ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2015; Early Online: 1–5 © 2015 Japan College of Rheumatology DOI: 10.3109/14397595.2015.1031722


Protracted arthritis in a Japanese patient with familial Mediterranean fever Kiyoshi Migita1, Sachi Hisanaga1, Yasumori Izumi1, Chieko Kawahara1, Yoshika Shigemitsu1, Nozomi Iwanaga1, Toshitaka Araki1, Masatsugu Kamata1, Masahiro Izumi2, Kenji Kumagai2, and Atsushi Kawakami3

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1Departments of General Internal Medicine and Rheumatology, Nagasaki medical Center, Omura City, Nagasaki, Japan, 2Department of Orthopedic

surgery, Nagasaki medical Center, Omura City, Nagasaki, Japan, and 3Department of Rheumatology, Nagasaki University Hospital, Sakamoto, Nagasaki, Japan Abstract


The most common arthritic involvement in familial Mediterranean fever (FMF) is acute selflimiting monoarthritis which typically lasts for 72 h. Hip joint involvement is uncommon in FMF and can result either from a process specific to this disease or from a coexisting inflammatory joint disease. We describe a 37-year-old woman with FMF and right osteoarthritis secondary to congenital hip dislocation. Periodic fever with right coxalgia lasting for 6 months was treated using colchicine. Genetic analysis revealed homozygous mutation in the MEFV gene (L110P-E148Q/ L110P-E148Q), confirming the FMF diagnosis. Although the clinical presentation and course of FMF arthritis are diverse, delineating these clinical patterns may help with early recognition and treatment to prevent destructive arthritis in FMF. Clinicians should consider the possibility of FMF development in unusual monoarthritis patients with recurrent febrile attacks.

Familial Mediterranean fever, Colchicine, Congenital hip dislocation, MEFV gene

Introduction Familial Mediterranean fever (FMF) is a hereditary disorder that affects persons with a Mediterranean heritage, typically Sephardic Jews and Armenians [1]. One form of FMF is characterized by brief and self-limiting attacks of arthritis, peritonitis, pleuritis, or an erysipelas-like erythema [1]. Arthritis (acute synovitis) appears in approximately 70% of the patients and the hip, knee, and ankle joints are affected in more than 80% of the cases [2]. The most common articular attack is an acute, painful large joint monoarthritis which usually affects the knee or hip and lasts for a few days [3]. By contrast, protracted arthritis has been also reported [4]. The striking feature of protracted FMF arthritis is full recovery, except for hip involvement [5]. Younes et  al. reported ten FMF patients who suffered from hip involvement, but only four of these patients had isolated FMF-related arthritis and two required hip arthroplasty [6]. They indicated the association of FMF and ankylosing spondylitis (AS) in the remaining patients [6]. Therefore, hip involvement in FMF can result either from a process specific to this disease, or from coexisting inflammatory joint diseases, including AS or juvenile idiopathic arthritis [7,8]. We report a case of a FMF patient who presented with destructive inflammatory arthritis secondary to congenital hip dislocation.

Case report A 37-year-old woman was admitted for right hip joint pain, which had become exacerbated over the past 3 weeks, and a high fever. Correspondence to: Kiyoshi Migita, Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan. Tel:  81-957-52-3121. Fax:  81-957-53-6675. E-mail: [email protected]

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History Received 10 December 2014 Accepted 17 March 2015 Published online 20 April 2015

At the age of 10 years, she had suffered a congenital right hip dislocation and underwent hip arthroplasty. Since then, she had made yearly visits to the orthopedic department of our hospital for regular examination of the right hip joint. She recognized no coxalgia until the age of 37 years. Six months prior to admission, she developed acute right coxalgia associated with fever, more than 39°C, which lasted for 2–3 days. This recurrent febrile attack occurred at an interval of 2 weeks. The findings of physical examination were consistent with painful and limited left hip joint motion and normal neurological findings. Blood analysis revealed a white blood cell count of 6,500 cells/mm3, hemoglobin of 11.5 g/dL, and a platelet count of 358,000/mm3 (Table 1). Her C-reactive protein levels were 3.4 mg/dL, erythrocyte sedimentation rate was 122 mm/h, antinuclear antibodies results were negative, and anti-cyclic citrullinated peptide antibodies results were negative. All other laboratory results were unremarkable, and her blood and joint fluid cultures were also negative. Radiography of the right hip joint revealed destructive and osteolytic changes of right femoral head, joint space narrowing, and sclerosis (Figure 1). Magnetic resonance imaging (MRI) with signal intensity on short tau inversion recovery (STIR) sequence showed thickened synovium, demonstrating active synovitis, in addition to the destructive changes in right femoral head (Figure 2). As the patient’s high fever and right hip joint pain were resolved with colchicine treatment (1.0 mg/day), and as genetic analysis (Figure 3) revealed compound heterozygous mutations in the MEFV gene (L110P/E148Q), she was diagnosed with FMF. After we initiated the colchicine treatment, she did not experience any subsequent arthritic attacks, and her right coxalgia pain reduced and limited hip motion improved after 2 weeks of treatment (Figure 4). In addition, her laboratory data showed

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Table 1. Laboratory Findings.

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Peripheral blood Red blood cells Hemoglobin White blood cells Neutrophil Monocyte Lymphocyte Eosinophil Basophil Platelet Blood chemistry Total protein Albumin Total bilirubin Glutamic-oxaloacetic transaminase Glutamic-pyruvic transaminase Lactate dehydrogenase Alkaline phosphatase Creatinine kinase Total cholesterol Blood urea nitrogen Creatinine Na K Cl

423  104/ml 11.5 g/dl 6500/ml 47.9% 6.9% 38.6% 6.2% 0.4% 35.8  104/ml 8.4 g/dl 3.4 g/dl 0.2 mg/dl 16 IU/l (7–33) 13 IU/l (5–30) 172 IU/l (260–480) 160 IU/l (80–250) 27 IU/l (60–160) 198 mg/dl 8.5 mg/dl 0.7 mg/dl 139 mEq/l 5.1 mEq/l 105 mEq/l

Serological tests C-reactive protein Erythrocyte sedimentation rate IgG IgA IgM C3 C4 Rheumatoid factor Anti-nuclear Ab PR-3-ANCA MPO-ANCA Anti-CCP Ab MMP-3

3.4 mg/dl ( 0.30) 122 mm/hr 2420 mg/dl (900–2000) 420 mg/dl 197 mg/dl 158 mg/dl (86–160) 25 mg/dl (17–45)  20 (U/ml) ( 17)  40 (Speckled)  1.0 U/ml ( 3.5)  1.0 U/ml ( 3.5)  1.4 U/ml ( 4.5) 35.9 ng/ml (17.3∼59.7)

Virological test HCV-Ab HBsAg

(–) (–)

Urinalysis Protein Sugar Occult blood Sediment

(–) (–) (–) np

HBsAg hepatitis B surface antigen, Anti-CCP Ab Anti-cyclic citrullinated peptide antibody, HCV hepatitis C virus, MMP-3 Matrix metalloproteinase-3, MPO-ANCA myeloperoxidase-anti-neutrophil cytoplasmic antibody, PR-3-ANCA proteinase 3-antineutrophil cytoplasmic antibody; soluble interleukin-2 receptor; vascular endothelial growth factor; human herpes virus 8.

that the markedly elevated levels of erythrocyte sedimentation rate had been close to the normal levels (Figure 4). The patient fulfilled the diagnostic criteria for typical FMF [9] according to the presence of major criteria of typical febrile attack ( 38°C), lasting 2–3 days with acute arthritis and the favorable response to colchicine treatment. Although a degree of limited right hip joint motion persisted, through colchicine treatment her hip joint pain and morning stiffness significantly reduced.

Discussion Along with periodic fever and abdominal pain attacks, articular attacks are one of the most common manifestations of FMF, and acute monoarthritic episodes in the ankle and knee joints are the most common joint involvements [3]. In addition, protracted cases of arthritis typically occur in the knee and hip joints [2]. Arthritis with FMF typically heals without sequelae, although it

Figure 1. Series of pelvic radiographies showing progressive and destructive arthritis of the right of hip joint. Progressive osteolytic changes in right femoral head and sclerotic changes in the right acetabular roof were observed.


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Figure 2. MRI with signal intensity on STIR sequence showed thickened synovium as depicted by high-intensity areas (white arrow).

occasionally has a chronic and destructive course (especially in the hip joint) that typically requires joint replacement therapy [6,10]. The chronic destruction in these cases may be related to either FMF or coexisting chronic degenerative diseases. In this report, we describe hip joint arthritis in a FMF patient with MEFV gene mutations, who experienced osteoarthritis secondary to congenital

Articular involvement in FMF  3 hip dislocation. The articular involvement in this patient appeared to be progressive and destructive. Whether the E148Q allele in the MEFV gene is a true diseasecausing mutation remains controversial [11]. The E148Q allele appears to confer an inflammatory phenotype in Turkish individuals [12]. In a Greek population, the E148Q allele was found to be significantly more frequent in FMF patients than that in healthy controls [13]. Although FMF patients with E148Q allele have a heterozygous clinical presentation, some patients are symptomatic and colchicine treatment is required as demonstrated in our patient. A diagnosis of FMF is often based on typical clinical manifestations, and the diagnosis may be complicated if there are only febrile episodes without serositis [14]. Therefore, the response to colchicine treatment has a unique diagnostic value when evaluating atypical FMF cases [15]. In the present case, the patient had recurrent fever with the arthritic symptoms, and colchicine treatment effectively resolved it. Therefore, the patient had 1 major criterion and 2 minor criteria, based on the Tel Hashomer criteria [9], and a diagnosis of typical FMF was confirmed. Sneh et  al. have reported on the progressive course of protracted hip joint arthritis in FMF [4], and Salai et al. have reported

Figure 3. MEFV gene analysis in a healthy control (wild type) and in the present case. In the patient, the T to C transition in codon 110 of MEFV gene converting a leucine (L) to proline (P), G to C transition in codon 148 converting a glutamic acid (E) to glutamine (Q) are shown.

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Figure 4. Clinical course of the present case.

­ 18 FMF patients who underwent 22 total hip replacements [16]. Based on this relatively high incidence, the hip appears to be the joint that is most vulnerable to FMF attacks, which can occasionally result in cartilage destruction. In addition, Lachmann et  al. have reported that asymptomatic relatives of patients with FMF, who were heterozygous for a MEFV mutation, had higher levels of acute-phase reactants compared with subjects without MEFV mutation [17]. Given the inflammatory aspect of osteoarthritis and the detrimental effects of MEFV mutations in other inflammatory diseases, a relatively early onset or more severe course can be expected in FMF patients. Our nationwide survey for Japanese patients with FMF showed that the prevalence of arthritis was 36.9% [18]. However, destructive arthritis requiring surgical treatment was rarely confirmed in the study [18]. By contrast, a FMF patient with unusual protracted arthritis requiring total hip arthroplasty was reported in an Asian country [19]. In the present case, destructive hip arthritis developed after the occurrence of periodic fever, suggesting that FMF per se can cause inflammatory arthropathy under the condition of congenital hip dislocation. A recent study has explored the significance of the MEFV gene in the expression of rheumatoid arthritis, and reported that patients carrying one common MEFV mutation may present with more severe rheumatoid arthritis [20]. In addition, another study has reported a severe prognosis for juvenile idiopathic arthritis when it is associated with FMF [8]. Therefore, further studies in a larger population of patients with inflammatory arthropathy appear to be warranted. It is still early to evaluate the impact of colchicine treatment on destructive arthritis that was manifested in the present case. However, early therapeutic intervention may improve the prognosis by preventing the complication of destructive arthritis in FMF. It was reported that colchicine is the first choice for treatment; however, sometimes synovectomy or joint replacement may be necessary for protracted arthritis [21]. Therefore, long-term effects of colchicine treatment should be monitored in the present case. In conclusion, arthritis of FMF has diverse clinical presentations. In contrast to the chronic joint involvement, concomitant FMF and congenital hip dislocation can result in severe destruction that requires surgical treatment. Therefore, cases of progressive destructive arthritis with periodic fever should be evaluated

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for FMF, and this step can facilitate early treatment to prevent the development of irreversible joint damage.­­

Conflict of interest None.

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14. Ozçakar ZB, Yalçinkaya F, Yüksel S, Ekim M. The expanded clinical spectrum of familial Mediterranean fever. Clin Rheumatol. 2007;26(9):1557–60. 15. Ben-Chetrit E, Peleg H, Aamar S, Heyman SN. The spectrum of MEFV clinical presentations–is it familial Mediterranean fever only? Rheumatology (Oxford). 2009;48(11):1455–9. 16. Salai M, Langevitz P, Blankstein A, Zemmer D, Chechick A, Pras M, Horoszowski H. Total hip replacement in familial Mediterranean fever. Bull Hosp Jt Dis. 1993;53(1):25–8. 17. Lachmann HJ, Sengül B, Yavuzşen TU, Booth DR, Booth SE, Bybee A, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45(6):746–50.

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Protracted arthritis in a Japanese patient with familial Mediterranean fever.

The most common arthritic involvement in familial Mediterranean fever (FMF) is acute self- limiting monoarthritis which typically lasts for 72 h. Hip ...
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