article information

Archives of Pediatric Infectious Diseases: Vol.3, issue 3; e21664
published online: July 14, 2015
article type: Case Report
received: July 1, 2014
accepted: July 30, 2014
DOI: https://doi.org/10.5812/pedinfect.21664v2
Crossmark

Treatment of Colchicine-Resistant Familial Mediterranean Fever With Anakinra

authors:

avatar Vadood Javadi Parvaneh 1 , avatar Reza Shiari ORCID 1 , *

Department of Pediatric Rheumatology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran

how to cite: Javadi Parvaneh V, Shiari R. Treatment of Colchicine-Resistant Familial Mediterranean Fever With Anakinra. Arch Pediatr Infect Dis. 2015;3(3):e21664. https://doi.org/10.5812/pedinfect.21664v2.

Abstract

Introduction:

Familial Mediterranean Fever (FMF) is an auto-inflammatory disease presenting with periodic fever and various clinical manifestations. Almost 10% of the patients with FMF do not respond to colchicine therapy.

Case Presentation:

Herein was reported a colchicine non-responsive patient with accurate diagnosis and early treatment of FMF. She had presented with recurrent and persistent acute abdominal pain attacks and several abdominal surgeries. Addition of recombinant interleukin-1 receptor antagonist (Anakinra) to colchicine was effective to decrease the number and severity of abdominal pain in the patient.

Conclusions:

This case showed the effect of additional Anakinra on children with FMF who were colchicine resistant.

1. Introduction

Familial Mediterranean Fever (FMF) is an autosomal recessive hereditary disease with periodic fever and auto-inflammatory diseases. It mainly affects Turks, Armenians, Arabs, Jews and other Mediterranean populations (1-5). Ardebil and Azerbaijan provinces are the endemic geographical distribution of FMF in Iran (6, 7). Clinical diagnosis is usually confirmed with the disease locus mutations in MEFV gene on chromosome 16p13.3 (8, 9). About 95% of the patients have significant improvement in signs and symptoms of the disease with colchicine and approximately 75% of them experience a complete remission (10). Colchicine non-responder cases are a challenge in treatment which leads to a variety of drugs, including interferon alpha, thalidomide, prazosin, etanercept and anakinra (11-14). Herein we reported a colchicine non-responsive patient with accurate diagnosis and early treatment of the disease that presented with recurrent and persistent acute abdominal pain attacks and several abdominal surgeries.

2. Case Presentation

A 15-year-old girl from Tabriz, East Azerbaijan province, Iran, with the known case of Familial Mediterranean Fever (FMF), presented with complaints of severe and recurrent abdominal pain. She was admitted to Pediatric Rheumatology ward of Mofid Children’s Hospital, Tehran, Iran. In the last month, leading to the hospitalization of the patient, abdominal pain worsened every evening and sometimes with non-bloody vomiting. She had been hospitalized two weeks ago with acute abdomen which led to diagnostic laparoscopy, but was not in favor of acute abdomen. The patient had been treated with colchicine 2 mg daily for her recurrent abdominal pain attacks with fever since three years ago. She had the history of ovarian cyst surgery for three times accompanied with abdominal pain and irregular menses three months ago. She also had the history of appendectomy almost four years ago. MEFV gene mutation analysis revealed component heterozygous mutation of M694V and R761H. On admission the patient had severe pain and tenderness in the right lower quadrant (RLQ) with radiation to lower extremities, neither fever nor systemic symptoms. The result of her acute phase reactants showed C-reactive protein (CRP) 47 mg/dL and erythrocyte sedimentation rate (ESR) 19 mm/h (first hour). Attacks of abdominal pain only responded to intramuscular injection of dexamethasone 0.15 mg/kg/day. After rectal biopsy to rule out amyloidosis, despite the absence of proteinuria, Anakinra began as a subcutaneous injection 1.5 mg/kg/day. She was advised to continue taking colchicine and a diet low in fat, lactose and gluten free. During the 12 month follow-up of the patient, she had only three attacks with short duration and low intensity of abdominal pain.

3. Discussion

In most of the cases, treatment with colchicine to prevent attacks of fever and systemic amyloidosis is very effective (15). In general, continuous treatment with colchicine is more effective than intermittent treatment during attacks. This way gives more subclinical inflammation control and reducing potentially amyloidosis (16). There are patients (about 5 - 10%) who do not respond to colchicine or cannot tolerate therapeutic doses (17). MEFV gene is located on the short arm of chromosome 16 that encodes a protein containing 781 amino acids, named pyrin. Normal pyrin inhibits activation of the precursor form of IL-1β to its biologically active components. Mutations in this gene result defective FMF pyrin production that leads to defective apoptosis and stimulates IL1 processing, and production of active IL-1β, which eventually leads to the uncontrolled inflammation (18). The role of IL-1β in the pathogenesis of the disease is the reason to use anakinra to treat FMF (19, 20). Anakinra is a recombinant form of interlukin-1 receptor antagonist (IL-1Ra). This receptor induced by IL-1 is an important physiological regulator. Anakinra may exert its effect with binding to the IL-1 receptor on the cell surface and preventing interaction with IL-1. Dramatic response to anakinra is observed in IL-1 origin disorders and auto-inflammatory syndromes such as systemic onset JIA, Muckle-Wells Syndrome (MWS), Deficiency of the interleukin-1 Receptor Antagonist Syndrome (DIRA) and Familial Cold Auto-inflammatory Syndrome (FCAS) (21, 22). Side effects are generally not serious. Injection site reactions, usually occur in the first four weeks and include rash, itching, erythema, and usually do not require drug discontinuation. Opportunistic and severe infections with mortality are not reported yet. For clinical monitoring purified protein derivative (PPD) test is recommended, although it is not associated with reactivation of latent Tuberculosis (TB). Complete blood count before, and monthly for three months after the start, and then four times a year to monitor laboratory data is also recommended (10). The rectal biopsy that was negative for amyloidosis, and dramatic response of the patient to daily treatment by anakinra after twenty-eight days, obliged the authors to continue anakinra only during the patient’s abdominal attacks, along with taking colchicine daily.

Acknowledgements

References

  • 1.

    Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77(4):268-97. [PubMed ID: 9715731].

  • 2.

    Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999;64(4):949-62. [PubMed ID: 10090880].

  • 3.

    Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, et al. Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet. 2000;8(4):307-10. [PubMed ID: 10854115]. https://doi.org/10.1038/sj.ejhg.5200446.

  • 4.

    Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet. 2001;9(8):634-7. [PubMed ID: 11528510]. https://doi.org/10.1038/sj.ejhg.5200672.

  • 5.

    Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, et al. Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet. 2001;9(7):553-5. [PubMed ID: 11464248]. https://doi.org/10.1038/sj.ejhg.5200674.

  • 6.

    Salehzadeh F, Emami D, Zolfegari AA, Yazdanbod A, Habibzadeh S, Bashardost B, et al. Familial Mediterranean fever in northwest of Iran (Ardabil): the first global report from Iran. Turk J Pediatr. 2008;50(1):40-4. [PubMed ID: 18365590].

  • 7.

    Farivar S, Shiari R, Hadi E. Molecular analysis of MEFV gene in Iranian children with Familial Mediterranean fever. Indian Journal of Rheumatology. 2010;5(2):66-8. https://doi.org/10.1016/s0973-3698(10)60543-2.

  • 8.

    Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90(4):797-807. [PubMed ID: 9288758].

  • 9.

    A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25-31. [PubMed ID: 9288094].

  • 10.

    Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of pediatric rheumatology. 6th ed. Saunders Elsvier; 2011.

  • 11.

    Tunca M, Akar S, Soyturk M, Kirkali G, Resmi H, Akhunlar H, et al. The effect of interferon alpha administration on acute attacks of familial Mediterranean fever: A double-blind, placebo-controlled trial. Clin Exp Rheumatol. 2004;22(4 Suppl 34):S37-40. [PubMed ID: 15515782].

  • 12.

    Seyahi E, Ozdogan H, Masatlioglu S, Yazici H. Successful treatment of familial Mediterranean fever attacks with thalidomide in a colchicine resistant patient. Clin Exp Rheumatol. 2002;20(4 Suppl 26):S43-4. [PubMed ID: 12371635].

  • 13.

    Kataoka H, Kumagai H, Hanai H. Treating familial Mediterranean fever with prazosin hydrochloride. Ann Intern Med. 1998;129(5):424. [PubMed ID: 9735077].

  • 14.

    Mor A, Pillinger MH, Kishimoto M, Abeles AM, Livneh A. Familial Mediterranean fever successfully treated with etanercept. J Clin Rheumatol. 2007;13(1):38-40. [PubMed ID: 17278949]. https://doi.org/10.1097/01.rhu.0000255772.25658.7c.

  • 15.

    Kallinich T, Haffner D, Niehues T, Huss K, Lainka E, Neudorf U, et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007;119(2):e474-83. [PubMed ID: 17242135]. https://doi.org/10.1542/peds.2006-1434.

  • 16.

    Livneh A, Zemer D, Langevitz P, Laor A, Sohar E, Pras M. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum. 1994;37(12):1804-11. [PubMed ID: 7986228].

  • 17.

    Calligaris L, Marchetti F, Tommasini A, Ventura A. The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever. Eur J Pediatr. 2008;167(6):695-6. [PubMed ID: 17588171]. https://doi.org/10.1007/s00431-007-0547-3.

  • 18.

    Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proc Natl Acad Sci U S A. 2006;103(26):9982-7. [PubMed ID: 16785446]. https://doi.org/10.1073/pnas.0602081103.

  • 19.

    Roldan R, Ruiz AM, Miranda MD, Collantes E. Anakinra: new therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine. Joint Bone Spine. 2008;75(4):504-5. [PubMed ID: 18541452]. https://doi.org/10.1016/j.jbspin.2008.04.001.

  • 20.

    Farivar S, Hassani M, Shiari R. Interleukin-1 as a Key Factor in the Development of Inflammatory Diseases. Arch Pediatr Infect Dis. 2014;1(3). eee18177. https://doi.org/10.5812/pedinfect.18177.

  • 21.

    Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364(9447):1779-85. [PubMed ID: 15541451]. https://doi.org/10.1016/S0140-6736(04)17401-1.

  • 22.

    Thornton BD, Hoffman HM, Bhat A, Don BR. Successful treatment of renal amyloidosis due to familial cold autoinflammatory syndrome using an interleukin 1 receptor antagonist. Am J Kidney Dis. 2007;49(3):477-81. [PubMed ID: 17336710]. https://doi.org/10.1053/j.ajkd.2006.10.026.