Diagnosing familial Mediterranean fever

6 minute read

A 34-year-old female presents with recurrent episodes of joint pain and swelling, starting from when she was a child.

My aim is to present a common case and work through the reasoning of why I order each test, what questions are most useful to help diagnose this condition and a simple approach to management.

A 34-year-old female presents with recurrent episodes of joint pain and swelling. The attacks are palindromic in nature, where one (or multiple) joints will be painful and swollen, lasting for a few days before settling, often without any specific intervention.

These attacks have been occurring for many years, starting from when she was a child. She is well between episodes. She usually takes paracetamol, codeine or non-steroidal anti-inflammatories but these provide only minor relief.

The episodes can be a monoarthritis, migratory oligoarthritis or polyarthritis. Any joint can be affected but more recently her wrists and fingers have been the major ones. It is hard for her to walk if her lower limb joints are affected. She typically rests until they settle. She has an attack every 3-4 weeks on average. 

Her past history reveals recurrent episodes of illness. She recalls being a “sickly child” with frequent school absences due to fever and “infection”. She recalls an episode of pericarditis as a child.

Over the past 20 years she has presented to the emergency department once or twice a year on average. The presentations involve a fever (frequently over 39°C) associated with extreme fatigue and pleuritic chest pain. She is usually diagnosed with “pleurisy”.

A viral cause has never been identified. Antibiotics have frequently been prescribed and she improves over the course of a week. She is often investigated for pulmonary emboli but tests have returned negative results. 

She has also presented to the emergency department with a number of episodes of fever and abdominal pain. She is typically observed in the emergency department and she improves with time. She had an appendicectomy in 2013 with removal of a normal appendix. She had an elective cholecystectomy, but this surgery did not prevent recurrent episodes of abdominal pain.

Examination at the time of outpatient consultation did not reveal any abnormalities. There is no peripheral joint synovitis and no features of a connective tissue disease. There is no abdominal organomegaly. There are no clinical features of pericarditis or pleurisy. There is no evidence of oral ulcers or lymphadenopathy. 

Her long history of recurrent short-lasting fevers associated with serositis and joint pain is suggestive of an autoinflammatory disorder. Autoinflammatory disorders are associated with genetic abnormalities of the innate immune system. This contrasts with autoimmune disease, where there are acquired abnormalities of the acquired immune system. Autoimmune serology is normal in autoinflammatory disorders; however, I performed a full screen as the differential diagnoses include systemic lupus erythematosus, rheumatoid arthritis or vasculitis.    

The most common (and best described) autoinflammatory condition is familial Mediterranean fever (FMF). In this condition there is an acquired mutation of the MEFV gene, which encodes for pyrin.

I order a gene test for mutations of the MEFV gene. This does not have a Medicare rebate and the test is usually performed only in a specialised laboratory where the out-of-pocket cost is around $250, but this will vary between laboratories. Her results show she is a heterozygote for a pathogenic mutation of this gene.

The diagnosis of FMF requires a typical clinical history (such as hers) and homozygote pathogenic mutations in the MEFV gene. Heterozygosity for pathogenic mutation of MEFV also requires a six-month trial of colchicine to make a clinical diagnosis. A significant reduction in attacks is required while taking colchicine. Colchicine resistance in FMF occurs in only around 5% of patients.

I prescribe colchicine 0.5mg twice daily. A month later, she has a minor attack with a low-grade fever of 37.8°C and joint pain. This episode is much less severe than her usual attacks. Over the subsequent four months she has no episodes. It is rare for her to go for this long without an attack, confirming that she has a clinical diagnosis of FMF likely. 

One year after diagnosis, she is hospitalised with a severe episode of myositis associated with low-grade fever. She has been adherent to colchicine. Non-adherence is one of the most common causes for a flare. She presents with pain in her thigh, forearm and proximal upper limb muscles. She is unable to walk or get out of a seat. CK is raised at 800 and MRI scan shows muscle oedema of the upper limb.

Myositis can occur in FMF. Colchicine is also reported to cause myopathy, although this is less likely to be myositis and less likely to have an abrupt onset, such as this presentation. She is treated with prednisone 50mg daily for one month with gradual recovery of muscle strength over the next six weeks. Given this severe episode, I advise a higher maintenance dose of colchicine 0.5mg three times daily, but gastrointestinal side effects (diarrhoea, abdominal pain and bloating) prevent the ongoing use of the higher dose.

Over the subsequent year, she has two very minor episodes involving fever, joint pain and headache. Overall, she is delighted with the improvement of her life since commencing colchicine. She will need to remain on colchicine to prevent recurrent attacks. 

Despite multiple generations of her family being born in Australia (with no known history of FMF), her family heritage does trace to Greece and Malta. She has three children, all teenagers. Two are healthy but one child has recurrent episodes of fever and infections, with frequent school absences due to sickness. These have all been attributed to viral infections. She now identifies that his episodes are similar to her own at the same age. An MEFV gene test is performed and her son carries the same mutation. He is placed on regular colchicine and the attacks subside. A diagnosis of FMF is also made for her son.  

Options to treat FMF refractory to colchicine include medications to block IL-1 (anakinra or canakinumab) or IL-6 (tocilizumab). These are not available on the PBS for this condition and either need to be purchased privately or paid by a hospital drug committee. 

Long-term monitoring for FMF includes monitoring for side effects of prolonged colchicine use (neuropathy, myopathy, hepatoxicity, bone marrow suppression) or proteinuria, as a complication of recurrent inflammatory episodes is renal amyloidosis.

The autoinflammatory disorders are increasingly being recognised and diagnosed. The key to identifying these conditions is a history of recurrent fevers and serositis or arthritis, typically starting in childhood. The attacks are episodic and the individual is well between attacks. The episodic nature frequently leads to considerable diagnostic delay. Gene tests are increasingly helpful in diagnosing autoinflammatory conditions.

Early identification will prevent recurrent inflammatory episodes, unnecessary hospitalisations, unnecessary surgery and greatly improve quality of life.

Dr Andrew Jordan is a rheumatologist based in Parramatta, Sydney, with a special interest in inflammatory arthritis, gout and PRP injections.

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