The factors considered as trigger for the attacks in patients with familial Mediterranean fever

Transcription

1 Rheumatol Int (2013) 33: DOI /s x ORIGINAL ARTICLE The factors considered as trigger for the attacks in patients with familial Mediterranean fever Omer Karadag Abdurrahman Tufan Veli Yazisiz Kemal Ureten Sedat Yilmaz Muhammet Cinar Ali Akdogan Hakan Erdem Mehmet Akif Ozturk Salih Pay Ayhan Dinc Received: 24 December 2011 / Accepted: 7 July 2012 / Published online: 20 July 2012 Ó Springer-Verlag 2012 Abstract Although the inflammatory cascade of familial Mediterranean fever (FMF) is partially understood, triggering factors of those attacks has not been studied well. It is supposed that physical stresses such as cold exposure, tiredness and emotional stresses could provoke attacks. This study is aimed to survey the factors regarded as triggering the attacks in patients with FMF and their relationship with MEFV gene mutations. Clinical findings and genetic mutations (consist of M694V, M694I, M680I, V726A, E148Q) of patients were recorded. Patients were questioned about cold exposure, emotional stress, tiredness, long-lasting standing, long-duration travel, starvation, high intake of food, trauma, and infection as triggering factors for the attacks with both serositis and musculoskeletal pain. The study is comprised of 275 FMF patients (male/female: 177/98). The most common triggering factors for the attacks with serositis were cold exposure (59.3 %), emotional stress (49.8 %), tiredness (40.0 %) and menstruation (33.7 % in females). Long-lasting O. Karadag V. Yazisiz S. Yilmaz M. Cinar H. Erdem S. Pay A. Dinc Division of Rheumatology, Gulhane School of Medicine, Ankara, Turkey A. Tufan (&) M. A. Ozturk Division of Rheumatology, Department of Internal Medicine, Gazi University Hospital, Besevler, Ankara, Turkey dratufan@hotmail.com K. Ureten Division of Rheumatology, Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey A. Akdogan Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey standing (78.8 %), long-duration travel (64.1 %) and tiredness (47.8 %) were the triggering factors for the attacks with musculoskeletal symptoms. The relationships between MEFV mutations and triggering factors were found as M694V allele with starvation, E148Q allele with high intake of food and V726A allele with long-duration travel. The attacks with serositis seem to be triggered by those factors to which whole body exposed, whereas the attacks with musculoskeletal complaints seem to be triggered by those factors to which regional or local part of body exposed. Since the number of alleles was small, a clear conclusion for a relationship between a particular gene variant and a specific trigger was not made. Keywords Familial Mediterranean fever Serositis Trigger Attack Stress Cold Introduction Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by the recurrent inflammatory febrile attacks of serosal and synovial membranes [1]. The FMF gene, which is located on the short arm of chromosome 16 and symbolized with MEFV (for MEditerranean FeVer), encodes a protein termed as pyrin or marenostrin. Pyrin is expressed mainly in neutrophils and monocytes [2]. Defective pyrin in FMF patients results in recurrent inflammatory events via an inappropriate and prolonged response to inflammatory stimuli and increased leukocyte migration to serosal sites [3]. However, how this cascade triggered is a lot more complicated and not fully understood yet. It is supposed that attacks of FMF can be triggered by various factors such as infection, trauma, psychological

2 894 Rheumatol Int (2013) 33: stress, exposure to cold [4] and menstrual cycle [5] and many others, which are still unknown. In this study, we aimed to survey a group of FMF patients to disclose the factors eliciting their attacks and investigate any association between the reported factors and detected MEFV mutations. Statistical analysis Statistical analysis was done using SPSS 11.5 for Windows. Values are shown as mean ± standard deviation (SD). Chi-square test was used for the comparison of categorical variables. Materials and methods The study protocol was approved by Local Ethics Committee of Gulhane School of Medicine, and all patients gave their informed consent. Between June 2009 and May 2010, 275 patients with FMF who fulfilled Tel-Hashomer diagnostic criteria [6] from four centers in Ankara were included in the study. Attack characteristics such as recurrent abdominal pain, fever, pleuritis, pericarditis, arthritis or arthralgia, erysipelas-like erythema, the family history for FMF and the presence of amyloidosis were noted in detail. The severity of disease was determined according to the FMF severity scoring (FSS), which includes age of onset, attack frequency, arthritis, erysipelas-like erythema, amyloidosis and daily colchicine dose [7]. Genetic test findings Genetic test results were also recorded. For the determination of MEFV variants, peripheral venous blood sample was collected in ethylenediaminetetraacetic acid (EDTA) containing tubes, and DNA is extracted by standard methods. Genetic material is screened for at least 5 common MEFV mutations: E148Q in exon 2 and M694V, M694I, M680I and V726A in exon 10. Triggering factors Patients were questioned about the factors that they consider as a trigger for their continuing attacks. To eliminate recall bias, a list of factors (cold exposure, emotional stress, tiredness, long-duration standing, long-duration travel, starvation, high intake of food, trauma and infection) were asked whether they have had experienced those in a few days preceding their attacks. We did not made any standard definition for each of those factors since the study was based on the patient s perception that a factor could provoke the attacks. Questionnaires for the attacks with serositis and musculoskeletal complaints were applied separately. Any additional factor which they strongly think as a trigger for themselves as well as individual measures to prevent an impending attack was also noted. Results Ninety-eight females and 177 males were included in the study. The mean age of the FMF patients was 28.6 ± 9.4 (range 17 58) years. The patients disease characteristics are summarized in Table 1. More than 95 % of patients had fever and peritonitis during attacks. Three out of four patients had had at least one musculoskeletal complaint. Half of the patients had mild disease severity (Table 2). Cold exposure was the most common trigger experienced before a serositis attack (59.3 %). Other frequent triggers were emotional stress, tiredness and menstruation for females (Table 3). Musculoskeletal attacks were mostly triggered by long-duration standing. Other triggers for musculoskeletal attacks were long-duration travel, tiredness and cold exposure (Table 4). Patients reported avoidance from the activities or situations which they consider as a trigger. Moreover, 16 % of patients described non-steroidal Table 1 Demographic and disease features of FMF patients n = 275 Gender, (female/male) 98/177 Age, years (mean ± SD) 28.6 ± 9.4 Age at the attack onset, years (mean ± SD) 14.0 ± 9.1 Age at the diagnosis, years (mean ± SD) 20.1 ± 11.2 Family history of FMF, n (%) 106 (38.5) Amyloidosis, n (%) 8 (2.9) Table 2 Attack features and disease severity among 275 FMF patients Fever 95.9 Peritonitis 96.7 Pleuritis and/or pericarditis 55.0 Arthritis 41.0 Any musculoskeletal attack including arthritis 78.9 Erysipelas-like erythema 25.6 FMF severity Mild 50.6 Moderate 32.9 Severe 16.5 Frequency (%)

3 Rheumatol Int (2013) 33: Table 3 Triggering factors noted prior to the attacks characterized with serositis Factor Frequency (%) Cold exposure 59.3 Psychological stress 49.8 Tiredness 40.0 Menstruation, female (n = 98) 33.7 Sleeplessness 14.9 Long-lasting standing 14.5 High intake of food 10.9 Starvation 7.3 Long-duration travel 9.8 Infection 4.0 Trauma 1.5 Table 4 Triggering factors noted prior to the attacks characterized with musculoskeletal pain Factor Frequency (%) Long-lasting standing 78.8 Long-duration travel 64.1 Tiredness 47.8 Cold exposure 35.4 Psychological stress 19.5 Sleeplessness 8.8 Trauma 1.8 Table 5 Distribution of detected MEFV mutations M694V 210 (60.4) M680I 47 (13.5) V726A 23 (6.6) E148Q 11 (6.0) Number of alleles n (%) anti-inflammatory drug (NSAID) use during the exposure of any unpreventable cause to preclude or abrogate an imminent attack. Other reported preventive measures were increasing fluid intake and having a warm bath. Genetic analysis was available for 174 patients. Seventy-eight (44.8 %) of them had homozygous, 55 (31.6 %) had compound heterozygous, 40 (23.0 %) had heterozygous mutation and 1 (0.6 %) had no mutation. Distribution of alleles was shown in Table 5. For the attacks with serositis, no relationship between trigger factors and genetic findings was found except for the tiredness (p \ 0.05) in patients with homozygous mutation (Table 6). On the other hand, for the attacks with musculoskeletal type, no association was found among the trigger factors and mutation findings. Table 6 Associations between the trigger factors and genetic findings Factor In the subgroup analysis of individual mutations and triggers, starvation has been reported frequently by the patients with M694V allele (p = 0.032). Similarly, high intake of food in patients with E148Q allele (p \ 0.001) and travel in patients with V726A allele (p = 0.01) were noted commonly as a trigger. In the comparison of FMF severity subgroups with mild, moderate or severe disease, no difference was found with respect to the triggering factors. Discussion Homozygous n = 78 (%) Compound heterozygous n = 55 (%) Heterozygous n = 40 (%) Cold exposure 52 (66.7) 32 (58.1) 21 (52.5) Psychological 39 (50.0) 30 (54.5) 19 (47.5) stress Tiredness* 43 (55.1) 18 (32.7) 15 (37.5) Menstruation, female (n = 98) 6 (37.5) 8 (38.0) 2 (14.2) High intake of 8 (10.3) 9 (16.3) 4 (10.0) food Starvation 7 (8.9) 2 (3.6) 1 (2.5) Long-lasting 15 (19.2) 7 (12.7) 5 (12.5) standing Sleeplessness 18 (23.1) 8 (14.5) 6 (15.0) Long-duration 12 (15.4) 3 (5.5) 3 (7.5) travel Infection 1 (1.3) 3 (5.5) 2 (5.0) Trauma 1 (1.3) 1 (1.8) 1 (2.5) * p \ 0.05 The classic clinical picture of FMF consists of recurrent febrile serositis and/or musculoskeletal symptoms. These episodes are usually with acute onset, variable frequency and with/without a recognized triggering factor [8]. It has been proposed that FMF attacks are the result of a failure of a balance, so that a minor inflammatory trigger can stimulate a robust response. But the concept of the triggers for FMF attacks is not very well understood. We questioned FMF patients about the trigger factors for the attacks both with serositis features or musculoskeletal pain. According to our study, the most common triggering factor for serositis-type attacks (59.3 %) was cold exposure, and longduration standing for musculoskeletal type attacks. The nature of triggers for the attacks with serositis seemed to affect the body more generally systemically rather than regionally, such as cold exposure, emotional

4 896 Rheumatol Int (2013) 33: stress, tiredness and menstruation for the females. Although, formerly, infection and trauma has been proposed as possible triggers [4], it was not found to be a common factor in our study. Cold exposure was the leading triggering factor for FMF. Due to lacking information about the direct or indirect effect of cold on inflammatory mechanisms, we could not speculate on that. Emotional stress was found to be a trigger factor in about half of our patients. This result was concordant with the previous study of Gidron et al. [9] in which they had showed relationship between psychosocial factors and incidence of FMF attacks. In a recent study, the number of attacks was positively correlated with the mean depression and anxiety scores of the FMF patients [10]. Ackerman et al. [11] had found an increase in macrophage-derived cytokines IL-1 beta, TNF-alpha and Th1 lymphocyte-derived IFN-gamma production but no change in the Th2 lymphocyte-derived cytokine IL-4 after asking to give a 5-min videotaped speech defending themselves in a hypothetical scenario in which they were wrongly accused of stealing. Maes et al. [12] had reported increments in the production of the pro-inflammatory cytokines and decrements in the immuno-regulatory cytokines during the homeostatic responses to psychological stress and that stress-induced anxiety is related to a T-helper-1-like response. Therefore, emotional psychological conditions might trigger FMF attacks by increasing proinflammatory cytokine levels. Tiredness was reported as a trigger for the attacks both with serositis and musculoskeletal pain. However, tiredness would be a part of FMF attack and could have seen during or after the attack. Clinical observation has shown that familial Mediterranean fever attacks may be preceded by menstruation. Previous studies had reported 7 15 % of patients with FMF had menstruation-associated familial Mediterranean fever attacks [5, 13]. One-third of our female patients had experienced peri-menstrual attacks. It is proposed that hormonal changes may lead to the FMF attacks during menstruation [13]. Because estrogen level decreases significantly in menstruation, it can be speculated that protective effect of estrogen may disappear leading to the acute attack. Another hypothesis may be suggested based upon the finding that colchicine and estrogens are substrates of the same cytochrome (3A4) in the liver [14]. When the levels of estrogens are decreased (during menstruation), more enzymes are available for colchicine metabolism, thereby decreasing its concentration and its protective effect. Yet, these speculations do not explain why only a group of patients experience the attacks during menstruation and suggests that other factors also may take place in this period. Although high intake of food was supposed to be a predisposing factor, in our study, both starvation and high intake of food seemed to be a trigger in about 10 % of patients. But it does not have enough power to classify them as a triggering factor; this may originate from that those are ill-defined and subjective situations. Attacks with musculoskeletal pain were mostly triggered by long-lasting standing. Other triggers for this kind of symptoms were long-duration travel and tiredness. Previously we had published non-periodic (at the attackfree periods) leg pain in patients with familial Mediterranean fever [15]. That study was based on the observation that leg complaints after prolonged standing or sitting, or both, in FMF patients, who usually experience these painful manifestations during evenings or after long-distance bus trips. This type of triggers may result in some inflammatory response involving lower extremities after sustained positioning extremity in an upright position. Generally, musculoskeletal complaints had been predisposed by regional local stressors. Probably, the inflammatory reaction is initiated in a stressful microenvironment caused by not only microtrauma but also increased local hydrostatic pressure. Long-lasting walking is not reported to be a trigger factor while long-lasting standing is; that is why we suggest not only physical stress but also local hydrostatic changes might be important in such circumstances. Hence, the effect of cold on the hydrostatic and circulatory mechanisms would also be determined to make a clear conclusion about the means of cold to trigger the attacks. Except tiredness, no difference was found for other factors, between patients with homozygous and heterozygous mutations. But in the subgroup analysis of individual mutations, starvation has been commonly regarded as a factor in patients with M694V allele (p = 0.032). Although high intake of food (E148Q) and long-duration travel (V726A) were also found to be related, the number of alleles was small to make a clear conclusion. A well-known factor for attack occurrence is colchicine withdrawal. We do not include it as a trigger factor since it is not regarded as trigger factor; instead, it creates a status by which a factor may exert its trigger action more easily. On the other hand, trigger factors do not differ between patient severity subgroups. The main limitation of the present study is its retrospective design and based on patients recall ability. Also it is a subjective but a general consideration of an individual patient about her or his attacks. Every patient s conclusion was derived from nearly all attacks experienced in his or her past history. This may strengthen the value of those factors as a cause to initiate the attacks. Our results reflect only adult FMF patients to evaluate candidate triggers in a retrospective data collection method. A prospective design may disclose additional trigger factors and the relationship between those factors and the severity of resultant attacks.

5 Rheumatol Int (2013) 33: As a conclusion, the body s inflammation system must be wired for balance; it must respond vigorously and systemically to a meaningful insult (e.g., cold, emotional stress or tiredness). The attacks with serositis seem to be triggered by those factors to which whole body exposed, whereas the attacks with musculoskeletal complaints seem to be triggered by those factors to which regional or local part of body exposed. Patient-reported evidence suggests that NSAIDs could be used to prevent an impending attack. Conflict of interest References None of authors declare any conflict of interest. 1. Livneh A, Langevitz P (2000) Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol 14: Ozen S (2003) Familial Mediterranean fever: revisiting an ancient disease. Eur J Pediatr 162(7 8): Bhat A, Naguwa SM, Gershwin ME (2007) Genetics and new treatment modalities for familial Mediterranean fever. Ann N Y Acad Sci 1110: Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, La Regina M, Gasbarrini G, Manna R (2009) Familial Mediterranean fever: a review for clinical management. Joint Bone Spine 76(3): Ben-Chetrit E, Ben-Chetrit A (2001) Familial Mediterranean fever and menstruation. BJOG 108(403):e7 6. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40(10): Mor A, Shinar Y, Zaks N, Langevitz P, Chetrit A, Shtrasburg S, Rabinovitz E, Livneh A (2005) Evaluation of disease severity in familial Mediterranean fever. Semin Arthritis Rheum 35(1): Makay B, Unsal E (2009) Altered circadian rhythm: possible trigger of familial Mediterranean fever attacks. Med Hypotheses 73: Gidron Y, Berkovitch M, Press J (2003) Psychosocial correlates of incidence of attacks in children with Familial Mediterranean Fever. J Behav Med 26(2): Makay B, Emiroğlu N, Unsal E (2010) Depression and anxiety in children and adolescents with familial Mediterranean fever. Clin Rheumatol 29(4): Ackerman KD, Martino M, Heyman R, Moyna NM, Rabin BS (1998) Stressor-induced alteration of cytokine production in multiple sclerosis patients and controls. Psychosom Med 60(4): Maes M, Song C, Lin A, De Jongh R, Van Gastel A, Kenis G, Bosmans E, De Meester I, Benoy I, Neels H, Demedts P, Janca A, Scharpé S, Smith RS (1998) The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 10(4): Golden RL, Weigers EW, Meagher JG (1973) Periodic fever and menses. Am J Obstet Gynecol 117: Ben-Chetrit E, Levy M (2003) Reproductive system in familial Mediterranean fever: an overview. Ann Rheum Dis 62(10): Dinç A (2000) Non-period leg pain in patients with familial Mediterranean fever. Ann Rheum Dis 59(5):400