Rheumatology International

, Volume 39, Issue 6, pp 1045–1051 | Cite as

Cancer incidence in familial Mediterranean fever patients: a retrospective analysis from central Anatolia

  • Emre Bilgin
  • Ömer Dizdar
  • Deniz Can Güven
  • Serdar Ceylan
  • Özge Aybi
  • Büşra Fırlatan
  • Rıza Can Kardaş
  • Tolga Yıldırım
  • Mutlu Kadir Hayran
  • Umut KalyoncuEmail author
  • Seza Özen
Observational Research


Although chronic inflammation has been associated with increased cancer risk in various disease including hepatitis or inflammatory bowel disease, a lower incidence of cancer has been reported recently in familial Mediterranean fever (FMF) which is an auto-inflammatory disease with persistent inflammation. We have assessed cancer incidence among FMF patients with or without amyloidosis to investigate this hypothesis. We performed a retrospective review of FMF patients, diagnosed and treated in Hacettepe University hospitals between 2001 and 2018. We identified patients from the hospital medical records using the ICD-10 code for FMF. We collected data on demographic and clinical features, drug history, the presence of amyloidosis and subsequent diagnosis of cancer. The expected cancer incidence was estimated using age- and gender-specific standardized incidence rates (SIRs) in comparison with the general Turkish population according to Turkish National Cancer Registry data at 2014. Total of 3899 FMF patients (120 patients had also amyloidosis) were included. Median age was 22 and 56% were females. Thirty-eight patients were diagnosed with cancer during 100,283 person-years of follow-up. The most common cancer was breast cancer in females (7/28 patients) and leukemia (2/10 patients) in males. The overall cancer incidence among patients with FMF was significantly lower in both males {SIR 0.42 [95% confidence interval; (CI) 0.21–0.75], p = 0.019} and females [SIR 065 (95% CI 0.44–0.93), p = 0.002]. The overall cancer incidence among patients with FMF and amyloidosis was [SIR 1.21 (95% CI 0.49–2.52), p = 0.73] without gender difference. Cancer incidence was significantly lower in FMF patients compared with the general Turkish population. We found no increased cancer incidence in FMF patients having amyloidosis. Possible underlying mechanisms need to be explained.


Familial Mediterranean fever Amyloidosis Cancer Standardized incidence ratio 



Language editing was done by an online and licensed tool.

Author contributions

All authors participated in study design, data collection, analysis, interpretation and writing equally.



Compliance with ethical standards

Conflict of interest

None of the authors have any potential conflict of interest.


  1. 1.
    Heller H, Kariv J, Sherf L, Sohar E (1955) Familial Mediterranean fever. Harefuah 48(5):91–94PubMedGoogle Scholar
  2. 2.
    Soylemezoglu O, Kandur Y, Gonen S, Duzova A, Ozcakar ZB, Fidan K, Yalcinkaya F (2016) Familial Mediterranean fever gene mutation frequencies in a sample Turkish population. Clin Exp Rheumatol 34(6 Suppl 102):97–100PubMedGoogle Scholar
  3. 3.
    Alghamdi M (2017) Familial Mediterranean fever, review of the literature. Clin Rheumatol 36(8):1707–1713. CrossRefPubMedGoogle Scholar
  4. 4.
    Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, Gumucio DL, Shoham NG, Kastner DL (2008) The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 112(5):1794–1803. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Doerr W (1985) Cohnheim's inflammation doctrine and the current debate. Zentralblatt fur allgemeine Pathologie u pathologische Anatomie 130(4):299–306PubMedGoogle Scholar
  6. 6.
    Nakamura S, Matsumoto T (2013) Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma: recent progress in pathogenesis and management. World J Gastroenterol 19(45):8181–8187. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Koizumi T, Kamata T, Nakamura M, Sugawa Y, Mitsuya N (1970) Case of primary cancer of the liver developing in the course of chronic hepatitis. Nihon rinsho Jpn J Clin Med 28(2):316–319Google Scholar
  8. 8.
    Johnson TM, Orr TG (1948) Carcinoma of the colon secondary to chronic ulcerative colitis. Am J Dig Dis 15(1):21–23CrossRefPubMedGoogle Scholar
  9. 9.
    Shalapour S, Karin M (2015) Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Investig 125(9):3347–3355. CrossRefPubMedGoogle Scholar
  10. 10.
    Moynihan KD, Irvine DJ (2017) Roles for innate immunity in combination immunotherapies. Cancer Res 77(19):5215–5221. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kantono M, Guo B (2017) Inflammasomes and cancer: the dynamic role of the inflammasome in tumor development. Front Immunol 8:1132. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ozen S, Batu ED, Demir S (2017) Familial Mediterranean fever: recent developments in pathogenesis and new recommendations for management. Front Immunol 8:253. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Na SJ, Kang MJ, Yu DS, Han KD, Lee JH, Park YG, Lee YB (2018) Cancer risk in patients with Behcet disease: a nationwide population-based dynamic cohort study from Korea. J Am Acad Dermatol 78(3):464–470.e462. CrossRefPubMedGoogle Scholar
  14. 14.
    Yu KH, Kuo CF, Huang LH, Huang WK, See LC (2016) Cancer risk in patients with inflammatory systemic autoimmune rheumatic diseases: a nationwide population-based dynamic cohort study in Taiwan. Medicine (Baltimore) 95(18):e3540. CrossRefGoogle Scholar
  15. 15.
    Wang LH, Wang WM, Hsu SM, Lin SH, Shieh CC (2015) Risk of overall and site-specific cancers in Behcet disease: a nationwide population-based study in Taiwan. J Rheumatol 42(5):879–884. CrossRefPubMedGoogle Scholar
  16. 16.
    Brenner R, Ben-Zvi I, Shinar Y, Liphshitz I, Silverman B, Peled N, Levy C, Ben-Chetrit E, Livneh A, Kivity S (2018) Familial Mediterranean fever and incidence of cancer: an analysis of 8,534 Israeli patients with 258,803 person-years. Arthritis Rheumatol 70(1):127–133. CrossRefPubMedGoogle Scholar
  17. 17.
    Turkish National Cancer Registry (TNCR) (2014).ılı-türkiye-kanser-istatistikleri.html. Accessed 1 July 2018Google Scholar
  18. 18.
    Berger NA (2014) Obesity and cancer pathogenesis. Ann N Y Acad Sci 1311:57–76. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ben-Zvi I, Livneh A (2011) Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 7(2):105–112. CrossRefPubMedGoogle Scholar
  20. 20.
    Brito-Zeron P, Kostov B, Fraile G, Caravia-Duran D, Maure B, Rascon FJ, Zamora M, Casanovas A, Lopez-Dupla M, Ripoll M, Pinilla B, Fonseca E, Akasbi M, de la Red G, Duarte-Millan MA, Fanlo P, Guisado-Vasco P, Perez-Alvarez R, Chamorro AJ, Morcillo C, Jimenez-Heredia I, Sanchez-Berna I, Lopez-Guillermo A, Ramos-Casals M (2017) Characterization and risk estimate of cancer in patients with primary Sjogren syndrome. J Hematol Oncol 10(1):90. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bernatsky S, Ramsey-Goldman R, Labrecque J, Joseph L, Boivin JF, Petri M, Zoma A, Manzi S, Urowitz MB, Gladman D, Fortin PR, Ginzler E, Yelin E, Bae SC, Wallace DJ, Edworthy S, Jacobsen S, Gordon C, Dooley MA, Peschken CA, Hanly JG, Alarcon GS, Nived O, Ruiz-Irastorza G, Isenberg D, Rahman A, Witte T, Aranow C, Kamen DL, Steinsson K, Askanase A, Barr S, Criswell LA, Sturfelt G, Patel NM, Senecal JL, Zummer M, Pope JE, Ensworth S, El-Gabalawy H, McCarthy T, Dreyer L, Sibley J, St Pierre Y, Clarke AE (2013) Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun 42:130–135. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Silman AJ, Petrie J, Hazleman B, Evans SJ (1988) Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 47(12):988–992CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Larocque K, Ovadje P, Djurdjevic S, Mehdi M, Green J, Pandey S (2014) Novel analogue of colchicine induces selective pro-death autophagy and necrosis in human cancer cells. PLoS One 9(1):e87064. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yunos NM, Beale P, Yu JQ, Strain D, Huq F (2010) Studies on combinations of platinum with paclitaxel and colchicine in ovarian cancer cell lines. Anticancer Res 30(10):4025–4037PubMedGoogle Scholar
  25. 25.
    Lin ZY, Wu CC, Chuang YH, Chuang WL (2013) Anti-cancer mechanisms of clinically acceptable colchicine concentrations on hepatocellular carcinoma. Life Sci 93(8):323–328. CrossRefPubMedGoogle Scholar
  26. 26.
    La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggieri V, Sisinni L, Bolognesi A, Rensen WM, Miele A, Nalli M, Alfonsi R, Di Marcotullio L, Gulino A, Brancale A, Novellino E, Dondio G, Vultaggio S, Varasi M, Mercurio C, Hamel E, Lavia P, Silvestri R (2014) New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer. J Med Chem 57(15):6531–6552. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lin ZY, Kuo CH, Wu DC, Chuang WL (2016) Anticancer effects of clinically acceptable colchicine concentrations on human gastric cancer cell lines. Kaohsiung J Med Sci 32(2):68–73. CrossRefPubMedGoogle Scholar
  28. 28.
    Kuo MC, Chang SJ, Hsieh MC (2015) Colchicine significantly reduces incident cancer in gout male patients: a 12-year cohort study. Medicine (Baltimore) 94(50):e1570. CrossRefGoogle Scholar
  29. 29.
    Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ (2017) Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet (London, England) 390(10105):1833–1842. CrossRefGoogle Scholar
  30. 30.
    Giat E, Ehrenfeld M, Shoenfeld Y (2017) Cancer and autoimmune diseases. Autoimmun Rev 16(10):1049–1057. CrossRefPubMedGoogle Scholar
  31. 31.
    Raaschou P, Soderling J, Turesson C, Askling J, Group AS (2018) Tumor necrosis factor inhibitors and cancer recurrence in Swedish patients with rheumatoid arthritis: a nationwide population-based cohort study. Ann Intern Med 169(5):291–299. CrossRefGoogle Scholar
  32. 32.
    van der Hilst JC, Simon A, Drenth JP (2005) Hereditary periodic fever and reactive amyloidosis. Clin Exp Med 5(3):87–98. CrossRefPubMedGoogle Scholar
  33. 33.
    Hemminki K, Li X, Forsti A, Sundquist J, Sundquist K (2014) Cancer risk in amyloidosis patients in Sweden with novel findings on non-Hodgkin lymphoma and skin cancer. Ann Oncol 25(2):511–518. CrossRefPubMedGoogle Scholar
  34. 34.
    Barrott JJ, Kafchinski LA, Jin H, Potter JW, Kannan SD, Kennedy R, Mosbruger T, Wang WL, Tsai JW, Araujo DM, Liu T, Capecchi MR, Lazar AJ, Jones KB (2016) Modeling synovial sarcoma metastasis in the mouse: PI3’-lipid signaling and inflammation. J Exp Med 213(13):2989–3005. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Maturu P (2016) The inflammatory microenvironment in wilms tumors. In: van den Heuvel-Eibrink MM (ed) Wilms tumor. Codon Publications, Brisban. (Copyright: The Author) CrossRefGoogle Scholar
  36. 36.
    Sowers JL, Johnson KM, Conrad C, Patterson JT, Sowers LC (2014) The role of inflammation in brain cancer. Adv Exp Med Biol 816:75–105. CrossRefPubMedGoogle Scholar
  37. 37.
    Thieblemont C, Bertoni F, Copie-Bergman C, Ferreri AJ, Ponzoni M (2014) Chronic inflammation and extra-nodal marginal-zone lymphomas of MALT-type. Semin Cancer Biol 24:33–42. CrossRefPubMedGoogle Scholar
  38. 38.
    Ting JP, Duncan JA, Lei Y (2010) How the noninflammasome NLRs function in the innate immune system. Science 327(5963):286–290. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lukens JR, Kanneganti TD (2014) Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease. Semin Immunopathol 36(5):595–609. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, Quadroni M, Drexler SK, Tschopp J (2012) Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36(3):388–400. CrossRefPubMedGoogle Scholar
  41. 41.
    Shouval DS, Biswas A, Kang YH, Griffith AE, Konnikova L, Mascanfroni ID, Redhu NS, Frei SM, Field M, Doty AL, Goldsmith JD, Bhan AK, Loizides A, Weiss B, Yerushalmi B, Yanagi T, Lui X, Quintana FJ, Muise AM, Klein C, Horwitz BH, Glover SC, Bousvaros A, Snapper SB (2016) Interleukin 1beta mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency. Gastroenterology 151(6):1100–1104. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD (2010) IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J İmmunol (Baltimore, Md: 1950) 185(8):4912–4920. CrossRefGoogle Scholar
  43. 43.
    Drexler SK, Bonsignore L, Masin M, Tardivel A, Jackstadt R, Hermeking H, Schneider P, Gross O, Tschopp J, Yazdi AS (2012) Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc Natl Acad Sci USA 109(45):18384–18389. CrossRefPubMedGoogle Scholar
  44. 44.
    Okamoto M, Liu W, Luo Y, Tanaka A, Cai X, Norris DA, Dinarello CA, Fujita M (2010) Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta. J Biol Chem 285(9):6477–6488. CrossRefPubMedGoogle Scholar
  45. 45.
    Guo B, Fu S, Zhang J, Liu B, Li Z (2016) Targeting inflammasome/IL-1 pathways for cancer immunotherapy. Sci Rep 6:36107. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Daley D, Mani VR, Mohan N, Akkad N, Pandian G, Savadkar S, Lee KB, Torres-Hernandez A, Aykut B, Diskin B, Wang W, Farooq MS, Mahmud AI, Werba G, Morales EJ, Lall S, Wadowski BJ, Rubin AG, Berman ME, Narayanan R, Hundeyin M, Miller G (2017) NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J Exp Med 214(6):1711–1724. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L (2014) Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab İnvestig J Tech Methods Pathol 94(1):52–62. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicineHacettepe University Medical SchoolAnkaraTurkey
  2. 2.Department of Preventive OncologyHacettepe University Medical SchoolAnkaraTurkey
  3. 3.Division of Medical Oncology, Department of Internal MedicineHacettepe University Medical SchoolAnkaraTurkey
  4. 4.Department of Internal MedicineHacettepe University Medical SchoolAnkaraTurkey
  5. 5.Division of Nephrology, Department of Internal MedicineHacettepe University Medical SchoolAnkaraTurkey
  6. 6.Division of Pediatric Rheumatology, Department of PediatricsHacettepe University Medical SchoolAnkaraTurkey

Personalised recommendations