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Chronic inflammation in FMF: markers, risk factors, outcomes and therapy

Abstract

Familial Mediterranean fever (FMF) is the most common of the hereditary periodic fever syndromes. Although the typical clinical course of FMF is characterized by bouts of painful inflammation, this presentation represents only the tip of the iceberg. In many patients inflammation can persist in attack-free periods, as shown by high levels of acute-phase proteins, cytokines and inflammation-induced proteins. This subclinical inflammation puts patients at risk of developing complications such as anemia, splenomegaly, decreased bone mineral density, heart disease and life-threatening amyloid A amyloidosis, among others. In this article, we review the published data on markers and other factors involved in the persistence of inflammation in patients with FMF during attack-free periods, examine the risk factors for the development of this subclinical inflammation, summarize the complications of chronic inflammation in FMF and propose a new strategy for treatment, based on these data.

Key Points

  • The hallmark feature of familial Mediterranean fever (FMF) is acute, painful episodes of inflammation, but chronic subclinical inflammation may persist between attacks

  • Chronic subclinical inflammation in patients with FMF might lead to complications, including amyloid A amyloidosis, anemia, splenomegaly and decreased bone density

  • In addition to the prevention of acute attacks, treatment of FMF should be aimed at decreasing the chronic subclinical inflammation and impeding its deleterious clinical outcome

  • Serum amyloid A protein is a sensitive marker of chronic inflammation in FMF that should be measured and the levels taken into account in treatment decisions

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Figure 1: 'Classic' versus 'non-classic' markers of inflammation in FMF.
Figure 2: Proposed algorithm for the treatment of patients with FMF.

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References

  1. Livneh, A. et al. The changing face of familial Mediterranean fever. Semin. Arthritis Rheum. 26, 612–627 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, 25–31 (1997).

  3. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).

  4. Stojanov, S. & Kastner, D. L. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr. Opin. Rheumatol. 17, 586–599 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Chae, J. J., Aksentijevich, I. & Kastner, D. L. Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br. J. Haematol. 146, 467–478 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dinarello, C. A. Interleukin-1beta and the autoinflammatory diseases. N. Engl. J. Med. 360, 2467–2470 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Kogan, A. et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am. J. Med. Genet. 102, 272–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Celkan, T. et al. The anemia of familial Mediterranean fever disease. Pediatr. Hematol. Oncol. 22, 657–665 (2005).

    Article  PubMed  Google Scholar 

  9. Inal, A., Yilmaz, M., Kendirli, S. G., Altintas, D. U. & Karakoc, G. B. The clinical and genetical features of 124 children with Familial Mediterranean fever: experience of a single tertiary center. Rheumatol. Int. 29, 1279–1285 (2009).

    Article  PubMed  Google Scholar 

  10. Duzova, A. et al. Bone mineral density in children with familial Mediterranean fever. Clin. Rheumatol. 23, 230–234 (2004).

    Article  PubMed  Google Scholar 

  11. Frensdorff, A., Sohar, E. & Heller, H. Plasma fibrinogen in familial Mediterranean fever. Ann. Intern. Med. 55, 448–455 (1961).

    Article  CAS  PubMed  Google Scholar 

  12. Zemer, D., Livneh, A., Danon, Y. L., Pras, M. & Sohar, E. Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum. 34, 973–977 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Korkmaz, C., Ozdogan, H., Kasapcopur, O. & Yazici, H. Acute phase response in familial Mediterranean fever. Ann. Rheum. Dis. 61, 79–81 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Duzova, A. et al. Role of A-SAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin. Exp. Rheumatol. 21, 509–514 (2003).

    CAS  PubMed  Google Scholar 

  15. Lachmann, H. J. et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford) 45, 746–750 (2006).

    Article  CAS  Google Scholar 

  16. Tunca, M. et al. Acute phase response and evolution of familial Mediterranean fever. Lancet 353, 1415 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Balci, B. et al. MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol. Dial. Transplant. 17, 1921–1923 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Livneh, A. [Amyloidosis of familial Mediterranean fever (FMF)--insights to FMF phenotype II]. Harefuah 145, 743–745, 782 (2006).

    PubMed  Google Scholar 

  19. Karatay, S. et al. Increased serum concentrations of homocysteine and lipoprotein (a) in familial Mediterranean fever. Ann. Clin. Lab. Sci. 40, 10–14 (2010).

    CAS  PubMed  Google Scholar 

  20. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Buckley, D. I., Fu, R., Freeman, M., Rogers, K. & Helfand, M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta- analyses for the, U. S. Preventive Services Task Force. Ann. Intern. Med. 151, 483–495 (2009).

    Article  PubMed  Google Scholar 

  22. Wittkowski, H. et al. S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin. Arthritis Rheum. 58, 3924–3931 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Foell, D., Wittkowski, H. & Roth, J. Mechanisms of disease: a 'DAMP' view of inflammatory arthritis. Nat. Clin. Pract. Rheumatol. 3, 382–390 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Foell, D. et al. Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum. 50, 1286–1295 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Kallinich, T., Wittkowski, H., Keitzer, R., Roth, J. & Foell, D. Neutrophil-derived S100A12 as novel biomarker of inflammation in familial Mediterranean fever. Ann. Rheum. Dis. 69, 677–82 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Balat, A. et al. Adrenomedullin and total nitrite levels in children with familial Mediterranean fever. J. Paediatr. Child. Health 42, 240–243 (2006).

    Article  PubMed  Google Scholar 

  27. Elsasser, T. H. & Kahl, S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc. Res. Tech. 57, 120–129 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Gang, N. et al. Activation of the cytokine network in familial Mediterranean fever. J. Rheumatol. 26, 890–897 (1999).

    CAS  PubMed  Google Scholar 

  29. Kiraz, S. et al. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Clin. Exp. Rheumatol. 16, 721–724 (1998).

    CAS  PubMed  Google Scholar 

  30. Notarnicola, C., Didelot, M. N., Seguret, F., Demaille, J. & Touitou, I. Enhanced cytokine mRNA levels in attack-free patients with familial Mediterranean fever. Genes Immun. 3, 43–45 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Bagci, S. et al. Continuity of cytokine activation in patients with familial Mediterranean fever. Clin. Rheumatol. 23, 333–337 (2004).

    Article  PubMed  Google Scholar 

  32. Haznedaroglu, S. et al. Serum interleukin 17 and interleukin 18 levels in familial Mediterranean fever. Clin. Exp. Rheumatol. 23, S77–S80 (2005).

    CAS  PubMed  Google Scholar 

  33. Simsek, I. et al. Serum proinflammatory cytokines directing T helper 1 polarization in patients with familial Mediterranean fever. Rheumatol. Int. 27, 807–811 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Erken, E., Ozer, H. T. & Gunesacar, R. Plasma interleukin-10 and interleukin-12 levels in patients with familial Mediterranean fever. Rheumatol. Int. 26, 862–864 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Manukyan, G. P. et al. Cytokine profile of Armenian patients with familial Mediterranean fever. Clin. Biochem. 41, 920–922 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Akcan, Y. et al. The importance of serial measurements of cytokine levels for the evaluation of their role in pathogenesis in familial Mediterraean fever. Eur. J. Med. Res. 8, 304–306 (2003).

    CAS  PubMed  Google Scholar 

  37. Melamed, A., Cabili, S., Zakuth, V. & Spirer, Z. The immune regulation in familial Mediterranean fever (FMF). J. Clin. Lab. Immunol. 26, 125–128 (1988).

    CAS  PubMed  Google Scholar 

  38. Dinarello, C. A. Blocking IL-1 in systemic inflammation. J. Exp. Med. 201, 1355–1359 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rozenbaum, M., Katz, R., Rozner, I. & Pollack, S. Decreased interleukin 1 activity released from circulating monocytes of patients with familial Mediterranean fever during in vitro stimulation by lipopolysaccharide. J. Rheumatol. 19, 416–418 (1992).

    CAS  PubMed  Google Scholar 

  40. Koklu, S. et al. Interferon-gamma levels in familial Mediterranean fever. Joint Bone Spine 72, 38–40 (2005).

    Article  PubMed  Google Scholar 

  41. Basar, O. et al. Plasma levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) in familial Mediterranean fever. Joint Bone Spine 74, 52–55 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Rigante, D. et al. Serum macrophage migration inhibitory factor (MIF) in the intercritical phase of hereditary periodic fevers and its relationship with the MIF-173G/C polymorphism. Scand. J. Rheumatol. 36, 307–310 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Direskeneli, H., Ozdogan, H., Korkmaz, C., Akoglu, T. & Yazici, H. Serum soluble intercellular adhesion molecule 1 and interleukin 8 levels in familial Mediterranean fever. J. Rheumatol. 26, 1983–1986 (1999).

    CAS  PubMed  Google Scholar 

  44. Bentancur, A. G., Naveh, N., Lancri, J., Selah, B. A. & Livneh, A. Urine leukotriene B4 in familial Mediterranean fever. Clin. Exp. Rheumatol. 22, S56–S58 (2004).

    CAS  PubMed  Google Scholar 

  45. Centola, M. et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95, 3223–3231 (2000).

    CAS  PubMed  Google Scholar 

  46. Musabak, U. et al. Does immune activation continue during an attack-free period in familial Mediterranean fever? Clin. Exp. Immunol. 138, 526–533 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Aypar, E. et al. Th1 polarization in familial Mediterranean fever. J. Rheumatol. 30, 2011–2013 (2003).

    PubMed  Google Scholar 

  48. Anton, P. A. et al. Enhanced neutrophil chemiluminescence in familial Mediterranean fever. J. Clin. Immunol. 8, 148–156 (1988).

    Article  CAS  PubMed  Google Scholar 

  49. Davtyan, T. K., Hakopyan, G. S., Avetisyan, S. A. & Mkrtchyan, N. R. Impaired endotoxin tolerance induction in patients with familial Mediterranean fever. Pathobiology 73, 26–39 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Simon, A. & van der Meer, J. W. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R86–R98 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Mor, A. et al. Evaluation of disease severity in familial Mediterranean fever. Semin. Arthritis Rheum. 35, 57–64 (2005).

    Article  PubMed  Google Scholar 

  52. Gershoni-Baruch, R., Brik, R., Lidar, M., Shinawi, M. & Livneh, A. Male sex coupled with articular manifestations cause a 4-fold increase in susceptibility to amyloidosis in patients with familial Mediterranean fever homozygous for the M694V-MEFV mutation. J. Rheumatol. 30, 308–312 (2003).

    PubMed  Google Scholar 

  53. Gershoni-Baruch, R. et al. The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum. 48, 1149–1155 (2003).

    Article  PubMed  Google Scholar 

  54. Padeh, S. et al. Clinical and diagnostic value of genetic testing in 216 Israeli children with familial Mediterranean fever. J. Rheumatol. 30, 185–190 (2003).

    PubMed  Google Scholar 

  55. Berkun, Y. et al. A single testing of serum amyloid A levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin. Arthritis Rheum. 37, 182–188 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Dinarello, C. A., Wolff, S. M., Goldfinger, S. E., Dale, D. C. & Alling, D. W. Colchicine therapy for familial mediterranean fever. A double-blind trial. N. Engl. J. Med. 291, 934–937 (1974).

    Article  CAS  PubMed  Google Scholar 

  57. Goldfinger, S. E. Colchicine for familial Mediterranean fever. N. Engl. J. Med. 287, 1302 (1972).

    CAS  PubMed  Google Scholar 

  58. Zemer, D. et al. A controlled trial of colchicine in preventing attacks of familial mediterranean fever. N. Engl. J. Med. 291, 932–934 (1974).

    Article  CAS  PubMed  Google Scholar 

  59. Ozcakar, Z. B. et al. Possible effect of subclinical inflammation on daily life in familial Mediterranean fever. Clin. Rheumatol. 25, 149–152 (2006).

    Article  PubMed  Google Scholar 

  60. Zung, A., Barash, G., Zadik, Z. & Barash, J. Familial Mediterranean fever and growth: effect of disease severity and colchicine treatment. J. Pediatr. Endocrinol. Metab. 19, 155–160 (2006).

    Article  PubMed  Google Scholar 

  61. Gough, A. K., Lilley, J., Eyre, S., Holder, R. L. & Emery, P. Generalised bone loss in patients with early rheumatoid arthritis. Lancet 344, 23–27 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Harrison, B. J., Hutchinson, C. E., Adams, J., Bruce, I. N. & Herrick, A. L. Assessing periarticular bone mineral density in patients with early psoriatic arthritis or rheumatoid arthritis. Ann. Rheum. Dis. 61, 1007–1011 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Carbone, L., Tylavsky, F., Wan, J., McKown, K. & Cheng, S. Bone mineral density in scleroderma. Rheumatology (Oxford) 38, 371–372 (1999).

    Article  CAS  Google Scholar 

  64. Yuksel, S. et al. Increased serum osteoprotegerin levels associated with decreased bone mineral density in familial Mediterranean fever. Tohoku J. Exp. Med. 217, 321–327 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Suyani, E. et al. Decreased bone mineral density in adult familial Mediterranean fever patients: a pilot study. Clin. Rheumatol. 27, 1171–1175 (2008).

    Article  PubMed  Google Scholar 

  66. Yildirim, K. et al. Bone mineral density in patients with familial Mediterranean fever. Rheumatol. Int. 30, 305–308 (2010).

    Article  PubMed  Google Scholar 

  67. Buskila, D. et al. Quality of life of patients with familial Mediterranean fever. Clin. Exp. Rheumatol. 15, 355–360 (1997).

    CAS  PubMed  Google Scholar 

  68. Makay, B., Unsal, E., Arslan, N. & Varni, J. W. Health-related quality of life of school-age children with familial Mediterranean fever. Clin. Exp. Rheumatol. 27, S96–S101 (2009).

    CAS  PubMed  Google Scholar 

  69. Deger, S. M. et al. Health-related quality of life and its associations with mood condition in familial Mediterranean fever patients. Rheumatol. Int. doi: 10.1007/s00296-009-1334–1334.

  70. Gimeno, D. et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol. Med. 39, 413–423 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Ehrenfeld, M., Brzezinski, A., Levy, M. & Eliakim, M. Fertility and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy. Br. J. Obstet. Gynaecol. 94, 1186–1191 (1987).

    Article  CAS  PubMed  Google Scholar 

  72. Ismajovich, B., Zemer, D., Revach, M., Serr, D. M. & Sohar, E. The causes of sterility in females with familial Mediterranean fever. Fertil. Steril. 24, 844–847 (1973).

    Article  CAS  PubMed  Google Scholar 

  73. Ofir, D., Levy, A., Wiznitzer, A., Mazor, M. & Sheiner, E. Familial Mediterranean fever during pregnancy: an independent risk factor for preterm delivery. Eur. J. Obstet. Gynecol. Reprod. Biol. 141, 115–118 (2008).

    Article  PubMed  Google Scholar 

  74. Ben-Chetrit, E. & Levy, M. Reproductive system in familial Mediterranean fever: an overview. Ann. Rheum. Dis. 62, 916–919 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Caliskan, M. et al. Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 195, e161–e167 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Tavil, Y. et al. The detailed assessment of left and right ventricular functions by tissue Doppler imaging in patients with familial Mediterranean fever. Clin. Rheumatol. 27, 189–194 (2008).

    Article  PubMed  Google Scholar 

  77. Akdogan, A. et al. Are familial Mediterranean fever (FMF) patients at increased risk for atherosclerosis? Impaired endothelial function and increased intima media thickness are found in FMF. J. Am. Coll. Cardiol. 48, 2351–2353 (2006).

    Article  PubMed  Google Scholar 

  78. Terekeci, H. M. et al. Increased asymmetric dimethylarginine levels in young men with familial Mediterranean fever (FMF): is it early evidence of interaction between inflammation and endothelial dysfunction in FMF? J. Rheumatol. 35, 2024–2029 (2008).

    CAS  PubMed  Google Scholar 

  79. Bilginer, Y. et al. Evaluation of intima media thickness of the common and internal carotid arteries with inflammatory markers in familial Mediterranean fever as possible predictors for atherosclerosis. Rheumatol. Int. 28, 1211–1216 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Ugurlu, S. et al. Intima-media thickening in patients with familial Mediterranean fever. Rheumatology (Oxford) 48, 911–915 (2009).

    Article  Google Scholar 

  81. Grimaldi, M. P. et al. Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population. J. Leukoc. Biol. 79, 611–615 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Langevitz, P. et al. Prevalence of ischemic heart disease in patients with familial Mediterranean fever. Isr. Med. Assoc. J. 3, 9–12 (2001).

    CAS  PubMed  Google Scholar 

  83. Heller, H., Sohar, E., Gafni, J. & Heller, J. Amyloidosis in familial Mediterranean fever. An independent genetically determined character. Arch. Intern. Med. 107, 539–550 (1961).

    Article  CAS  PubMed  Google Scholar 

  84. Knecht, A., de Beer, F. C. & Pras, M. Serum amyloid A protein in familial Mediterranean fever. Ann. Intern. Med. 102, 71–72 (1985).

    Article  CAS  PubMed  Google Scholar 

  85. Zemer, D., Pras, M., Sohar, E. & Gafni, J. Colchicine in familial Mediterranean fever. N. Engl. J. Med. 294, 170–171 (1976).

    Article  CAS  PubMed  Google Scholar 

  86. Tweezer-Zaks, N., Rabinovich, E., Lidar, M. & Livneh, A. Interferon-alpha as a treatment modality for colchicine-resistant familial Mediterranean fever. J. Rheumatol. 35, 1362–1365 (2008).

    CAS  PubMed  Google Scholar 

  87. Lidar, M. et al. The prodrome: a prominent yet overlooked pre-attack manifestation of familial Mediterranean fever. J. Rheumatol. 33, 1089–1092 (2006).

    PubMed  Google Scholar 

  88. Mor, A., Pillinger, M. H., Kishimoto, M., Abeles, A. M. & Livneh, A. Familial Mediterranean fever successfully treated with etanercept. J. Clin. Rheumatol. 13, 38–40 (2007).

    Article  PubMed  Google Scholar 

  89. Rilonacept for treatment of familial Mediterranean fever. ClinicalTrials.gov [online], (2010).

  90. Gillmore, J. D., Lovat, L. B., Persey, M. R., Pepys, M. B. & Hawkins, P. N. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358, 24–29 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Lachmann, H. J. et al. Natural history and outcome in systemic AA amyloidosis. N. Engl. J. Med. 356, 2361–2371 (2007).

    Article  CAS  PubMed  Google Scholar 

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I. Ben-Zvi and A. Livneh contributed equally to researching the data for the article, discussing the content, writing the article and reviewing and/or editing of the manuscript before submission.

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Correspondence to Avi Livneh.

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Ben-Zvi, I., Livneh, A. Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 7, 105–112 (2011). https://doi.org/10.1038/nrrheum.2010.181

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