International Journal of Rheumatic Diseases 2014
APLAR Ground Round Case
Two elderly cases of familial mediterranean fever with rheumatoid arthritis Naoki MATSUOKA,1 Junko IWANAGA,1 Yasufumi ICHINOSE,1 Kaoru FUJIYAMA,1 Masahiko TSUBOI,1 Atsushi KAWAKAMI2 and Kiyoshi MIGITA3 1
Nagasaki Medical Hospital of Rheumatology, 2Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Hospital, Nagasaki, and 3Department of Rheumatology, Clinical Research Center, NHO National Nagasaki Medical Center, Omura, Japan
Abstract Familial Mediterranean fever (FMF) is a genetic autoinflammatory disorder that usually develops before 20 years of age and is characterized by periodic fever with serositis and arthritis. Both FMF and rheumatoid arthritis (RA) involve arthritis; however, their coexistence is rare. We describe two RA patients with an MEFV mutation in exon 2, who were diagnosed with FMF at an age of over 50 years. We also discuss the possibility that MEFV mutations could modulate RA disease activity. Key words: familial Mediterranean fever, MEFV gene, rheumatoid arthritis.
INTRODUCTION Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serositis and arthritis. In approximately 90% of all cases, onset occurs before 20 years of age.1 Although the age of onset among Japanese FMF patients tends to be much later than that in the Mediterranean population, in only 6% of all reported cases did onset occur after 50 years of age.2–4 Almost all FMF patients carry a mutation in the MEFV gene which is known to be associated with rheumatic diseases5–10; however, the coexistence of FMF with rheumatoid arthritis (RA) is quite rare,11,12 although it has been suggested that there may be an association between a mutation of the MEFV gene in exon 2 and the severity of RA.13 Here we describe two cases of RA patients diagnosed with FMF and carrying a mutation of the MEFV gene in exon 2.
Correspondence: Naoki Matsuoka, MD, Nagasaki Medical Hospital of Rheumatology, 1-21 Aburaya-Machi, Nagasaki 850-0832, Japan. Email: [email protected]
Case 1 was diagnosed with FMF at 75 years of age, and Case 2 experienced lack of efficacy of multiple diseasemodifying antirheumatic drugs (DMARDs) at the age of 52.
CASE REPORTS Case 1 A 75-year-old woman was admitted to our hospital with chest pain and fever. At the age of 53, she had experienced fever and persistent proteinuria accompanied by thrombocytopenia and positive titer for antinuclear antibodies (ANAs) and anti-double-stranded (ds)DNA antibodies. She was diagnosed with systemic lupus erythematosus (SLE) according to the 1997 American College of Rheumatology (ACR) criteria.14 Two years later, she suffered morning stiffness and swelling of the wrist and knee joints with positive titer of rheumatoid factor (RF). She was diagnosed with RA according to the 1987 ACR criteria.15 The activities of both diseases had been stable with a combination therapy of methotrexate (MTX) and corticosteroids. Two years before her admission to our
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
N. Matsuoka et al.
hospital, she experienced a sudden onset of hip joint pain and fever with a remarkable elevation of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which spontaneously disappeared after several days. This was considered to be an increase in the severity of her RA, and tacrolimus (TAC) was added to the MTX. The following year, she experienced a similar attack of febrile arthralgia and tocilizumab (TCZ) was administered and the MTX stopped. At the time of admission, physical examination revealed marked cardiomegaly and slight leg edema. Laboratory findings showed a white blood cell (WBC) count of 7780/lL and a CRP level of 0.36 mg/dL, and anti-nuclear antibodies (ANA 1 : 320) and anti-cyclic citrullinated peptide (CCP 753.6 U/mL) antibodies were positive with a high titer. The complements were within normal range, and anti-dsDNA antibodies were negative. Computed tomography (CT) demonstrated massive pericardial effusion (Fig. 1). After admission, the patient suffered periodic fever twice accompanied by chest pain and arthritis of the ankle joints, which spontaneously disappeared within a couple of days. Laboratory tests during febrile episodes showed evidence of increased inflammation, such as elevated CRP (7.8–10.3 mg/dL) and ESR (90–132) (Fig. 2). Mutation analysis was carried out by sequencing all exons of the MEFV gene as previously described.11
Figure 2 The clinical course of Case 1. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
MEFV gene analysis showed a heterozygous mutation of E148Q in exon 2. Based on the presence of periodic fever and pericarditis, and the results of the MEFV gene analysis, we diagnosed this patient with FMF and treated her with colchicine (0.5 mg/day). A few days later, the periodic fever, chest and hip joint pain, and pericardial effusion had completely disappeared (Fig. 2). One year after diagnosis, the patient suffered a recurrence of pericardial effusion and was successfully treated with colchicine (1.0 mg/day). The same regime of TAC with TCZ was continued during the follow-up periods.
Case 2
Figure 1 Computed tomography (CT) of Case 1 demonstrating massive pericardial effusion.
2
A 52-year-old woman was admitted to our hospital with arthralgia and fever. At the age of 48, she had suffered swelling of both wrist joints and right elbows with a positive high titer of anti-CCP antibodies and elevated CRP. She was diagnosed with RA according to the 2010 ACR and the European League Against Rheumatism (EULAR) classification criteria for RA.16 She had been treated with several DMARDs, including MTX, leflunomide (LEF), sulfasalazine (SSZ), etanercept (ETN), adalimumab (ADM), TCZ and abatacept (ABT), but most were discontinued because of adverse events or, most often, lack of efficacy (Fig. 3). One month before her admission to our hospital, she had experienced fever with severe hip joint pain lasting a few hours. Similar episodes occurred with a cycle of 3–4 weeks. Physical examination revealed only fever. Laboratory findings showed a WBC count of 11600/lL, and a CRP level of 16.37 mg/dL. ANA was negative and anti-CCP antibodies were 186.2 U/mL. MEFV gene analysis showed a compound heterozygous mutation of
International Journal of Rheumatic Diseases 2014
MEFV mutations and RA disease activity
Figure 3 Disease modifying anti-rheumatic drugs administered to Case 2. LEF and SSZ were stopped by adverse events. MTX, ETN, TAC, ADM and TCZ were discontinued due to lack of efficacy. MTX and ABT have been continued. MTX, methotrexate; LEF, leflunomide; SSZ, sulfasalazine; ETN, etanercept; TAC, tacrolimus; ADM, adalimumab; TCZ, tocilizumab; ABT, abatacept; SDAI, Simplified Disease Activity Index; CDAI, Clinical Disease Activity Index; DAS28-CRP; Disease Activity Score of 28 joints – C-reactive protein; DAS28-ESR, Disease Activity Score of 28 joints – erythrocyte sedimentation rate.
E148Q/L110P in exon 2. Based on the presence of periodic fever with hip joint pain and the results of the MEFV gene analysis, we diagnosed her with FMF and started treatment with colchicine (1.0 mg/day). The symptoms disappeared within a couple of days. However, because her symptoms recurred 2 weeks after this therapy was initiated, colchicine was increased to 1.5 mg/day, and the patient’s symptoms have not flared up again (Fig. 4). A combination therapy of ABT with MTX was continued for RA during the follow-up periods.
Figure 4 The clinical course of Case 2. MTX, methotrexate; ABT, abatacept; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
eliminated the pericardial effusion. Two years before her diagnosis, she had experienced her first attack of fever with hip joint pain; therefore, the onset of FMF was assumed to be 2 years before diagnosis. The Turkish FMF Study Group reports that the mean period from disease onset to diagnosis in Turkey is 6.9 7.65 years.19 In a nationwide survey in Japan, the time lag was reported to be 9.1 years.2 In the present case, the delay in diagnosis was assumed to be due to the reasons below. It is important to note that a few cases may occur in the elderly and rare cases of the coexistence of
DISCUSSION The age of onset among Japanese FMF patients is typically much later than that among Mediterranean patients.1,17 Based on a nationwide survey of FMF in Japan, the mean age of onset is 19.6 15.9 years and in only 6% of all reported cases did onset occur after 50 years of age.2–4 Onset in patients in their 50s and 60s has also been reported,12,18 but to the best of our knowledge, there has been no report of any patient with onset in his or her 70s, even in Japan. Case 1 was diagnosed with FMF due to pericarditis. Although pericarditis can occur in RA, FMF was considered to be the pathogenesis, because the patient’s chest pain spontaneously disappeared and colchicine
International Journal of Rheumatic Diseases 2014
Figure 5 The course of the RA activity index of Case 1 before the patient was diagnosed with FMF. TAC, tacrolimus; TCZ, tocilizumab; SDAI, Simplified Disease Activity Index; CDAI, Clinical Disease Activity Index; DAS28-CRP, Disease Activity Score of 28 joints – C-reactive protein; DAS28-ESR, Disease Activity Score of 28 joints – erythrocyte sedimentation rate; FMF, familial Mediterranean fever.
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FMF and RA have been demonstrated.11,13 We should not exclude the possibility of the coexistence of FMF and RA in the elderly. When Case 1 experienced her first attack of fever with hip joint pain, she was diagnosed with increasing disease activity of RA. She was admitted to our hospital due to acute exacerbation of Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) values. In contrast, her Disease Activity Score (DAS)28 remained almost steady (Fig. 5). In the calculation of these disease activity indexes, the contribution of the Visual Analogue Scale (VAS) is greater in SDAI/CDAI, which is recommended for the 2011 ACR/EULAR remission criteria,20 than in DAS28. The discrepancy in disease activity indexes was caused by an acute elevation of patient VAS. The patient’s fever and elevated CRP and ESR values lasted only a few days but the patient’s lasting impression of her febrile episode was assumed to have influenced her VAS. Therefore, coexisting FMF and RA might be suspected where there is a discrepancy between SDAI/CDAI and DAS28. The most common arthritis in FMF is acute large joint monoarthritis most frequently affecting the knee, hip or foot.2,21,22 In contrast, RA affects primarily the hand and ankle joints. In Case 2, arthritis had affected only the patient’s wrist and elbow until she was diagnosed with FMF. In her febrile episode, arthralgia occurred at the hip joint, which had never before been affected. An acute change of arthritis location, especially in the lower extremities, may suggest the onset of FMF in cases of RA. According to previous studies on the correlation between the MEFV genotype and the severity of disease in FMF, mutations in exon 2 (E148Q, E148Q/L110P) are associated with milder clinical features.12,17,23,24 Case 2 was diagnosed with FMF because of recurring high-grade fever and the change in arthritis location; however, the patient had no serositis, and in her febrile attacks, the fever was sometimes only low grade and ended within a few hours. MEFV gene analysis showed a compound heterozygous mutation of E148Q/L110P in exon 2; therefore, this case was considered to have a phenotype associated with milder clinical features, that is, incomplete FMF. Rabinovich et al.13 suggest that mutations in MEFV exon 2 may be associated with a worse clinical status of RA. The present Case 2 experienced lack of efficacy of many DMARDs before being diagnosed with FMF. It is possible that MEFV mutations modulate RA disease activity. Therefore, we recommend examining MEFV mutation and suspecting the complication of FMF in difficult cases of RA.
4
CONFLICT OF INTEREST None.
AUTHORS CONTRIBUTIONS NM: Involved in drafting of the manuscripts, contributions to conception and design, analysis of data. JI: Involved in acquisition of data, conception and design. Revised the manuscript. YH, KF, MT: Contributed to conception and design. AK: Contributed to conception and design. Revised the manuscript. KM: Carried out the molecular genetic studies. Revised the manuscript.
REFERENCES 1 Ben-Chetrit E, Levy M (1998) Familial Mediterranean fever. Lancet 351, 659–64. 2 Migita K, Agematsu K (2011) Clinical aspects of Familial Mediterranean fever. Jpn J Clin Immunol 34, 55–60. 3 Tsuchiya-Suzuki A, Yazaki M, Nakamura A et al. (2009) Clinical and genetic features of familial Mediterranean fever in Japan. J Rheumatol 36, 1671–6. 4 Migita K, Uehara R, Nakamura Y et al. (2012) Familial Mediterranean fever in Japan. Medicine 91, 337–43. 5 Langevitz P, Livneh A, Zemer D, Shemer J, Pras M (1997) Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum 27, 67–72. 6 Tanaka M, Migita K, Miyashita T et al. (2009) Coexistence of familial Mediterranean fever and Sj€ ogren’s syndrome in a Japanese patient. Rheumatology 48, 23–5. 7 Ayaz NA, Ozen S, Bilginer Y et al. (2006) MEFV mutations in systemic onset juvenile idiopathic arthritis. Clin Exp Rheumatol 24, 120–2. 8 Kalyoncu M, Acar BC, Cakar N et al. (2010) Are carriers for MEFV mutations “healthy”? Arthritis Rheum 62, 3059– 63. 9 Akkoc N, Sari I, Akar S et al. (2013) Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial Mediterranean fever. Mod Rheumatol 23, 374–8. 10 Eguchi M, Miyashita T, Shirouzu H et al. (2013) Coexistence of polymyositis and familial Mediterranean fever. Mod Rheumatol 23, 374–8. 11 Migita K, Abiru S, Sasaki O et al. (2012) Coexistence of familial Mediterranean fever and rheumatoid arthritis. Mod Rheumatol 24, 212–6. 12 Mori S, Yonemura K, Migita K (2013) Familial Mediterranean fever occurring in an elderly Japanese woman with recent-onset rheumatoid arthritis. Intern Med 52, 385–8. 13 Rabinovich E, Livneh A, Langevitz P et al. (2005) Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis 64, 1009–14.
International Journal of Rheumatic Diseases 2014
MEFV mutations and RA disease activity
14 Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40, 1725. 15 Arnett FC, Edworthy SM, Bloch DA et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31, 315–24. 16 Aletaha D, Neogi T, Silman AJ et al. (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62, 2569–81. 17 Onen F (2006) Familial Mediterranean fever. Rheumatol Int 26, 489–96. 18 Inoue K, Torii K, Yoda A et al. (2012) Familial Mediterranean fever with onset at 66 years of age. Intern Med 51, 2649–53. 19 Tunca M, Akar S, Onen F et al. (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 84, 1–11.
International Journal of Rheumatic Diseases 2014
20 Shahouri SH, Michaud K, Mikuls TR et al. (2011) Remission of rheumatoid arthritis in clinical practice: application of the American College of Rheumatology/European League Against Rheumatism remission criteria. Arthritis Rheum 63, 3204–15. 21 Uthman I, Hajj-Ali RA, Arayssi T, Masri AF, Nasr F (2001) Arthritis in familial Mediterranean fever. Rheumatol Int 20, 145–8. 22 Garcia-Gonzalez A, Weisman MH (1992) The arthritis of familial Mediterranean fever. Semin Arthritis Rheum 22, 139–50. 23 Touitou I (2001) The spectrum of familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 9, 473–83. 24 Topaloglu R, Ozaltin F, Yilmaz E et al. (2005) E148Q is a disease-causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis 64, 750–2.
5
APLAR Ground Round Case
Two elderly cases of familial mediterranean fever with rheumatoid arthritis Naoki MATSUOKA,1 Junko IWANAGA,1 Yasufumi ICHINOSE,1 Kaoru FUJIYAMA,1 Masahiko TSUBOI,1 Atsushi KAWAKAMI2 and Kiyoshi MIGITA3 1
Nagasaki Medical Hospital of Rheumatology, 2Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Hospital, Nagasaki, and 3Department of Rheumatology, Clinical Research Center, NHO National Nagasaki Medical Center, Omura, Japan
Abstract Familial Mediterranean fever (FMF) is a genetic autoinflammatory disorder that usually develops before 20 years of age and is characterized by periodic fever with serositis and arthritis. Both FMF and rheumatoid arthritis (RA) involve arthritis; however, their coexistence is rare. We describe two RA patients with an MEFV mutation in exon 2, who were diagnosed with FMF at an age of over 50 years. We also discuss the possibility that MEFV mutations could modulate RA disease activity. Key words: familial Mediterranean fever, MEFV gene, rheumatoid arthritis.
INTRODUCTION Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serositis and arthritis. In approximately 90% of all cases, onset occurs before 20 years of age.1 Although the age of onset among Japanese FMF patients tends to be much later than that in the Mediterranean population, in only 6% of all reported cases did onset occur after 50 years of age.2–4 Almost all FMF patients carry a mutation in the MEFV gene which is known to be associated with rheumatic diseases5–10; however, the coexistence of FMF with rheumatoid arthritis (RA) is quite rare,11,12 although it has been suggested that there may be an association between a mutation of the MEFV gene in exon 2 and the severity of RA.13 Here we describe two cases of RA patients diagnosed with FMF and carrying a mutation of the MEFV gene in exon 2.
Correspondence: Naoki Matsuoka, MD, Nagasaki Medical Hospital of Rheumatology, 1-21 Aburaya-Machi, Nagasaki 850-0832, Japan. Email: [email protected]
Case 1 was diagnosed with FMF at 75 years of age, and Case 2 experienced lack of efficacy of multiple diseasemodifying antirheumatic drugs (DMARDs) at the age of 52.
CASE REPORTS Case 1 A 75-year-old woman was admitted to our hospital with chest pain and fever. At the age of 53, she had experienced fever and persistent proteinuria accompanied by thrombocytopenia and positive titer for antinuclear antibodies (ANAs) and anti-double-stranded (ds)DNA antibodies. She was diagnosed with systemic lupus erythematosus (SLE) according to the 1997 American College of Rheumatology (ACR) criteria.14 Two years later, she suffered morning stiffness and swelling of the wrist and knee joints with positive titer of rheumatoid factor (RF). She was diagnosed with RA according to the 1987 ACR criteria.15 The activities of both diseases had been stable with a combination therapy of methotrexate (MTX) and corticosteroids. Two years before her admission to our
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
N. Matsuoka et al.
hospital, she experienced a sudden onset of hip joint pain and fever with a remarkable elevation of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which spontaneously disappeared after several days. This was considered to be an increase in the severity of her RA, and tacrolimus (TAC) was added to the MTX. The following year, she experienced a similar attack of febrile arthralgia and tocilizumab (TCZ) was administered and the MTX stopped. At the time of admission, physical examination revealed marked cardiomegaly and slight leg edema. Laboratory findings showed a white blood cell (WBC) count of 7780/lL and a CRP level of 0.36 mg/dL, and anti-nuclear antibodies (ANA 1 : 320) and anti-cyclic citrullinated peptide (CCP 753.6 U/mL) antibodies were positive with a high titer. The complements were within normal range, and anti-dsDNA antibodies were negative. Computed tomography (CT) demonstrated massive pericardial effusion (Fig. 1). After admission, the patient suffered periodic fever twice accompanied by chest pain and arthritis of the ankle joints, which spontaneously disappeared within a couple of days. Laboratory tests during febrile episodes showed evidence of increased inflammation, such as elevated CRP (7.8–10.3 mg/dL) and ESR (90–132) (Fig. 2). Mutation analysis was carried out by sequencing all exons of the MEFV gene as previously described.11
Figure 2 The clinical course of Case 1. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
MEFV gene analysis showed a heterozygous mutation of E148Q in exon 2. Based on the presence of periodic fever and pericarditis, and the results of the MEFV gene analysis, we diagnosed this patient with FMF and treated her with colchicine (0.5 mg/day). A few days later, the periodic fever, chest and hip joint pain, and pericardial effusion had completely disappeared (Fig. 2). One year after diagnosis, the patient suffered a recurrence of pericardial effusion and was successfully treated with colchicine (1.0 mg/day). The same regime of TAC with TCZ was continued during the follow-up periods.
Case 2
Figure 1 Computed tomography (CT) of Case 1 demonstrating massive pericardial effusion.
2
A 52-year-old woman was admitted to our hospital with arthralgia and fever. At the age of 48, she had suffered swelling of both wrist joints and right elbows with a positive high titer of anti-CCP antibodies and elevated CRP. She was diagnosed with RA according to the 2010 ACR and the European League Against Rheumatism (EULAR) classification criteria for RA.16 She had been treated with several DMARDs, including MTX, leflunomide (LEF), sulfasalazine (SSZ), etanercept (ETN), adalimumab (ADM), TCZ and abatacept (ABT), but most were discontinued because of adverse events or, most often, lack of efficacy (Fig. 3). One month before her admission to our hospital, she had experienced fever with severe hip joint pain lasting a few hours. Similar episodes occurred with a cycle of 3–4 weeks. Physical examination revealed only fever. Laboratory findings showed a WBC count of 11600/lL, and a CRP level of 16.37 mg/dL. ANA was negative and anti-CCP antibodies were 186.2 U/mL. MEFV gene analysis showed a compound heterozygous mutation of
International Journal of Rheumatic Diseases 2014
MEFV mutations and RA disease activity
Figure 3 Disease modifying anti-rheumatic drugs administered to Case 2. LEF and SSZ were stopped by adverse events. MTX, ETN, TAC, ADM and TCZ were discontinued due to lack of efficacy. MTX and ABT have been continued. MTX, methotrexate; LEF, leflunomide; SSZ, sulfasalazine; ETN, etanercept; TAC, tacrolimus; ADM, adalimumab; TCZ, tocilizumab; ABT, abatacept; SDAI, Simplified Disease Activity Index; CDAI, Clinical Disease Activity Index; DAS28-CRP; Disease Activity Score of 28 joints – C-reactive protein; DAS28-ESR, Disease Activity Score of 28 joints – erythrocyte sedimentation rate.
E148Q/L110P in exon 2. Based on the presence of periodic fever with hip joint pain and the results of the MEFV gene analysis, we diagnosed her with FMF and started treatment with colchicine (1.0 mg/day). The symptoms disappeared within a couple of days. However, because her symptoms recurred 2 weeks after this therapy was initiated, colchicine was increased to 1.5 mg/day, and the patient’s symptoms have not flared up again (Fig. 4). A combination therapy of ABT with MTX was continued for RA during the follow-up periods.
Figure 4 The clinical course of Case 2. MTX, methotrexate; ABT, abatacept; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
eliminated the pericardial effusion. Two years before her diagnosis, she had experienced her first attack of fever with hip joint pain; therefore, the onset of FMF was assumed to be 2 years before diagnosis. The Turkish FMF Study Group reports that the mean period from disease onset to diagnosis in Turkey is 6.9 7.65 years.19 In a nationwide survey in Japan, the time lag was reported to be 9.1 years.2 In the present case, the delay in diagnosis was assumed to be due to the reasons below. It is important to note that a few cases may occur in the elderly and rare cases of the coexistence of
DISCUSSION The age of onset among Japanese FMF patients is typically much later than that among Mediterranean patients.1,17 Based on a nationwide survey of FMF in Japan, the mean age of onset is 19.6 15.9 years and in only 6% of all reported cases did onset occur after 50 years of age.2–4 Onset in patients in their 50s and 60s has also been reported,12,18 but to the best of our knowledge, there has been no report of any patient with onset in his or her 70s, even in Japan. Case 1 was diagnosed with FMF due to pericarditis. Although pericarditis can occur in RA, FMF was considered to be the pathogenesis, because the patient’s chest pain spontaneously disappeared and colchicine
International Journal of Rheumatic Diseases 2014
Figure 5 The course of the RA activity index of Case 1 before the patient was diagnosed with FMF. TAC, tacrolimus; TCZ, tocilizumab; SDAI, Simplified Disease Activity Index; CDAI, Clinical Disease Activity Index; DAS28-CRP, Disease Activity Score of 28 joints – C-reactive protein; DAS28-ESR, Disease Activity Score of 28 joints – erythrocyte sedimentation rate; FMF, familial Mediterranean fever.
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N. Matsuoka et al.
FMF and RA have been demonstrated.11,13 We should not exclude the possibility of the coexistence of FMF and RA in the elderly. When Case 1 experienced her first attack of fever with hip joint pain, she was diagnosed with increasing disease activity of RA. She was admitted to our hospital due to acute exacerbation of Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) values. In contrast, her Disease Activity Score (DAS)28 remained almost steady (Fig. 5). In the calculation of these disease activity indexes, the contribution of the Visual Analogue Scale (VAS) is greater in SDAI/CDAI, which is recommended for the 2011 ACR/EULAR remission criteria,20 than in DAS28. The discrepancy in disease activity indexes was caused by an acute elevation of patient VAS. The patient’s fever and elevated CRP and ESR values lasted only a few days but the patient’s lasting impression of her febrile episode was assumed to have influenced her VAS. Therefore, coexisting FMF and RA might be suspected where there is a discrepancy between SDAI/CDAI and DAS28. The most common arthritis in FMF is acute large joint monoarthritis most frequently affecting the knee, hip or foot.2,21,22 In contrast, RA affects primarily the hand and ankle joints. In Case 2, arthritis had affected only the patient’s wrist and elbow until she was diagnosed with FMF. In her febrile episode, arthralgia occurred at the hip joint, which had never before been affected. An acute change of arthritis location, especially in the lower extremities, may suggest the onset of FMF in cases of RA. According to previous studies on the correlation between the MEFV genotype and the severity of disease in FMF, mutations in exon 2 (E148Q, E148Q/L110P) are associated with milder clinical features.12,17,23,24 Case 2 was diagnosed with FMF because of recurring high-grade fever and the change in arthritis location; however, the patient had no serositis, and in her febrile attacks, the fever was sometimes only low grade and ended within a few hours. MEFV gene analysis showed a compound heterozygous mutation of E148Q/L110P in exon 2; therefore, this case was considered to have a phenotype associated with milder clinical features, that is, incomplete FMF. Rabinovich et al.13 suggest that mutations in MEFV exon 2 may be associated with a worse clinical status of RA. The present Case 2 experienced lack of efficacy of many DMARDs before being diagnosed with FMF. It is possible that MEFV mutations modulate RA disease activity. Therefore, we recommend examining MEFV mutation and suspecting the complication of FMF in difficult cases of RA.
4
CONFLICT OF INTEREST None.
AUTHORS CONTRIBUTIONS NM: Involved in drafting of the manuscripts, contributions to conception and design, analysis of data. JI: Involved in acquisition of data, conception and design. Revised the manuscript. YH, KF, MT: Contributed to conception and design. AK: Contributed to conception and design. Revised the manuscript. KM: Carried out the molecular genetic studies. Revised the manuscript.
REFERENCES 1 Ben-Chetrit E, Levy M (1998) Familial Mediterranean fever. Lancet 351, 659–64. 2 Migita K, Agematsu K (2011) Clinical aspects of Familial Mediterranean fever. Jpn J Clin Immunol 34, 55–60. 3 Tsuchiya-Suzuki A, Yazaki M, Nakamura A et al. (2009) Clinical and genetic features of familial Mediterranean fever in Japan. J Rheumatol 36, 1671–6. 4 Migita K, Uehara R, Nakamura Y et al. (2012) Familial Mediterranean fever in Japan. Medicine 91, 337–43. 5 Langevitz P, Livneh A, Zemer D, Shemer J, Pras M (1997) Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum 27, 67–72. 6 Tanaka M, Migita K, Miyashita T et al. (2009) Coexistence of familial Mediterranean fever and Sj€ ogren’s syndrome in a Japanese patient. Rheumatology 48, 23–5. 7 Ayaz NA, Ozen S, Bilginer Y et al. (2006) MEFV mutations in systemic onset juvenile idiopathic arthritis. Clin Exp Rheumatol 24, 120–2. 8 Kalyoncu M, Acar BC, Cakar N et al. (2010) Are carriers for MEFV mutations “healthy”? Arthritis Rheum 62, 3059– 63. 9 Akkoc N, Sari I, Akar S et al. (2013) Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial Mediterranean fever. Mod Rheumatol 23, 374–8. 10 Eguchi M, Miyashita T, Shirouzu H et al. (2013) Coexistence of polymyositis and familial Mediterranean fever. Mod Rheumatol 23, 374–8. 11 Migita K, Abiru S, Sasaki O et al. (2012) Coexistence of familial Mediterranean fever and rheumatoid arthritis. Mod Rheumatol 24, 212–6. 12 Mori S, Yonemura K, Migita K (2013) Familial Mediterranean fever occurring in an elderly Japanese woman with recent-onset rheumatoid arthritis. Intern Med 52, 385–8. 13 Rabinovich E, Livneh A, Langevitz P et al. (2005) Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene. Ann Rheum Dis 64, 1009–14.
International Journal of Rheumatic Diseases 2014
MEFV mutations and RA disease activity
14 Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40, 1725. 15 Arnett FC, Edworthy SM, Bloch DA et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31, 315–24. 16 Aletaha D, Neogi T, Silman AJ et al. (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62, 2569–81. 17 Onen F (2006) Familial Mediterranean fever. Rheumatol Int 26, 489–96. 18 Inoue K, Torii K, Yoda A et al. (2012) Familial Mediterranean fever with onset at 66 years of age. Intern Med 51, 2649–53. 19 Tunca M, Akar S, Onen F et al. (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 84, 1–11.
International Journal of Rheumatic Diseases 2014
20 Shahouri SH, Michaud K, Mikuls TR et al. (2011) Remission of rheumatoid arthritis in clinical practice: application of the American College of Rheumatology/European League Against Rheumatism remission criteria. Arthritis Rheum 63, 3204–15. 21 Uthman I, Hajj-Ali RA, Arayssi T, Masri AF, Nasr F (2001) Arthritis in familial Mediterranean fever. Rheumatol Int 20, 145–8. 22 Garcia-Gonzalez A, Weisman MH (1992) The arthritis of familial Mediterranean fever. Semin Arthritis Rheum 22, 139–50. 23 Touitou I (2001) The spectrum of familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 9, 473–83. 24 Topaloglu R, Ozaltin F, Yilmaz E et al. (2005) E148Q is a disease-causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis 64, 750–2.
5
