the Diagnosis and Treatment of Familial Mediterranean Fever during Childhood and Adolescence
- Introduction
Familial Mediterranean fever (FMF) is a monogenic inherited autoinflammatory disorder characterized by self-limited recurrent attacks of fever, serositis, arthritis and erythema. Several factors associated with emotional and physical stress are proposed to trigger FMF attacks (1,2).
The febrile attacks are accompanied by a strong acute phase response, and the most severe complication is the development of renal amyloidosis. FMF occurs most commonly among people from the Mediterranean basin (non-Ashkenazi Jews, Arabs, Armenians, Greeks, and Turks) and in other countries, but the epidemiological information remains quite scarce. The emergence, in most patients, occurs before the age of 30 (60% before 10 years and 90% before20 years of age) (3,4)
FMF diagnosis is mainly clinical, and the genetic testing is indicated to support it (5). Laboratory tests are not specific, with high ESR, C-reactive protein and serum amyloid A (SAA) protein in the acute phase of this disease, but often, high levels are found even between attacks. SAA levels may be particularly useful in monitoring the effectiveness of treatment. (6)
Typical attacks are defined as recurrent (≥3 of the same type), febrile (rectal temperature of 38 °C or higher), and short (lasting between 12 hours and 3 days). Patients remain asymptomatic between attacks. Incomplete attacks are defined as painful and recurrent attacks that differ from typical attacks in one or two features, as follows (5):
1. The temperature is normal or lower than 38 °C.
2. The attacks are longer or shorter than specified (but not shorter than 6 hr or longer than a week).
3. No signs of peritonitis are recorded during the abdominal attacks.
4. The abdominal attacks are localized.
5. The arthritis involves joints other than hip, knee and ankle.
- 9 -Genetic diagnosis:
FMF is associated with mutations in the Mediterranean fever (MEFV) gene encoding the protein pyrin. MEFV gene is located in the chromosome 16 p13.3 and was first identified in 1997. Approximately one-third of the patients have either a single or no gene mutation (7).
Previous studies on FMF patients and animal models suggest that MEFV mutations lead to dysregulation of the inflammasome, a complex intracellular multiprotein structure, ending in gain of pyrin function with increased IL-1b secretion by monocytes and a prolonged inflammatory response (8).
The gene mutations E148Q, V726A, M680I, M694V and M694I were reported to be the most frequent mutations among Egyptian FMF children(9).Early onset and severe phenotypes were commonly associated with M694V (10).
The inheritance of FMF, unlike other monogenic SAIDs, is not an ordinary autosomal recessive disorder. Presence of clinical phenotype among heterozygous patients of FMF was reported in about one quarter of clinically diagnosed patients. Thus, FMF was suggested to be a dominant condition with low penetrance (11).
Comorbidities and complications
Many inflammatory and autoimmune diseases have been seen in association with FMF whether related to the activated innate immune system and high pro-inflammatory state or incidentally discovered. Yildiz et al. studied a large cohort of pediatric FMF patients and observed that nearly a fifth of them had comorbid diseases and needed additional medications. The most common was juvenile idiopathic arthritis, henoch-schonlein purpura, uveitis, inflammatory bowel diseases, polyarteritis nodosa, and PFAPA (12).
Arthritis is one of the common clinical features of FMF, and concomitant presence of FMF and juvenile idiopathic arthritis or ankylosing spondylitis has been described. Mutations of MEFV gene might be one of the genetic determinants of JIA especially systemic onset type with elevated IL-1 cytokines (13).
- 10 -Amyloidosis, the most serious complication of FMF, is the deposition of an insoluble serum protein called serum amyloid A, which is produced by the liver, and is considered one of acute phase reactants. The persistence of subclinical inflammation and delay of diagnosis are important risk factors for the development of amyloidosis in FMF (14).It usually involves the kidneys with early proteinuria and later development of renal impairment. It was observed in up to 10.5% of FMF patients. Amyloidosis could be also seen involving liver, intestine, or heart (15).
Increased awareness of the disease with good control of the inflammation, strict follow up, and judicious use of colchicine and biologics could greatly prevent the development of amyloidosis. (13).
➡️Treatment
Colchicine is the mainstay for treatment of FMF. The exact mechanism of action by which colchicine prevents the attacks of FMF and suppresses the inflammation is not well understood. Colchicine prevents activation of neutrophils, it binds to β-tubulin making β- tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover, its mode of action includes modulation of chemokines, prostanoids production, and inhibition of neutrophil and endothelial cell adhesion molecules(16). It is thought that colchicine has an effect on the transcription and the expression of the genes involved in neutrophils migration and activation. This latter effect is delayed and doesn’t happen immediately after administration of colchicine, a matter that may explain why colchicine doesn’t have an immediate effect in the acute attacks of FMF (17).
There are two main goals of colchicine therapy in FMF. First, to prevent the clinical FMF attacks and the second is to stop the ongoing subclinical inflammation, hence prevention of the progression to amyloidosis. Initiation of colchicine therapy is recommended as soon as the clinical diagnosis has been made. Individuals who have positive genotype (one or more MEFV mutation) however do not express clinical disease and do not have elevated acute phase reactants, are not recommended to start treatment.
- 11 -Special attention and close follow up should be given to individuals with homozygous
M694V/M694V as they have a higher risk to develop amyloidosis, so they should start treatment as soon as they express the clinical manifestations associated with elevation of the acute phase reactants (18).
The usual initial dose is ≤0.5 mg/day (≤0.6 mg/day if tablets contain 0.6 mg) for children <5 years of age, 0.5–1.0 mg/day (1.2 mg/day if tablets contain 0.6 mg) for children 5–10 years of age, 1.0–1.5 mg/day (1.8 mg/day in case tablets contain 0.6 mg) in children >10 years of age. The maximum dose in children is 2mg/day. All patients should be monitored for disease control as evidenced by minimizing the number of clinical attacks and normalization of the acute phase reactants and SAA in between the attacks. The dose of colchicine should be adjusted according to the degree of disease control. Colchicine is a lifelong therapy especially in poorly controlled cases and in cases with high risk for amyloidosis. Some experts currently suggest that if the patient remained attack free with normal acute phase reactants for more than five years, dose reduction can be considered with close monitoring and after expert consultation (18).
In general, colchicine has a good safety profile and is well tolerated with minimal side effects. The main side effects include GIT disturbances, lactose intolerance, and elevation of the liver enzymes, alopecia, neutropenia and peripheral neuropathy. Dividing the dose of colchicine and dietary modifications markedly decrease the side effects. In case of elevated liver enzymes, transient reduction or stoppage of the colchicine will eventually be helpful then the usual dose can be resumed. Colchicine has been theoretically incriminated to affect the spermatogenesis as it acts by suppressing the microtubules and arrest of mitosis, however, recent and old studies showed no effect of colchicine on spermatogenesis nor any teratogenic effect and if there is any fertility problem in patients with FMF it is better to be attributed to the disease itself and the amyloidosis of testis or ovaries. For these reasons, it is now recommended not to stop colchicine neither before nor during pregnancy (18).
There is no standard definition for refractory or resistant FMF however, the recent guidelines stated that FMF can be considered resistant to treatment if:(18)
- 12 -1- The patient continued to have ≥ one attack per month despite the maximally tolerated continuous colchicine dose for ≥ 6 months.
2- Persistent subclinical inflammation that is a risk factor for amyloidosis.
3- If the patient developed renal amyloidosis.
In case of uncontrolled disease, the second line drugs, the biological agents, should be added. Anti-interleukin I (anti-IL-1) biological drugs are recommended in the patients with FMF. Several types of anti-IL-1 are available namely; recombinant homologue of IL-1 receptors (anakinra)(20),fully human immunoglobulin G1 monoclonal antibody against IL- 1 (canakinumab)(21), and the third one is Rilonacept, dimeric FC fusion protein capturing IL-1.
Despite the marked efficacy of these biologic drugs in the treatment of FMF and their ability to reverse proteinuria in cases with renal amyloidosis; their efficacy in prevention of amyloidosis is not yet proven and colchicine should continue during biological drug treatment to prevent amyloidosis. Of note, the three anti-IL-1 agents are not interchangeable, and the patient may respond to one drug and not to the other one. This role applies to FMF and other diseases treated by biologics (18).
Treatment of amyloidosis includes measures to support failing organ function, including blood pressure control and dialysis for patients with renal disease (18). The majority of patients with FMF and amyloidosis will eventually require renal replacement therapy (22). Recent experience of renal transplantation in selected patients has been encouraging with long-term graft and patient survival matching that of the age-matched general transplant population (20).
Management of the acute attacks include continuation of the colchicine therapy on the same dose and adding nonsteroidal anti-inflammatory drugs to alleviate the pain. There is no evidence to support increasing the dose of colchicine during the acute attack. Other drugs may include glucocorticoids in severe attacks and in the syndrome of protracted febrile myalgia, disease modifying anti-rheumatic drugs (DMARDs) in chronic arthritis accompanying the FMF. Tumor necrosis factor receptor antagonists (anti-TNF) may also be used in chronic arthritis (23,24).
➡️Purpose and Scope
These guidelines have been developed to standardize the delivery of services and to implement the guidance on the prevention, diagnosis and management of Familial Mediterranean Fever (FMF).
It provides guidance to primary health care providers, pediatricians and specially trained nurses.
The guidelines aimed to
1) Provide accurate diagnosis of FMF to avoid over and under diagnosis.
2) Define the role of investigations in diagnosis and optimizing management and prevention of complications
3) Identify the best practice management of FMF patients.
This version of the guideline includes recommendations and good practice statements for diagnosis and treatment of Familial Mediterranean Fever.