Arterial stiffness in Familial Mediterranean Fever: correlations with disease-related parameters and colchicine treatment



Familial Mediterranean Fever is the most common autoinflammatory disease. As chronic inflammation may result in increased arterial stiffness, we aimed to investigate indices of arterial stiffness in patients with Familial Mediterranean Fever and their associations with disease-related factors and colchicine treatment.


The study was conducted with 43 patients with Familial Mediterranean Fever, including 30 children, in attack free period and 42 healthy controls. Arterial stiffness was assessed by carotid-femoral pulse wave velocity and augmentation index.


Patients with Familial Mediterranean Fever presented similar carotid-femoral pulse wave velocity values to controls, but significantly higher augmentation index values (patients versus controls, 19.76% and 9.96%, P < 0.05). Augmentation index, adjusted for age and sex, was associated with complete response compared with partial response to treatment (B = − 17.78, 95% CI − 31.17 to − 4.40, P < 0.05) and the presence of M694V.M680I genotype (B = − 16.75, 95% CI − 33.81 to 0.30, P = 0.05). Carotid-femoral pulse wave velocity presented an inverse relationship with colchicine treatment duration (B = − 0.003, 95% CI − 0.006 to − 0.00, P < 0.05). Pulse wave velocity values adjusted for age and systolic blood pressure were associated with attack frequency (B = 0.48, 95% CI 0.01 to 0.96, P < 0.05). Addition of colchicine treatment duration to the model attenuated the association between carotid-femoral pulse wave velocity and attack frequency supporting the protective role of colchicine.


The normal values of carotid-femoral pulse wave velocity in Familial Mediterranean Fever patients may reflect the compliance to colchicine treatment, which seems to have a protective role against arterial stiffness. However, the increased values of augmentation index need further investigation.

Key points

FMF patients are prone to present increased cardiovascular risk possibly due to inflammation.

Colchicine treatment may have protective role against arterial stiffness in FMF.

The normal values of cf-PWV in FMF patients may reflect the compliance to colchicine.

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  1. 1.

    Kishida D, Nakamura A, Yazaki M, Tsuchiya-Suzuki A, Matsuda M, Ikeda SI (2014) Genotype-phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations. Arthritis Res Ther 16(5):439.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Aksentijevich I, Centola M, Deng Z, Sood R, Balow JE, Wood G et al (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90(4):797–807.

    Article  Google Scholar 

  3. 3.

    Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar M, Shainberg B, Livneh A (2007) A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin Arthritis Rheum 37(3):182–188.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Jamilloux Y, Lefeuvre L, Magnotti F, Martin A, Benezech S, Allatif O, Penel-Page M, Hentgen V, Se´ve P, Gerfaud-Valentin M, Duquesne A, Desjonque’res M, Laurent A, Re´my-Piccolo V, Cimaz R, Cantarini L, Bourdonnay E, Walzer T, Py BF, Belot A, Henry T (2018) Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the pyrin inflammasome. Rheumatology 57:100–111

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Gangemi S, Manti S, Procopio V, Casciaro M, Di Salvo E, Cutrupi M, Ganci G, Salpietro C, Chimenz R, Cuppari C (2018) Lack of clear and univocal genotype-phenotype correlation in Familial Mediterranean Fever patients: a systematic review. Clin Genet 94(1):81–94

  6. 6.

    Procopioa V, Mantia S, Biancoa G, Contib G, Romeoa A, Maimonea F, Arrigoa T, Cutrupia MC, Salpietroa C, Cupparia C (2018) Genotype-phenotype correlation in FMF patients: a “non classic” recessive autosomal or “atypical” dominant autosomal inheritance? Gene 641:279–286

    Article  CAS  Google Scholar 

  7. 7.

    Ozkaya N, Yalcınkaya F (2003) Colchicine treatment in children with familial Mediterranean fever. Clin Rheumatol 22:314–317

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Gul A (2016) Approach to the patients with inadequate response to colchicine in familial Mediterranean fever. Best Pract Res Clin Rheumatol 30(2):296–303

    Article  PubMed  Google Scholar 

  9. 9.

    Rongen G, van Ingen I, Kok M, Vonkeman H, Janssen M, Jansen T (2018) Vasodilator function worsens after cessation of tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis only if a flare occurs. Clin Rheumatol 37:909–916

    Article  PubMed  Google Scholar 

  10. 10.

    Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM (2001) Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 103:987–992

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Biesbroek S, Heslinga SC, van de Ven PM, Peters MJL, Amier RP, Konings T, Maroules C, Ayers C, Joshi P, van der Horst-Bruinsma IE, van Halm VP, van Rossum AC, Nurmohamed M, Nijveldt R (2018) Assessment of aortic stiffness in patients with ankylosing spondylitis using cardiovascular magnetic resonance. Clin Rheumatol 37:2151–2159

    Article  PubMed  Google Scholar 

  12. 12.

    Fragouli E, Eliopoulos E, Petraki E, Sidiropoulos P, Aksentijevich I, Galanakis E, Kritikos H, Repa A, Fragiadakis G, Boumpas D, Goulielmos GN (2008) Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of intermediate risk. Clin Genet 73:152–159

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Yılmaz F, Ulu S, Akcı O, Ahsen A, Demir K, Yüksel S (2014) Evaluation of arterial stiffness with plasma GGT levels and pulse wave velocity measurement in patients with FMF. Eur J Rheum 1:11–13

    Article  Google Scholar 

  14. 14.

    Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G et al (2016) EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 75:644–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, DeBacker T et al (2012) Artery Society; European Society of Hypertension Working Group on Vascular Structure and Function; European Network for Noninvasive Investigation of Large Arteries. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid–femoral pulse wave velocity. J Hypertens 30:445–448

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Stabouli S, Printza N, Zervas C, Dotis J, Chrysaidou K, Maliahova O, Antza C, Papachristou F, Kotsis V (2018) Comparison of the SphygmoCor XCEL device with applanation tonometry for pulse wave velocity and central blood pressure assessment in youth. J Hypertens:1.

  17. 17.

    Butlin M, Qasem A, Battista F, Bozec E, McEniery CM, Millet-Amaury E et al (2013) Carotid–femoral pulse wave velocity assessment using novel cuffbased techniques: comparison with tonometric measurement. J Hypertens 31:2237–2243

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, StruijkerBoudier H (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27:2588–2605

    Article  PubMed  Google Scholar 

  19. 19.

    Georgianos PI, Mpoutsiouki F, Sabani E, Stamatiadis DN, Liakopoulos V, Balaskas EV, Zebekakis PE, Sarafidis PA (2016) Hemodialysis patients with intradialytic rise in blood pressure display higher baseline aortic stiffness and negligible drop in augmentation index with dialysis. Int Urol Nephrol 48:601–608

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Mattace-Raso F, Hofman A, Verwoert GC, Wittemana JC, Wilkinson I, Cockcroft J, McEniery C, Yasmin, Laurent S, Boutouyrie P, Bozec E, Hansen TW, Torp-Pedersen C, Ibsen H, Jeppesen J, Vermeersch SJ, Rietzschel E, De Buyzere M, Gillebert TC, Van Bortel L, Segers P, Vlachopoulos C, Aznaouridis C, Stefanadis C, Benetos A, Labat C, Lacolley P, Stehouwer C, Nijpels G, Dekker JM, Stehouwer C, Ferreira I, Twisk JW, Czernichow S, Galan P, Hercberg S, Pannier B, Guérin A, London G, Cruickshank JK, Anderson SG, Paini A, Agabiti Rosei E, Muiesan ML, Salvetti M, Filipovsky J, Seidlerova J, Dolejsova M (2010) Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J 31:2338–2350

  21. 21.

    Reusz G, Cseprekal O, TemmarMm KE, Cherif A, Thaleb A, Fekete A, Szabo A, Benetos A, Salvi P (2010) Reference values of pulse wave velocity in healthy children and teenagers. Hypertension 56:217–224

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    McEniery CM, Wilkinson IB (2005) Large artery stiffness and inflammation. J Hum Hypertens 19:507–509

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Terekeci HM, Oktenli C, Ozgurtas T, Nalbant S, Top C, Celik S, Tapan S, Kucukardali Y, Sanisoglu YS, Solmazgul E, Sahan B, Sayan O (2008) 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

    CAS  PubMed  Google Scholar 

  24. 24.

    Ozalper V, Kara M, Tanoglu A, Cetındaglı I, Ozturker C, Hancerlı Y, Hıra S, Kara K, Beyazıt Y, Yazgan Y (2017) Evaluation of endothelial dysfunction in patients with familial Mediterranean fever: the relationship between the levels of asymmetric dimethylarginine and endocan with carotid intima-media thickness and endothelium-dependent vasodilation. Clin Rheumatol 36(9):2071–2077

    Article  PubMed  Google Scholar 

  25. 25.

    Yildiz M (2010) Arterial distensibility in chronic inflammatory rheumatic disorders. Open Cardiovasc Med J 4:83–88

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Akdogan A, Calguneri M, Yavuz B, Arslan EB, Kalyoncu U, Sahiner L, Karadag O, Ertenli I, Kiraz S, Aytemir K, Akata D, Tokgozoglu L, Oto A (2006) 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

    Article  PubMed  Google Scholar 

  27. 27.

    ROSS R (1999) Atherosclerosis--an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Vlachopoulos C, Aznaouridis K, Stefanadis C (2010) Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 55:1318–1327

    Article  PubMed  Google Scholar 

  29. 29.

    Ozer S et al (2015) Simple markers for subclinical inflammation in patients with Familial Mediterranean Fever. Med Sci Monit 21:298–303

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ahsen A, Ulu M, Yuksel S, Demir K, Uysal M, Erdogan M, Acarturk G (2013) As a new inflammatory marker for Familial Mediterranean Fever: neutrophil-to-lymphocyte ratio. Inflammation 36:1357–1362

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Yildiz M, Masatlýoglu S, Seymen P, Aytac E, Sahin B, Seymen H (November 2006) The carotid-femoral (aortic) pulse wave velocity as a marker of arterial stiffness in familial Mediterranean fever. Can J Cardiol 22(13):1127–1131

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Çakar M, Akhan M, Doğan T, Taşkın G, Oztürk K, Çınar M, Arslan E, Yılmaz S (2017) Investigation of the arterial stiffness and associated factors in patients with familial Mediterranean fever. Anatol J Cardiol 17:132–138

    PubMed  Google Scholar 

  33. 33.

    Kukuy O, Livneh A, Mendel L, Benor A, Giat E, Perski O, Feld O, Kassel Y, Ben-Zvi I, Lidar M, Holtzman EJ, Leiba A (2017) Normal arterial stiffness in familial Mediterranean fever. Evidence for a possible cardiovascular protective role of colchicine. Clin Exp Rheumatol 35(Suppl. 108):S32–S37

    Google Scholar 

  34. 34.

    Erken E, Erken E (2018 Jan) Cardiac disease in familial Mediterranean fever. Rheumatol Int 38(1):51–58

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Vlachopoulos C, Aznaouridis K, O’Rourke MF, Safar ME, Baou K, Stefanadis C (2010) Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 31:1865–1871

    Article  PubMed  Google Scholar 

  36. 36.

    Garcίa-Ortiz L, Recio-Rodrıguez J, Agudo-Conde C, Maderuelo-Fernandez J, Patino-Alonso M, Cabo-Laso A, Rodriguez-Martın C, Gonzalez-Sanchez J, Rodriguez-Sanchez E, Gomez-Marcos M, on behalf the EVA Investigators group (2018) Noninvasive validation of central and peripheral augmentation index estimated by a novel wrist-worn tonometer. J Hypertens 36:2204–2214

    Article  CAS  Google Scholar 

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We thank the patients and their parents who participated in this study.

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Correspondence to Vasiliki Sgouropoulou.

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The study complies with the 1964 Declaration of Helsinki and its later amendments and the institutional bioethics committee has approved the research protocol. Informed consent to participate in the study has been obtained prior to their inclusion in the study from the parents or the participants themselves when age was greater than 18 years.

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Sgouropoulou, V., Stabouli, S. & Trachana, M. Arterial stiffness in Familial Mediterranean Fever: correlations with disease-related parameters and colchicine treatment. Clin Rheumatol 38, 2577–2584 (2019).

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  • Arterial stiffness
  • Augmentation index
  • Colchicine
  • Familial Mediterranean Fever
  • Pulse wave velocity