M694I.

http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(2): 349–352 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.852844

CASE REPORT

Amyloid A amyloidosis in a Japanese patient with familial Mediterranean fever associated with homozygosity for the pyrin variant M694I/M694I Tadashi Nakamura1, Kiyoshi Migita2, Yukio Ando3, Hirokazu Takaoka1, Hitoshi Suzushima4, and Naoki Shiraishi5

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1Section of Internal Medicine and Rheumatology, Kumamoto Shinto General Hospital, Japan, 2Department of Rheumatology, Nagasaki Medical Center,

Nagasaki, Japan, 3Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, 4Section of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan, and 5Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Abstract Familial Mediterranean fever (FMF) is an autoinflammatory disease common in eastern Mediterranean populations. The most severe complication is the development of secondary amyloid A (AA) amyloidosis. A 51-year-old Japanese male who had been suffering from periodic fever since in his twenties was referred to our hospital for proteinuria. Histological findings from renal biopsy revealed the deposition of AA amyloid fibrils, suggesting that renal dysfunction was due to AA amyloidosis. Gene analysis of the patient and his mother showed that both were homozygous for the M694I mutation in the MEFV gene. His mother was also a carrier of the SAA1.3 allele, which is not only a univariate predictor of survival but also a risk factor for the association of AA amyloidosis with rheumatoid arthritis in Japanese patients, and the SAA1-13T allele in the 13T/C polymorphism on the 5′-flanking region of the SAA1 gene. The patient was also a carrier of the SAA-13T allele. Colchicine resulted in not only an amelioration of the acute febrile attacks of FMF inflammation, but also an improvement in kidney dysfunction due to AA amyloidosis.

Introduction Familial Mediterranean fever (FMF) is the most common autoinflammatory syndrome. Patients with FMF typically present with recurrent attacks of fever and serositis with significant acute-phase inflammation. The disease is associated with mutations in the responsible Mediterranean fever gene (MEFV) that codes for pyrin expressed mainly in neutrophils and monocytes [1] and is transmitted in an autosomal-recessive manner [2]. The clinical symptoms of FMF are believed to vary according to the specific MEFV mutation. Secondary amyloid A (AA) amyloidosis is the most severe form of disease course in FMF [3]. Although FMF is a major cause of AA amyloidosis in Mediterranean areas, in Japan FMF is an extremely rare disease because of the low allele frequencies of the MEFV gene mutations [4]. Renal involvement with AA amyloidosis secondary to FMF may cause end-stage renal disease. Here, we describe the case of a Japanese patient with FMF who was homozygous for the M694I mutation presenting with proteinuria due to renal AA amyloidosis.

Case report A 51-year-old Japanese male was referred to our clinic in February, 2010 with complaints of proteinuria that had persisted for 2 years. He had had periodic fever arising once or twice a

Correspondence to: Tadashi Nakamura, Section of Internal Medicine and Rheumatology, Kumamoto Shinto General Hospital, 1-17-27 Shinyashiki, Chuo-ku, Kumamoto 862-8655, Japan. Tel: +81-96-3646000. Fax: +8196-3643139. E-mail: [email protected]

Keywords Familial Mediterranean fever, AA amyloidosis, M694I homozygosity, SAA1.3 allele, Colchicine History Received 6 July 2012 Accepted 30 August 2012 Published online 29 September 2012

month and abdominal pain attacks since he was 20 years old. His attacks were self-limiting and lasted for 2–3 days. When he was 29 years old, he had severe left knee joint swelling and tenderness, and the etiologies were screened with a focus on the orthopedic aspects, but in vain. His medical history was otherwise unremarkable. His mother had similar febrile episodes after labor following the birth of the patient. The two children of the patient had no febrile history at presentation of the patient. The parents had a nonconsanguineous marriage and had been born in different towns. On physical examination, the patient had some bilateral pitting edema. Laboratory studies showed proteinuria (182 mg/dl) with normal albuminemia (4.1 g/dl) and renal functions; serum creatinine, 0.87 mg/dl; serum blood urea nitrogen, 11.8 mg/ml; estimated glomerular filtration rate (eGFR), 74 ml/min/1.73 m2; elevated C-reactive protein (CRP), 7.1 mg/dl. Histopathological findings of the specimens obtained by renal needle biopsy revealed the presence of amorphous depositions in both mesangium and arteriole regions by hematoxylin-eosin staining (Fig. 1a) and periodic acid-Schiff staining (Fig. 1b); these depositions were positive for Congo Red staining (Fig. 1c, d). The presence of AA amyloid deposits was confirmed histologically based on positive Congo Red staining, potassium permanganate oxidation susceptibility, and the green birefringence seen by polarization microscopy after Congo Red staining, as well as by the immunohistochemical analysis using anti-AA antibody and anti-immunoglobulin light-chain (AL) antibody to differentiate AL amyloidosis. After receiving the patient’s informed consent, we performed a genetic analysis of all exons (from exon 1 to exon 10) of the MEFV gene by direct sequencing. For this analysis, we collected 2 ml of peripheral blood samples. Genomic DNA was extracted from

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Fig 1. Histopathological findings of the specimen obtained by needle renal biopsy. Both hematoxylin– eosin staining (a) and periodic acid–Schiff (b) staining revealed amorphous deposits in the areas of glomerulus tissues. (c, d) Congo Red staining showed positivity of the amorphous substances, which could suggest amyloid fibril deposits

whole blood using the Promega Wizardâ Genomic DNA Purification kit (Promega, Madison, WI). The PCR was performed using forward and reverse primers for each exon as described previously [5]. PCR products were purified with the ExoSAP-IT (GE Healthcare Japan, Tokyo, Japan) and sequenced directly, using specific primers and BigDye Terminator v1.1 (Applied Biosystems, Foster City, CA). The analysis revealed that the patient and his mother carried the homozygous MEFV (M694I/M694I) mutation (G → A transversion of nucleotide that results in substitution of isoleucine for methionine). Genetic analysis on the family, including other gene polymorphisms associated with AA amyloidosis, was carried out as previously described [6, 7] and the results are shown in Fig. 2 and Table 1. The patient not only met the criteria of FMF [8], but the results of the genomic search for the MEFV gene (Fig. 2) confirmed the

Fig. 2 Pedigree of the patient’s family and genetic analysis of the MEFV mutation, SAA1 polymorphism, and SAA1-13T polymorphism. Black symbols denote individuals who are clinically symptomatic, circle patient’s mother, squares male family members. Black square Our patient, who carries the homozygous M694I MEFV mutation, the homozygous SAA1.5 allele, and the SAA1-13T polymorphism

diagnosis of FMF, which was attributable to AA amyloidosis, resulting in proteinuria. The episodes were successfully prevented by the administration of colchicine (1.0 mg/day), and various surrogate markers ameliorated in the clinical course. Changes in the values in these markers in the chronological order February, June, August, and November, 2011 were: CRP, 7.1 , 2.5, 0.7, 0.6 mg/dl; erythrocyte sedimentation rate, 34, 29, 26, 23 mm/h; eGFR, 63.1, 70.8, 70.8. 72.6 ml/min/1.73 m2; proteinuria, 0.94, 0.98, 0.61, 0.52 g/day; serum AA protein 638, 489, 39.9, 16.0 μg/ml, respectively. The patient and his parents provided written consent to participate in the study as a requirement for ethical approval. The study design and protocols were approved by the Ethical Committee of the Kumamoto Shinto General Hospital, Kumamoto, Japan.

Discussion Familial Mediterranean fever is a hereditary autosomal recessive disease characterized by recurrent attacks of fever and polyserositis [9]. In most patients with FMF, the onset of the first attack occurs before the age of 20 years, the attacks of FMF last 1–3 days, and they are self-limiting; therefore, patients are asymptomatic in the attack-free intervals. The severity and frequency of the attacks Table 1. Genetic analysis of MEFV in the patient and his immediate family Family relationship Patient (present case) Father Mother

Gene polymorphism M694I/M694I/P588P/P588P D102D/G138G/A165A/R202Q/R314R/M694I M694I/M694I

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DOI 10.3109/14397595.2013.852844

vary among patients and even sometimes in the same patient. As the dominant manifestation is abdominal pain, it is often difficult to distinguish abdominal pain attacks in FMF from acute abdomen, and an urgent exploratory laparotomy seems to be necessary in 30–40 % of cases. Pleuritic chest pain or arthritis due to pleuritis or synovitis may be other manifestations of FMF [10]. The clinical profile in FMF, including its major manifestation, AA amyloidosis, is influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. Homozygosity for the M694V allele and the presence of the SAA1.1/1.1 genotype are significantly and independently associated with renal AA amyloidosis in eastern Mediterranean patients with FMF [11]. In this population, disease severity was found to be mainly influenced by MEFV mutations and not to be associated with genotypes at the SAA1 locus. The SAA1-13T allele was rare, associated mainly with the SAA1.3 isoform, and not related to renal AA amyloidosis. These observations led the authors to conclude that disease severity and the development of AA amyloidosis in eastern Mediterranean patients with FMF are differentially affected by genetic variations within and outside the MEFV gene. Renal involvement with AA amyloidosis secondary to FMF is the most important long-term complication, varying from asymptomatic proteinuria to nephrotic syndrome and possibly progressing to end-stage renal disease. In most cases with renal AA amyloidosis, chronic renal failure may develop within 5 years after the onset of proteinuria [12, 13]. Our patient was homozygous for both the M694I mutation and SAA1.5 allele (Fig. 2). In the light of the association of AA amyloidosis secondary to FMF, the MEFV mutation might have a more strong effect on the pathogenesis of AA amyloidosis than SAA1 allelic polymorphisms. A meta-analysis study on the founder populations (Jews, Armenians, Arabs, and Turks) for MEFV mutations revealed that the most frequent mutations detected in FMF patients are the M694V (39.6 %), V726A (13.9 %), M680I (11.4 %), E148Q (3.4 %), and M694I (2.9 %) mutations [14]. The four major diseasecausing mutations (M694V, M694I, M680I, and V726A) in exon 10 of MEFV have low allele frequencies in normal Japanese individuals [15]. Our patient carried only the M694I homo-variant in exon 10 (Table 1). Even for M694I, which seems to be the most common mutation in Japanese FMF patients [4], allele frequency is ⬍0.001 [15]. The multiple variables governing the development of AA amyloidosis in FMF have not yet been fully elucidated. Susceptibility to AA amyloidosis has been reported to be related to sex and genotype at the MEFV and the SAA1 loci [11, 16]. Further, the risk factor for renal AA amyloidosis has been found to be higher among those carrying the SAA1.1/1.1 genotype in Caucasian populations; in contrast, the SAA1.3 allele is the most predominant genotype among Japanese patients with renal AA amyloidosis [6]. It has been suggested that the -13C/T polymorphism in the 5′-flanking region of the SAA1 gene is presumably associated with susceptibility to AA amyloidosis in both Caucasian and Japanese populations [17]. However, the difference in the prevalence of AA amyloidosis among the different ethnic groups of patients, not only with FMF but also with rheumatoid arthritis (RA), remains as yet unexplained [18]. The mechanisms by which the protein polymorphisms derived from SAA1 genotypes predispose to renal AA amyloidosis remain to be unraveled. One possible explanation is that the SAA protein polymorphism is associated with more severe inflammation compared with other SAA products. Another possibility is that the AA derived from different SAA alleles is either more easily deposited or less easily metabolized after deposition. The only established fact is that more severe inflammation is associated with higher levels of SAA and that higher levels of SAA are amyloidogenic [19, 20]. Whether this may explain the association of AA amyloidosis with arthritis attacks presum-

ably associated with higher SAA levels remains to be explored. The factors governing disease activity and amyloidogenesis are complex and multiple. In an earlier publication, we reported a significant association between the SAA1.3 allele and AA amyloidosis in Japanese patients with RA [6]. The contribution of genotypes at the MEFV and SAA 1 loci is paramount; therefore, many other factors still remain to be further elucidated. Colchicine prevents episodic inflammatory attacks and the development of AA amyloidosis in almost all FMF patients compliant to therapy and also reverses the clinical manifestations of organ involvement in established AA amyloid cases [21]. However, it is generally believed that although AA amyloidosis seems to be clinically cured by colchicine therapy, a large amount of AA amyloid deposits still remains in the involved organs. In our patient, colchicine not only improved the clinical disease activity of FMF but also ameliorated AA amyloidosis, based on the better renal function following treatment, as evidenced by the biological markers. Colchicine is very important in preventing AA amyloidosis secondary to FMF, and it may also arrest the progression of AA amyloidosis in those who already have the complication. However, the specific mode of action of colchicine in AA amyloidosis secondary to FMF has not been determined despite the reported effectiveness of this treatment in a number of anecdotic cases [22–24]. Colchicine is believed to inhibit the enhanced chemotactic activity for polymorphonuclear leukocytes through interleukin 8 and leukotriene B4, which would lead to a suppression of SAA synthesis. The actual mode of action of colchicine in the mechanisms in FMF await further investigation and more conclusive evidence. To ensure clinical improvement in our patient’s disease course, if this is possible, a sequential biopsy of the upper gastrointestine and/or kidney is advisable. The aim of specific treatments of AA amyloidosis caused by FMF is to slow down and halt SAA production because AA amyloidosis is caused by the deposition of AA amyloid fibrils in various organs, which in turn derives from the circulatory acute-phase reactant SAA. Thus, the levels of SAA should be monitored and kept to ⬍10 μg/ml [25] in the long-term follow-up, which in turn requires frequent assessment of SAA concentrations. With respect to our patient, bone marrow suppression and other adverse effects have not emerged to date, but careful observation is needed.

Acknowledgments This work was supported in part by a Grant-in-Aid for scientific research from the Japanese Ministry of Health, Labor, and Welfare and the Amyloidosis Research Committee for Intractable Diseases, Epochal Diagnosis, and Treatment in Japan.

Conflict of interest None.

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