Clin Rheumatol (2006) 25:149 152 DOI 10.1007/s10067-005-1148-z Z . Birsin ( ) z g a k a r • Fato~ Y a l ~ m k a y a • S e l f u k Yiiksel Banu Acar • D e r y a G 6 k m e n • M e s i h a E k i m Possible effect off subclinical inflammation on daily life in familial Mediterranean fever Received: 26 November 2004/ Revised: 21 March 2005/Accepted: 21 March 2005/Published online: 20 September 2005 © Clinical Rheumatology 2005 Abstract This study was performed to investigate the attack-free complaints of patients with familial Mediterranean fever (FMF) and the impact of colchicine on these symptoms and on subclinical inflammation. A questionnaire that includes information about the disease course and symptoms during the attack-free period was administered to the parents of 50 F M F patients. For evaluation of the attack-free period, questions were asked about four items concerning daily activities of the children--weakness, lack of appetite, sleep problems, and decreased activity. The respondents rated the items and the total score was taken as the sum of all of the specific items. The laboratory values were noted from the patients' files. During the attack-free period, patients with mild disease had higher total scores, higher weakness, and decreased activity scores than patients with moderate disease. When we compared the daily activity scores before and after colchicine therapy, a statistically significant increase was observed in the total scores and in all of the specific item scores. Also a significant decrease was seen in the erythrocyte sedimentation rate and white blood cell counts, and a significant increase was seen in the hemoglobin levels during the attack-free period after colchicine usage. Regression of inflammation together with improvement in daily activities were observed. F M F patients seem to have complaints during the attack-free period that may be related to subclinical inflammation. Moreover, colchicine besides preventing Z. B. 6z~akar • F. Yal~mkaya - S. Yfiksel B. Acar • M. Ekim Department of Pediatric Nephrology, Ankara University Medical School, Ankara, Turkey D. G6kmen Department of Biostatistics, Ankara University Medical School, Ankara, Turkey Z. B. Ozqakar ([~) Yeni Ankara Sokak 27/1, Cebeci, Ankara, Turkey E-mail: zbozcakar@yahoo.com Tel.: + 90-312-3632728 Fax: + 90-312-3620581 the F M F attacks and the dangerous complication of amyloidosis also seems to hinder the symptoms of the attack-free period in children with F M F . Attack-flee period - Children • Colchicine Familial Mediterranean fever • Subclinical inflammation Keywords Introduction Familial Mediterranean fever ( F M F ) is an autosomal recessive disease, characterized by recurrent, self-limited attacks of fever with serositis involving the peritoneum, pleura, and joints. The disease is caused by mutations in the F M F gene (MEFV) located on chromosome 16 and primarily affects Jewish, Armenian, Turkish, and Arab populations. Amyloidosis is the most severe complication of F M F [1-4]. Daily colchicine treatment was first suggested by Goldfinger [5] and Ozkan et al. [6] in 1972. Later it was shown that it is an effective treatment for the prevention of F M F attacks and development of amyloidosis in all compliant patients [7-9]. Most of the previous reports revealed that acute phase reactants (APR) are generally elevated during the attacks of F M F and return to normal with clinical remission [10]. Recently, it was shown that in some patients, A P R could remain high during the intervals between the attacks. This has led to the suggestion that subclinical inflammation continues during the attack-free periods [11, 12], but the influence of subclinical inflammation on daily life has not been investigated previously. The aim of this study was to investigate the attack-free complaints of patients with F M F and the impact of colchicine on these symptoms and on subclinical inflammation. Methods This was a cross-sectional study that comprised 50 children of the 500 F M F patients who have been 150 followed and regularly seen every 6-12 months. All patients fulfilled the clinical criteria for the diagnosis of F M F [13]. To evaluate the colchicine response, patients were required to be on colchicine therapy for at least 6 months. Patients were recruited during their routine follow-up visits to the clinic between the dates of February 2004 and June 2004 and all patients who came to control visits during that time were included. The parents o f each patient signed an informed consent and all patients underwent a clinical interview and examination. A questionnaire that included patient age, age at disease onset, age o f therapy, symptoms before and after colchicine therapy, duration and dosage of therapy, compliance with the medication, and side effects was prepared and administered to the parents of each patient by the same clinician. The overall severity of their disease was estimated according to Tel H as hom er criteria, accounting for the age of onset, frequency o f attacks at any site, presence of arthritis and erysipelas-like lesion, amyloidosis, and colchicine dosage [14]. For evaluation o f the attack-free period, questions were asked about four items concerning daily activities of the child r e n - w e a k n e s s , lack of appetite, sleep problems (decrease in the duration or quality of sleep), and decreased activity (unwillingness to do daily activities). The respondents were asked to rate the items as " 1 " if their answers were "yes, exactly," " 2" if "yes, sometimes," and " 3 " if their answers were simply " n o . " The total score was taken as the sum of all of the specific items. Patients who had no complaints about these four items would get a total score of 12, but if they had severe complaints they would only have taken a total score of four. Their hemoglobin (Hb), white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and Creactive protein (CRP) and fibrinogen levels during the attacks and attack-free periods--before and after the use o f colchicine--were noted from the patients' files. Laboratory values during attacks were routinely obtained when the patients were symptomatic and the attack-free values were obtained at least 10 days after the attack. The results were analyzed using the Social Package for Statistical Sciences 11.0 and expressed as median (minimum-maximum) for data not showing normal distribution and as mean 4- standard deviation (SD) for data showing normal distribution. The paired samples ttest and Wilcoxon's test were used for comparison of the dependent groups. The independent samples t-test and Mann-Whitney U tests were used for comparison of independent groups. Values o f p < 0.05 were considered statistically significant. Results Demographic features Demographic features and colchicine dosages o f the study group are summarized in Table 1. Past history revealed that colchicine was increased from 1 to 1.5 mg/ day or from 1.5 to 2 mg/day in 25 patients: for frequent attacks in 17 (68%), for the elevated A PR during the attack-free period in 6 (24%), and for intermittent proteinuria in 2 (8%) patients. Colchicine and the attacks The frequency and the characteristics of the clinical symptoms before and after colchicine therapy are shown in Tables 2 and 3. Antipyretic response was obtained in 73% of the 34 patients before therapy and in 100% of the 24 patients after therapy. Pretreatment and posttreatment mean attack WBC counts and CRP, ESR, and fibrinogen levels did not differ. Colchicine and the attack-free period When we compared the scores of daily activities before colchicine therapy, patients with mild disease had higher Table 1 Demographic features and colchicine dosages of the study group Study group, n = 50 mean-t-SD Sex Age at time of study (years) Age at disease onset (years) Age at onset of therapy (years) Mean duration of therapy (years) Disease severity Compliance to therapy Colchicine dosage Mean colchicine dosage per kilogram (mg/kg) Mean colchicine dosage per body surface area (mg/m2) Boys Girls Mild Moderate Severe Yes No 1 mg/day 1.5 mg/day 2 mg/day 24 (48%) 26 (52%) 11.914- 3.85 4.18 4-3.10 7.364-3.21 4.54+ 3.24 10 (20%) 39 (78%) 1 (2%) 46 (92%) 4 (8%) 28 (56%) 15 (30%) 7 (14%) 0.035 4-0.015 1.11 4-0.34 Range 422.5 6 months-12 2-14 6 months-15.5 0.01~?.08 0.62-2.0 151 Table 2 Frequency of the clinical symptoms Abdominal pain Chest pain Arthritis Arthralgia Erysipelas-like erythema Fever Myalgia Before colchicine, n = 50 (%) After colchicine, n = 50 (%) 46 (92) 18 (36) 11 (22) 14 (28) 2 (4) 47 (94) 9 (18) 27 (54) 13 (26) 5 (10) 5 (10) 1 (2) 28 (56) 5 (10) total scores (median: 11, min.: 9, max.: 12) than patients with m o d e r a t e disease (median: 9, min.: 6, max.: 12) (p<0.01). Weakness and decreased activity scores o f patients with mild disease (median: 3, min.: 2, max.: 3) were also higher than patients with moderate disease (median: 2, min.: 1, max.: 3) (p < 0.01 and 0.05). Scores o f appetite loss and sleep problems did not differ statistically between the two groups (p>0.05). Scores o f daily activities during the attack-free period before and after colchicine t h e r a p y are given in Table 4. In attackfree periods, m e d i a n E S R and mean W B C c o u n t decreased and m e a n H b increased after colchicine therapy (p < 0.05). A l t h o u g h m e a n C R P levels tended to decrease after colchicine therapy, no statistically significant difference was f o u n d in C R P and fibrinogen values (Table 5). H e p a t o s p l e n o m e g a l y was detected in four (8%) patients before colchicine. H e p a t o m e g a l y disappeared and splenomegaly was detected in only one (2%) patient after colchicine therapy. T w o patients had intermittent proteinuria and none o f the patients had developed amyloidosis. D i a r r h e a as a side effect o f colchicine therapy was seen in 14 (28%) patients and 78% o f the diarrhea episodes occurred at the beginning o f therapy or together with increased dosage and disappeared shortly thereafter. Alopecia, leukopenia, myalgia, and m y o p a t h y did not occur in any patient. Discussion Although F M F is a periodic disease and the patients seem to be s y m p t o m free in between the episodes, we have observed that they have some subtle complaints, in other words they are not completely normal. We thus investigated the attack-free period by asking simple and short questions that could easily be answered by the parents. In our study, we f o u n d that as the severity o f the disease increased the patients had more complaints between the attacks affecting their daily activities. W h e n we c o m p a r e d the daily s y m p t o m scores, a statistically significant increase was observed in the total scores and in all o f the specific item scores o f all o f the patients after colchicine therapy c o m p a r e d to the ones before therapy. Patients' weakness, lack o f appetite, decreased activity, and sleep problems improved after colchicine therapy. Recently, it was shown that enhanced A P R is present in some o f the F M F patients between the attacks. This finding was interpreted as subclinical inflammation in patients who had no complaints [11, 12]. Likewise, in our six patients the reason for the increment in colchicine dosage was elevated A P R between the attacks. Accordingly, some points are extremely i m p o r t a n t and worth mentioning: one is the fact that some F M F patients could have complaints during the attack-free period, not so severe but seemingly affecting their daily activities. Second, in keeping with the aforementioned studies f r o m T u r k e y [11, 12], these complaints seem to be related to chronic inflammation. We had also detected a significant decrease in E S R and W B C c o u n t and a significant increase in the H b levels after colchicine therapy. A l t h o u g h not statistically significant, C R P levels decreased and thus regression o f inflammation together with the i m p r o v e m e n t in daily activities were observed in the attack-free period. The rise in the H b levels was suggested to be due to the regression o f the inflammation, but also increased appetite after colchicine could have had a role. The results o f o u r study obviously show that prophylactic colchicine therapy is a safe and effective m e t h o d o f eliminating the attacks without any important side effects. W e had n o patient refractory to medical treatment. C o m p l e t e remission was achieved in several o f our patients, and the frequency and severity o f the attacks decreased significantly in the remaining ones. Dosing regimens for colchicine therapy in childhood remain largely empirical and vary according to local practice. Recently, we had proposed a new dosing Table 3 Characteristics of the clinical symptoms before and after colchicine therapy Abdominal pain Chest pain Joint manifestations Fever Frequency (years x) Duration (h) Frequency (years -1 ) Duration (h) Frequency (years-x ) Duration (h) 1 Frequency (years-) Duration (h) Degree of fever (°C) Before colchicine median (min.-max.), mean ± SD After colchicine median (min.-max.), mean + SD p 24 1-120) 72 10-168) 24 0.5-96) 57.60 ± 20.23 17.87± 15.67 72 (24-168) 24 (0.5-120) 60 (12-240) 39 (38-40) 2 (0.5-48) 24 (1-96) 2 (0.5-96) 37.20 ± 31.05 3.87 ± 3.94 36 (24-120) 2 (0.5-48) 24 (1-72) 38.5 (37-39) < 0.001 < 0.001 <0.01 < 0.05 < 0.05 < 0.05 < 0.001 <0.001 <0.01 152 Table 4 Scores of daily activities during the attack-free period before and after colchicine Weakness Lack of appetite Sleep problems Decreased activity Total score Before colchicine (n = 50) After colchicine (n = 50) Median Min./max. Median Min./max. 2 2 3 3 10 1/3 1/3 1/3 1/3 6/12 3 3 3 3 12 2/3 2/3 3/3 3/3 10/12 P < 0.001 < 0.001 < 0.05 < 0.001 < 0.001 Table 5 Laboratory values during the attack-free period before and after colchicine therapy WBC count (mm 3) ESR (ram/h) CRP (mg/dl) Fibrinogen (mg/dl) Hb (g/dl) Before colchicine median (min./max.), mean ± SD After colchicine median (min./max.), mean ± SD p 8000 + 2619 21 (5/109) 0.90 + 1.39 308.27 ± 119.44 11.73 + 1.15 6907 + 1893 14 (3/54) 0.32 + 0.35 309 -4-52.90 12.86± 1.09 < 0.05 <0.01 >0.05 > 0.05 < 0.001 regimen and showed that prescribing colchicine therapy a c c o r d i n g to b o d y w e i g h t a n d b o d y s u r f a c e a r e a w o u l d b e m o r e a p p r o p r i a t e in c h i l d h o o d [15]. T h e c r o s s - s e c tional design might be a limitation of our study. T h e r e f o r e , we s u g g e s t t h a t a p r o s p e c t i v e s t u d y i n c l u d i n g a h i g h e r n u m b e r o f p a t i e n t s m i g h t b e d o n e to s u p p o r t our preliminary results. A s a c o n c l u s i o n , this s t u d y s e e m s to e s t a b l i s h the v a l u e o f d a i l y c o l c h i c i n e a d m i n i s t r a t i o n in d e c r e a s i n g t h e c o m p l a i n t s d u r i n g t h e a t t a c k - f r e e p e r i o d in F M F . Recurrent attacks together with the complaints during t h e a t t a c k - f r e e p e r i o d m a y w e l l affect t h e e d u c a t i o n a n d s o c i a l a c t i v i t i e s o f t h e c h i l d r e n . T h u s , we h i g h l i g h t t h e importance of colchicine treatment, which besides preventing the attacks and dangerous complication of a m y l o i d o s i s a l s o i m p r o v e s t h e d a i l y s y m p t o m s in t h e interim between the attacks. 3. 4. 5. 6. 7. 8. 9. 10. Take home message FMF patients seem to have complaints during the att a c k - f r e e p e r i o d t h a t m a y b e r e l a t e d to s u b c l i n i c a l inflammation, and colchicine improves these daily s y m p t o m s in t h e i n t e r i m b e t w e e n t h e a t t a c k s . References 1. Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 43:227-253 2. Yal~mkaya F, Tfimer N, Tekin M, (~akar N, Akqaku~ M (1997) Familial Mediterranean fever in Turkish children (analysis of 110 cases). In: Sohar E, Gafni J, Pras M (eds) First International Conference on Familial Mediterranean Fever 11. 12. 13. 14. 15. (FMF) (abstract book). Freund Publishing House, London, pp 157-161 The French F M F Consortium (1997) A candidate gene for familial Mediterranean fever. 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