eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis

Mediterranean Fever, Familial: Treatment & Medication

Author: John O Meyerhoff, MD, Assistant Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine; Clinical Scholar in Rheumatology, Department of Medicine, Sinai Hospital of Baltimore
Contributor Information and Disclosures

Updated: Nov 13, 2009

Treatment

Medical Care

Colchicine is so effective in preventing attacks of familial Mediterranean fever (FMF) and preventing the development of amyloidosis that the most important aspects of medical care are to make the correct diagnosis and to institute therapy.

  • Administer colchicine therapy daily (0.6 mg bid or 0.5 mg bid, depending on the dosage form available) in patients at risk of developing amyloidosis (eg, North African Jewish people, Turkish people, Armenian people living in Armenia). Other Sephardic Jewish people and Arabic people are at lower risk but also probably require daily colchicine therapy.
  • Ashkenazi Jewish people and Armenian people living in America seem to be at extremely low risk of amyloidosis and may need treatment only to prevent attacks. If attacks are rare and patients can determine when they are beginning, treatment with intermittent colchicine therapy at the onset of attacks may be sufficient.
  • The regimen for acute attacks in patients not taking daily colchicine is 0.6 mg every hour for 4 doses, then 0.6 mg every 2 hours for 2 doses and then 0.6 mg every 12 hours for 4 doses. Colchicine should be started as soon as the patient recognizes that an attack is occurring. If the initial doses are effective, patients may be able to do without the later doses, but this varies from patient to patient.
  • In patients who do not respond to twice-a-day dosing, administer colchicine 3, or even 4, times a day. In patients who have difficulty tolerating colchicine, start therapy at once-a-day dosing and gradually increase the dose. In patients whose conditions were not responsive to oral colchicine, the addition of 1 mg IV once a week reduced the number of attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients.5
  • Some patients develop lactose intolerance and may respond to a lactose-free diet.
  • In patients whose conditions do not respond to colchicine, the use of interferon alpha, the tumor necrosis factor–blocking drug etanercept,6 and the IL-1 receptor antagonist anakinra7 may be effective. Interferon alpha has been used in an intermittent fashion and as prophylaxis, with varying results.8,9,10
  • Colchicine also stabilizes the amount of proteinuria in patients with amyloid nephropathy. Renal disease may resolve in patients with a creatinine level of less than 1.5 mg/dL who are treated with more than 1.5 mg/d of colchicine.
  • Hemodialysis can be used for patients who develop renal failure. Peritoneal dialysis tends to increase the number of abdominal attacks.
  • Patients who experience episodes of prolonged myalgia with fever and severe pain may need treatment with prednisone (1 mg/kg) for as long as 6 weeks.
  • Patients with exertional lower extremity muscle pain respond to rest.
  • Treat patients with fibromyalgia with the usual agents for this condition.
  • Patients who develop seronegative spondyloarthropathy are treated with nonsteroidal anti-inflammatory drugs. Some of these patients require remission-type drugs (as used in rheumatoid arthritis) and receive follow-up care by a rheumatologist.

Surgical Care

Before the advent of colchicine therapy, renal transplantation was performed in patients with end-stage renal disease due to amyloid nephropathy. Now, renal failure develops only in patients who are not compliant with therapy or those who cannot tolerate adequate doses of colchicine.

Consultations

  • Since the advent of colchicine therapy, most treated patients are asymptomatic and do not need consultation with a specialist.
  • Consider consultation with a nephrologist for patients with proteinuria that is not responsive to colchicine.
  • Consultation with a rheumatologist is indicated in patients with the following conditions:
    • Seronegative spondyloarthropathy not responsive to nonsteroidal anti-inflammatory drugs
    • Fibromyalgia not responsive to the usual treatments
    • Coexistent Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease

Medication

The goals of therapy are to reduce morbidity and to prevent complications.

Anti-inflammatory agents

Colchicine is the drug of choice for familial Mediterranean fever (FMF).


Colchicine (Colcrys)

Decreases leukocyte motility and phagocytosis in inflammatory responses.

Adult

1.2-2 mg PO in divided doses

Colcrys (new product labeling)
1.2-2.4 mg PO qd or divided bid; increase or decrease in 0.3-mg/d increments; not to exceed 2.4 mg/d
Strong CYP3A4 inhibitors: Not to exceed 0.6 mg PO qd
Moderate CYP3A4 inhibitors: Not to exceed 1.2 mg PO qd
P-glycoprotein inhibitors: Not to exceed 0.6 mg PO qd
Severe renal impairment (CrCl <30 mL/min) or hemodialysis: 0.3 mg PO qd initially; any increase must include close monitoring for adverse effects
Severe hepatic impairment: Administer usual dose, but do not repeat more frequently than q2wk

Pediatric

Colcrys (new product labeling)
<4 years: Not established
4-6 years: 0.3-1.8 mg PO qd or divided bid
6-12 years: 0.9-1.8 mg PO qd or divided bid
>12 years: Administer as in adults qd or divided bid
Increase or decrease in 0.3-mg/d increments; not to exceed maximum recommended daily dose

Cytochrome P450 isoenzyme 3A4 inhibitors (eg, grapefruit juice, clarithromycin, cyclosporine, erythromycin, itraconazole, telithromycin) may significantly increase toxicity; sympathomimetic agent toxicity and effect of CNS depressants significantly increased with colchicine

Documented hypersensitivity; renal or hepatic impairment if using P-glycoprotein or strong cytochrome P450 isoenzyme 3A4 inhibitors (life-threatening and fatal toxicity reported with therapeutic doses); GI or cardiac disorders; blood dyscrasias

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Inform patients about risk of fatal drug interactions that can occur at prescribed doses and with medications given for short times (eg, antibiotics that are cytochrome P450 isoenzyme 3A4 inhibitors); monitor for signs of toxicity, including muscle numbness/pain (myotoxicity, including rhabdomyolysis), numbness/tingling in extremities, unusual bleeding/bruising (myelosuppression), severe diarrhea/vomiting, weakness/fatigue, increased infections, and pale or grey lips, tongue, or palms; patients should avoid consuming grapefruit and grapefruit juice; caution with severe renal or hepatic impairment (adjust dose)
In pregnant patients with FMF, treatment may increase infertility and miscarriage rates; no evidence of teratogenic effects in males or females; may be excreted in breast milk (no evidence of adverse effects in breastfed children); may cause both myopathy and neuropathy in elderly persons and people with renal insufficiency; risk of permanent hair loss, disseminated intravascular coagulopathy, and decreased sperm count; dose-dependent GI upset is common

More on Mediterranean Fever, Familial

Overview: Mediterranean Fever, Familial
Differential Diagnoses & Workup: Mediterranean Fever, Familial
Treatment & Medication: Mediterranean Fever, Familial
Follow-up: Mediterranean Fever, Familial
References
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References

  1. Gershoni-Baruch R, Brik R, Shinawi M, Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet. Feb 2002;10(2):145-9. [Medline]. [Full Text].

  2. Tomiyama N, Higashiuesato Y, Oda T, et al. MEFV mutation analysis of familial Mediterranean fever in Japan. Clin Exp Rheumatol. Jan-Feb 2008;26(1):13-7. [Medline].

  3. Kim S, Ikusaka M, Mikasa G, et al. Clinical study of 7 cases of familial Mediterranean fever with MEFV gene mutation. Intern Med. 2007;46(5):221-5. [Medline]. [Full Text].

  4. Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med. Oct 2007;65(9):318-24. [Medline]. [Full Text].

  5. Lidar M, Kedem R, Langevitz P, et al. Intravenous colchicine for treatment of patients with familial Mediterranean fever unresponsive to oral colchicine. J Rheumatol. Dec 2003;30(12):2620-3. [Medline].

  6. Mor A, Pillinger MH, Kishimoto M, et al. Familial Mediterranean fever successfully treated with etanercept. J Clin Rheumatol. Feb 2007;13(1):38-40. [Medline].

  7. Roldan R, Ruiz AM, Miranda MD, et al. Anakinra: new therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine. Joint Bone Spine. Jul 2008;75(4):504-5. [Medline].

  8. Tunca M, Akar S, Soyturk M, et al. The effect of interferon alpha administration on acute attacks of familial Mediterranean fever: A double-blind, placebo-controlled trial. Clin Exp Rheumatol. Jul-Aug 2004;22(4 Suppl 34):S37-40. [Medline].

  9. Tweezer-Zaks N, Rabinovich E, Lidar M, et al. Interferon-alpha as a treatment modality for colchicine- resistant familial Mediterranean fever. J Rheumatol. Jul 2008;35(7):1362-5. [Medline].

  10. Calguneri M, Apras S, Ozbalkan Z, et al. The efficacy of continuous interferon alpha administration as an adjunctive agent to colchicine-resistant familial Mediterranean fever patients. Clin Exp Rheumatol. Jul-Aug 2004;22(4 Suppl 34):S41-4. [Medline].

  11. Ben-Chetrit E, Berkun Y, Ben-Chetrit E, et al. The outcome of pregnancy in the wives of men with familial mediterranean fever treated with colchicine. Semin Arthritis Rheum. Oct 2004;34(2):549-52. [Medline].

  12. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. Feb 28 1998;351(9103):659-64. [Medline].

  13. Lidar M, Kedem R, Mor A, et al. Arthritis as the sole episodic manifestation of familial Mediterranean fever. J Rheumatol. May 2005;32(5):859-62. [Medline].

  14. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. Oct 1997;40(10):1879-85. [Medline].

  15. Livneh A, Langevitz P, Zemer D, et al. The changing face of familial Mediterranean fever. Semin Arthritis Rheum. Dec 1996;26:612-27. [Medline].

  16. Majeed HA, El-Khateeb M, El-Shanti H, et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. Jun 2005;34(6):813-8. [Medline].

  17. Meyerhoff J. Familial Mediterranean fever: report of a large family, review of the literature, and discussion of the frequency of amyloidosis. Medicine (Baltimore). Jan 1980;59(1):66-77. [Medline].

  18. Samuels J, Aksentijevich I, Torosyan Y, 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). Jul 1998;77:268-97. [Medline].

  19. Sohar E, Gafni J, Pras M, et al. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med. Aug 1967;43(2):227-53. [Medline].

  20. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). Jan 2005;84(1):1-11. [Medline].

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Further Reading

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Keywords

familial Mediterranean fever, FMF, recurrent polyserositis, periodic fever syndrome, amyloidosis, secondary amyloidosis, colchicine therapy, colchicine, appendicitis, peritonitis, amyloid nephropathy, MEFV gene, pyrin, marenostrin, amyloid A, serum amyloid A, nephrotic syndrome, paroxysm, renal vein thrombosis, proteinuria, vasculitis, arthritis, myalgia syndrome, peritonitis, pleuritis, peritoneum, seronegative spondyloarthropathy, chemotactic factor

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Contributor Information and Disclosures

Author

John O Meyerhoff, MD, Assistant Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine; Clinical Scholar in Rheumatology, Department of Medicine, Sinai Hospital of Baltimore
John O Meyerhoff, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology
Disclosure: Pfizer  Honoraria Speaking and teaching

Medical Editor

Carlos J Lozada, MD, Director of Rheumatology Fellowship Program, Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, Jackson Memorial Medical Center, University of Miami School of Medicine
Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

 
 
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