http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(1): 93–96 © 2013 Japan College of Rheumatology DOI 10.3109/14397595.2013.854049
ORIGINAL ARTICLE
MEFV gene variations in patients with systemic lupus erythematosus
Mod Rheumatol Downloaded from informahealthcare.com by Dicle Univ. on 11/16/14 For personal use only.
Burak Erer • Fulya Cosan • Basar Oku • Duran Ustek • Murat Inanc • Orhan Aral Ahmet Gul
•
Received: 8 August 2012 / Accepted: 2 February 2013 Ó Japan College of Rheumatology 2013
Abstract Objective The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE). Methods The study group comprised 190 SLE patients and 101 healthy controls of Turkish origin with no clinical features of FMF. All individuals were genotyped for the four most common MEFV gene variations (M694V, M680I, V726A and E148Q) by PCR-restriction fragment length polymorphism analysis. Results The frequency of carrying any of the four MEFV gene variations under study was 15 % in patients with SLE and 10 % in the healthy controls (p = 0.23). After the exclusion of the less penetrant E148Q variation, re-analysis for the three penetrant mutations revealed a significant association between exon 10 variations and pericarditis [p = 0.038, odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.0–12.1], and pleural effusion (p = 0.043, OR 5.2, 95 % CI 0.8–30.9). No significant association was detected between the MEFV gene variations and a higher acute phase response. Conclusions The MEFV gene variations analyzed in our study do not seem to increase the overall susceptibility to SLE and do not have any strong association with its clinical B. Erer (&) F. Cosan M. Inanc O. Aral A. Gul (&) Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul 34390, Turkey e-mail: [email protected] A. Gul e-mail: [email protected] B. Oku D. Ustek A. Gul Department of Genetics, Institute for Experimental Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey Published online: 24 February 2013
manifestations. The possibility of a modest effect of penetrant exon 10 MEFV variants on the development of serosal effusions needs to be explored in a larger series of patients. Keywords Systemic lupus erythematosus MEFV Serositis Pericarditis Pleuritis
Introduction Familial Mediterranean fever (FMF), an autosomal recessively inherited autoinflammatory disorder, is characterized by recurrent, self-limited inflammatory attacks involving mainly serosal membranes. The disease has been associated with variations in the MEFV gene, which encodes the pyrin protein, in the great majority of patients [1, 2]. Pyrin is mainly expressed in mature granulocytes and fibroblasts, and it has been suggested that it plays a role in the regulation of inflammasome-mediated interleukin-1b (IL-1b) activation [3]. More than 50 missense mutations associated with the FMF phenotype have been described to date (http://fmf.igh.cnrs.fr/ISSAID/infevers/) that are considered to cause disordered activation and release of IL-1b and episodic inflammation [4]. FMF is the most common type of autoinflammatory disorder, and the heterozygous carrier rate for MEFV gene variations is quite high in Eastern Mediterranean countries, including Turkey, Israel, and Armenia [5, 6]. A higher acute phase response has been reported in asymptomatic heterozygous carriers, and heterozygosity for MEFV variations has been suggested to affect the course of other inflammatory disorders [7–11]. Systemic lupus erythematosus (SLE), the prototypical systemic autoimmune disease of unknown etiology, also affects serosal membranes frequently together with other
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organs or systems, either singly or in combination, during the course of the disease. The aim of our study was to investigate whether the most common variations in the MEFV gene are associated with SLE and/or certain disease manifestations, such as serositis, in Turkey, a country with a considerably high carrier rate for the MEFV variants.
Mod Rheumatol, 2014; 24(1): 93–96
using a chi-square test (Pearson or Fisher’s exact test, as appropriate), and odds ratios (OR) were given with 95 % confidence intervals (CI). Statistical significance was defined as p \ 0.05. Since this was a pilot screening study, no correction for multiple comparisons was carried out.
Results Patients and methods
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Study population The pilot study group comprised 191 consecutive SLE patients (166 female, 25 male) followed at the Lupus Clinic of the Division of Rheumatology. All patients met four or more of the American College of Rheumatology (ACR) criteria for the diagnosis of SLE, but one patient was excluded from the study because she also had the typical additional clinical features compatible with the diagnosis of FMF according to revised Tel-Hashomer criteria [12]. The mean age of the remaining 190 patients (165 female, 25 male) was 39 ± 12 years, and the mean disease duration was 9.1 ± 7 years. An ethnically matched group of 101 healthy individuals (30 female, 71 male), all of whom had already been genotyped for the most common variations in the MEFV gene, comprised the controls. The local ethics committee approved the study protocol, and each participant provided written informed consent. The clinical and laboratory data of the patients were recorded using a standard form. Data obtained from each patient included demographic characteristics (e.g., age, sex, disease duration, family history of FMF) and SLE findings, including those overlapping with the findings of FMF, such as pleural effusion, pericarditis, peritonitis/abdominal pain, and arthritis. The presence of pleural effusion, pericarditis, or peritonitis was confirmed with an imaging method, including chest X-ray, thorax computed tomography (CT), echocardiography, and/or abdominal ultrasonography/CT. DNA extraction and genotyping Genomic DNA was isolated from venous blood using standard methodology. All individuals were genotyped for the M694V, M680I, V726A, and E148Q variations, which are the most common MEFV gene variations in FMF patients and healthy controls of Turkish origin, by using a PCR–restriction fragment length polymorphism method as described previously [13].
Clinical features of SLE patients and the frequency of variations in MEFV gene carrier status according to the SLE manifestations used in the classification are given in Tables 1 and 2. The MEFV gene variations under study were detected in 29 of the 190 patients with SLE (15 %) and in ten of the 101 healthy controls (10 %); the difference was not statistically significant (p = 0.23). The frequency of carriers of the MEFV gene variations in SLE patients and healthy controls is shown in Fig. 1. All but two SLE patients and two healthy controls were heterozygous for the screened variations. Of these two SLE patients, one was homozygous for M694V and the other patient was compound heterozygous for one exon 10 (M694V) and one exon 2 (E148Q) variation. The patient with the homozygous M694V variation had a positive family history for FMF, but there were no clinical findings compatible with FMF before the diagnosis of SLE. Her disease started with manifestations of fever, pleuritis, pericarditis, and proliferative glomerulonephritis when she was aged 27 years, and she did not develop any other FMF manifestations while being treated for SLE. The SLE patient with M694V/E148Q variation had developed
Table 1 Clinical features of the systemic lupus erythematosus patients (n = 190) Parameter
n (%)
Female/male
165/25 (87/13)
Fever
49 (27)
Pleuritis
6 (3.2)
Pericarditis
17 (8.9)
Pleuritis and/or pericarditis
21 (11.1)
Documented peritonitis
0
Abdominal pain
15 (7.9)
Arthritis
141 (74.2)
Renal involvement
99 (52.1)
Hematological findings Neurological involvement
143 (75.2) 19 (10)
Statistical analysis
Elevated C-reactive protein ([5 mg/l)
52 (28)
Elevated erythrocyte sedimentation rate ([20 mm/h)
130 (69.5)
The collected data were presented using frequency tables and percentages. Data for the two groups were compared
Family history for familial Mediterranean fever
4 (2.2)
SLE systemic lupus erythematosus
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DOI 10.3109/14397595.2013.854049
Table 2 The frequency of MEFV variation carrier status according to the SLE manifestations used in the classification SLE manifestations used in the classification
Exon 10 variations (?) [n = 18 (9 %)]
Exon 10 variations (-) [n = 172 (91 %)]
Malar rash
7 (39)
Discoid rash
1 (6)
6 (3)
10 (56)
108 (63)
Photosensitivity Oral ulcers
99 (58)
7 (38)
36 (21)
11 (56)
130 (76)
Serositis
6 (33)
15 (9)
Pleuritis
2 (11)
4 (2)
Pericarditis
4 (22)
13 (8)
Renal involvement
9 (50)
90 (52)
Neurologic involvement
4 (22)
15 (9)
Arthritis
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MEFV variation status
Hematologic findings
10 (56)
133 (77)
Antinuclear antibody positivity
16 (89)
163 (95)
7
Pericarditis was observed in 17 SLE patients (8.9 %) and pleural effusion was detected in six patients (3.2 %). When the association between these three penetrant variations and FMF-related serosal findings was analyzed, we found a significant association between the presence of the exon 10 MEFV variations and pericarditis (p = 0.038; OR 3.5, 95 % CI 1.0–12.1) and pleural effusion (p = 0.043; OR 5.2, 95% CI 0.9–30.9). Of the 21 patients with either pericarditis or pleuritis, six patients (28.5 %) were carrying at least one exon 10 variation, and this variation was significantly more frequent than those in patients without these manifestations (p = 0.033; OR 3.7, 95 % CI 1.1–11.8). On the other hand, there was no patient with a history of documented peritonitis, and no association was found between the exon 10 variations and the presence of abdominal pain. Also, exon 10 variations were not associated with elevated acute phase response [erythrocyte sedimentation rate (ESR) [20 mm/h or C-reactive protein (CRP) [5 mg/l]. A positive family history for FMF diagnosed according to the revised Tel-Hashomer criteria [12] was obtained in 4 patients, and the positive family history was significantly associated with the presence of exon 10 variations in the patients (p = 0.002).
6 5
Discussion
4
% 3 2 1 0 SLE patients M694V
Healthy controls M680I
V726A
E148Q
Fig. 1 Frequency of MEFV variation carriers in systemic lupus erythematosus (SLE) patients and healthy controls
pleuritis, pericarditis, and arthritis when she was aged 40 years, and similar to the SLE patient with the homozygous M694V variation she had no episodes of transient serositis attacks suggesting the diagnosis of FMF. The two healthy controls carrying the M694V/E148Q and V726A/E148Q variation, respectively, were asymptomatic. After the exclusion of the less penetrant E148Q variation of exon 2 from the analysis, the carrier rate for the remaining three most penetrant exon 10 variations was found to be increased in the patient group compared to controls; however, the difference was again not statistically significant (9.5 vs. 5 %, respectively; p = 0.19).
This study was designed as a pilot study to investigate the frequency of the common FMF-related MEFV gene variations and their effects on the disease phenotype in SLE patients of Turkish origin. We did not find a significant increase in the frequency of commonly observed MEFV gene variations in our cohort of SLE patients, despite a slight excess of the most penetrant exon 10 variations. We also observed a tendency for the development of pericarditis and/or pleural effusion in SLE patients carrying one of the penetrant exon 10 variations, which may suggest a possible effect of MEFV gene variations on the SLE phenotype. However, the study was not powered for a subgroup analysis, and the association of exon 10 variations with the increased risk for serosal findings of SLE should be regarded as a preliminary finding awaiting to be confirmed in a larger independent group. Although gastrointestinal symptoms are commonly reported in SLE patients [14], a detailed examination of the underlying causes, especially for peritonitis, were not routinely carried out among our patients. Abdominal pain, which is usually considered to be a more typical feature of FMF, has many causes in SLE patients, including disease activity and the adverse effects of medications, and it can not be used as a replacement for the analysis of an association between transient peritonitis and MEFV variations.
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Peritonitis or ascites were not explored routinely in our patients without any abdominal complaints, so that some asymptomatic patients might have been overlooked. Also, SLE patients with recurrent peritonitis attacks, fulfilling revised Tel-Hashomer criteria, were excluded from our study, which may explain the low frequency of patients with abdominal pain. Matsuda et al. [15] reported an SLE patient with heterozygous exons 2 and 3 polymorphisms (E148Q, R202Q, P369S and R408Q) who showed periodic peritonitis and responded to colchicine treatment. Therefore, a prospective analysis of SLE patients focusing on the presence of peritonitis or ascites along with other serosal findings in association with a wider spectrum of MEFV variations may provide more reliable and conclusive results. The significance of the E148Q variation as a diseasecausing mutation or as a polymorphism is still controversial. The studies reported by Ben-Chetrit et al. [16] and Tchernitchko et al. [17] suggest that the E148Q is just a polymorphic variant and not a typical FMF-associated mutation. In our study, we could not observe any association between the four MEFV variations and SLE findings, while there is suggestive evidence for an association between the MEFV carrier state and pericarditis/pleural effusion after the exclusion of E148Q. These results support the finding that E148Q has little or no effect on phenotype or on overall inflammation in FMF and other conditions. A transient systemic inflammation is evident in FMF, with an increased acute phase response that is considered to be the result of increased and uncontrolled IL-1b activation [7]. In our study, we could not find any association between the three penetrant MEFV variations and elevated ESR and CRP levels. These results also suggest that inflammasome pathways do not play a critical role in SLE pathogenesis and that increased acute phase response in SLE relies on different mechanisms. In conclusion, these preliminary results suggest that the carrier state for the MEFV variations does not increase the overall susceptibility to SLE, but these variations may increase the risk for serosal inflammation. Possible effects of penetrant MEFV variants on the tendency for developing pericarditis, pleural effusion, and/or peritonitis need to be explored in a larger prospective series of SLE patients. Conflict of interest
None.
References 1. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25–31.
2. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90:797–807. 3. 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;95:3223–31. 4. Martinin F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26. 5. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68. 6. Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, et al. Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet. 2001;9:553–5. 7. Lachmann HJ, Sengul B, Yavuzsen 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;45:746–50. 8. Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, Picco P, et al. MEFV mutations in Behc¸et’s disease. Hum Mutat. 2000;16:271–2. 9. Cosan F, Ustek D, Oku B, Duymaz-Tozkir J, Cakiris A, Abaci N, et al. Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis Rheum. 2010;62: 3232–6. 10. Koca SS, Etem EO, Isik B, Yuce H, Ozgen M, Dag MS, Isik A. Prevalence and significance of MEFV gene mutations in a cohort of patients with rheumatoid arthritis. Joint Bone Spine. 2010; 77:32–5. 11. Shinar Y, Livneh A, Villa Y, Pinhasov A, Zeitoun I, Kogan A, et al. Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun. 2003;4: 197–203. 12. 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;40:1879–85. 13. Ustek D, Ekmekc¸i C, Oku B, Cos¸ an F, Cakiris A, Abaci N, Celik S, Kamali S, Hatemi G, Kasapc¸opur O, Ozdog˘an H, Gu¨l A. MEFV gene 30 -UTR Alu repeat polymorphisms in patients with familial Mediterranean fever. Clin Exp Rheumatol. 2008; 26[Suppl 50]:72–6. 14. Sultan SM, Ioannou Y, Isenberg DA. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology (Oxford). 1999;38:917–32. 15. Matsuda M, Kishida D, Tsuchiya-Suzuki A, Fukushima K, Shimojima Y, Yazaki M, Ikeda S. Periodic peritonitis due to familial Mediterranean fever in a patient with systemic lupus erythematosus. Intern Med. 2010;49:2259–62. 16. Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D. The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat. 2000;15:385–6. 17. Tchernitchko D, Legendre M, Cazeneuve C, Delahaye A, Niel F, Amselem S. The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat. 2003; 22:339–40.
ORIGINAL ARTICLE
MEFV gene variations in patients with systemic lupus erythematosus
Mod Rheumatol Downloaded from informahealthcare.com by Dicle Univ. on 11/16/14 For personal use only.
Burak Erer • Fulya Cosan • Basar Oku • Duran Ustek • Murat Inanc • Orhan Aral Ahmet Gul
•
Received: 8 August 2012 / Accepted: 2 February 2013 Ó Japan College of Rheumatology 2013
Abstract Objective The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE). Methods The study group comprised 190 SLE patients and 101 healthy controls of Turkish origin with no clinical features of FMF. All individuals were genotyped for the four most common MEFV gene variations (M694V, M680I, V726A and E148Q) by PCR-restriction fragment length polymorphism analysis. Results The frequency of carrying any of the four MEFV gene variations under study was 15 % in patients with SLE and 10 % in the healthy controls (p = 0.23). After the exclusion of the less penetrant E148Q variation, re-analysis for the three penetrant mutations revealed a significant association between exon 10 variations and pericarditis [p = 0.038, odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.0–12.1], and pleural effusion (p = 0.043, OR 5.2, 95 % CI 0.8–30.9). No significant association was detected between the MEFV gene variations and a higher acute phase response. Conclusions The MEFV gene variations analyzed in our study do not seem to increase the overall susceptibility to SLE and do not have any strong association with its clinical B. Erer (&) F. Cosan M. Inanc O. Aral A. Gul (&) Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul 34390, Turkey e-mail: [email protected] A. Gul e-mail: [email protected] B. Oku D. Ustek A. Gul Department of Genetics, Institute for Experimental Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey Published online: 24 February 2013
manifestations. The possibility of a modest effect of penetrant exon 10 MEFV variants on the development of serosal effusions needs to be explored in a larger series of patients. Keywords Systemic lupus erythematosus MEFV Serositis Pericarditis Pleuritis
Introduction Familial Mediterranean fever (FMF), an autosomal recessively inherited autoinflammatory disorder, is characterized by recurrent, self-limited inflammatory attacks involving mainly serosal membranes. The disease has been associated with variations in the MEFV gene, which encodes the pyrin protein, in the great majority of patients [1, 2]. Pyrin is mainly expressed in mature granulocytes and fibroblasts, and it has been suggested that it plays a role in the regulation of inflammasome-mediated interleukin-1b (IL-1b) activation [3]. More than 50 missense mutations associated with the FMF phenotype have been described to date (http://fmf.igh.cnrs.fr/ISSAID/infevers/) that are considered to cause disordered activation and release of IL-1b and episodic inflammation [4]. FMF is the most common type of autoinflammatory disorder, and the heterozygous carrier rate for MEFV gene variations is quite high in Eastern Mediterranean countries, including Turkey, Israel, and Armenia [5, 6]. A higher acute phase response has been reported in asymptomatic heterozygous carriers, and heterozygosity for MEFV variations has been suggested to affect the course of other inflammatory disorders [7–11]. Systemic lupus erythematosus (SLE), the prototypical systemic autoimmune disease of unknown etiology, also affects serosal membranes frequently together with other
94
B. Erer et al.
organs or systems, either singly or in combination, during the course of the disease. The aim of our study was to investigate whether the most common variations in the MEFV gene are associated with SLE and/or certain disease manifestations, such as serositis, in Turkey, a country with a considerably high carrier rate for the MEFV variants.
Mod Rheumatol, 2014; 24(1): 93–96
using a chi-square test (Pearson or Fisher’s exact test, as appropriate), and odds ratios (OR) were given with 95 % confidence intervals (CI). Statistical significance was defined as p \ 0.05. Since this was a pilot screening study, no correction for multiple comparisons was carried out.
Results Patients and methods
Mod Rheumatol Downloaded from informahealthcare.com by Dicle Univ. on 11/16/14 For personal use only.
Study population The pilot study group comprised 191 consecutive SLE patients (166 female, 25 male) followed at the Lupus Clinic of the Division of Rheumatology. All patients met four or more of the American College of Rheumatology (ACR) criteria for the diagnosis of SLE, but one patient was excluded from the study because she also had the typical additional clinical features compatible with the diagnosis of FMF according to revised Tel-Hashomer criteria [12]. The mean age of the remaining 190 patients (165 female, 25 male) was 39 ± 12 years, and the mean disease duration was 9.1 ± 7 years. An ethnically matched group of 101 healthy individuals (30 female, 71 male), all of whom had already been genotyped for the most common variations in the MEFV gene, comprised the controls. The local ethics committee approved the study protocol, and each participant provided written informed consent. The clinical and laboratory data of the patients were recorded using a standard form. Data obtained from each patient included demographic characteristics (e.g., age, sex, disease duration, family history of FMF) and SLE findings, including those overlapping with the findings of FMF, such as pleural effusion, pericarditis, peritonitis/abdominal pain, and arthritis. The presence of pleural effusion, pericarditis, or peritonitis was confirmed with an imaging method, including chest X-ray, thorax computed tomography (CT), echocardiography, and/or abdominal ultrasonography/CT. DNA extraction and genotyping Genomic DNA was isolated from venous blood using standard methodology. All individuals were genotyped for the M694V, M680I, V726A, and E148Q variations, which are the most common MEFV gene variations in FMF patients and healthy controls of Turkish origin, by using a PCR–restriction fragment length polymorphism method as described previously [13].
Clinical features of SLE patients and the frequency of variations in MEFV gene carrier status according to the SLE manifestations used in the classification are given in Tables 1 and 2. The MEFV gene variations under study were detected in 29 of the 190 patients with SLE (15 %) and in ten of the 101 healthy controls (10 %); the difference was not statistically significant (p = 0.23). The frequency of carriers of the MEFV gene variations in SLE patients and healthy controls is shown in Fig. 1. All but two SLE patients and two healthy controls were heterozygous for the screened variations. Of these two SLE patients, one was homozygous for M694V and the other patient was compound heterozygous for one exon 10 (M694V) and one exon 2 (E148Q) variation. The patient with the homozygous M694V variation had a positive family history for FMF, but there were no clinical findings compatible with FMF before the diagnosis of SLE. Her disease started with manifestations of fever, pleuritis, pericarditis, and proliferative glomerulonephritis when she was aged 27 years, and she did not develop any other FMF manifestations while being treated for SLE. The SLE patient with M694V/E148Q variation had developed
Table 1 Clinical features of the systemic lupus erythematosus patients (n = 190) Parameter
n (%)
Female/male
165/25 (87/13)
Fever
49 (27)
Pleuritis
6 (3.2)
Pericarditis
17 (8.9)
Pleuritis and/or pericarditis
21 (11.1)
Documented peritonitis
0
Abdominal pain
15 (7.9)
Arthritis
141 (74.2)
Renal involvement
99 (52.1)
Hematological findings Neurological involvement
143 (75.2) 19 (10)
Statistical analysis
Elevated C-reactive protein ([5 mg/l)
52 (28)
Elevated erythrocyte sedimentation rate ([20 mm/h)
130 (69.5)
The collected data were presented using frequency tables and percentages. Data for the two groups were compared
Family history for familial Mediterranean fever
4 (2.2)
SLE systemic lupus erythematosus
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DOI 10.3109/14397595.2013.854049
Table 2 The frequency of MEFV variation carrier status according to the SLE manifestations used in the classification SLE manifestations used in the classification
Exon 10 variations (?) [n = 18 (9 %)]
Exon 10 variations (-) [n = 172 (91 %)]
Malar rash
7 (39)
Discoid rash
1 (6)
6 (3)
10 (56)
108 (63)
Photosensitivity Oral ulcers
99 (58)
7 (38)
36 (21)
11 (56)
130 (76)
Serositis
6 (33)
15 (9)
Pleuritis
2 (11)
4 (2)
Pericarditis
4 (22)
13 (8)
Renal involvement
9 (50)
90 (52)
Neurologic involvement
4 (22)
15 (9)
Arthritis
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MEFV variation status
Hematologic findings
10 (56)
133 (77)
Antinuclear antibody positivity
16 (89)
163 (95)
7
Pericarditis was observed in 17 SLE patients (8.9 %) and pleural effusion was detected in six patients (3.2 %). When the association between these three penetrant variations and FMF-related serosal findings was analyzed, we found a significant association between the presence of the exon 10 MEFV variations and pericarditis (p = 0.038; OR 3.5, 95 % CI 1.0–12.1) and pleural effusion (p = 0.043; OR 5.2, 95% CI 0.9–30.9). Of the 21 patients with either pericarditis or pleuritis, six patients (28.5 %) were carrying at least one exon 10 variation, and this variation was significantly more frequent than those in patients without these manifestations (p = 0.033; OR 3.7, 95 % CI 1.1–11.8). On the other hand, there was no patient with a history of documented peritonitis, and no association was found between the exon 10 variations and the presence of abdominal pain. Also, exon 10 variations were not associated with elevated acute phase response [erythrocyte sedimentation rate (ESR) [20 mm/h or C-reactive protein (CRP) [5 mg/l]. A positive family history for FMF diagnosed according to the revised Tel-Hashomer criteria [12] was obtained in 4 patients, and the positive family history was significantly associated with the presence of exon 10 variations in the patients (p = 0.002).
6 5
Discussion
4
% 3 2 1 0 SLE patients M694V
Healthy controls M680I
V726A
E148Q
Fig. 1 Frequency of MEFV variation carriers in systemic lupus erythematosus (SLE) patients and healthy controls
pleuritis, pericarditis, and arthritis when she was aged 40 years, and similar to the SLE patient with the homozygous M694V variation she had no episodes of transient serositis attacks suggesting the diagnosis of FMF. The two healthy controls carrying the M694V/E148Q and V726A/E148Q variation, respectively, were asymptomatic. After the exclusion of the less penetrant E148Q variation of exon 2 from the analysis, the carrier rate for the remaining three most penetrant exon 10 variations was found to be increased in the patient group compared to controls; however, the difference was again not statistically significant (9.5 vs. 5 %, respectively; p = 0.19).
This study was designed as a pilot study to investigate the frequency of the common FMF-related MEFV gene variations and their effects on the disease phenotype in SLE patients of Turkish origin. We did not find a significant increase in the frequency of commonly observed MEFV gene variations in our cohort of SLE patients, despite a slight excess of the most penetrant exon 10 variations. We also observed a tendency for the development of pericarditis and/or pleural effusion in SLE patients carrying one of the penetrant exon 10 variations, which may suggest a possible effect of MEFV gene variations on the SLE phenotype. However, the study was not powered for a subgroup analysis, and the association of exon 10 variations with the increased risk for serosal findings of SLE should be regarded as a preliminary finding awaiting to be confirmed in a larger independent group. Although gastrointestinal symptoms are commonly reported in SLE patients [14], a detailed examination of the underlying causes, especially for peritonitis, were not routinely carried out among our patients. Abdominal pain, which is usually considered to be a more typical feature of FMF, has many causes in SLE patients, including disease activity and the adverse effects of medications, and it can not be used as a replacement for the analysis of an association between transient peritonitis and MEFV variations.
Mod Rheumatol Downloaded from informahealthcare.com by Dicle Univ. on 11/16/14 For personal use only.
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B. Erer et al.
Mod Rheumatol, 2014; 24(1): 93–96
Peritonitis or ascites were not explored routinely in our patients without any abdominal complaints, so that some asymptomatic patients might have been overlooked. Also, SLE patients with recurrent peritonitis attacks, fulfilling revised Tel-Hashomer criteria, were excluded from our study, which may explain the low frequency of patients with abdominal pain. Matsuda et al. [15] reported an SLE patient with heterozygous exons 2 and 3 polymorphisms (E148Q, R202Q, P369S and R408Q) who showed periodic peritonitis and responded to colchicine treatment. Therefore, a prospective analysis of SLE patients focusing on the presence of peritonitis or ascites along with other serosal findings in association with a wider spectrum of MEFV variations may provide more reliable and conclusive results. The significance of the E148Q variation as a diseasecausing mutation or as a polymorphism is still controversial. The studies reported by Ben-Chetrit et al. [16] and Tchernitchko et al. [17] suggest that the E148Q is just a polymorphic variant and not a typical FMF-associated mutation. In our study, we could not observe any association between the four MEFV variations and SLE findings, while there is suggestive evidence for an association between the MEFV carrier state and pericarditis/pleural effusion after the exclusion of E148Q. These results support the finding that E148Q has little or no effect on phenotype or on overall inflammation in FMF and other conditions. A transient systemic inflammation is evident in FMF, with an increased acute phase response that is considered to be the result of increased and uncontrolled IL-1b activation [7]. In our study, we could not find any association between the three penetrant MEFV variations and elevated ESR and CRP levels. These results also suggest that inflammasome pathways do not play a critical role in SLE pathogenesis and that increased acute phase response in SLE relies on different mechanisms. In conclusion, these preliminary results suggest that the carrier state for the MEFV variations does not increase the overall susceptibility to SLE, but these variations may increase the risk for serosal inflammation. Possible effects of penetrant MEFV variants on the tendency for developing pericarditis, pleural effusion, and/or peritonitis need to be explored in a larger prospective series of SLE patients. Conflict of interest
None.
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