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benign paroxysmal peritonitis [keywords]
- Neutrophil extracellular traps regulate IL-1β-mediated inflammation in familial Mediterranean fever. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Sep 26.
Inflammatory attacks of familial Mediterranean fever (FMF) are characterised by circulation and influx of high number of polymorphonuclear neutrophils (PMN) in the affected sites and profound therapeutic effect of IL-1β inhibitors. We investigated the role of neutrophil extracellular traps (NET) in the pathogenesis of FMF, and their involvement in IL-1β production.Blood samples were obtained from six FMF patients during remissions and from three patients during attacks. NET formation and NET components were studied by fluorescence techniques, immunobloting and MPO-DNA complex ELISA.PMNs from patients released NETs decorated with IL-1β during disease attacks. On the other hand, PMNs from patients during remission were resistant to inflammatory stimuli that induce NET release in PMNs from control subjects. Lower basal autophagy levels were identified in PMNs during remission, while induction of autophagy facilitated NET release, suggesting that autophagy is involved in the regulation of NET release. During the resolution of attacks, inhibition of NET formation by negative feedback mechanism was also observed. The anti-inflammatory agents, colchicine and DNAse I, inhibited IL-1β production in PMNs and IL-1β activity in NETs, respectively.We suggest two additive events for triggering the FMF attack; the production of IL-1β by PMNs and its release through NETs. At the same time NETs, homeostatically, downregulate further NETosis, facilitating the resolution of attack. Compensatorly, lower basal autophagy of PMNs may protect from crises by attenuating the release of pro-inflammatory NETs.
- Genotype-phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations. [JOURNAL ARTICLE]
- Arthritis Res Ther 2014 Sep 27; 16(5):439.
IntroductionFamilial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent self-limiting fever and serositis that mainly affects Mediterranean populations. Many patients with FMF have been reported in Japan due to increasing recognition of this condition and the availability of genetic analysis for the gene responsible, MEFV. The present study was performed to elucidate the clinical characteristics of Japanese FMF patients and to examine the precise genotype-phenotype correlation in a large cohort of Japanese FMF patients.MethodsWe analyzed the MEFV genotypes and clinical manifestations in 116 patients clinically diagnosed as having FMF and with at least one mutation.ResultsThe most frequent mutation in Japanese patients was E148Q (40.2%), followed by M694I (21.0%), L110P (18.8%), P369S (5.4%), and R408Q (5.4%). In contrast, common mutations seen in Mediterranean patients, such as M694V, V726A, and M680I, were not detected in this population. The clinical features with M694I were associated with more severe clinical course compared to those seen with E148Q. P369S/R408Q showed variable phenotypes with regard to both clinical manifestations and severity. Patients with M694I showed a very favorable response to colchicine therapy, while those with P369S and R408Q did not.ConclusionsClinical features and efficacy of treatment in Japanese FMF patients vary widely according to the specific MEFV gene mutation, and therefore genetic analysis should be performed for diagnosis in cases of Japanese FMF.
- Familial Mediterranean fever in which Crohn's disease was suspected: a case report. [JOURNAL ARTICLE]
- BMC Res Notes 2014 Sep 27; 7(1):678.
Familial Mediterranean fever is a hereditary autoinflammatory disease, mainly characterized by periodic fever and serositis. The level of awareness about familial Mediterranean fever is far from sufficient, and it is assumed that there may be many patients with this disease who are under observation without an accurate diagnosis.A 30-year-old Japanese man presented to us with a few years' history of recurrent episodes of fever, abdominal pain and diarrhea. He often visited a hospital when the attacks occurred; however, acute enteritis was diagnosed each time, and the symptoms resolved spontaneously within a few days. When he noticed a shortening of the interval between the attacks, he visited the hospital again. Upper endoscopy and colonoscopy performed at this hospital revealed no significant abnormal findings. He was then referred to our hospital under the suspicion of a small intestinal disease. Abdominal computed tomography revealed wall thickening and increased density of the mesenteric adipose tissue in the jejunum, which led us to suspect Crohn's disease. Oral double-balloon enteroscopy was performed; because this revealed only mild mucosal edema in the jejunum, Crohn's disease was considered to be highly improbable. Based on the patient's clinical course, we suspected familial Mediterranean fever. As the Livneh criteria for familial Mediterranean fever were satisfied, the patient was started on oral colchicine for the purpose of diagnostic treatment. A definitive diagnosis of familial Mediterranean fever was then made based on the detection of a mutation of the Mediterranean fever gene. A marked reduction in the frequency of attacks was observed in response to colchicine treatment.Although Crohn's disease may be considered first in the differential diagnosis of young patients presenting with periodic fever, abdominal pain and diarrhea, the possibility of familial Mediterranean fever should also be borne in mind.
- Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE patients. [JOURNAL ARTICLE]
- Lupus 2014 Sep 24.
MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.
- Dysregulated mature IL-1β production in familial Mediterranean fever. [JOURNAL ARTICLE]
- Rheumatology (Oxford) 2014 Sep 19.
The aim of this study was to analyse the role of circulating cleaved IL-1β in patients with FMF.We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1β was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1β antibody.Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1β (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1β were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1β (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase.The cleaved form of IL-1β is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1β-mediated inflammatory disorders.
- Familial Mediterranean fever phenotype and MEFV variations. [JOURNAL ARTICLE]
- Clin Exp Rheumatol 2014 Sep 10.
- MEFV gene mutations in Egyptian children with Henoch-Schonlein purpura. [Journal Article]
- Pediatr Rheumatol Online J 2014.:41.
Due to an increased frequency of vasculitis in FMF patients, many investigators have studied MEFV mutations in patients with HSP. The aim of the study is to investigate the frequency and clinical significance of MEFV mutations in Egyptian children with Henoch-Schonlein purpura (HSP). Investigating MEFV mutations in controls may help in estimating the prevalence of MEFV mutation carrier rate in Egyptian children.The study enrolled 90 individuals, sixty children with Henoch-Schonlein purpura (HSP), together with 30 sex-and age-matched apparently healthy controls. The entire study group was screened for 12 common MEFV mutations using a reverse hybridization assay of biotinylated PCR products.Patients with HSP had a significantly higher frequency of MEFV mutations (61.7%), when compared to the apparently healthy control population (36.7%). V726A was the most frequent mutation with an allelic frequency of 10.8%. Ninety- one percent of patients with MEFV mutations were heterozygous for one mutation, while 8.1% had a compound heterozygous MEFV gene mutations. The mutation V726A, followed by E148Q, were the leading mutations, present in 16.6% and in 13.3% of controls.MEFV mutations may be related to HSP susceptibility in children. The mutations were not associated with any clinical and laboratory manifestations. Screening for MEFV mutations in larger number of HSP children may be beneficial to evaluate any possible relationship between certain types of MEFV mutations and HSP, and compare the HSP MEFV mutations to the types of MEFV mutations associated with FMF.
- Exertional leg pain in Familial Mediterranean Fever: A manifestation of an underlying enthesopathy and a marker of a more severe disease. [JOURNAL ARTICLE]
- Arthritis Rheumatol 2014 Sep 15.
Background and aim: Exertional leg pain is a characteristic musculoskeletal manifestation of FMF. We aimed to define the frequency and characteristics of exertional leg pain in a large cohort of FMF patients and to evaluate for additional signs and symptoms of spondyloarthropathy in this patient population. Methods: FMF patients were allocated into study or control groups based on the presence or absence of exertional leg pain. Randomly selected patients underwent an ankle MRI as well as plain films of the sacroiliac joints. Results: The prevalence of exertional leg pain among the 170 FMF patients included in the study was 58.5%. Patients with exertional leg pain suffered from an excess of joint (74.7% vs. 40.8%, p<0.0001), febrile (35.3% vs. 15.4%, p=0.004) and pleuritic (48.4% vs. 29.5%, p=0.013) attacks as well as more frequent attacks per year. Inflammatory markers were significantly higher among the study group (high ESR: 44.4% vs. 21.1%, p=0.016, high CRP: 48.4% vs. 31.8%, p=0.013) and M694V homozygosity was more prevalent (62.6% vs. 30.9%, p<0.0001). Signs compatible with enthesopathy on MRI were significantly more common among the study group (73.5% vs. 33.3% p=0.046). Definite SpA was diagnosed in 42.2% of the patients in the study group vs. none of the controls (p=0.07), OR 1.7 (1.2-2.3). Conclusion: Exertional leg pain is a common manifestation of FMF and a marker of a more severe disease phenotype. Additionally, exertional leg pain is frequently associated with sacroiliitis and an underlying ankle enthesopathy and thus should be considered a new feature of spondyloarthropathy. © 2014 American College of Rheumatology.
- Anti-IL-1 treatment in familial Mediterranean fever and related amyloidosis. [JOURNAL ARTICLE]
- Clin Rheumatol 2014 Sep 13.
Colchicine is the standard treatment in familial Mediterranean fever (FMF) patients. New treatment strategies are needed in FMF patients who were unresponsive to colchicine therapy or who had developed amyloidosis. The aim of this study was to present clinical-laboratory features and treatment responses of pediatric FMF patients that were treated with anti-IL-1 therapies. Files of patients who had been followed in our department with diagnosis of FMF were retrospectively evaluated. Patients that have been receiving anti-IL-1 therapies (anakinra or canakinumab) were included to the study. All patients were interpreted with respect to the demographic data, clinical and laboratory features of the disease, genetic analysis of MEFV mutations and treatment responses. Among 330 currently registered FMF patients, 13 patients were included to the study. Seven of them received anti-IL-1 therapy due to colchicine resistance and 6 due to FMF-related amyloidosis (1 of them with nephrotic syndrome, 2 with chronic kidney disease, 3 with renal transplantation). In all treated patients, attacks completely disappeared or decreased in frequency; partial remission occured in nephrotic syndrome patient; and their life quality improved. Anti-IL-1 therapies can be successfully used in colchicine-resistant FMF patients and patients with amyloidosis during childhood and adolescent period without major side effects.
- TLR2 and TLR4 gene expression levels and associated factors during acute attack and attack-free periods in familial Mediterranean fever. [JOURNAL ARTICLE]
- Clin Rheumatol 2014 Sep 12.
The purpose of this clinical study was to determine if the expression of the TLR2 and/or TLR4 genes is involved in triggering the auto-inflammatory attacks in patients with familial Mediterranean fever (FMF). Thirty patients with FMF and 20 healthy control subjects were recruited. Comparisons were made in TLR2 and TLR4 gene expression levels during FMF attack episodes and attack-free periods, as well as with baseline levels in healthy control subjects. There was no significant difference in TLR2 and TLR4 gene expression between the attacks and attack-free periods in the entire group of FMF patients. However, among female patients, expression level of TLR4 gene was significantly higher during the attack than in the attack-free period (TLR2 Log 2.04 ± 0.14 vs. 2.52 ± 0.10, respectively, P = 0.02). There was not a significant difference between FMF patients and healthy subjects. The patients who had higher levels of TLR2 expression during the acute attack experienced their first attacks at an earlier age (r = -0.571; P = 0.001). The frequency of attacks, acute-phase response, MEFV mutations, and colchicine response were not associated with TLR2 and TLR4 levels. We conclude that changes in the expression of TLR2 and TLR4 genes do not appear to be involved in triggering FMF attacks. A higher level of TLR2 expression during acute attack may be related to the early onset of the disease. Further studies using specific cell populations such as neutrophils, monocytes, and dendritic cells may be useful to explore any changes in the sensitivity of toll-like receptors to their agonists, such as lipopolysaccharides, in the onset of attacks.