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.

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).

FMF diagnosis is mainly clinical, and the genetic testing is indicated to support it . 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.

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.

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. The gene mutations E148Q, V726A, M680I, M694V and M694I were reported to be the most frequent mutations among Egyptian FMF children.

Colchicine is the mainstay for treatment of FMF. 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.

➡️Scope

This guideline focuses on diagnosis and management of FMF. In children below 18 year of age to help early and appropriate diagnosis and safe and efficient management by the physicians.

➡️Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG recommended using the following source original clinical practice guidelines (CPGs):

1-EULAR recommendations for the management of familial Mediterranean fever 2016

2- Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever 2016 (Brazilian)

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -  Adoption for most of the guideline recommendations.

         -  Development of Good Practice Statements

Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. Diagnosis of Familial Mediterranean Fever(FMF)

The guideline covers (Age group) Children and Adolescents (Less than 18 years old)

This guideline emphasis on the clinical criteria for diagnosis

B. Management of Familial Mediterranean Fever

This section includes recommendations and good practice statements on Therapeutic intervention and guarding against complications and drug toxicity.

We can summarize the guidelines’ recommendations for Familial Mediterranean Fever (FMF) in the following:

FMF Diagnosis

1-  FMF should be suspected when there are recurrent febrile episodes associated with abdominal and/or chest pain caused by serositis (peritonitis, pericarditis or pleurisy) and arthritis/synovitis of large joints, accompanied by erysipeloid erythema. QOE Very Low, Strength Conditional

2- The presence of at least 2 of the following 5 criteria after exclusion of other causes can diagnose FMF with high sensitivity: QOE Very Low, Strength GPS

         -  Fever axillary temperature of >38ᵒC, 6–72 h of duration, ≥3 attacks

         -  Abdominal pain 6–72 h of duration ≥3 attacks

         - Chest pain 6–72 h duration≥ 3 attacks

         -  Arthritis 6–72 h duration ≥3 attacks, oligoarthritis

         -  Family history of FMF*(26)

3-  Genetic testing can support the clinical diagnosis but cannot exclude it. QOE Very Low, Strength    GPs

4-  Laboratory tests are not specific, demonstrating high serum levels of inflammatory proteins in the acute phase of the disease, but also often showing high levels even between attacks. SAA serum levels may be especially useful in monitoring the effectiveness of treatment. QOE Low, Strength Conditional

➡️FMF Management

1-  Ideally, FMF should be diagnosed and initially treated by a physician with experience in FMF. QOE Very Low, Strength Conditional

2- The ultimate goal of treatment in FMF is to obtain complete control of unprovoked attacks and minimize subclinical inflammation in between attacks.           QOE Low, Strength Conditional

3- Treatment with colchicine should be started as soon as a clinical diagnosis is made. QOE High, Strength : Strong.

4- Genetic testing is ideally requested and interpreted by immunology/rheumatology specialist. QOE Very Low, Strength GPS

5- Asymptomatic individuals with homozygous pathogenic mutations, particularly M694V, should be evaluated and followed up by an expert for possible intervention.QQOE Very Low, Strength : GPS     

6- Dosing can be in single or in divided doses, depending on tolerance and compliance.QOE Very Low, Strength Conditional

7- The persistence of attacks or subclinical inflammation represents an indication to increase colchicine dose. QOE Low, Strength Conditional

8- FMF treatment needs to be intensified in AA amyloidosis using the maximal tolerated dose of colchicine and supplemented with biologics as required. QOE Low, Strength Conditional.QOE Intermediate, Strength Conditional.

9- Colchicine toxicity is a serious complication that should be given adequate consideration and be prevented. QOE Low, Strength Conditional.

10- Liver enzymes should be monitored regularly in patients with FMF treated with colchicine; if liver enzymes are elevated greater than twofold the upper limit of normal, colchicine shouldbe reduced, and the cause further investigated. QOE Low, Strength Conditional.

11- In patients with decreased renal function, the risk of colchicine toxicity is very high and therefore evidence of toxicity should routinely be sought, and the colchicine dose reduced accordingly. QOE Low, Strength Conditional.

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/