Modern Rheumatology
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Pulmonary Necrotizing Granulomas in a patient with familial mediterranean fever Hisako Kushima, Hiroshi Ishii, Koji Ishii & Jun-ichi Kadota To cite this article: Hisako Kushima, Hiroshi Ishii, Koji Ishii & Jun-ichi Kadota (2015) Pulmonary Necrotizing Granulomas in a patient with familial mediterranean fever, Modern Rheumatology, 25:5, 806-809, DOI: 10.3109/14397595.2013.844398 To link to this article: http://dx.doi.org/10.3109/14397595.2013.844398
Published online: 21 Oct 2013.
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Date: 06 November 2015, At: 03:26
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2015; 25(5): 806–809 © 2013 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844398
CASE REPORT
Pulmonary Necrotizing Granulomas in a patient with familial mediterranean fever Hisako Kushima1, Hiroshi Ishii1, 2, Koji Ishii3, and Jun-ichi Kadota1 1Department of Respiratory Medicine, Oita University Hospital, Oita, Japan, 2Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka,
Downloaded by [University of Florida] at 03:26 06 November 2015
Japan, 3Department of Connective Tissue Diseases, Oita University Hospital, Oita, Japan Abstract
Keywords
We herein report a case of familial Mediterranean fever (FMF) presenting with granulomatous lung lesions with neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomeraseassociated protein (TP1) (NACHT) leucine-rich-repeat 1-positive inflammatory cell infiltrates. FMF is an autoinflammatory disorder characterized by recurrent and self-limited attacks of pyrexia, arthritis and erysipelas-like skin lesions. Lung disorders associated with FMF are extremely rare. This is the first report of an immunologically-confirmed case of pulmonary manifestations of this disease.
familial Mediterranean fever, Immunohistochemistry, Lung
Introduction Familial Mediterranean fever (FMF) is an autosomal recessive disorder that is particularly common in Mediterranean populations but is rare in the rest of the world, especially Asia. It is characterized by recurrent and self-limited attacks of pyrexia, arthritis, erysipelas-like skin lesions and secondary amyloidosis. Coexistence with inflammatory diseases, including spondyloarthritis, ulcerative colitis and various types of systemic vasculitis, has been reported [1]. There are only a few reports of lung involvement in patients with FMF, including amyloidosis, transient pleuritis during attacks and mesothelioma of the pleura [2]. This report describes the first case of pulmonary necrotizing granuloma associated with FMF.
Case report A 49-year-old Japanese female was referred to our hospital due to pyrexia and systemic exanthema lasting for 2 days in addition to an abnormal chest roentgenogram. She was an office worker and had no history of dust exposure, such as exposure to silicon, which includes nanoparticles acting as inflammasomes. She had experienced several episodes of pyrexia (⬎ 38°C) with arthralgia, exanthema, leukocytopenia and pulmonary infiltrates with and without pleural effusion every few years since 35 years of age. All of these manifestations continued for 1–3 days and spontaneously diminished. At 45 years of age, she exhibited rapidly appearing and disappearing patchy ground-glass attenuation in the lungs with peripheral blood eosinophilia. One year later, at 46 years of age, she underwent a surgical lung biopsy for emerging multiple pulmonary nodules (Figure 1a–c); however, the episodes of pyrexia, arthralgia, exanthema and leukocytopenia and pulmonary lesions repeated without a definitive diagnosis. The patient was
Correspondence to: Hisako Kushima, Department of Respiratory Medicine, Oita University Hospital, 1-1 Idaigaoka, Yufu-city, Oita, Japan, 879-5593. Tel: ⫹ 81-97-549-4411. Fax: ⫹ 81-97-549-4245. E-mail: [email protected]
History Received 27 May 2013 Accepted 29 July 2013 Published online 18 October 2013
finally diagnosed with FMF at 48 years of age based on the diagnostic criteria [3]. A genetic analysis using DNA extracted from her peripheral blood lymphocytes was performed after obtaining her informed consent. According to the results of a polymerase chain reaction analysis of the sections of exons 1–10 of the Mediterranean fever gene (MEFV), a heterozygous mutation in MEFV (TCC–TGC) at codon 503 in exon 5 of the gene was identified. The mutation resulted in a substitution of cysteine for serine (S503C). No NOD-like receptor 3 gene mutations, found in approximately 70% of patients with cryopyrin-associated periodic syndromes, were detected. In addition, no tumor necrosis factor (TNF) receptor superfamily member 1A gene mutations, found in patients with TNF receptor-associated periodic syndrome, were detected. The patient’s family members and relatives did not provide permission for genetic testing. On admission, the patient’s body temperature was 39.4°C, her pulse rate was 110 beats/min and her blood pressure was 100/55 mmHg. A physical examination disclosed no crackles on chest auscultation; however, there was swelling in all finger joints and erythematous eruptions with edema on the face, palms, legs and hips. Laboratory tests revealed mild leukocytopenia (a white blood cell count of 2,280/μl with 82.0% of neutrophils), a C-reactive protein level of 20.2 (⬍ 0.21) mg/dl, a serum amyloid A (SAA) level of 1,619 (⬍ 8) μg/ml, an interleukin-1β (IL-1β) level of 1.88 (⬍ 0.93) pg/ml, an IL-6 level of 188 (⬍ 4) pg/ml, a TNF-α level of 2.0 (⬍ 0.55) pg/ml and a soluble interleukin-2 receptor (sIL-2R) level of 808 (⬍ 519) U/ml. The patient was negative for all autoantibodies measured. She had no electrocardiographic abnormalities. Chest computed tomography (Figure 1d–f) revealed ground-glass opacity and multiple nodules in the upper lobes, with a small amount of pleural effusion. The bronchoalveolar lavage fluid exhibited increased proportions of lymphocytes (18.4%) and eosinophils (20.6%), while there were no pathogenic microbes in the fluid. An analysis of the surgical biopsy specimen obtained at 46 years of age revealed a leukocytoclastic necrotizing granuloma surrounded by eosinophil and lymphocyte infiltration and numer-
Pulmonary Necrotizing Granulomas in FMF 807
DOI 10.3109/14397595.2013.844398
Downloaded by [University of Florida] at 03:26 06 November 2015
Figure 1. (a–c) Chest computed tomography (CT) performed 3 years before admission showed multiple nodules in the right upper lobe. (d–f) Chest CT performed on admission showed bilateral ground-glass opacity and a new lung nodule in the right upper lobe.
ous lymphoid follicles (Figure 2). In addition, although there was no amyloid deposition with Congo red staining of the lung specimen, immunohistochemistry demonstrated the overexpression of neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1) (NACHT) leucine-rich-repeat and pyrin-domain (PYD)containing protein-1 (NALP1) predominantly in ubiquitin carboxy-terminal hydrolase L1 (UCHL1)-positive T-lymphocytes in the area of cellular infiltration around the granuloma (Figure 3). The patient’s symptoms, including pyrexia, swelling of the joints and eruptions, subsided after the initial treatment with betamethasone (4 mg/day), and improvements in the areas of lung opacity, except for the solid nodules, were observed. In addition, the serum levels of CRP, SAA, IL-1β, IL-6 and sIL-2R were sub-
sequently decreased to the normal range, and the white blood cell count returned to a normal value. Following the administration of betamethasone for 8 days, maintenance therapy consisting of oral colchicine at a dose of 0.5 mg/day was started. Subsequently, the patient’s disease condition has been stable for ⬎ 2 years without any febrile attacks. No additional abnormal shadows have been observed on chest CT.
Discussion FMF is an autoinflammatory disorder, and the mutations responsible for FMF are in proteins involved in the modulation of inflammation and apoptosis. The MEFV is expressed in neutrophils, eosinophils and monocytes and is located in the short arm of chromosome 16, which encodes a 781-amino acid protein called pyrin [4]. Pyrin
808
H. Kushima et al.
Mod Rheumatol, 2015; 25(5): 806–809
Downloaded by [University of Florida] at 03:26 06 November 2015
Figure 2. A surgical lung biopsy specimen of the nodule in the right upper lobe showed a necrotizing granuloma (a; Hematoxylin–Eosin staining, original magnification 40⫻) surrounded by eosinophil and lymphocyte infiltration and numerous lymphoid follicles (b; 100⫻). Leukocytoclastic changes were observed inside the granuloma (c; 400⫻), and most of the cells were positive for Eosinophil Cationic Protein EG2 (d; EG2 staining, 400⫻).
is thought to be a downregulator of inflammation and apoptosis [5]. Mutated forms of pyrin proteins may be involved in alternations of inflammatory processes that ultimately result in the uncontrolled expression of the potent proinflammatory cytokine IL-1β. In turn, the overexpression of IL-1β leads to bursts of systemic inflammation. Pyrin interacts with apoptosis-associated speck-like proteins containing a caspase recruitment domain (CARD; ASC) and modulates ASC-induced apoptosis. ASC interacts with the PYD of NALP1 in vitro. NALP1 is a regulator of the innate immune system and induces apoptosis when it overexpressed [6]. The biopsied lung specimen obtained in the present case demonstrated cells positive for anti-NALP1 antibodies, which recognize the PYD of human NALP1. Therefore, the areas of lung opacity observed in the present case were highly suspected to be involved in FMF. Certain mutations of MEFV play an important role in the pathogenesis of FMF and are strongly associated with the FMF phenotype. Most mutations of MEFV are located in exon 10, and approximately 30 mutations or polymorphisms are associated with FMF [1]. A mutation analysis of MEFV, which has been introduced in recent years, has revealed a significant correlation between the M694V, E148Q and V726A mutations and clinical findings [7]. Furthermore, Aldea et al. found a H478Y variant
alone in a Spanish family that produces a severe FMF phenotype with amyloidosis [8]. In Japan, the M694I and E148Q mutations are most frequently detected [9, 10]. Although an S503C mutation in exon 5, which has thus far not been identified in Japan, may be relevant to the pulmonary necrotizing granuloma observed in the present case, further studies are needed to determine the relationship between mutations in MEFV and lung involvement in FMF patients. Approximately 90% of cases of FMF develop in patients under 20 years of age. Although the cause of late-onset FMF, such as that observed in the present case, is unclear, heterozygosity of MEFV mutations may contribute to the pathogenesis of this disease. Mutation analyses of MEFV and therapeutic trials with colchicine should be considered in patients exhibiting recurrent febrile attacks, even in adulthood. We herein described the first case of a pulmonary necrotizing granuloma in a patient with FMF with the MEFV mutation of S503C in exon5, although the common form of thoracic involvement of this disease is pleurisy. In this case, the serum level of TNF-α was slightly increased, and this cytokine has the potential to promote the formation of granulomatous lesions [11]. In addition, Nakamura et al. reported FMF cases that were successfully treated with a TNF antagonist [12]. Based on these findings, we
DOI 10.3109/14397595.2013.844398
Pulmonary Necrotizing Granulomas in FMF 809
Downloaded by [University of Florida] at 03:26 06 November 2015
Figure 3. Immunohistochemistry for NACHT leucine-rich-repeat and PYD-containing protein-1 (NALP1; a and c), L26 (b) and UCHL1 (d) (a-d; original magnification 800⫻) using serial sections of the lung specimen. In the area of cellular infiltration around the granuloma, the NALP1positive cells were not L26-positive B-cells (arrows in a and b), but rather UCHL1-positive T-cells (arrowheads in c and d).
believe that this is a rare case of FMF presenting with granulomatous lung lesions. Furthermore, we also demonstrated the presence of NALP1-positive inflammatory cell infiltration in the lungs. Clinicians should be aware that granulomatous nodules and ground-glass opacity may be pulmonary manifestations of FMF.
Acknowledgements We thank Dr. Yoshinori Kawabata (Division of Pathology, Saitama Cardiovascular Respiratory Center, Saitama), Dr. Kenji Kashima and Ms. Kanako Ito (Oita University Faculty of Medicine, Oita) for their valuable assistance in the pathological diagnosis.
Conflicts of interest None.
References 1. Ozen S. Mutations/polymorphisms in a monogenetic autoinflammatory disease may be susceptibility markers for certain rheumatic diseases: lessons from the bedside for the benchside. Clin Exp Rheumatol. 2009;27(2 Suppl 53):S29–31. 2. Lidar M, Pras M, Langevitz P, Livneh A. Thoracic and lung involvement in familial Mediterranean fever (FMF). Clin Chest Med. 2002;23(2):505–11.
3. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–85. 4. Fischel-Ghodsian N, Bu X, Prezant TR, Oeztas S, Huang ZS, Bohlman MC, et al. Regional mapping of the gene for familial Mediterranean fever on human chromosome 16p13. Am J Med Genet. 1993;46(6):689–93. 5. Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95(10):3223–31. 6. Mille F, Thibert C, Fombonne J, Rama N, Guix C, Hayashi H, et al. The Patched dependence receptor triggers apoptosis through a DRALcaspase-9 complex. Nat Cell Biol. 2009;11(6):739–46. 7. Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J, et al. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A. 2004;124A(1):67–73. 8. Baykal Y, Saglam K, Yilmaz MI, Taslipinar A, Akinci SB, Inal A. Serum sIL-2r, IL-6, IL-10 and TNF-alpha level in familial Mediterranean fever patients. Clin Rheumatol. 2003;22(2):99–101. 9. Nakamura A, Matsuda M, Tazawa K, Shimojima Y, Ikeda S. Successful treatment with infliximab and low-dose methotrexate in a Japanese patient with familial Mediterranean fever. Intern Med. 2007;46(15):1247–49.
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Pulmonary Necrotizing Granulomas in a patient with familial mediterranean fever Hisako Kushima, Hiroshi Ishii, Koji Ishii & Jun-ichi Kadota To cite this article: Hisako Kushima, Hiroshi Ishii, Koji Ishii & Jun-ichi Kadota (2015) Pulmonary Necrotizing Granulomas in a patient with familial mediterranean fever, Modern Rheumatology, 25:5, 806-809, DOI: 10.3109/14397595.2013.844398 To link to this article: http://dx.doi.org/10.3109/14397595.2013.844398
Published online: 21 Oct 2013.
Submit your article to this journal
Article views: 31
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=imor20 Download by: [University of Florida]
Date: 06 November 2015, At: 03:26
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2015; 25(5): 806–809 © 2013 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844398
CASE REPORT
Pulmonary Necrotizing Granulomas in a patient with familial mediterranean fever Hisako Kushima1, Hiroshi Ishii1, 2, Koji Ishii3, and Jun-ichi Kadota1 1Department of Respiratory Medicine, Oita University Hospital, Oita, Japan, 2Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka,
Downloaded by [University of Florida] at 03:26 06 November 2015
Japan, 3Department of Connective Tissue Diseases, Oita University Hospital, Oita, Japan Abstract
Keywords
We herein report a case of familial Mediterranean fever (FMF) presenting with granulomatous lung lesions with neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomeraseassociated protein (TP1) (NACHT) leucine-rich-repeat 1-positive inflammatory cell infiltrates. FMF is an autoinflammatory disorder characterized by recurrent and self-limited attacks of pyrexia, arthritis and erysipelas-like skin lesions. Lung disorders associated with FMF are extremely rare. This is the first report of an immunologically-confirmed case of pulmonary manifestations of this disease.
familial Mediterranean fever, Immunohistochemistry, Lung
Introduction Familial Mediterranean fever (FMF) is an autosomal recessive disorder that is particularly common in Mediterranean populations but is rare in the rest of the world, especially Asia. It is characterized by recurrent and self-limited attacks of pyrexia, arthritis, erysipelas-like skin lesions and secondary amyloidosis. Coexistence with inflammatory diseases, including spondyloarthritis, ulcerative colitis and various types of systemic vasculitis, has been reported [1]. There are only a few reports of lung involvement in patients with FMF, including amyloidosis, transient pleuritis during attacks and mesothelioma of the pleura [2]. This report describes the first case of pulmonary necrotizing granuloma associated with FMF.
Case report A 49-year-old Japanese female was referred to our hospital due to pyrexia and systemic exanthema lasting for 2 days in addition to an abnormal chest roentgenogram. She was an office worker and had no history of dust exposure, such as exposure to silicon, which includes nanoparticles acting as inflammasomes. She had experienced several episodes of pyrexia (⬎ 38°C) with arthralgia, exanthema, leukocytopenia and pulmonary infiltrates with and without pleural effusion every few years since 35 years of age. All of these manifestations continued for 1–3 days and spontaneously diminished. At 45 years of age, she exhibited rapidly appearing and disappearing patchy ground-glass attenuation in the lungs with peripheral blood eosinophilia. One year later, at 46 years of age, she underwent a surgical lung biopsy for emerging multiple pulmonary nodules (Figure 1a–c); however, the episodes of pyrexia, arthralgia, exanthema and leukocytopenia and pulmonary lesions repeated without a definitive diagnosis. The patient was
Correspondence to: Hisako Kushima, Department of Respiratory Medicine, Oita University Hospital, 1-1 Idaigaoka, Yufu-city, Oita, Japan, 879-5593. Tel: ⫹ 81-97-549-4411. Fax: ⫹ 81-97-549-4245. E-mail: [email protected]
History Received 27 May 2013 Accepted 29 July 2013 Published online 18 October 2013
finally diagnosed with FMF at 48 years of age based on the diagnostic criteria [3]. A genetic analysis using DNA extracted from her peripheral blood lymphocytes was performed after obtaining her informed consent. According to the results of a polymerase chain reaction analysis of the sections of exons 1–10 of the Mediterranean fever gene (MEFV), a heterozygous mutation in MEFV (TCC–TGC) at codon 503 in exon 5 of the gene was identified. The mutation resulted in a substitution of cysteine for serine (S503C). No NOD-like receptor 3 gene mutations, found in approximately 70% of patients with cryopyrin-associated periodic syndromes, were detected. In addition, no tumor necrosis factor (TNF) receptor superfamily member 1A gene mutations, found in patients with TNF receptor-associated periodic syndrome, were detected. The patient’s family members and relatives did not provide permission for genetic testing. On admission, the patient’s body temperature was 39.4°C, her pulse rate was 110 beats/min and her blood pressure was 100/55 mmHg. A physical examination disclosed no crackles on chest auscultation; however, there was swelling in all finger joints and erythematous eruptions with edema on the face, palms, legs and hips. Laboratory tests revealed mild leukocytopenia (a white blood cell count of 2,280/μl with 82.0% of neutrophils), a C-reactive protein level of 20.2 (⬍ 0.21) mg/dl, a serum amyloid A (SAA) level of 1,619 (⬍ 8) μg/ml, an interleukin-1β (IL-1β) level of 1.88 (⬍ 0.93) pg/ml, an IL-6 level of 188 (⬍ 4) pg/ml, a TNF-α level of 2.0 (⬍ 0.55) pg/ml and a soluble interleukin-2 receptor (sIL-2R) level of 808 (⬍ 519) U/ml. The patient was negative for all autoantibodies measured. She had no electrocardiographic abnormalities. Chest computed tomography (Figure 1d–f) revealed ground-glass opacity and multiple nodules in the upper lobes, with a small amount of pleural effusion. The bronchoalveolar lavage fluid exhibited increased proportions of lymphocytes (18.4%) and eosinophils (20.6%), while there were no pathogenic microbes in the fluid. An analysis of the surgical biopsy specimen obtained at 46 years of age revealed a leukocytoclastic necrotizing granuloma surrounded by eosinophil and lymphocyte infiltration and numer-
Pulmonary Necrotizing Granulomas in FMF 807
DOI 10.3109/14397595.2013.844398
Downloaded by [University of Florida] at 03:26 06 November 2015
Figure 1. (a–c) Chest computed tomography (CT) performed 3 years before admission showed multiple nodules in the right upper lobe. (d–f) Chest CT performed on admission showed bilateral ground-glass opacity and a new lung nodule in the right upper lobe.
ous lymphoid follicles (Figure 2). In addition, although there was no amyloid deposition with Congo red staining of the lung specimen, immunohistochemistry demonstrated the overexpression of neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1) (NACHT) leucine-rich-repeat and pyrin-domain (PYD)containing protein-1 (NALP1) predominantly in ubiquitin carboxy-terminal hydrolase L1 (UCHL1)-positive T-lymphocytes in the area of cellular infiltration around the granuloma (Figure 3). The patient’s symptoms, including pyrexia, swelling of the joints and eruptions, subsided after the initial treatment with betamethasone (4 mg/day), and improvements in the areas of lung opacity, except for the solid nodules, were observed. In addition, the serum levels of CRP, SAA, IL-1β, IL-6 and sIL-2R were sub-
sequently decreased to the normal range, and the white blood cell count returned to a normal value. Following the administration of betamethasone for 8 days, maintenance therapy consisting of oral colchicine at a dose of 0.5 mg/day was started. Subsequently, the patient’s disease condition has been stable for ⬎ 2 years without any febrile attacks. No additional abnormal shadows have been observed on chest CT.
Discussion FMF is an autoinflammatory disorder, and the mutations responsible for FMF are in proteins involved in the modulation of inflammation and apoptosis. The MEFV is expressed in neutrophils, eosinophils and monocytes and is located in the short arm of chromosome 16, which encodes a 781-amino acid protein called pyrin [4]. Pyrin
808
H. Kushima et al.
Mod Rheumatol, 2015; 25(5): 806–809
Downloaded by [University of Florida] at 03:26 06 November 2015
Figure 2. A surgical lung biopsy specimen of the nodule in the right upper lobe showed a necrotizing granuloma (a; Hematoxylin–Eosin staining, original magnification 40⫻) surrounded by eosinophil and lymphocyte infiltration and numerous lymphoid follicles (b; 100⫻). Leukocytoclastic changes were observed inside the granuloma (c; 400⫻), and most of the cells were positive for Eosinophil Cationic Protein EG2 (d; EG2 staining, 400⫻).
is thought to be a downregulator of inflammation and apoptosis [5]. Mutated forms of pyrin proteins may be involved in alternations of inflammatory processes that ultimately result in the uncontrolled expression of the potent proinflammatory cytokine IL-1β. In turn, the overexpression of IL-1β leads to bursts of systemic inflammation. Pyrin interacts with apoptosis-associated speck-like proteins containing a caspase recruitment domain (CARD; ASC) and modulates ASC-induced apoptosis. ASC interacts with the PYD of NALP1 in vitro. NALP1 is a regulator of the innate immune system and induces apoptosis when it overexpressed [6]. The biopsied lung specimen obtained in the present case demonstrated cells positive for anti-NALP1 antibodies, which recognize the PYD of human NALP1. Therefore, the areas of lung opacity observed in the present case were highly suspected to be involved in FMF. Certain mutations of MEFV play an important role in the pathogenesis of FMF and are strongly associated with the FMF phenotype. Most mutations of MEFV are located in exon 10, and approximately 30 mutations or polymorphisms are associated with FMF [1]. A mutation analysis of MEFV, which has been introduced in recent years, has revealed a significant correlation between the M694V, E148Q and V726A mutations and clinical findings [7]. Furthermore, Aldea et al. found a H478Y variant
alone in a Spanish family that produces a severe FMF phenotype with amyloidosis [8]. In Japan, the M694I and E148Q mutations are most frequently detected [9, 10]. Although an S503C mutation in exon 5, which has thus far not been identified in Japan, may be relevant to the pulmonary necrotizing granuloma observed in the present case, further studies are needed to determine the relationship between mutations in MEFV and lung involvement in FMF patients. Approximately 90% of cases of FMF develop in patients under 20 years of age. Although the cause of late-onset FMF, such as that observed in the present case, is unclear, heterozygosity of MEFV mutations may contribute to the pathogenesis of this disease. Mutation analyses of MEFV and therapeutic trials with colchicine should be considered in patients exhibiting recurrent febrile attacks, even in adulthood. We herein described the first case of a pulmonary necrotizing granuloma in a patient with FMF with the MEFV mutation of S503C in exon5, although the common form of thoracic involvement of this disease is pleurisy. In this case, the serum level of TNF-α was slightly increased, and this cytokine has the potential to promote the formation of granulomatous lesions [11]. In addition, Nakamura et al. reported FMF cases that were successfully treated with a TNF antagonist [12]. Based on these findings, we
DOI 10.3109/14397595.2013.844398
Pulmonary Necrotizing Granulomas in FMF 809
Downloaded by [University of Florida] at 03:26 06 November 2015
Figure 3. Immunohistochemistry for NACHT leucine-rich-repeat and PYD-containing protein-1 (NALP1; a and c), L26 (b) and UCHL1 (d) (a-d; original magnification 800⫻) using serial sections of the lung specimen. In the area of cellular infiltration around the granuloma, the NALP1positive cells were not L26-positive B-cells (arrows in a and b), but rather UCHL1-positive T-cells (arrowheads in c and d).
believe that this is a rare case of FMF presenting with granulomatous lung lesions. Furthermore, we also demonstrated the presence of NALP1-positive inflammatory cell infiltration in the lungs. Clinicians should be aware that granulomatous nodules and ground-glass opacity may be pulmonary manifestations of FMF.
Acknowledgements We thank Dr. Yoshinori Kawabata (Division of Pathology, Saitama Cardiovascular Respiratory Center, Saitama), Dr. Kenji Kashima and Ms. Kanako Ito (Oita University Faculty of Medicine, Oita) for their valuable assistance in the pathological diagnosis.
Conflicts of interest None.
References 1. Ozen S. Mutations/polymorphisms in a monogenetic autoinflammatory disease may be susceptibility markers for certain rheumatic diseases: lessons from the bedside for the benchside. Clin Exp Rheumatol. 2009;27(2 Suppl 53):S29–31. 2. Lidar M, Pras M, Langevitz P, Livneh A. Thoracic and lung involvement in familial Mediterranean fever (FMF). Clin Chest Med. 2002;23(2):505–11.
3. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–85. 4. Fischel-Ghodsian N, Bu X, Prezant TR, Oeztas S, Huang ZS, Bohlman MC, et al. Regional mapping of the gene for familial Mediterranean fever on human chromosome 16p13. Am J Med Genet. 1993;46(6):689–93. 5. Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95(10):3223–31. 6. Mille F, Thibert C, Fombonne J, Rama N, Guix C, Hayashi H, et al. The Patched dependence receptor triggers apoptosis through a DRALcaspase-9 complex. Nat Cell Biol. 2009;11(6):739–46. 7. Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J, et al. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A. 2004;124A(1):67–73. 8. Baykal Y, Saglam K, Yilmaz MI, Taslipinar A, Akinci SB, Inal A. Serum sIL-2r, IL-6, IL-10 and TNF-alpha level in familial Mediterranean fever patients. Clin Rheumatol. 2003;22(2):99–101. 9. Nakamura A, Matsuda M, Tazawa K, Shimojima Y, Ikeda S. Successful treatment with infliximab and low-dose methotrexate in a Japanese patient with familial Mediterranean fever. Intern Med. 2007;46(15):1247–49.
