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

      research-article
      1 , 2 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 1 , 2 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 13 , 22 , 3 , 3 , 3 , 4 , 4 , 4 , 6 , 6 , 6 , 7 , 7 , 7 , 1 , 2 , 8 , 8 , 9 , 9 , 1 , 2 , 10 , 10 , 23 , 14 , 15 , 2 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 1 , 2 , 35 , 3 , 16 , 35 , 36 , 36 , 37 , 38 , 39 , 40 , 41 , 1 , 2 , 1 , 2 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 36 , 51 , 2 , 52 , 1 , 2 , 1 , 2 ,
      Frontiers in Immunology
      Frontiers Media S.A.
      autoinflammatory diseases, FMF, tumor, neoplasm, rare diseases, treatment

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          Abstract

          Objective

          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.

          Methods

          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.

          Results

          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).

          Conclusions

          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.

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          Most cited references46

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          2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria.

          The provisional criteria of the American College of Rheumatology (ACR) 2010 and the 2011 self-report modification for survey and clinical research are widely used for fibromyalgia diagnosis. To determine the validity, usefulness, potential problems, and modifications required for the criteria, we assessed multiple research reports published in 2010-2016 in order to provide a 2016 update to the criteria.
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            Inflammation and Cancer

            Inflammation is often associated with the development and progression of cancer. The cells responsible for cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance; therefore, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammations can result in immunosuppression, thereby providing a preferred background for tumor development. The current review provides a link between inflammation and cancer development.
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              Preliminary criteria for classification of adult Still's disease.

              We have attempted to design classification criteria for adult Still's disease by analyzing the data obtained through a multicenter survey of 90 Japanese patients with this disease and of 267 control patients. The proposed criteria consisted of fever, arthralgia, typical rash, and leukocytosis as major, and sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and the absence of rheumatoid factor and antinuclear antibody as minor criteria. Requiring 5 or more criteria including 2 or more major criteria yielded 96.2% sensitivity and 92.1% specificity. However, an exclusion process will be needed for an accurate classification, since this disease is relatively rare.
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                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                10 May 2024
                2024
                : 15
                : 1397890
                Affiliations
                [1] 1 Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease Clinic, University of Siena , Siena, Italy
                [2] 2 Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center] , Siena, Italy
                [3] 3 Gazi University Hospital, Department of Internal Medicine, Division of Rheumatology , Ankara, Türkiye
                [4] 4 Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University , Giza, Egypt
                [5] 5 Faculty of Medicine, Newgiza University, 6th of October City , Giza, Egypt
                [6] 6 Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University School of Medicine , Ankara, Türkiye
                [7] 7 Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro , Bari, Italy
                [8] 8 Division of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello , Palermo, Italy
                [9] 9 Pediatric Nephrology and Rheumatology Unit, Azienda Ospedaliera Universitaria (AOU), “G. Martino” , Messina, Italy
                [10] 10 Department of Translational Medical Sciences, Section of Clinical Immunology, University of Naples Federico II , Naples, Italy
                [11] 11 Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II , Naples, Italy
                [12] 12 Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy
                [13] 13 Rare Diseases and Periodic Fevers Research Center, Università Cattolica del Sacro Cuore , Rome, Italy
                [14] 14 Department of Woman, Child and of General and Specialized Surgery, University of Campania “Luigi Vanvitelli” , Naples, Italy
                [15] 15 Division of Rheumatology, Department of Internal Medicine, Sivas Cumhuriyet University Medical Faculty , Sivas, Türkiye
                [16] 16 Department of Pediatrics, Pediatric Rheumatology Center, Giovanni XXIII Pediatric Hospital, University of Bari , Bari, Italy
                [17] 17 Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J) Policlinic Hospital, University of Bari , Bari, Italy
                [18] 18 Pediatrics Clinic, University of Brescia and Spedali Civili of Brescia, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center] , Brescia, Italy
                [19] 19 University Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) “G. D’Alessandro”, University of Palermo , Palermo, Italy
                [20] 20 Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center] , Rome, Italy
                [21] 21 Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center] , Athens, Greece
                [22] 22 Department of Aging, Neurological, Orthopedic and Head and Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) , Rome, Italy
                [23] 23 Department of Pediatric Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy
                [24] 24 Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena , Siena, Italy
                [25] 25 Department of Rheumatology, “Evangelismos” General Hospital , Athens, Greece
                [26] 26 Department of Autoimmune Diseases, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic of Barcelona [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], University of Barcelona , Barcelona, Spain
                [27] 27 Department of Experimental and Clinical Medicine, University of Florence , Florence, Italy
                [28] 28 Rheumatology and Internal Medicine Department, Carol Davila University of Medicine and Pharmacy , Bucharest, Romania
                [29] 29 Pediatric Rheumatology Unit, Department of integrated Maternal-Child and Reproduction Activity AOU “Policlinico-San Marco” , Catania, Italy
                [30] 30 Department of Dermatology, Allergology and Venerology, University Hospital Schleswig-Holstein , Lübeck, Germany
                [31] 31 Autoinflammatory and Autoimmune Diseases (RITA) Center, European Reference Network (ERN) for Rare Immunodeficiency , Lübeck, Germany
                [32] 32 Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan , Milan, Italy
                [33] 33 Rheumatology Unit, Department of Medicine, University of Padua , Padua, Italy
                [34] 34 Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo , São Paulo, Brazil
                [35] 35 Department of Internal Medicine, Pneumonology, Allergology and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine, National Research Institute , Warsaw, Poland
                [36] 36 Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Mexico City, Mexico
                [37] 37 Rheumatology Unit, Department of Medical Sciences, University and AOU of Cagliari , Cagliari, Italy
                [38] 38 Ospedale San Paolo di Civitavecchia, U.O. Medicina Generale, ASL Roma 4 , Civitavecchia, Rome, Italy
                [39] 39 Department of Medical, Surgical and Health Sciences, University of Trieste, Italy, and Clinical Medicine and Rheumatology Unit, Cattinara University Hospital , Trieste, Italy
                [40] 40 Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University , Clayton, VIC, Australia
                [41] 41 Rheumatology Unit, Hospital S. Giovanni di Dio, Azienda USL-Toscana Centro , Florence, Italy
                [42] 42 Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila , L’Aquila, Italy
                [43] 43 Pediatric and Neonatology Unit, Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome , Latina, Italy
                [44] 44 Rheumatology and Immunology Unit, Internal Medicine Department, Mansoura University , Mansoura, Egypt
                [45] 45 Department of Internal Medicine, Faculty of Medicine, Horus University , New Damietta, Egypt
                [46] 46 Department of Biomedical and Clinical Sciences, Fatebenefratelli Hospital, Università di Milano , Milan, Italy
                [47] 47 Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of Antwerp , Antwerp, Belgium
                [48] 48 Antwerp Center for Translational Immunology and Virology, Vaccine and Infectious Disease Institute, University of Antwerp , Antwerp, Belgium
                [49] 49 Department of Pediatrics, Antwerp University Hospital , Antwerp, Belgium
                [50] 50 Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp , Antwerp, Belgium
                [51] 51 Bioengineering and Biomedical Data Science Lab, Department of Medical Biotechnologies, University of Siena , Siena, Italy
                [52] 52 Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena , Siena, Italy
                Author notes

                Edited by: Ozgur Kasapcopur, Istanbul University-Cerrahpasa, Türkiye

                Reviewed by: Sezgin Sahin, Istanbul University-Cerrahpasa, Türkiye

                Oya Koker, Istanbul University, Türkiye

                *Correspondence: Luca Cantarini, cantariniluca@ 123456hotmail.com

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2024.1397890
                11116561
                38799474
                fb392773-1391-47e5-85f6-5ffd09836084
                Copyright © 2024 Vitale, Caggiano, Tufan, Ragab, Batu, Portincasa, Aragona, Sota, Conti, De Paulis, Rigante, Olivieri, Şahin, La Torre, Lopalco, Cattalini, Maggio, Insalaco, Sfikakis, Verrecchia, Yildirim, Kucuk, Kardas, Laymouna, Ghanema, Saad, Sener, Ercan Emreol, Ozen, Jaber, Khalil, Di Ciaula, Gaggiano, Malizia, Affronti, Patroniti, Romeo, Sbalchiero, Della Casa, Mormile, Silvaroli, Gicchino, Çelik, Tarsia, Karamanakos, Hernández-Rodríguez, Parronchi, Opris-Belinski, Barone, Recke, Costi, Sfriso, Giardini, Gentileschi, Wiesik-Szewczyk, Vasi, Loconte, Jahnz-Różyk, Martín-Nares, Torres-Ruiz, Cauli, Conforti, Emmi, Li Gobbi, Biasi, Terribili, Ruscitti, Del Giudice, Tharwat, Brucato, Ogunjimi, Hinojosa-Azaola, Balistreri, Fabiani, Frediani and Cantarini

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 March 2024
                : 22 April 2024
                Page count
                Figures: 1, Tables: 7, Equations: 0, References: 47, Pages: 12, Words: 5138
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We thank the University of Siena for the financial support in supporting the open access fees.
                Categories
                Immunology
                Original Research
                Custom metadata
                Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders

                Immunology
                autoinflammatory diseases,fmf,tumor,neoplasm,rare diseases,treatment
                Immunology
                autoinflammatory diseases, fmf, tumor, neoplasm, rare diseases, treatment

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