6
Approach to the patients with inadequate response to colchicine in familial Mediterranean fever

https://doi.org/10.1016/j.berh.2016.09.001Get rights and content

Abstract

Familial Mediterranean fever (FMF) is the most common form of monogenic autoinflammatory conditions, and response to colchicine has been considered as one of its distinctive features among other hereditary periodic fever disorders. Prophylactic colchicine has been shown to be effective in the prevention of inflammatory attacks and development of amyloidosis. However, the highest tolerable doses of colchicine may not be adequate enough to manage these goals in approximately 5% of FMF patients. Inadequate response to colchicine in fully compliant FMF patients may be associated with genetic and/or environmental factors affecting disease severity and colchicine bioavailability. Clarification of the molecular pathogenic mechanisms of FMF has revealed that interleukin-1 beta (IL-1β) cytokine is the most likely target to attack, and several case reports and case series have already documented the efficacy and safety of available anti-IL-1 agents, such as anakinra, rilonacept, and canakinumab in those patients inadequately responding to colchicine. Characterization and early identification of those FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages.

Section snippets

Terminology

Familial Mediterranean fever (FMF), the most common type of hereditary autoinflammatory disorders, is characterized by recurrent episodes of inflammation in serosal and synovial membranes and a tendency for secondary amyloidosis [1], [2]. FMF is more prevalent in Jews, Arabs, Armenians, and Turks, and analysis of the typical patients revealed an autosomal recessive mode of inheritance pattern [2]. Variations in the MEFV gene encoding pyrin protein were identified through positional cloning in

Assessment of disease severity in FMF

FMF may run a variable course in terms of its severity, and the MEFV variations have been shown to be the most important factor affecting its inflammatory characteristics and phenotypic variability [16]. Contributions of environmental factors and other modifier genes were estimated as 12% and 17% on an average, respectively [16].

Penetrance of the disease-associated MEFV variants, especially p.Met694Val, has been considered as the main factor determining the severity of inflammatory response,

Optimum use of colchicine and compliance

Colchicine has a prophylactic activity in FMF patients, and its efficacy can be observed when it is used regularly at stable doses. Colchicine treatment should aim to prevent both the recurrence of inflammatory episodes and the development of amyloidosis, and effective doses required for the latter goal may be higher [9]. Colchicine is usually given at tolerable doses to children and adults [31], and the doses need to be adjusted according to the ongoing disease activity determined by number

Evaluation of response to treatment

There is no universally accepted tool to evaluate the efficacy of colchicine or other treatments in FMF patients, and recent attempts to develop criteria for the evaluation of the treatment response have usually been praised with reservations [26], [36]. The FMF50 score developed by Özen and colleagues requires observing a 50% improvement in five of the six criteria without worsening of the sixth criterion, which are determined by two rounds of Delphi exercise, followed by a consensus

Efficacy of biologic agents in inadequate colchicine responders

MEFV-encoded pyrin is an important component of multiprotein inflammasome platforms, which regulates caspase 1 activity and processing of pro-IL-1β and pro-IL-18 into their active forms. Despite its identification in 1997, physiological functions of pyrin has recently been clarified by studies showing a specific function in sensing the virulence of certain exogenous threats by detecting downstream effects of decreased RhoA GTPase activity [41], [42], [43]. Exposure to glucosylating TcdB toxin

Conclusion

Although response to colchicine is one of the distinctive features of FMF, its narrow therapeutic window may limit its efficacy at the highest tolerable doses in a group of patients with a more severe disease course. IL-1 appears as the most reasonable target in these patients based on the findings showing the MEFV variations cause increased inflammasome activation, and reports showing the efficacy and safety of available anti-IL-1 agents need to be confirmed in randomized clinical trials

Disclosure

Dr. Gül received royalties for invited lectures and advisory board meetings and clinical trial support from Novartis.

References (74)

  • U. Meinzer et al.

    Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature

    Semin Arthritis Rheum

    (2011)
  • H. Heller et al.

    Familial Mediterranean fever

    AMA Arch Intern Med

    (1958)
  • Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever

    The International FMF Consortium

    Cell

    (1997)
  • A candidate gene for familial Mediterranean fever

    Nat Genet

    (1997)
  • G. Giancane et al.

    Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever

    Ann Rheum Dis

    (2015)
  • A. Omenetti et al.

    Increased NLRP3-dependent interleukin 1beta secretion in patients with familial Mediterranean fever: correlation with MEFV genotype

    Ann Rheum Dis

    (2014)
  • D. Zemer et al.

    A controlled trial of colchicine in preventing attacks of familial mediterranean fever

    N. Engl J Med

    (1974)
  • C.A. Dinarello et al.

    Colchicine therapy for familial mediterranean fever. A double-blind trial

    N. Engl J Med

    (1974)
  • D. Zemer et al.

    Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever

    N. Engl J Med

    (1986)
  • A. Gul

    Treatment of familial Mediterranean fever: colchicine and beyond

    Isr Med Assoc J

    (2014)
  • A. Livneh et al.

    Criteria for the diagnosis of familial Mediterranean fever

    Arthritis Rheum

    (1997)
  • D. Zemer et al.

    Long-term colchicine treatment in children with familial Mediterranean fever

    Arthritis Rheum

    (1991)
  • M. Stoffels et al.

    MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease

    Ann Rheum Dis

    (2014)
  • S.L. Masters et al.

    Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

    Sci Transl Med

    (2016)
  • I. Ben-Zvi et al.

    Colchicine-free remission in familial Mediterranean fever: featuring a unique subset of the disease-a case control study

    Orphanet J Rare Dis

    (2014)
  • I. Ben-Zvi et al.

    Familial Mediterranean fever without MEFV mutations: a case-control study

    Orphanet J Rare Dis

    (2015)
  • E. Demirkaya et al.

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

    Ann Rheum Dis

    (2016)
  • I. Eshed et al.

    Exertional leg pain in familial Mediterranean fever: a manifestation of an underlying enthesopathy and a marker of more severe disease

    Arthritis Rheumatol

    (2014)
  • Z.B. Ozcakar et al.

    Can colchicine response be predicted in familial Mediterranean fever patients?

    Rheumatol Oxf

    (2014)
  • I. Touitou et al.

    Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever

    Arthritis Rheum

    (2007)
  • H.J. Lachmann et al.

    Autoinflammation: when is familial Mediterranean fever 'severe'?

    Nat Rev Rheumatol

    (2016)
  • D. Zemer et al.

    Reversal of the nephrotic syndrome by colchicine in amyloidosis of familial Mediterranean fever

    Ann Intern Med

    (1992)
  • A. Blum et al.

    Amyloidosis as the sole manifestation of familial Mediterranean fever (FMF). Further evidence of its genetic nature

    Ann Intern Med

    (1962)
  • F. Cosan et al.

    Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis

    Arthritis Rheum

    (2010)
  • Y. Kirino et al.

    Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behcet disease

    Proc Natl Acad Sci U. S. A

    (2013)
  • T. Kallinich et al.

    Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement

    Pediatrics

    (2007)
  • A. Tufan et al.

    Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever

    J Rheumatol

    (2007)
  • Cited by (30)

    • Familial Mediterranean fever

      2018, Revue de Medecine Interne
    View all citing articles on Scopus
    View full text