9060842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360537PMC
May 2019

An International Delphi Survey for the Definition of New Classification Criteria for Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF Receptor-associated Periodic Fever Syndromes, and Cryopyrin-associated Periodic Syndrome.

J Rheumatol 2019 04 1;46(4):429-436. Epub 2018 Nov 1.

Istituto Giannina Gaslini, Clinica Pediatrica e Reumatologia, PRINTO, Genoa, Italy;

Objective: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF.

Methods: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1.

Results: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF.

Conclusion: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.
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http://dx.doi.org/10.3899/jrheum.180056DOI Listing
April 2019

Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study.

Ann Rheum Dis 2018 11 12;77(11):1558-1565. Epub 2018 Aug 12.

Clinica Pediatrica e Reumatologia-PRINTO, Istituto Giannina Gaslini, Genoa, Italy.

Autoinflammatory diseases (AIDs) are a relatively new family of disorders, defined about 19 years ago. Some of them are hereditary and some are not. The names given to these diseases do not follow any systematic guidelines, and sometimes the same disorder carries several names. The aim of this study is to refine the definition of AIDs and to provide some conventions for their naming. We focused mainly on monogenetic AIDs. Delphi technique, which enables consensus among a group of experts through internet and mail communication and questionnaires, was employed. After achieving 100% consensus among six members of a steering committee, the questionnaire containing AID definitions and the agreed-upon conventions were sent to 26 physicians and researchers working in the field of AIDs in order to gain broader support for the committee's proposals. The committee proposed the following definition for AIDs: "Autoinflammatory diseases are clinical disorders caused by defect(s) or dysregulation of the innate immune system, characterized by recurrent or continuous inflammation (elevated acute phase reactants-APR) and the lack of a primary pathogenic role for the adaptive immune system (autoreactive T-cells or autoantibody production)." Several rules were defined for guiding the naming of these diseases among which are: abandoning eponyms and preferring the name of the gene over its encoded protein. The new definition for AIDs allows inclusion of clinical disorders mainly associated with defects in the innate immune system. The new conventions propose names with clinical meaning and in some cases even clues for treatment.
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http://dx.doi.org/10.1136/annrheumdis-2017-212515DOI Listing
November 2018

Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.

N Engl J Med 2018 05;378(20):1908-1919

From the Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome (F.D.B.), Clinica Pediatrica e Reumatologia, Unità Operativa Semplice Dipartimentale di Malattie Autoinfiammatorie e Immunodeficienze, IRCCS, Istituto G. Gaslini, Genoa (M.G.), the Pediatric Clinic, University of Brescia and Spedali Civili, Brescia (M.C.), and the Amyloidosis Research and Treatment Center, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia (L.O.) - all in Italy; the Division of Pediatric Rheumatology, Hospital Sant Joan de Déu, Universitat de Barcelona (J.A.), and the Internal Medicine Department, Autoimmune and Systemic Diseases Unit, Hospital Vall d'Hebron (S.B.-R.), Barcelona, and the Pediatric Rheumatology Unit, Hospital Universitario y Politécnico La Fe, Valencia (I.C.P.) - all in Spain; the Rheumatology Unit, Hadassah-Hebrew University Hospital (E.B.-C.), and the Pediatric Rheumatology Unit, Shaare Zedek Medical Center (P.J.H.), Jerusalem, and Heller Institute of Medical Research and Medicine Faculty, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (A.L.) - all in Israel; the Division of Pediatrics, University Medical Center Utrecht, Utrecht (J.F.), and the Radboud Expertise Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Radboud University Medical Center, Nijmegen (A. Simon) - both in the Netherlands; the Departments of Pediatrics and Medicine, University of California at San Diego and Rady Children's Hospital San Diego, San Diego (H.M.H.); the Department of Pediatric Rheumatology, Centre de Référence des Maladies Auto-inflammatoires et de l'Amylose Inflammatoire, Centre Hospitalier Universitaire (CHU) de Bicêtre, Assistance Publique-Hopitaux de Paris (APHP), Université de Paris Sud (I.K.-P.), and Paris-Descartes University, Imagine Institute, Unité d'Immuno-Hématologie et Rhumatologie Pédiatrique, Hôpital Necker-Enfants Malades, APHP (P.Q.), Paris; the National Amyloidosis Centre, University College London Division of Medicine, Royal Free Campus (H.J.L.), and University College London, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust (P.B.), London; the Department of Pediatrics, Hacettepe University, Ankara (S.O.), and the Department of Pediatric Rheumatology, Cerrahpasa Medical School (O.K.), and Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology (A.G.), Istanbul University, Istanbul - all in Turkey; the Department of Pediatrics, Division of Pediatric Rheumatology, Cleveland Clinic, Cleveland (A.Z.); the Department of Infectious Diseases and General Internal Medicine, CHU Sart-Tilman, University of Liège, Liege (M.M.), and the Department of Infectious Diseases and Immunity, Jessa Hospital, University of Hasselt, Hasselt (J.V.H.) - both in Belgium; the Department of Clinical Immunology, Center for Pediatric Hematology, Oncology, and Immunology, Moscow (A. Shcherbina); Pediatric Rheumatology of Western Switzerland, University of Lausanne, Lausanne, (M.H.), and Novartis, Basel (K.L., A. Speziale, G.J.) - both in Switzerland; the Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan (R.H.); and the Department of Pediatrics, Semmelweis Egyetem, Budapest, Hungary (T.C.).

Background: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares.

Methods: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab.

Results: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years).

Conclusions: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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http://dx.doi.org/10.1056/NEJMoa1706314DOI Listing
May 2018

Reply.

Arthritis Rheumatol 2018 07 14;70(7):1167-1168. Epub 2018 May 14.

Sheba Medical Center, Tel Hashomer, Israel.

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http://dx.doi.org/10.1002/art.40496DOI Listing
July 2018

Familial Mediterranean Fever and Incidence of Cancer: An Analysis of 8,534 Israeli Patients With 258,803 Person-Years.

Arthritis Rheumatol 2018 01 7;70(1):127-133. Epub 2017 Dec 7.

Tel Aviv University, Tel Aviv, Israel.

Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested as recurrent serosal inflammation. An association between FMF and malignancy has not been evaluated. The aim of this study was to estimate cancer risk in a large cohort of FMF patients from a single institution.

Methods: The study cohort consisted of 8,534 FMF patients registered at the National FMF Center in Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and then stratified by age and sex. Standardized incidence ratios (SIRs) for cancers were calculated.

Results: Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. The overall cancer risk among patients with FMF was significantly lower than was expected in specific sex and ethnic groups of the Israeli population: for males of Jewish ethnicity, SIR 0.66 (95% confidence interval [95% CI] 0.55-0.77), P < 0.001; for females of Jewish ethnicity, SIR 0.75 (95% CI 0.64-0.86), P < 0.001; and for males of Arab ethnicity, SIR 0.34 (95% CI 0.07-0.99), P = 0.024.

Conclusion: FMF patients have a significantly lower incidence of cancer than the general population of Israel. This pattern was demonstrated in 2 ethnic populations: Jewish and Arab. We speculate that the lower cancer incidence could be attributed to a direct physiologic effect of FMF or to its treatment.
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http://dx.doi.org/10.1002/art.40344DOI Listing
January 2018

Can we make a diagnosis of autoinflammatory diseases based upon clinical features only?

Clin Exp Rheumatol 2017 Nov-Dec;35 Suppl 108(6):16-18. Epub 2017 Sep 21.

Rheumatology Unit, Cerrahpasa Medical Faculty, Istanbul, Turkey.

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September 2019

The Missing Conduit….

Isr Med Assoc J 2017 Sep;19(9):590-594

Department of Medicine A, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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September 2017

A novel cluster of patients with Familial Mediterranean Fever (FMF) in southern Italy.

Eur J Clin Invest 2017 Sep 2;47(9):622-629. Epub 2017 Aug 2.

Department of Biomedical Sciences & Human Oncology, University "Aldo Moro" of Bari Medical School, Bari, Italy.

Background: Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disorder characterised by recurrent attacks of fever and serositis (peritonitis, pleuritic or synovitis) affecting mainly populations of Mediterranean origin.

Aim: To describe a relatively new cluster of FMF subjects from Apulia and Basilicata regions (southern Italy).

Patients And Methods: Subjects were screened for FMF using the Tel-Hashomer criteria and genetic analysis. Demographic data were taken from patients' files and direct interviews. Patients were investigated about attack duration, intensity and site, body temperature, skin manifestations and overall quality of life before and after treatment with colchicine. Inflammatory parameters were also measured between these periods.

Results: Forty-nine subjects had FMF (M : F = 26 : 23, age 38 years ± 2 SE) and followed-up up to 8 years. The age at disease onset was 22·1 years ± 1·2SE and the diagnostic delay was 15·5 years ± 1·9SE. The majority of patients (82%) suffered from abdominal pain, and 35% had undergone prior abdominal surgery or laparotomy. Severity score (ISSF) was mild in 43% of patients and intermediate in 57% of patients. Serum amyloid A (SAA) was increased in 20% of patients (16·9 ± 3·7, normal range < 6·4 mg/dL). In over 95% of patients, inflammation markers, duration and intensity of febrile painful attacks, quality of life and ISSF score improved dramatically following colchicine treatment.

Conclusion: The Apulia region represents a new endemic area for FMF. Clinical presentation of FMF can be misleading and requires a complete and early workup to recognise the disease and avoid unjustified surgery. Colchicine remains the gold standard therapy to prevent FMF attacks and fatal long-term complications.
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http://dx.doi.org/10.1111/eci.12783DOI Listing
September 2017

The liver in familial Mediterranean fever: is it involved?

Clin Exp Rheumatol 2017 Nov-Dec;35 Suppl 108(6):108-112. Epub 2017 Jun 9.

Department of Rheumatology, Academic Hospital, Istanbul, Turkey.

Objectives: Familial Mediterranean fever (FMF) is characterised by recurrent attacks of fever and serositis. It may affect the peritoneum, pleura, synovia and the skin. Usually the liver is intact in FMF. Recently, this concept was challenged by some groups which claimed that hepatitis is a feature of FMF and that non-alcoholic liver disease (NAFLD) and cryptogenic cirrhosis are more common among FMF patients. Scope of this paper is to critically review the relevant literature and to answer the question whether or not the liver is involved in FMF.

Methods: We used Medline, Embase, Scopus and Web of Science database for searching articles dealing with FMF and the liver since 1960. We also reviewed some manuscripts which were not identified by the above searching engines.

Results: Some cases reported that hepatitis is a feature of FMF based upon transaminase elevations without liver biopsy. Due to this questionable diagnosis and the paucity of similar reports, it seems that hepatitis is not a feature of FMF. Cryptogenic cirrhosis is considered as the end stage of NAFLD. Since NAFLD is prevalent in 25% of the general population it is more plausible to relate the occurrence of cryptogenic cirrhosis in FMF patients to NAFLD rather than to FMF. M694V mutation carriage was relatively more frequent among FMF patients with cryptogenic cirrhosis or "hepatitis".

Conclusions: The literature review indicates that FMF and liver disease are not generally associated. However, carriage of M694V mutations may play a role in the pathogenesis of liver disease.
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February 2018

Willie Sutton Strikes Again.

Isr Med Assoc J 2016 Dec;18(12):756-760

Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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December 2016

MEFV and SAA1 genotype associations with clinical features of familial Mediterranean fever and amyloidosis in Armenia.

Clin Exp Rheumatol 2016 Sep-Oct;34(6 Suppl 102):72-76. Epub 2016 Oct 25.

Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Objectives: Familial Mediterranean fever (FMF) is a hereditary periodic disease characterised by recurrent attacks of fever and serositis. The most devastating complication of FMF is amyloidosis (AA) affecting mainly the kidneys. Aim of the study is to search for correlations between the MEFV genotype and the SAA polymorphisms with the clinical manifestations of FMF and the occurrence of amyloidosis in a large cohort of Armenian patients.

Methods: Information about the MEFV mutations, SAA polymorphisms and FMF clinical features, were obtained for 1017 FMF patients, from the database of the Center of Medical Genetics in Yerevan. For identifying probable correlation between the MEFV and SAA genotype and clinical features of FMF, regression logistic analyses were conducted between the genotype and phenotype of the patients.

Results: Patients homozygous for M694V were highly associated with all the clinical features of FMF and its complications - proteinuria and amyloidosis. None of the SAA1 polymorphisms had any correlation with FMF clinical features. However, homozygosis for SAA1 α/α polymorphism was associated with proteinuria and amyloidosis whereas carrying the β/β polymorphism was found to be protective for amyloidosis.

Conclusions: The SAA1 α allele is strongly associated with amyloidosis in FMF patients. This observation is valid in inflammatory diseases other than FMF too. SAA1 polymorphism has no effect on the clinical features of FMF. M694V homozygosis is highly associated withal typical features of FMF and with amyloidosis. FMF course in Armenia is similar to that in Middle Eastern countries where FMF disease is common.
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February 2017

Vasculitis in the autoinflammatory diseases.

Curr Opin Rheumatol 2017 01;29(1):4-11

Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Purpose Of Review: This article addresses the prevalence and relationship between autoinflammatory diseases and vasculitis.

Recent Findings: Autoimmune diseases (AIDs) are a group of syndromes characterized by episodes of unprovoked inflammation due to dysregulation of the innate immune system. Despite the common occurrence of rashes and other skin lesions in these diseases, vasculitis is reported in only a few. On the other hand, neutrophilic dermatoses are more prevalent. Large vessel vasculitis is reported in patients with Behcet's and Blau's syndromes. Small and medium size vasculitides are reported in familial Mediterranean fever mainly as Henoch-Schonlein purpura and polyarteritis nodosa, respectively. It is rarely described in hyper IgD with periodic fever syndrome, cryopyrin associated periodic syndromes, TNF receptor-associated periodic syndrome, deficiency of interleukin-1 receptor antagonist and pyoderma gangrenosum and acne syndrome. In most AID where bones and skin are mainly involved (CRMO, Majeed syndrome, Cherubism and DITRA) - vasculitis has not been described at all. In AID small vessel vasculitis affects mainly the skin with no involvement of internal organs.

Summary: In AID, neutrophilic dermatoses are more common and prominent than vasculitis. This may reflect a minor role for interleukin-1 in the pathogenesis of vasculitis. The rarity of vasculitis in AID suggests that in most reported cases its occurrence has been probably coincidental rather than being an integral feature of the disease.
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http://dx.doi.org/10.1097/BOR.0000000000000347DOI Listing
January 2017

Is plasmapheresis a potential treatment for familial Mediterranean fever patients resistant or intolerant to colchicine?

Int J Rheum Dis 2017 Dec 1;20(12):2230-2232. Epub 2016 Mar 1.

Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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http://dx.doi.org/10.1111/1756-185X.12853DOI Listing
December 2017

Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF).

Ann Rheum Dis 2016 Jun 28;75(6):1051-6. Epub 2016 Jan 28.

Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Objective: To develop widely accepted international severity score for children and adult patients with familial Mediterranean fever (FMF) that can be easily applied, in research and clinical practice.

Methods: Candidate severity criteria were suggested by several FMF expert physicians. After three rounds of Delphi survey, the candidate criteria, defined by the survey, were discussed by experts in a consensus meeting. Each expert brought data of clinical manifestations, laboratory findings and physician's global assessments (PGAs) of minimum 20 patients from their centres. We used the PGAs for disease severity as a gold standard. Logistic regression analysis was used to evaluate the predicting value of each item, and receiver operating characteristic curve analysis was performed to demonstrate the success of the criteria set.

Results: A total of 281 patients consist of 162 children and 119 adults with FMF were enrolled and available for validity analysis: Nine domains were included in the final core set of variables for the evaluation of disease severity in FMF. The International Severity Score for FMF (ISSF) may reach a maximum of 10 if all items are maximally scored. The threshold values to determine: severe disease ≥6, intermediate disease 3-5, mild disease ≤2. Area under the curve was calculated as 0.825 for this set in the whole group.

Conclusions: The initial validity of ISSF both in children and adult with FMF was demonstrated. We anticipate that it will provide a robust tool to objectively define disease severity for clinical trials, future research as well as for therapeutic decisions in managing patients with FMF.
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http://dx.doi.org/10.1136/annrheumdis-2015-208671DOI Listing
June 2016

EULAR recommendations for the management of familial Mediterranean fever.

Ann Rheum Dis 2016 Apr 22;75(4):644-51. Epub 2016 Jan 22.

Instituto de Salud Musculoesquelética, Madrid, Spain.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.
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http://dx.doi.org/10.1136/annrheumdis-2015-208690DOI Listing
April 2016

Efficacy and safety of treatments in Familial Mediterranean fever: a systematic review.

Rheumatol Int 2016 Mar 19;36(3):325-31. Epub 2015 Dec 19.

Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Familial Mediterranean fever (FMF) is an autoinflammatory disease, which can be well controlled with lifelong use of colchicine. Since studies dealing with the efficacy and safety of colchicine were conducted mainly in the sixties and seventies of the previous century, it seems that this topic needs to be updated. Recently, an international expert panel was undertaken for the establishment of recommendations on how to manage FMF. We aimed to summarize the efficacy and safety of the current treatments available to prevent FMF attacks and to avert the appearance of amyloidosis secondary to FMF. A systematic review was performed. Two reviewers and methodologist established the protocol of the review and the epidemiological questions in PICO terms. MEDLINE through PubMed, Embase, and Cochrane Central Trials Register all up to May 31, 2014, were searched, and only randomized controlled trials or quasicontrolled trials were accepted. For each study, a judgment on risk of bias was then rated as high, moderate, or low. Of 1222 initially captured publications, 153 articles were studied in detail. Finally, only seven studies met all criteria and were included. Among these seven studies, four were randomized crossover clinical trials of colchicine including a total of 57 patients, one RCT of Andrographis paniculata Herba Nees extract employed in 24 patients, one randomized crossover clinical trial of Rilonacept used in 12 patients, and one RCT of interferon treating 34 acute abdominal attacks in 22 patients. The quality of the colchicine trials was low compared with the other drugs trials. Safety was not clearly mentioned in the trials. Colchicine is an effective treatment in FMF.
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http://dx.doi.org/10.1007/s00296-015-3408-9DOI Listing
March 2016

Familial Mediterranean fever in Armenia in 2015: some interesting lessons.

Clin Exp Rheumatol 2015 Nov-Dec;33(6 Suppl 94):S15-8. Epub 2015 Oct 19.

Center of Medical Genetics and Primary Health Care, Yerevan, Armenia.

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January 2016

Non-thrombocytopenic purpura in familial Mediterranean fever-comorbidity with Henoch-Schönlein purpura or an additional rare manifestation of familial Mediterranean fever?

Rheumatology (Oxford) 2016 07 13;55(7):1153-8. Epub 2015 Oct 13.

Department of Rheumatology, Academic Hospital, Istanbul, Turkey.

Henoch-Schönlein purpura is a relatively common vasculitis mainly affecting children. It is characterized by purpuric skin rash, abdominal cramping, and haematuria. Skin biopsies taken from Henoch-Schönlein purpura lesions disclose perivascular IgA deposits. FMF is an autoinflammatory disease characterized by recurrent attacks of fever lasting 2-3 days which resolve spontaneously. Typical manifestations of the disease are peritonitis, pleuritis, pericarditis, arthritis and erysipelas-like erythema usually affecting the lower limbs. Over the years many reviews emphasized the clinical impression that Henoch-Schönlein purpura is more common among FMF patients than in healthy control population. In this review we summarize these reports and show that sometimes Henoch-Schönlein purpura associated with FMF differs from typical isolated Henoch-Schönlein purpura, and this is also the case with polyarteritis nodosa and SpA associated with FMF. It is suggested that these clinical manifestations (polyarteritis nodosa, Henoch-Schönlein purpura and SpA) should be considered to be associated with FMF as part of what we call FMF rather than as co-existing additional separate clinical entities.
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http://dx.doi.org/10.1093/rheumatology/kev378DOI Listing
July 2016

19-Year-Old Male With a History of Recurrent Episodes of Calf Pain, Headache, and Fever.

Arthritis Care Res (Hoboken) 2015 Dec;67(12):1757-61

Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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http://dx.doi.org/10.1002/acr.22549DOI Listing
December 2015

Behçet's syndrome and pregnancy: course of the disease and pregnancy outcome.

Clin Exp Rheumatol 2014 Jul-Aug;32(4 Suppl 84):S93-8. Epub 2014 Sep 30.

Rheumatology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Objectives: To review the current available literature on the mutual effect of pregnancy or contraceptives and Behçet's disease (BD) in order to guide our patients more wisely before they take contraceptives or decide to conceive.

Methods: We performed a systematic review of the literature regarding the above issues using PubMed, Cochrane and EMBase databases.

Results: We have found 21 case reports and 11 series dealing with the mutual effect of pregnancy or contraceptives and Behçet's disease and 5 case reports dealing with BD and contraceptives. In most cases the course of BD was ameliorated or unchanged during pregnancy. The outcome of pregnancy in BD patients was poorer than that in healthy individuals. Contraceptives have various effects on the course of BD.

Conclusions: Despite the above impression, it is quite difficult to predict the course of the disease during pregnancy in an individual BD patient. Patients with BD and a history of thrombosis are recommended to avoid contraceptive pills.
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December 2014
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