Familial Mediterranean Fever: Risk Factors, Causes of Death, and Prognosis in the Colchicine Era : Medicine

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Original Study

Familial Mediterranean Fever

Risk Factors, Causes of Death, and Prognosis in the Colchicine Era

Akar, Servet MD; Yuksel, Feride MD; Tunca, Mehmet MD; Soysal, Ozgul MD; Solmaz, Dilek MD; Gerdan, Vedat MD; Celik, Ali MD; Sen, Gercek MD; Onen, Fatos MD; Akkoc, Nurullah MD

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Medicine 91(3):p 131-136, May 2012. | DOI: 10.1097/MD.0b013e3182561a45
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Abstract

INTRODUCTION

Familial Mediterranean fever (FMF) is a genetic disease characterized by recurrent episodes of fever and serositis, generally lasting 24–72 hours.4,27 It is more prevalent among non-Ashkenazi Jewish, Turkish, Armenian, and Arab populations. Turkey appears to have the highest global concentration of FMF patients,4 with a reported FMF prevalence ranging from 1:400 to 1:1000.12,28 The gene responsible for FMF (MEFV) is located on the short arm of chromosome 16 and encodes an immuno-regulatory protein called pyrin.2,3 The most devastating complication of FMF is amyloid A (AA) protein deposition, which carries with it the potential risk for developing end-stage renal disease. In the pre-colchicine era, amyloidosis was the most important prognostic determinant for FMF, since the majority of patients developed amyloidosis before reaching 40 years of age,14,31 and only a few patients with FMF survived to the age of 50 years.14,36 On the other hand, it was recently hypothesized that homozygous or heterozygous MEFV carrier status may provide a selective advantage against contracting certain infectious agents such as tuberculosis.7,8

Since 1972,16,30 colchicine has become the standard treatment for patients with FMF, and it has been demonstrated that regular colchicine use is not only effective for the prevention and amelioration of FMF attacks,16,17 but that it also decreases the likelihood of developing amyloidosis.42 Moreover, some studies have pointed out the therapeutic effects of colchicine even in patients with established amyloidosis.29,41

Although factors influencing the development of amyloidosis in patients with FMF have been investigated in the past few decades, to our knowledge factors influencing overall FMF patient mortality have not been evaluated in the colchicine era. Thus we conducted the current study to determine the survival rate and causes of death, and to explore the prognostic factors in patients with FMF.

PATIENTS and METHODS

Dokuz Eylul University School of Medicine serves as a tertiary referral center in Izmir, in western Turkey. We reviewed the medical records of the internal medicine, rheumatology and nephrology clinics to obtain the contact information of all FMF patients registered since July 1992. In total, we identified 650 patients with FMF: 333 (51%) were women, and the mean age was 38.6 ± 12.6 years. Between February and December 2009, we attempted to contact every patient by telephone. All contacted patients were invited to the rheumatology clinic for a formal evaluation. A detailed telephone interview was conducted with patients who could not come to the hospital. A structured questionnaire was used for both in-person and telephone interviews. Every patient seen at the hospital had a general clinical and laboratory examination that included urinalysis.

The following data were collected using a structured questionnaire: the patient’s socioeconomic and demographic characteristics (age, sex, ethnicity, parental consanguinity, marital status, health insurance, work status), health-related behaviors (smoking, alcohol consumption), age at onset of attacks, presenting and cumulative clinical features of FMF, colchicine use, and response to colchicine. A patient disease severity score was calculated according to scoring criteria developed by the Sheba Medical Center.23 Patient MEFV gene mutation status was recorded, if available.

Patient survival time was calculated from the date of first admission to the interview date or until the date of patient death or the date of last contact for patients lost to follow-up. Causes of death were ascertained by review of patient case records, or discussions with the patient’s relatives or attending physicians. This study was approved by the local ethics committee, and each patient signed informed consent.

Statistical Analysis

Unless otherwise stated, values are presented as the mean ± standard deviation (SD) or the percentage as appropriate. Comparisons of categorical data between groups were made using the chi-square test. Mann-Whitney U test was used to analyze continuous data. During the follow-up period, FMF patients’ observed mortality was compared with the expected mortality in the age- and sex-matched Turkish population to calculate a standardized mortality ratio (SMR). Mortality data for the Turkish population were obtained from the 2007 Turkish Mortality Table (http://tuikapp.tuik.gov.tr/adnksdagitapp/adnks.zul).

Univariate survival analysis was performed by the Kaplan-Meier method, and the differences between survival curves were evaluated using the log-rank test. Multivariate survival analysis was performed using the Cox proportional hazards method to evaluate the relative effect of each covariate on the survival function. All statistical tests were 2-tailed, and a p value < 0.05 was considered statistically significant. All statistical analyses were performed using StatsDirect Statistical Software, v. 2.0.0 (Cheshire, UK).

RESULTS

The status of 587 (90.3%) patients from 509 families was determined. The remaining 63 patients (9.7%) could not be reached by telephone or mail. The procedure used for patient evaluations is summarized in Figure 1. Clinical characteristics of the patients who could and could not be contacted for this study were similar (Table 1). There were no significant differences in patient demographic and initial clinical features between patients evaluated at the clinic compared with those who were interviewed by telephone (Table 2), except for the location of residence. More patients interviewed in person were living in Izmir or a nearby city compared with the patients reached by telephone (93.9% vs. 66.7%; p < 0.001).

T1-2
TABLE 1:
Selected Demographic and Clinical Characteristics of FMF Patients
T2-2
TABLE 2:
Selected Demographic and Clinical Characteristics of FMF Patients Evaluated in Clinic and Interviewed by Phone
F1-2
FIGURE 1:
Flow diagram summarizing the FMF patients’ evaluation procedure.

As expected, the most common clinical features in this patient cohort were fever and peritonitis. The vast majority of patients (97.7%) were of Turkish origin, with 1.6% of Arab origin. The parental consanguinity rate was 17.8% in 509 index cases. Most of the socioeconomic, demographic, and clinical features were similar for male and female patients (data not shown). However, female patients reported having arthritis more frequently than males (52.3% vs. 43.3%; p = 0.034), and the Sheba Medical Center disease severity score was higher in female than in male patients (49.6% vs. 37.9%; p = 0.006).

Every FMF patient admitted or referred to our clinic was prescribed colchicine at the initial visit; consequently, almost all of the patients in this study (94.2%) were on colchicine treatment. However, only 61.4% of patients used colchicine regularly (Table 3). The median colchicine dosage was 1.5 mg/d (range, 0–3 mg/d).

T3-2
TABLE 3:
Characteristics of Contacted Patients

Genetic analysis was available for 436 patients, and M694V was the leading mutation identified (383 of 872 alleles [43.9%], and homozygous in 91 patients). The next most common mutations were M680I (141 alleles; 16.2%) and V726A (87 alleles; 9.9%). These genetic analysis results are similar to those reported in the nationwide FMF series.39 Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were obtained for 234 patients who came to the clinic for evaluation. The mean ESR was 19.5 mm/h (range, 2–110 mm/h), and the mean CRP level was 9.8 mg/L (range, 0–149 mg/L).

Of the 587 FMF patients who were contacted during the study period, 84 patients had hypertension (14.3%; 45 female [14.9%] and 39 male [13.7%]), 26 patients had diabetes mellitus (4.4%; 15 female [5%] and 11 male [3.9%]), and 14 patients had coronary heart disease (2.4%; 3 female [1%] and 11 male [3.9%]).

Biopsy-proven amyloidosis was present in 37 (6.3%) patients. Three of these patients had asymptomatic proteinuria, 12 had nephritic syndrome, and 22 had renal failure (17 of the 22 patients with renal failure required dialysis). Another 4 patients had renal failure due to non-amyloid kidney diseases. Three other patients had proteinuria (2 patients) or renal failure (1 patient) and declined biopsy. In total, 44 (7.5%) patients had renal disease. The presence of amyloidosis or renal disease was not related to age at disease onset, disease duration, types of attacks, disease severity score, colchicine usage, colchicine dosage, or M694V mutation carrier status. Data for the dates of amyloidosis and FMF diagnosis were available for 34 patients. Amyloidosis was diagnosed in 21 of these 34 (62%) patients either before or concomitantly with their FMF diagnosis.

During a median 6 years of follow-up (interquartile range, 2–10 yr), 14 of 587 FMF patients died. The causes of death are listed in Table 4. In univariate analysis, factors associated with mortality were amyloidosis (χ2 = 46.57; p < 0.001), renal disease (χ2 = 59.44; p < 0.001), increasing age (χ2 = 174.65; p < 0.001), coronary heart disease (χ2 = 6.67; p = 0.01), and hypertension (χ2 = 22.61; p < 0.001). In the multivariate model, amyloidosis was the only independent predictor of mortality (hazard ratio, 17.5; 95% confidence interval [CI], 3.8–81.4; p < 0.001) in this patient cohort (Figure 2).

T4-2
TABLE 4:
Causes of Death in Study Population
F2-2
FIGURE 2:
Survival curves of FMF patients with and without amyloidosis.

Overall mortality during the follow-up period was found not to be significantly different from the age- and sex-matched general Turkish population (SMR, 1.48; 95% CI, 0.81–2.49).

DISCUSSION

In the current study we evaluated survival of patients with FMF in an era when colchicine is the standard therapy for the disease and can be easily obtained. The clinical picture of FMF is characterized by short-lived episodes of fever and localized inflammation. In some patients, attacks last up to 1 month and usually present as arthritis, febrile myalgia, and sacroiliitis.5 The most serious complication of FMF is AA amyloidosis. In the pre-colchicine era the prevalence of amyloidosis was reported to be as high as 75% in patients 43 years or older,14 and it was responsible for most patient deaths.36 This situation led to the assumption that “in most patients with FMF, amyloidosis eventually develops and once amyloid appears it will probably cause the patient’s death at an early age.”18 As seen in the current study, however, in the colchicine era the overall mortality may not be different from that of the general population. Our FMF mortality results may be an optimistic estimate, since in the present study we were not able to contact approximately 10% of patients. However, the names or identity numbers of all of the 14 dead patients, but none of the 67 FMF patients who could not be contacted, were registered as deceased in the Izmir Branch of General Directorate of Civil Registration and Nationality database.

In our study population, the rate of biopsy-proven amyloidosis was 6.3% and of renal disease was 7.5%. These findings suggest that the decreased frequency of amyloidosis in the colchicine era could be the main reason for improved FMF patient survival. In 2005, the nationwide study of FMF reported that the prevalence of amyloidosis was 12.9%.39 However, in line with our findings, a recent study from Turkey1 that evaluated the renal biopsies of pediatric FMF patients also showed a significant decrease in amyloidosis compared to previous observations. In the aforementioned study, 12% of all biopsies displayed secondary amyloidosis between the years 1978 and 1990, compared to just 2% between 2000 and 2009. The factors associated with this decrease have yet to be elucidated. Nevertheless, the authors suggested that the decreased rate of childhood amyloidosis may be the result of better education of Turkish physicians, increased use of colchicine, and an improvement in the infectious milieu of young children.

Colchicine is the treatment of choice for patients with FMF. Although the drug has a low therapeutic index, typical doses of colchicine in FMF range between 1.5 and 2.0 mg/day, which is far from the lowest reported lethal doses of 7–26 mg.13 Continuous daily use of colchicine in adequate doses has been shown to prevent amyloid deposition.34,42 Colchicine has also been shown to effectively prevent the development of amyloidosis even in patients whose attacks are not relieved by the drug.42 Furthermore, when used appropriately in patients with amyloidosis, colchicine can decrease the level of proteinuria and delay the development of chronic renal failure.29,41

In the present study, almost all of the patients reported being on colchicine treatment. Of the 34 patients whose dates of FMF and amyloidosis diagnosis were both known, in only 13 was the diagnosis of amyloidosis made after the diagnosis of FMF was established. It is likely that not all patients were compliant with colchicine therapy, but definitive, objective evidence of this possibility was almost impossible to obtain. Thus we believe that the widespread use of colchicine was the primary basis for the lower prevalence of amyloidosis in this population compared to the reported prevalence in earlier studies. However, it was also evident from the present study that even in Turkey, where FMF is prevalent, the diagnosis of FMF may still be delayed as long as 13 years. This delay was probably a primary contributing factor to the development of amyloidosis before FMF diagnosis in more than half of the patients.

Although the frequency of amyloidosis has been decreasing, the present study shows that it is still the most important prognostic factor in patients with FMF. The underlying basis for AA fibril deposition in FMF remains largely unknown. It has been reported that there is no relationship between the appearance of amyloidosis and the time of FMF onset or the type, number, or severity of attacks.36,39 Additionally, amyloidosis has been occasionally reported in individuals with no history of an acute febrile attack of serositis.6 In agreement with published observations, we could not demonstrate any correlation between renal disease, including amyloidosis, and age at FMF onset, disease duration, the type of attack, patient genotype, or disease severity.

Development of amyloidosis has been shown to be associated with certain MEFV mutations, family history of amyloidosis, and male sex.20,21,31,32,35 Following the discovery of the MEFV gene, numerous studies evaluated possible genotype-phenotype correlations in FMF. Patients carrying M694V, M694I, or M680I mutations were reported to have more severe disease, more joint involvement, and a greater chance of developing amyloidosis.4 The MEFV M694V mutation has been associated with renal amyloidosis in FMF patients of Armenian,9 Jewish,15 and Arabic heritage.22 However, most studies conducted in Turkey,11,37–39 including the current study, did not confirm this association. Thus there may be additional genetic and environmental factors that contribute to FMF disease complications. Indeed, there is some evidence that environmental factors may influence the development of amyloidosis. In 1974 Schwabe et al33 showed a higher frequency of amyloidosis in Armenian FMF patients living in Armenia than in Armenians living in the United States. Likewise, a worldwide study of 2482 FMF patients revealed that patient country of recruitment was the key risk factor for FMF-associated AA amyloidosis,38 showing a 3-fold increased risk for patients recruited from Arabian countries, Turkey, and Armenia compared with FMF patients recruited from other countries.

A sustained and long-term elevation in serum AA (SAA) protein is the only known prerequisite for the development of AA amyloidosis.10 We have previously reported that in patients with FMF, levels of CRP and SAA are higher than normal during the attack-free period.19,40 Substantial and prolonged subclinical inflammation may indicate that patients receiving colchicine who have relatively infrequent clinical attacks may still be at risk for amyloidosis and that this type of subclinical inflammatory process may lead to the development of amyloidosis.19 Similarly, in the present patient cohort, there was also evidence of ongoing inflammatory activity during attack-free periods, confirming our previous findings.

Although a univariate analysis demonstrated that hypertension and coronary heart disease are correlated with mortality in the current FMF patient cohort, these conditions were not found to be statistically significant in a subsequent multivariate survival analysis. Considering the relatively young age of our patients, it is difficult to compare the prevalence figures for this cohort with the general Turkish population. However, the reported national frequencies of hypertension,25 diabetes mellitus,26 and coronary heart diseases24 in patients aged 35–44 years were quite similar to the frequencies reported in the current study for this FMF patient cohort.

The main limitation of the present study is its retrospective design. Another concern is that we included only adult patients, thus we could not detect FMF patients who had developed amyloidosis earlier in life or who had already died. Moreover, amyloid deposition was evident either before or at the same time as the FMF diagnosis in a significant proportion of our patients with amyloidosis.

In conclusion, the prognosis for FMF patients in the colchicine era may no longer be worse than that of the general Turkish population. However, renal disease is still the most important determinant of FMF patient survival. Thus, every effort should be made to ensure early initiation of colchicine treatment and to achieve FMF patient compliance in order to prevent amyloidosis in this population.

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