Different disease subtypes with distinct clinical expression in familial Mediterranean fever: results of a cluster analysis.

OBJECTIVE: The aim of this study was to evaluate whether there are clinical subgroups that may have different prognoses among FMF patients. METHODS: The cumulative clinical features of a large group of FMF patients [1168 patients, 593 (50.8%) male, mean age 35.3 years (s.d. 12.4)] were studied. To analyse our data and identify groups of FMF patients with similar clinical characteristics, a two-step cluster analysis using log-likelihood distance measures was performed. For clustering the FMF patients, we evaluated the following variables: gender, current age, age at symptom onset, age at diagnosis, presence of major clinical features, variables related with therapy and family history for FMF, renal failure and carriage of M694V. RESULTS: Three distinct groups of FMF patients were identified. Cluster 1 was characterized by a high prevalence of arthritis, pleuritis, erysipelas-like erythema (ELE) and febrile myalgia. The dosage of colchicine and the frequency of amyloidosis were lower in cluster 1. Patients in cluster 2 had an earlier age of disease onset and diagnosis. M694V carriage and amyloidosis prevalence were the highest in cluster 2. This group of patients was using the highest dose of colchicine. Patients in cluster 3 had the lowest prevalence of arthritis, ELE and febrile myalgia. The frequencies of M694V carriage and amyloidosis were lower in cluster 3 than the overall FMF patients. Non-response to colchicine was also slightly lower in cluster 3. CONCLUSION: Patients with FMF can be clustered into distinct patterns of clinical and genetic manifestations and these patterns may have different prognostic significance.

FMF50: a score for assessing outcome in familial Mediterranean fever.

BACKGROUND: Colchicine is the main treatment for familial Mediterranean fever (FMF). However, biological agents and other treatments are available for patients who are unable to receive optimal treatment. OBJECTIVE: To develop outcome criteria that define response to treatment. METHODS: Two rounds of Delphi exercise were followed by a consensus conference enabling the definition of the criteria to be employed. Data for patients with FMF responding and resistant to their treatment were obtained from the FMF Arthritis Vasculitis and Orphan disease Research in paediatric rheumatology (FAVOR) website. The suggested criteria were analysed and validated in this patient cohort. Sensitivity/specificity measures and the ability of the score to discriminate between patients with active and inactive disease via the best cut-off score were calculated by a receiver operating characteristic analysis. RESULTS: Compliance with the maximum dose of the drug was considered essential for evaluation of the patients. Seven criteria were suggested in the consensus conference. The performance of each criterion, in differentiating between resistant and responsive patients, was tested. The final set of criteria was defined as at least 50% improvement in five of six criteria, without worsening in any one defined response to treatment with a very high sensitivity and specificity. The items of this FMF50 included: 1. Percentage change in the frequency of attacks with the treatment. 2. Percentage change in the duration of attacks with the treatment. 3. Patients/parents' global assessment of disease severity (10 cm visual analogue scale (VAS)). 4. Physicians' global assessment of disease severity (10 cm VAS). 5. Percentage change in arthritis attacks with the treatment. 6. Percentage change in C-reactive protein, erythrocyte sedimentation rate or serum amyloid A level with the treatment. CONCLUSIONS: The FMF50 produced is a user-friendly measurement tool to guide physicians and can be used in clinical trials.

Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine.

OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by paroxysmal attacks of serosal inflammation. Colchicine is highly effective in preventing these attacks but it may also disrupt the intestinal absorption of vitamin B12. We hypothesised that patients treated with colchicine for a prolonged period could develop deficiency of the vitamin. METHODS: Ninety-five adult FMF patients on regular colchicine treatment for at least 2 years and age and sex-matched 90 healthy controls were enrolled and complete blood count with platelets, vitamin B12 and folic acid were measured in each person. We also investigated 15 adult FMF patients who were not yet on colchicine. RESULTS: The mean vitamin B12 values were not significantly different between the groups (352.12 (SD=171.62) pg/mL vs. 360.96 (SD=146.53) pg/mL, p=0.71), but there were significantly more vitamin B12 deficient cases among FMF patients (12 vs. 3; p=0.021) and 3 out of these 12 had megaloblastic anaemia. None of the vitamin B12 deficient controls had anaemia. We could not identify any disorder which might have causative effect for the deficiency among this subgroup. The mean vitamin B12 value of 15 colchicine-naïve cases was not significantly different from patients on colchicine (p=0.356). CONCLUSIONS: We did not observe significant vitamin B12 deficiency among colchicine-treated FMF patients but some cases may be more prone to developing this potentially serious disorder.

High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: further evidence for the connection.

INTRODUCTION: Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by recurrent attacks of fever and serositis. Limited data suggest that the prevalence of sacroiliitis is increased in patients with FMF. In our present study, we assessed the prevalence of spondyloarthritis (SpA), including ankylosing spondylitis (AS), among a cohort of FMF patients and their unaffected first-degree relatives (FDRs). METHODS: The current study cohort comprised a consecutive group of 201 unrelated patients with FMF and 319 FDRs (≥16 years old). These subjects were examined according to a standard protocol. RESULTS: A total of 157 FMF patients (78.1%) and 233 (73%) unaffected FDRs reported back pain. Fifteen FMF patients (7.5%) and nine unaffected FDRs fulfilled the modified New York (mNY) criteria for AS. One additional FDR with AS was identified after review of the medical records. None of the FMF patients with AS was HLA-B27 positive. The allele frequency of M694V among the FMF patients with radiographic sacroiliitis was significantly higher in comparison with those without sacroiliitis (OR 4.3). When compared with the general population, the risk ratios for SpA and AS among the FDRs of our FMF patients were 3.3 (95% CI; 2.0 to 5.5) and for AS 2.9 (95% CI; 1.3 to 6.4), respectively. CONCLUSIONS: Our study suggests that a) factors other than HLA-B27 play a role in the association of FMF and SpA/AS; b) MEFV gene variations may be one of the geographic/region-specific potential pathogenetic links between these two disorders in the Turkish population.

Familial Mediterranean fever: risk factors, causes of death, and prognosis in the colchicine era.

We assessed the risk factors and causes of death in patients with familial Mediterranean fever (FMF) in an era when colchicine is the standard therapy for all patients.This study included all FMF patients who had presented to any of the internal medicine, rheumatology, or nephrology clinics at Dokuz Eylul University Hospital between 1992 and 2009. Of the 650 patients with FMF identified, 587 (90.3%) had either a face-to-face (n = 380) or telephone (n = 193) interview, or were confirmed as deceased. A structured questionnaire was used to obtain socioeconomic and demographic data, presenting and cumulative clinical features, and disease severity scores.During the follow-up period mortality was analyzed by calculating age- and sex-standardized mortality ratio (SMR) according to the mortality statistics of the Turkish population. Factors predictive of mortality were evaluated using Kaplan-Meier and Cox proportional hazard models. Sixty-three (9.7%) patients whose initial demographic and major clinical characteristics were similar to the rest of the group could not be contacted during the study period.Most (94.2%) patients were on colchicine at the time of the study. Thirty-seven (6.3%) patients had biopsy-verified amyloidosis, and 44 (7.5%) had renal disease. During a median follow-up of 6 years, 14 patients (9 women) died, and amyloidosis and its related complications were the leading causes of death in 7 patients. Univariate analysis revealed that increasing age, coronary heart disease, hypertension, renal disease, and amyloidosis were associated with mortality. However, Cox regression analysis showed amyloidosis as the only significant predictor of mortality (p < 0.001). The overall patient survival rate was not significantly different from the age- and sex-matched Turkish general population (SMR, 1.48; 95% confidence interval, 0.817-2.49).Our findings suggest that although the survival of FMF patients in the colchicine era is comparable to that of the general population, renal involvement still predicts mortality.

TLR polymorphisms in FMF: association of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly, Thre399Ile) polymorphisms and myeloid cell TLR-2 and TLR-4 expression with the development of secondary amyloidosis in FMF.

Amyloidosis is the major complication of familial Mediterranean fever (FMF). Toll-like receptors (TLR) are involved in the activation of an innate immune system TLR-2 and TLR-4 recognize lipoteichoic acid and lipopolysaccharides (LPS), respectively. While TLR-2 Arg753Gln polymorphism upregulates, TLR-4 Asp299Gly and Thre399Ile polymorphisms downregulate inflammation. We investigated the effect of these polymorphisms on the development of amyloidosis in FMF patients. We also investigated myeloid cell TLR-2 and TLR-4 expressions in these patients. We studied 26 FMF patients and 13 FMF patients with amyloidosis. TLR-2 Arg753Gln and TLR-4 Asp299Gly and Thr399Ile polymorphisms were analyzed with the polymerase chain reaction-restriction fragment length polymorphism method. Myeloid cell baseline TLR-2 and TLR-4 and LPS-induced TLR-4 expressions were evaluated. The TLR-2 and TLR-4 polymorphism rate was compared with the results of 100 healthy subjects in our previous study. In addition, 13 healthy controls were enrolled for leukocyte TLR-2 and TLR-4 expressions. Serum amyloid A (SAA) levels were measured in these 13 control cases and in FMF patients during attack-free periods. The frequency of TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms in healthy controls in our previous study were 1%, 3%, and 2%, respectively. The frequency of these polymorphisms were not different in FMF patients (with or without amyloidosis) compared to the control group. Likewise, myeloid cell TLR-2 and TLR-4 expressions were not different among the controls and FMF patients. However, LPS-induced TLR-4 expression in granulocytes was more prominent in FMF patients. There was no correlation between TLR-2 and TLR-4 expressions and SAA levels. Neither myeloid cell TLR-2 and TLR-4 expressions nor TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms seem to affect the development of secondary amyloidosis in FMF patients in our study population.

Assessment of aortic stiffness and ventricular functions in familial Mediterranean fever.

OBJECTIVE: To investigate systolic and diastolic ventricular functions, aortic elastic properties and the presence of pericardial effusion in familial Mediterranean fever (FMF) patients. METHODS: A case-controlled, cross-sectional study was performed on 44 FMF patients and 27 controls. Subjects with hypertension, diabetes mellitus and hyperlipidemia were excluded. Left and right ventricular functions were measured using echocardiography including two-dimensional, M-mode, and conventional Doppler as well as pulsed wave tissue Doppler imaging (TDI). Aortic elasticity was analyzed using M-mode tracing guided by the two-dimensional echocardiography. Statistical analysis was performed using Mann Whitney U, Spearman rho correlation and Fisher's exact tests. RESULTS: Age, sex, body mass index, smoking status and lipids were comparable in patients and controls (p>0.05). None of the subjects had pericarditis and/or pericardial effusion. Aortic wall properties were similar between groups (p>0.05). The TDI parameters of mitral lateral annulus revealed significantly lower Em/Am ratios in patients compared to controls [1.77 (0.6-3.4) vs. 1.79 (0.9-4.8), p=0.02]. Mitral flow propagation velocity was significantly lower in patients than healthy subjects [63 (39-100) vs. 74 (40-94) cm/s, p=0.008]. Tricuspid annular plane systolic excursion (TAPSE) was significantly reduced in FMF group than in controls [2 (1.3-2.5) vs. 2.5 (1.7-3.2) cm; p<0.001]. Eight of the patients and one control had impaired TAPSE (<2 cm; p=0.025). There was no difference regarding right ventricular diastolic dysfunction (RVDD) as assessed by using standard Doppler echocardiography (p>0.05). However, pronounced RVDD was observed in FMF patients documented by TDI (Em/Am<1; 19 patients vs. 0 controls, p<0.001). CONCLUSION: Subclinical myocardial involvement is present in a cohort of relatively young FMF patients who were also free of classical cardiovascular risk factors. Pericardium and aorta seem to be spared during attack free periods of FMF.

Oxidative DNA damage in polymorphonuclear leukocytes of patients with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessively inherited disorder characterized by recurrent, inflammatory self-limited episodes of fever and other symptoms. This disease is caused by more than 25 mutations in the gene MEFV. During fever attacks, there is a substantial influx of polymorphonuclear leukocytes into the affected tissues. Attack-free periods are accompanied by the up-regulation of neutrophil and monocyte phagocytic activity and oxidative burst. These facts led us to hypothesize that oxidative damage by free radicals to DNA may accumulate in FMF patients. To test this hypothesis, we investigated oxidative DNA damage in polymorphonuclear leukocytes of FMF patients during the attack-free period in comparison with FMF-free control individuals. DNA was isolated from polymorphonuclear leukocytes of 17 FMF patients and 10 control individuals. DNA samples were analyzed by liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry to measure the levels of various typical oxidatively induced products of DNA. We show, for the first time, that FMF patients accumulate statistically significant levels of these lesions in their DNA when compared to FMF-free control individuals. This work suggests that the persistent oxidative stress with excess production of free radicals in FMF patients may lead to accumulation of oxidative DNA damage. Defective DNA repair may also contribute to this phenomenon, perhaps due to mutations in the MEFV gene. The accumulation of mutagenic and cytotoxic DNA lesions may contribute to increased mutations and apoptosis in FMF patients, thus to worsening of the disease and well-being of the patients. Future research should deal with prevention of oxidative DNA damage and apoptosis in FMF patients, and also the elucidation of a possible role of DNA repair in this disease.

Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis. METHODS: Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis). RESULTS: Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. CONCLUSION: Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.

Early ultrasonographic markers of atherosclerosis in patients with familial Mediterranean fever.

Systemic inflammation plays an important role in the development of atherosclerosis (AS). The aim of this study was to evaluate the presence of early AS in patients with familial Mediterranean fever (FMF) that is characterized by recurrent inflammatory attacks of serositis. Sixty-one FMF patients (30 Male/31 Female; 31.5 [18-54] years) and 31 healthy controls (16 Male/15 Female; 31 [22-58] years) were studied. All FMF patients were on regular daily colchicine treatment and during attack-free periods. Both the FMF patients and controls with a history of diabetes mellitus (DM), hypertension, and hyperlipidemia were excluded. Body mass index (BMI) was calculated. Serum lipids, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were assessed. Two-hour oral glucose tolerance test was performed to rule out DM and glucose intolerance. To investigate early AS "endothelium-dependent flow-mediated dilatation (FMD%)," "nitroglycerin-induced endothelium-independent peripheral vasodilatation (NTG%)," and intima-media thickness (IMT) of common carotid arteries (CCA) were measured by ultrasonograpy. The median disease duration for FMF patients was 16 (1-45) years. Age, sex, BMI, smoking status, and serum lipids were comparable in patients and controls (p > 0.05). However, ESR and standard CRP were significantly higher in the patients group (p < 0.05). There were no differences in the measurements of right, left, and averaged IMT of CCA between patients and controls ([0.49 vs 0.5], [0.51 vs 0.52] and [0.5 vs 0.51]; p > 0.05, respectively). None of the subjects had carotid artery plaques. FMD% and NTG% were also similar in patients and controls group ([18.2 vs 20.6] and [24.2 vs 22.5]; p > 0.05, respectively). This study suggests that the markers of early AS are not impaired in FMF patients on regular daily colchicine treatment.

The relations between attacks and menstrual periods and pregnancies of familial Mediterranean fever patients.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by short lived, febrile serosal inflammatory attacks. Although majority of patients have random pattern of attacks, some reports described precipitating factors. There are also contradictory reports relating FMF attacks with menstruation and the natural course of their pregnancies. Seventy-two female patients with FMF with a mean age of 34.9+/-12.4 were interviewed. A standardized questionnaire was used inquiring any associations of FMF attacks of the patients with their menstruations and pregnancies. Thirty-eight patients (53%) reported that their attacks frequently coincided with their menstrual cycles and 17 patients noticed pleuritic chest pain in addition to their abdominal attacks. One patient experienced only febrile pleural attacks during her menstrual cycles. Unlike dysmenorrhoea, none of these patients' attacks responded to non-steroidal anti-inflammatory drugs. All of the patients could correctly differentiate their FMF attacks from dysmenorrhoea. Forty patients could give detailed information about the frequency and severity of their FMF attacks during 73 pregnancies: 25 patients (62.5%) experienced complete symptomatic remissions; the attacks were aggravated (7 patients), ameliorated (6 patients) or did not change (2 patients) in the rest of the pregnancies. Four patients continued to use colchicine during their pregnancies and delivered healthy babies. One patient gave birth to a child with Down's syndrome although she was not on colchicine therapy. Although FMF attacks and discomforts of menstrual cycles do overlap frequently, patients can easily differentiated them. Patients can be reasonably assured that the period of pregnancy will be comfortable but abstaining from colchicine should not be recommended. Gynecologists must be aware of FMF in the differential diagnosis of dysmenorrhoea or endometriosis.

Molecular and genetic characteristics of hereditary autoinflammatory diseases.

Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

A case of familial Mediterranean fever and polyarteritis nodosa complicated by spontaneous perirenal and subcapsular hepatic hemorrhage requiring multiple arterial embolizations.

The association of familial Mediterranean fever (FMF) and polyarteritis nodosa (PAN) has been well established. These patients have been reported to have an overall better prognosis than other PAN patients. Herein we report a patient with FMF and PAN who died of sepsis following a severe course of recurrent bleeding episodes which required multiple embolization attempts. The 39-year-old Turkish male presented with abdominal pain of 1-month duration. He had been diagnosed with FMF at the age of 24. On admission, he had pallor with general ill appearance. Rebound tenderness was obtained in the right upper abdominal quadrant. He had mild anemia, leukocytosis, thrombocytosis, and hypoalbuminemia. On the 2nd day of his admission, he developed hypotension with a rapid decline in hemoglobin level. Abdominal angiography showed multiple aneurysms in the branches of renal arteries, superior mesenteric artery, and hepatic arterial system including left renal infarct, suggesting PAN. He was put on high-dose steroids and oral cyclophosphamide. Despite medical treatment, he developed intense abdominal pain, hypotension, tachycardia, and a rapid fall in hemoglobin on four occasions. Active bleeding sites were embolized in two different angiography sessions. Although the patient experienced no more recurrent bleeding, he died of multiorgan dysfunction syndrome resulting from sepsis 6 weeks after admission. Polyarteritis nodosa associated with FMF may follow a grave course despite immunosuppressive therapy. Arterial embolization should be considered in the presence of bleeding aneurysms in addition to immunosuppressive therapy.

The significance of paired MEFV mutations in individuals without symptoms of familial Mediterranean fever.

The majority of patients with familial Mediterranean fever (FMF) have identifiable mutations in both alleles of the MEFV gene, while some individuals with paired MEFV mutations do not have clinical symptoms of the disease. During family studies we identified nine such individuals from six kindreds, most of whom either subsequently developed FMF or had other clinically significant inflammatory disease; one case benefiting substantially from colchicine therapy. Four individuals remained asymptomatic. Two further asymptomatic subjects with paired MEFV mutations were identified among 49 healthy controls from western Turkey, of whom a further 18.4 per cent were simple heterozygotes. This carrier rate was higher than would be expected from prevalence of FMF in this region, suggesting that penetrance of paired recognised pathogenic MEFV mutations may frequently be incomplete. MEFV genotyping results must be interpreted with due caution, and follow-up of apparently asymptomatic subjects with paired mutations is advisable.

Alanine aminotransferase deficiency in a hepatitis B surface antigen positive patient presenting with acute hepatitis.

This report presents a hepatitis B surface antigen positive case presenting with acute hepatitis and with findings of low serum alanine aminotransferase in contrast to very high levels of aspartate aminotransferase. A 64 year-old female patient was admitted to our hospital with fatigue and jaundice. Hepatitis B surface antigen was positive. During follow up, aspartate aminotransferase levels remained very high, while alanine aminotransferase levels continued to be extremely low. Additionally, all of the patients five daughters had low alanine aminotransferase levels. The clinical importance of alanine aminotransferase deficiency is still unclear.