Let's learn about familial Mediterranean fever

Author: Xue Yuan Beijing Children's Hospital, Capital Medical University

Reviewer: Deng Jianghong, Chief Physician, Beijing Children's Hospital, Capital Medical University

【Review of the condition】

Xiao Shuai (pseudonym) is 17 years old this year. He has had recurrent fever since he was 2 and a half years old. His body temperature can reach as high as 40°C. After a few hours, the temperature returns to normal on its own and he has a fever again after 24 to 48 hours. Each fever lasts for several days to weeks. The fever is accompanied by pain in major joints and rash. He has visited the local hospital many times and was diagnosed with "juvenile idiopathic arthritis". He has used non-steroidal anti-inflammatory drugs, glucocorticoids, immunosuppressants, biologics (tumor necrosis factor α inhibitors) and traditional Chinese medicine for treatment, but he still has recurrent fever. Recently, the child had high fever again. The white blood cell count was 26×109/L, mainly neutrophils. Cardiac ultrasound showed pericardial effusion, chest CT showed a small amount of pleural effusion, and autoantibody spectrum examination showed that antinuclear antibody (ANA) was 1:80 positive and anti-soluble antigen (ENA) spectrum was negative. The child was treated with broad-spectrum antibiotics, methylprednisolone, methotrexate, and anti-tumor necrosis factor inhibitors, but the child's fever did not improve. Therefore, autoinflammatory disease-related gene testing was performed. The results showed that there was a heterozygous missense mutation in the MEFV gene, which was related to familial Mediterranean fever. Combined with the child's clinical manifestations, he was diagnosed with familial Mediterranean fever.

It can be said that:

Repeated high fever since childhood, severe symptoms are daunting

Multiple drugs have no feedback, genetic testing determines the location

Figure 1 Erysipelas-like rash on the lower limbs of a FMF patient (copyrighted image is not authorized for reproduction)

【Disease Introduction】

Familial Mediterranean fever (FMF), also known as familial paroxysmal polyserosis, is an autosomal recessive genetic disease. The disease was first reported in 1947. In 1992, the pathogenic gene MEFV of FMF was first confirmed to be located on chromosome 16p13.3. It is currently the longest-studied autoinflammatory disease. The gene encodes a protein composed of 781 amino acids. The protein product is called "pyrin" and is involved in regulating the inflammatory response in the body. It was found that the gene has three types of mutations, and one of the three mutations was found in the chromosomes of 85% of the carriers. The gene mutation leads to the occurrence of systemic inflammatory response. After this discovery was reported in September 1997, it became the highlight of the FMF International Conference held in Jerusalem.

The disease is mainly manifested by recurrent fever and serositis, and some patients may first present with amyloidosis. About 20% of patients first develop the disease before the age of 2, and 90% develop the disease before the age of 20. At present, there is a lack of a large amount of epidemiological survey data in my country.

Clinical characteristics

The disease is divided into two different subtypes, and the clinical manifestations of the two types are different.

(1) Type 1 familial Mediterranean fever: This type is characterized by recurrent inflammation and serositis, with common clinical manifestations of fever, abdominal pain, serositis, etc. ① Periodic recurrent fever: can be induced by strenuous exercise, cold, infection, etc., often lasting for 1 to 3 days before spontaneously resolving; ② Abdominal pain: often spontaneously resolving after 24 to 48 hours; ③ Joint swelling and pain: often involving large joints of the lower limbs, such as the hip and knee joints; ④ Rash: the typical rash is erysipelas-like erythema, often involving the lower limbs; ⑤ Pleurisy, pericarditis, etc.

Figure 2 Erysipelas-like rash on the lower limbs of a patient with FMF (copyrighted image is not authorized for reproduction)

(2) Familial Mediterranean fever type 2: Patients with this type often present with amyloidosis, which may manifest as persistent large amounts of proteinuria, myocardial damage, liver function damage, etc. Biopsy and genetic testing can help to clarify the diagnosis.

【diagnosis】

The most commonly used standard for adults is the Tel Hashomer standard, which requires the diagnosis to be made if the following two major criteria or one major criterion plus two minor criteria are met.

Key criteria included recurrent fever with serositis, secondary amyloidosis, and response to colchicine.

Minor criteria were simple recurrent fever, erysipelas, and a family history of familial Mediterranean fever.

Yalqinkaya et al. proposed and verified diagnostic criteria applicable to children, namely, meeting two of the following five criteria: fever (axillary temperature >38°C, lasting for 6 to 72 hours, with more than three episodes), abdominal pain, sore throat or synovitis (all of the above manifestations should last for 6 to 72 hours and occur more than three times), and a family history of familial Mediterranean fever.

Genetic testing can determine the presence of mutated genes associated with familial Mediterranean fever, but currently only 70% to 80% of children with familial Mediterranean fever have been found to have gene mutations. Therefore, the judgment of clinicians is crucial to avoid misdiagnosis and missed diagnosis.

Figure 3 Copyright image, no permission to reprint

【Diagnosis and Differentiation】

Familial Mediterranean fever needs to be differentiated from diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus, ankylosing spondylitis, acute abdomen, and IgG4-related diseases.

【treat】

Colchicine is the first-line drug for familial Mediterranean fever, and the dosage should be determined according to the patient's fever frequency and the severity of the disease; thalidomide, sulfasalazine, interleukin-1 receptor antagonists and tumor necrosis factor α inhibitors are second-line drugs, and non-steroidal anti-inflammatory drugs can be used as auxiliary drugs for fever and anti-inflammation. If you cannot tolerate the adverse reactions of colchicine or are resistant to colchicine (i.e., poor response after treatment), you can use interleukin-1 receptor antagonists such as canakinumab, anakinra, and lelocept. It should be noted that glucocorticoids have no significant effect on improving the symptoms and prognosis of this disease.

[Prognosis]

Patients may suffer from intestinal obstruction, fallopian tube obstruction (complication of infertility) due to repeated inflammatory attacks, and long-term amyloidosis may lead to chronic renal failure, myocardial damage, etc. The promotion and use of colchicine and new anti-inflammatory drugs have greatly improved the prognosis of familial Mediterranean fever compared with the past. After diagnosis, children must take medication for life. Regular treatment can reduce attacks by about 60%, but 5% to 10% of patients still have no effect on treatment. Timely diagnosis and early treatment are extremely important to improve the prognosis of patients.

References

[1]Primary Immunodeficiency Diseases - Definition, Diagnosis, and Management (2nd Edition).

[2] Rheumatology Group of the Pediatric Branch of the Chinese Medical Association, Pediatric Group of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association, Pediatric Group of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association, etc. Expert consensus on the diagnosis and treatment of pediatric autoinflammatory diseases [J]. Chinese Journal of Practical Pediatrics, 2022, 37(3): 161-172.

[3]Kelley and Firestein's Textbook of Rheumatology (10th edition).