Sacroiliitis in familial Mediterranean fever and seronegative spondyloarthropathy: importance of differential diagnosis
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- Balaban, B., Yasar, E., Ozgul, A. et al. Rheumatol Int (2005) 25: 641. doi:10.1007/s00296-004-0578-2
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Familial Mediterranean fever (FMF) is a multisystemic autosomal recessive disease, occasionally accompanied by sacroiliitis. Transient and non-erosive arthritis of the large joints is the most frequent articular involvement. Amyloidosis is also the most significant complication of FMF, leading to end stage renal disease. Here we present three cases of FMF with sacroiliitis and review the literature for spinal arthritic involvement of FMF. All cases were referred to our clinic with a diagnosis of seronegative spondyloarthropathy and with low back pain sourced by sacroiliitis. They also had homozygous M694V gene mutations and negative HLA B27 antigens. Molecular analysis of the gene mutation is recommended during the evaluation of uncertain cases in order to clarify diagnostic discrimination. We suggest that FMF with sacroiliitis, which is rare in rheumatological practice, should be considered in the differential diagnosis of seronegative spondyloarthropathy or other rheumatologic diseases causing spinal involvement.
KeywordsFamilial Mediterranean feverSeronegative spondyloarthropathySacroiliitisMEFV
Familial Mediterranean fever (FMF) is an autosomal recessive disease predominantly affecting individuals of Jewish, Armenian, Turkish and Arabic origin. It is characterized by recurrent episodes of fever associated most commonly with pleuritis, peritonitis, synovitis, and pericarditis. In 1992, the gene responsible for FMF, MEFV, was found to reside on the short arm of chromosome 16 . Articular disease is the second most common manifestation after abdominal pain. It occurs in 75% of patients, and articular symptoms might be the first presenting sign in a third of these patients. Short articular attacks, terminating within two or three days, are the most common, but protracted articular attacks persisting for months or even years have also been described [2, 3]. Rarely, sacroiliitis can occur, with or without spine involvement. The most severe complication of FMF is the development of amyloidosis, leading to renal disease. We report herein, three cases of FMF referred to our clinic with a diagnosis of seronegative spondyloarthropathy. A review of the literature for spinal arthritic involvement and gene mutations in patients with FMF is also discussed.
A 20-year-old Turkish man suffered from knee, ankle and low back pain, recurring every month for ten years, without any known reason. His complaints exacerbated upon standing for a long time as well as walking and traveling. His articular attacks began with diarrhea episodes lasting for 4–5 days, accompanied by abdominal pain. The patient had a history of exploratory laparatomy, following an abdominal pain attack. After further inquiry, we learned that his two brothers had similar complaints.
He was a slim young man. Physical examination revealed minimally restricted lumbar movements (Schober test; 4 cm). Straight leg raising and femoral stretch tests were negative. Sacral compression and Patrick-Fabere tests were positive bilaterally, with pain radiating from the sacroiliac joint. He had swelling and pain in his left ankle. Neurological examination revealed normal findings. His chest expansion, occiput-to-wall, tragus-to-wall, and chin-to-chest measurements were within normal limits. Laboratory investigations revealed that HLA B-27 antigen, rheumatoid factor (RF) and antistreptolysin O (ASO) were negative. His erythrocyte sedimentation rate (ESR) (38 mm/h) was raised. His urine contained 2 g/day protein. Rectal biopsy was performed and showed a trace of amyloid. Blood hemoglobin and hematocrit values were 12.2 g/dl and 38.1% respectively. Other values from urinalysis, liver function tests, and blood chemistry were within normal limits. An anteroposterior view of the pelvis showed marked sclerosis and narrowing of the sacroiliac joints, and periostal bone growth at the ischial tuberosities. Molecular analysis showed that the patient was homozygous for M694V mutation at the Mediterranean fever (MEFV) gene.
A 22-year-old Turkish man had recurrent and migratory knee and ankle pain accompanied by abdominal pain for ten years, and lower back pain for three years with morning stiffness. Physical examination revealed minimally restricted lumbar movements (Schober test; 3.5 cm). Straight leg raising and femoral stretch tests were negative. Sacral compression and Patrick-Fabere tests were negative. Neurological examination revealed normal findings. His chest expansion was 5 cm at the nipple line. His occiput-to-wall, tragus-to-wall, and chin-to-chest distances were within normal limits. Laboratory investigations revealed that HLA B-27 antigen, rheumatoid factor and ASO were negative. C reactive protein (CRP) (31 mg/dl) was raised. The urine contained no protein. Radiographs of the sacroiliac joints showed subchondral sclerosis on both sides. He was positive for homozygous M694V gene mutation.
Our three cases all had lower back pain, and their radiological and physical findings were also all consistent with the diagnosis of seronegative spondyloarthropathy (SNSA), although their clinical presentations and histories were somewhat different. Complaints for the first two cases were similar, but Case 3 had no previous abdominal pain and fever attacks. At first, all were diagnosed as having SNSA and received second-line treatment, resulting in dissatisfaction. However, their complaints were reduced following regular colchicine treatment. They all had a history of antibiotic therapy, with a diagnosis of acute rheumatic fever in childhood. Neither they nor their family members had any evidence of psoriasis or inflammatory bowel disease.
Although the occurence of spondyloarthropathy in FMF is possible, it is a rare condition. Nevertheless, chronic inflammation of the sacroiliac joints appears to occur more commonly in FMF patients than in the general population . Using results from their wide study, Langevitz et al  proposed that the prevalence of SNSA is 0.4%, with a frequency of 11 in 3,000 FMF patients. These patients had chronic arthritis, inflammatory back pain, and sacroiliitis without having syndesmophytes, bamboo spine, and decreased chest expansion. RF and HLA B-27 were all negative. The authors concluded that SNSA might have been caused by FMF despite colchicine therapy and recommended specific treatment [5, 6]. There were three other patients with bamboo spine, bilateral sacroiliitis, and positive HLA B-27 antigen. These cases were considered to be suffering from ankylosing spondylitis (AS) occurring incidentially with FMF. However, HLA B-27 occurrence might have been a worse prognostic factor for the severe form in the clinical spectrum of FMF-related SNSA . In the same manner, Kaushik et al  claimed that it was difficult to say whether these two diseases were causally related or not, and the coexistence of two diseases in the same subject might have been another possibility.
Our first and third cases had proteinury and their biopsy specimens showed pathologic findings of amyloidisis. Although chronic arthritis due to RA or SNSA is the underlying disorder in 8% of amyloidosis cases, FMF is still the major cause of secondary amyloidosis in Turkey . Renal amyloidosis might be a late complication of FMF, whereas the type II FMF phenotype presents with amyloidosis without preceding typical FMF attacks . Clinical and radiological evidence of sacroiliitis was detected in 6% of patients with amyloidosis and 11% of patients without amyloidosis in the Turkish population .
Cloning of MEFV facilitates a new and reliable diagnostic test for FMF. A set of polymerizing chain reaction primers can be used to demonstrate the mutations responsible for the disease. This important diagnostic tool has become essential in the diagnosis of patients with FMF who have typical clinical courses and manifestations .
Recently, 18 mutations of the MEFV gene have been identified. Initial studies demonstrated that amyloidosis was associated with homozygosity for the 694 substitution in the MEFV gene in patients with FMF [12– 14]. Morever, such patients had a more severe disease, manifested by early onset, more frequent attacks, joint disease, and requiring higher doses of colchicine treatment . The patients with the M694V/M694V genotype were therefore strongly encouraged to adhere to the treatment protocol . On the other hand, FMF patients without the M694V mutation were also at risk of developing amyloidosis .
Two thirds of the disease alleles in the Turkish population were attributed to three common mutations—M694V, M680V, V726A—and the patients suffering from amyloidosis carried at least one of five mutations, M694V being the most common . However, Yalcinkaya et al  reported that none of the four missense mutations (M694V, M680I, V726A, M694I) was associated with severe disease or the development of amyloidosis in Turkish FMF patients living in Turkey.
HLA B-27 is not counted among the criteria used to diagnose spondyloarthropathy. However, it shows a strong association with AS, although the strength of this association may depend upon the racial and/or ethnic group . All published cases with SNSA in FMF are HLA B-27 negative and have no significant radiological lumbar spine involvement .
Since a specific laboratory test is not yet available, the diagnosis of FMF remains clinical . Genetic testing will probably turn out to be most effectively used in patients with an uncertain diagnosis, where two mutations in MEFV would highly support the diagnosis of FMF .
It is widely accepted that regular and compliant use of colchicine not only decreases the frequency of acute attacks in FMF but also prevents the development of systemic amyloidosis in the long term . It is therefore important to differentiate SNSA of FMF from AS before beginning colchicine therapy.
The patients described herein had lower back pain with sacroiliac joint involvement. Cases like these can mimic the presentation of SNSA. The presence of a clinical course with amyloidosis raises the suspicion of FMF. The ethnic origins of our patients, their clinical histories and findings, and the absence of the HLA B-27 antigen also increase the possibility of FMF-related spondyloarthropathy instead of SNSA. We think that the presence of homozygous M694 mutation at the MEFV gene strongly confirms the diagnosis of FMF.
Our cases show that in patients not responding to the usual theurapeutic interventions for sacroiliitis, the diagnostic evaluation should also include the search for uncommon causes of spinal involvement. A lack of awareness of FMF among patients with sacroiliitis may cause misdiagnosis and delay the early treatment approach. Molecular analysis of gene mutation and determination of HLA B-27 antigen may be helpful to physicians in diagnostic evaluations of uncertain cases.
As a result, we suggest that FMF with sacroiliitis, which is rare in rheumatological practice, should be considered in the differential diagnosis of seronegative spondyloarthropathy or other rheumatologic diseases causing spinal involvement.