A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever

OBJECTIVES: In a significant proportion of patients with familial Mediterranean fever (FMF), serum amyloid A (SAA) remains elevated during attack-free periods, thereby increasing the risk of developing amyloidosis. The aim of the study was to determine various correlates of elevated SAA and evaluate the role of SAA measurement in the diagnosis and management of FMF. METHODS: We reviewed the medical files of all 204 patients from our FMF center in whom SAA measurements were performed. SAA levels and the resulting diagnostic and therapeutic decisions were analyzed in relation to the reasons of SAA testing and to several clinical and genetic parameters. RESULTS: SAA measurements were made for diagnostic purposes in 29% of the patients. In the remainder, SAA measurements were used for adjustment of colchicine dose. Elevated SAA levels are found in a third of FMF patients during an attack-free period. The highest rate of elevated SAA levels was found in patients with proteinuria (60% of this patient group), followed by noncompliant (40%) and genetically positive asymptomatic patients (38%). Elevated SAA levels during remission were associated with family history of FMF, M694V homozygosity, and elevated C-reactive protein (CRP) (P<0.05 for each). Patients homozygous for the M694V mutation had the highest level of SAA. SAA measurement led to a change in colchicine dose in 30% of the patients, predominantly in noncompliant patients and patients with proteinuria or with atypical manifestations. CONCLUSIONS: Measurement of SAA level may help in the diagnosis of FMF and in adjustment of the colchicine dose.     

Evaluation of disease severity in familial Mediterranean fever

OBJECTIVE: To establish a new, objective, statistically based severity score for familial Mediterranean fever (FMF). METHODS: One hundred consecutive FMF patients were evaluated independently by 2 FMF experts for severity of their disease and were assigned to 1 of 3 severity levels: mild, intermediate, or severe. Nine candidate criteria, reflecting objective suffering and disability, were analyzed to determine their weight for patient placement in the 3 predefined severity groups. RESULTS: Candidate criteria best differentiating between the 3 patient categories were the frequency of attacks, the number of sites affected during an attack and during the course of the disease, and the duration of the attacks. These criteria were applied in a classification-tree model to establish a new FMF-severity score (F-SS). The first set of F-SS (F-SS-1) was highly sensitive and specific. Integrating F-SS-1 with clinical parameters strongly associated with disease severity resulted in a simplified score, the second set of F-SS (F-SS-2). CONCLUSIONS: New, useful, objective, and valid severity scores were established and found to distinguish between patients with mild, intermediate, and severe diseases with high sensitivity and specificity. RELEVANCE: The F-SS established may be important for treatment decisions, prognosis evaluation, and comparative analysis of patient populations.     

Microarray analysis of circulating microRNAs in familial Mediterranean fever

Objectives: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in MEFV. Mutations in exon 10 are associated with typical FMF phenotypes, whereas the pathogenic role of variants in exons 2 and 3 remains uncertain. Recent evidence suggests that circulating microRNAs (miRNAs) are potentially useful biomarkers in several diseases. Therefore, their expression was assessed in FMF.

Methods: The subjects were 24 patients with FMF who were between attacks: eight with exon 10 mutations (group A), eight with exon 3 mutations (group B), and eight without exon 3 or 10 mutations (group C). We also investigated eight cases of PFAPA as disease controls. Exosome-rich fractionated RNA was subjected to miRNA profiling by microarray.

Results: Using the expression patterns of 26 miRNAs, we classified FMF (groups A, B, and C) and PFAPA with 78.1% accuracy. In FMF patients, groups A and B, A and C, and B and C were distinguished with 93.8, 87.5, and 100% accuracy using 24, 30, and 25 miRNA expression patterns, respectively.

Conclusions: These findings suggest that expression patterns of circulating miRNAs differ among FMF subgroups based on MEFV mutations between FMF episodes. These patterns may serve as a useful biomarker for detecting subgroups of FMF.     

Fatigue in pediatric patients with familial Mediterranean fever

Abstract

Objectives: Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited attacks of fever with serositis involving the peritoneum, pleura and joints. Fatigue is a common problem in many pediatric rheumatic diseases; however, has not been evaluated systematically in FMF patients. Accordingly, the aim of this study was to evaluate fatigue and its possible allied factors in patients with FMF.

Methods: Patients with FMF, aged between 10 and 21 years, were assessed by completed validated fatigue questionnaire (Checklist Individual Strength-20). As a control group, patients with chronic rheumatic diseases and healthy children without any chronic disease were included.

Results: The study group comprised 111 patients with FMF, 54 with other chronic rheumatic diseases and 79 healthy subjects. While the CIS-20 total score and subscale scores (including subjective experience of fatigue) were similar between patients with FMF and those with other chronic rheumatic diseases (p?>?.05); both groups had significantly higher scores when compared with healthy subjects (p?<?.05). FMF patients with musculoskeletal complaints had significantly higher scores of subjective experiences of fatigue when compared to those without those complaints.

Conclusions: Fatigue is a common but unrecognized complaint in patients with FMF. Familial Mediterranean fever seems to be a chronic disease with inter attack ongoing complaints.     

Multinodular fatty liver after herpes-zoster vaccine: Case report and review of the literature: Case Report

Multinodular fatty liver (MNFL) is a pattern of fatty infiltration of the liver characterized by multiple well-circumscribed nodules on hepatic imaging, often raising the concern of metastatic malignancy. Here we describe a case of MNFL and review the published literature. There is likely some association between traditional risk factors for hepatic steatosis (e.g. alcohol, rapid weight change, metabolic syndrome, medications, TPN) and MNFL. Further study and reporting of cases of MNFL are needed to better characterize its pathogenesis and natural history.     

The frequency of the celiac disease among children with familial Mediterranean fever

We aimed to assess the frequency of celiac disease (CD) in patients with Familial Mediterranean Fever (FMF). This prospective study was carried out from October 2015 to March 2016 and included 303 patients with FMF. We used 98 sex- and age-matched healthy subjects as a control group. Levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in all groups. Those with increased level of tTG IgA were tested for anti-endomysium IgA antibodies (EMA). Patients with positive EMA underwent gastro-duodenoscopy and intestinal biopsy for a definite diagnosis of CD. Only 9 of 303 patients (2.9%) were positive for tTG IgA. Patients positive for tTG IgA were then tested for EMA and only one of them (0.3%) had a positive result. This patient underwent gastro-duodenoscopy. The pathological report was compatible with Marsh 0 classification score for the diagnosis of CD. Two subjects from the control group were positive for tTG IgA but none of them had positive EMA antibodies. We did not find CD in the large cohort of childhood FMF patients. The prevalence of CD did not show association with presence of childhood FMF in this study and CD would not be a considerable complication of childhood FMF.     

Long‐term prognosis of nonalcoholic fatty liver disease: Is pharmacological therapy actually necessary?

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) comprises a wide spectrum of liver injury, ranging from steatosis and steatohepatitis to cirrhosis. Reasons for the different natural course in individuals with NAFLD are still unclear. The aim of this study was to describe the natural course of disease in individuals with NAFLD who did not receive pharmacological therapy. Methods: A total of 27 individuals with NAFLD (male/female ratio: 10/17, mean age 49.7 years) were prospectively enrolled. Management after diagnosis consisted of establishment of an appropriate diet and exercise (walking and jogging) program, treatment of associated metabolic conditions such as diabetes and dyslipidemia, and discontinuation of potentially hepatotoxic drugs if the patient was taking these. Liver tests were performed at diagnosis and at 3‐month intervals during the follow‐up period. Mean follow‐up period was 43.3 months (range 36–49 months). Results: From baseline to the end of the follow‐up period, although there was no significant difference observed in terms of the mean body mass index, serum aminotransferase levels significantly improved (48.8 ± 29.9 U/L to 31.6 ± 16.0 U/L for aspartate aminotransferase [AST] and 66.3 ± 38.3 U/L to 39.6 ± 22.9 U/L for alanine aminotransferase [ALT]; P < 0.05). No significant differences in platelet counts, serum albumin level or prothrombin time were observed (P > 0.05). No patient developed signs of advanced liver disease during the follow‐up period. Conclusion: A treatment strategy comprising diet, exercise and management of associated metabolic conditions is associated with improvement in aminotransferases among patients with NAFLD. Further investigation is needed to examine the long‐term efficacy of this approach on liver histology and clinical outcomes.     

Anti-TNF agents in familial Mediterranean fever: report of three cases and review of the literature

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent fever, peritonitis/pleuritis, or arthritis attacks. Patients may have FMF-associated mutations of pyrin. The role of biologics such as anti-tumor necrosis factor (TNF) agents (infliximab, etanercept, adalimumab, golimumab) and anakinra, canakinumab, or rilonacept in the treatment of FMF needs to be clarified. Herein we present reports of three patients (all were positive for HLA B27) with typical spondylitis associated with FMF who were successfully managed with anti-TNF agents, along with a literature review. The patients were a 37-year-old man with concomitant Crohn’s disease and amyloidosis who was treated with infliximab (INF, 5 mg/kg for 3 years) and switched to adalimumab (ADA), and two female patients (a 24-year-old and a 31-year-old) with FMF who developed severe spondylitis and who were also treated with ADA. Anti-TNF agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF-associated amyloidosis and spondylitis.     

MEFV mutations in Tunisian patients suffering from familial Mediterranean fever

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Tunisian patients. PATIENTS AND METHODS: This study was performed in the Genetic Department of Tunis University Hospital. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed in the Human Genetic Laboratory of the "Faculté de Medecine de Tunis" for 8 mutations including the 5 most common known mutations M694V, V726A, M694l, M680l, and E148Q. The tests performed were polymerase chain reaction (PCR) restriction-digestion for M694V, V726A, M680l, R761H, E148Q; amplification refractory mutation system for A744S, M694l; and PCR-electrophoresis assay for l692del. RESULTS: Of the 139 unrelated patients investigated, 61 (44%) had 1 or 2 mutations. In 78 (56%) probands no mutation was identified: 28 patients were homozygous; 16 were compound-heterozygous; 2 had complex alleles; and 17 had only 1 identifiable mutation. Of the mutations, M680l, M694V, M694l, V726A, A744S, R761H, l692DEL, and E148Q accounted for 32, 27, 13, 5, 3, 1, 1, and 18%, respectively. CONCLUSION: The profile of the MEFV gene mutations in the Tunisian population is concordant with other Arab populations but with some differences. M680l is the most common mutation, while V726A, the commonest mutation among Arabs, is rare in our population.     

Egyptian tale from India: application of whole‐exome sequencing in diagnosis of atypical familial Mediterranean fever

Clinical diagnosis of autoinflammatory diseases requires a high degree of clinical suspicion and clinching molecular evidence to substantiate the diagnosis. This is more so in populations with low prevalence of these disorders. In this report, we describe the case of a young man from India with recurrent fever and persistent arthritis. The patient's forefathers were of Egyptian ancestry who practiced consanguinity. Molecular genetic analysis using whole‐exome sequencing suggested the presence of variants c.443A>T:p.E148V and c.442G>C:p.E148Q in the MEFV gene, earlier independently shown to be associated with familial Mediterranean fever (FMF) in a compound heterozygous state. The variants were further confirmed by capillary sequencing. This report also highlights the application of whole exome sequencing to delineate the allelic differences in the variants apart from serving as a quick genetic screening approach for autoinflammatory diseases. To the best of our knowledge, this is the first report of a compound heterozygosity for the two well‐characterized variants associated with atypical FMF in a patient.