Inflammation In Familial Mediterranean Fever Patients Research Articles

Can RDW be used as a screening test for subclinical inflammation in children with FMF? Is RDW related to MEFV gene mutations?

Subclinical inflammation, an insidious feature of familial Mediterranean fever (FMF), can lead to life-threatening amyloidosis. We aimed to investigate acute phase reactants and complete blood count parameters to identify a useful marker for subclinical inflammation in children with FMF. A secondary aim was to identify an association between subclinical inflammation and specific Mediterranean fever (MEFV) gene mutations. This study included 420 pediatric patients with FMF. Laboratory parameters of patients during the attack-free period and MEFV gene mutation analyses were recorded. Of the 420 patients, 88 (21%) had subclinical inflammation. Of those with subclinical inflammation, 48 (55%) had mutations in exon 10, 36 (41%) had M694V mutation, and 10 (11%) had M694V homozygous mutation. Red cell distribution width (RDW) value was higher in exon 10, M694V, and M694V homozygous mutations compared to other mutations. RDW was positively correlated with serum amyloid A (SAA) (r = 0.390, p = 0.0001). Analysis of a receiver-operating characteristic curve of RDW revealed that its optimal cut-off value for subclinical inflammation was 12.69%, its sensitivity was 64.10%, and its specificity was 50.90%. The area under the curve was 0.616 (p = 0.004, 95% confidence interval = 0.538-0.695). We suggest that RDW can be used as a screening test as a marker of subclinical inflammation. A high RDW value should alert the clinician about subclinical inflammation in FMF children's patients with M694V (heterozygous, homozygous, compound heterozygous) mutation. Key Points • Subclinical inflammation in FMF patients can lead to amyloidosis. • RDW can be a predictor of subclinical inflammation. • RDW can be used as a screening test for subclinical inflammation in FMF patients with M694V mutation.

The PRY/SPRY domain of pyrin/TRIM20 interacts with \u03b22-microglobulin to promote inflammasome formation

Pyrin/TRIM20 is expressed in the neutrophils and monocytes/macrophages and regulates caspase-1 activation and interleukin-1β maturation. Although the mutations in the PRY/SPRY domain of pyrin cause familial Mediterranean fever (FMF), the mechanism of how mutated pyrin provokes excessive inflammation in FMF patients is not well understood. The present study investigated the role of pyrin/TRIM20 in inflammation and the pathogenesis of FMF. β2-Microglobulin (β2MG) was identified as the novel pyrin ligand binding to the PRY/SPRY domain by yeast two-hybrid screenings and co-immunoprecipitation analysis. β2MG was co-localized with pyrin not only in the HEK293 cells overexpressing these proteins but also in the monosodium urate-stimulated human neutrophils in the speck-like structures. The pyrin–β2MG interaction triggered the binding of pyrin and proline–serine–threonine phosphatase interacting protein 1 (PSTPIP1) and then the subsequent recruitment of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). Caspase-1 p20 subunit, produced by pyrin inflammasome, also interacted with the pyrin PRY/SPRY domain and inhibited the pyrin–β2MG interaction. FMF-associated pyrin mutation M694V did not affect pyrin–β2MG interaction but weakened this inhibition. Our findings suggest that β2MG functions as the pyrin ligand inducing pyrin inflammasome formation and that the FMF-associated pyrin mutations weakened negative feedback of caspase-1 p20 subunit.

Differential Expression of micro RNAs and their Association with the Inflammatory Markers in Familial Mediterranean Fever Patients

Background: Familial Mediterranean fever (FMF) is an auto inflammatory genetic disease resulted from the mutation of pyrin, which contributes to the formation of inflamma some complex. Therefore, activation of cytokines is one of the hallmarks of FMF pathogenesis. This study aimed to investigate the role of miRNAs as regulatory biomarkers for inflammation in patients with FMF. Methods: 50 FMF patients and 25 healthy subjects were included in this study. Q RT-PCR was used to determine plasma expressions of miR-181a and miR-125a, while IFN-γ and IL-17 were estimated using ELISA technique. Results: Our results indicated that, the expression of miR-181a was significantly decreased (p = 0.006) while miR-125a expression was insignificantly reduced (p = 0.101) also IL-17 levels were significantly higher(p = 0.003) and plasma IFN-γ levels were insignificantly increased (p = 0.322) in FMF patients than control group. Correlation analysis revealed a positive correlation between miR-181a expression and lymphocyte percentages (p = 0.048),while a significant negative association was observed between miR-125a and C-reactive protein (CRP) (p = 0.005) in FMF patients. However, there were no associations between miR-125a and miR-181a with IFN-γ and IL-17 in FMF patients. Conclusion: miR-181a and miR-125a could be used as regulatory biomarkers for inflammation in FMF patients.

The Importance of MPV as a Marker of Subclinical Inflammation in FMF Patients and It’s Correlation with Disease Severity

Objective: Inflammation markers increase during Familial Mediterranean Fever (FMF) attacks and often return to normal within a few days. It is known that a subclinical inflammation continues in FMF patients in the inter-episode period, which increases the risk of developing amyloidosis. In recent years, several works have been conducted showing the relationship between platelet indices and inflammation, such as platelet count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), plateletrite (PCT). In this study, we aimed to investigate the relationship between platelet indices and disease severity in FMF patients without attacks. 
 Method: The records of all FMF patients followed by us were reviewed retrospectively. Patients with a hematological or oncological disease, patients with data deficiency for the study, and patients under 18 years of age were excluded. While the laboratory data were recorded, the condition of patients to be at least 3 months without attack was required. As the control group, the automation records of all healthcare professionals working in the internal medicine clinic of our hospital were examined. Our clinical staff, who did not have chronic diseases and regular drug use, were taken as a healthy control group. 173 patients and 20 control groups who met the conditions mentioned above were included in the study. Platelet indices were compared between patient and control groups. 
 Results: It was determined that the value of MPV, one of the platelet indices, in the patient group was statistically significantly higher than the value in the healthy control group (p = 0.029). MPV was also found to correlate with disease severity (p

Familial Mediterranean Fever and COVID-19: Friends or Foes?

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein – whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.

Fecal calprotectin in children with familial Mediterranean fever in the attack-free period.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of fever and serosal inflammation. The aim of this study was to evaluate fecal calprotectin (FC) in children with FMF during the non-attack period. A retrospective evaluation was made of the data of a total 66 patients diagnosed with FMF in an attack-free period and without amyloidosis or inflammatory bowel disease (IBD). FC level in the FMF patients was compared with that in the patients with IBD and healthy control subjects. The FMF patients consisted of 37 boys (56.1%) with a mean age of 10.1 ± 3.9years. Mean FC was 192.5μg/g (range, 19.5-800 μg/g) in the FMF group, 597.9 μg/g (range, 180-800 μg/g) in the IBD group, and 43.8 μg/g (range, 19.5-144 μg/g) in the control group. The FC level in the children with FMF was higher than in the control group (P < 0.001), and the FC level of the IBD patients was higher than both the FMF and the control groups (P = 0.020, P < 0.001, respectively). FC was higher in FMF patients compared with healthy children even in the absence of IBD/amyloidosis. Even though colonoscopy is the gold standard in identifying intestinal inflammation in FMF patients, FC, a non-invasive and inexpensive method, can be used for screening. The presence of subclinical intestinal inflammation was also quantitatively identified in children with FMF.

Chronic inflammation in adult familial Mediterranean fever patients: underlying causes and association with amyloidosis

Background: Chronic inflammation, as determined by persistently elevated acute-phase reactants in attack-free periods, can occasionally be observed in patients with familial Mediterranean fever (FMF) and is suggested to be a risk factor for the development of amyloidosis. We aimed to investigate the underlying causes of chronic inflammation in FMF patients and its association with amyloidosis in long-term follow-up.Method: Electronic medical records of FMF patients who had regular follow-up for ≥ 5 years in our cohort were utilized. As part of routine evaluation, detailed history, physical examination, and pertinent laboratory and radiographic investigations were performed in all patients to determine potential causes of elevated C-reactive protein (CRP) levels.Results: The study included 146 FMF patients who had no evidence of amyloidosis at baseline and had regular follow-up for ≥ 5 years. Thirty-seven patients (25.3%) were found to have chronic inflammation in the disease course. Twenty-five (67.5%) of them had either very frequent attacks or chronic manifestations of disease. In the entire study group, amyloidosis developed in five patients (3.42%) during the 5 year follow-up, four in the FMF with chronic inflammation group (10.8%), and only one of the 109 patients without chronic inflammation (odds ratio 13.09, 95% confidence interval 1.41–121.2).Conclusions: The results suggest that persistently high CRP levels during the attack-free periods may be a strong risk factor for the development of amyloidosis in patients with FMF. The vast majority of FMF patients with chronic inflammation had active FMF.

Correlation between pulmonary function tests and inflammatory markers in familial mediterranean fever patients

Background: Familial mediterranean fever (FMF) is a disease frequently seen in some races and characterized by recurrent attacks affecting various organs with chronic inflammation. As a result of chronic inflammation, microvascular changes may occur. In this study, we aimed to investigate the association between pulmonary function tests and inflammatory markers in FMF patients.Methods: Seventy-five FMF patients followed up at the Department of Internal Medicine who did not have any comorbidity affecting lung functions and 64 healthy subjects were enrolled. Both groups underwent CO (carbon monoxide) diffusion analysis and pulmonary function tests. Inflammatory markers of the groups were recorded as well and compared with CO diffusion and pulmonary function tests.Results: FVC%, FEV1, FEV1%, FEV1/FVC, PEF, FEF25-75% values of the patient group was significantly lower than those in the control group. When compared, DLCO%, DLCO/VA, DLCO/VA% were also significantly lower than controls. There was a significant correlation between pulmonary function tests and ESR, hsCRP and fibrinogen levels.Conclusions: Inflammation in FMF patients may lead to damage on pulmonary tissue that causes an impairment in pulmonary functions.

Evaluation of hematological parameters in children with FMF.

In this study, we aimed to investigate whether neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and mean platelet volume (MPV) might be helpful in the diagnosis of subclinical inflammation of familial Mediterranean fever (FMF). Clinical, laboratory, and genetic results of the patients who were followed up with the diagnosis of FMF were obtained retrospectively from the hospital files and recorded to standardized form. Age- and sex-matched healthy subjects were included as the control group. Eighty-three of the 143 patients (58.0%) were male and 60 (42.0%) were female. The mean age of our patients was 164.62 ± 51.20months and the mean age of the control group was 164.92 ± 51.10months. The mean diagnosis age of our patients was 98.10 ± 49.11months. The mean follow-up time of the patients was 66.03 ± 36.37months. 91.60% of our patients had abdominal pain, 78.32% fever, and 28.67% joint pain. The mean NLR of the patients was significantly higher than the mean levels at attack-free period and the control group. However, no statistically significant difference was found between the mean levels at attack-free period and the control group. MPV levels were statistically significantly high during acute attack when compared with the control group. However, they showed no statistically significant difference between acute attack and attack-free period. NLR is a useful marker to predict inflammation in FMF patients. However, our results did not support the idea that MPV might reflect acute attack and attack-free period.

Assessment of neutrophil to lymphocyte ratio and mean platelet volume in pediatric familial Mediterranean fever patients.

Background:Blood neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) both have been used as a simple marker of inflammation in many disorders. Here, we aimed to investigate the relationship between NLR, MPV, and familial Mediterranean fever (FMF).Materials and Methods:In this retrospective study, the files of FMF patients in pediatric rheumatology outpatient clinic were reviewed. There were 160 participants (68.4%) in the FMF patient group and 74 participants (31.6%) in the control group. Ninety of patients were in attack-free period, and 70 were in attack period.Results:The highest values of NLR were found in the patients at attack period. Patients in attack-free period and the participants in control group had similar levels of NLR (1.71 ± 0.83 and 1.91 ± 1.86 respectively) (P = 0.457), and they had lower ratios than the patients did at attack period (4.10 ± 3.11) (P < 0.001 for both). There was no significant difference between MPV values of attack patients (8.35 ± 4.91) and attack-free patients (8.43 ± 1.15) (P = 0.074). MPV values of attack patients and attack-free patients were significantly higher than control group (7.99 ± 0.81) (P < 0.001 for both).Conclusion:NLR ratio may indicate FMF attack period. Since there was no significant difference between attack-free patients and control groups, NLR ratio cannot be used as a subclinical inflammation marker. However, NLR could be a useful predictor of inflammation in FMF patients. On the other hand, since our attack and attack-free patients have similar MPV values and both had greater MPV values than control group, we suggest that MPV may be used to show subclinical inflammation.

The Relationship Among the Level of Serum Amyloid A, High-Density Lipoprotein and Microalbuminuria in Patients With Familial Mediterranean Fever.

Serum amyloid A (SAA), which is produced in the liver, acts as an apoprotein of high-density lipoprotein (HDL) accumulation in extracellular matrix of tissues and organs. SAA elevations play a significant role in the development of amyloidosis. Microalbuminuria (MAU) is the early period of amyloidosis in patients with familial Mediterranean fever (FMF). We assessed the association between SAA as an important factor for the development of amyloidosis in patients with FMF and cytokines, HDL, and MAU. A total of 40 FMF patients diagnosed with Tel-Hashomer criteria and making regular follow-up visits at the tertiary referral center from 2012 to 2013 were included in this study, besides 40 age- and sex-matched individuals as controls. Compared with controls, FMF patients had higher SAA (25.20 ± 45.78 vs. 1.68 ± 0.63 ng/ml; P = 0.002). Also, FMF patients had higher MAU than controls (23.20 ± 39.86 vs. 9.40 ± 5.32 mg/day; P = 0.036). HDL was significantly lower in the patient group than in controls (39.35 ± 10.45 vs. 47.82 ± 15.31 mg/dl; P = 0.023). Interleukin-1 beta (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) levels were higher in the FMF group than in controls (P < 0.0001, P = 0.009, P = 0.003, respectively). Our results suggest that IL-1, IL-6, TNF-α, SAA, and HDL may serve as markers of subclinical inflammation in FMF patients. Due to increased plasma HDL levels, antiinflammatory and antioxidant effects may elevate in FMF patients.

Evaluation of IL-1β, IL-1ra, and IL-10 levels and outcome of periodontal therapy in chronic periodontitis with familial Mediterranean fever.

This study aimed to examine the IL-1β, IL-1ra, and IL-10 cytokine levels in gingival crevicular fluid (GCF) and serum of familial Mediterranean fever (FMF) and chronic periodontitis (CP) patients, and their response to nonsurgical periodontal therapy. A total of 50 patients, 15 FMF patients with generalized chronic periodontitis (FMF-CP), 15 systemically healthy patients with generalized chronic periodontitis (CP), ten systemically and periodontal healthy controls (HC), and ten periodontally healthy FMF patients (FMF-HC) were enrolled in the study. The cytokine levels in GCF and serum were determined by ELISA. Probing depth, clinical attachment level, and gingival and plaque indices in each participant were also measured. The GCF and clinical parameters at baseline and 6weeks were recorded. The study indicated statistically significant healing of the clinical parameters in both FMF-CP and CP groups after periodontal treatment. GCF IL-1β levels at 6weeks in FMF-CP group were significantly lower than the CP group (p<0.05), and GCF IL-1ra levels were significantly decreased at 6week in the FMF-CP group (p<0.05). GCF IL-10 levels were significantly higher in the FMF-CP group than in the other groups at baseline and 6weeks (p<0.05). There were no significant differences in serum-IL-1β, IL-1ra, and IL-10 levels either FMF-CP or CP groups at baseline or 6weeks (p>0.05). The results of our study suggested that there was a positive correlation between gingival inflammation and serum cytokine levels in FMF patients and also colchicine treatment showed protective effects on GCF cytokine levels in FMF-CP group. Following treatment, GCF IL-1β and GCF IL-1ra levels were decreased in FMF-CP group. GCF IL-10 levels were increased in FMF-CP group compared to other groups. Also, the serum cytokine levels associated with periodontal inflammation in FMF patients.

The relationship between red cell distribution width and homozygous M694V mutation in familial Mediterranean fever patients.

BACKGROUND AND OBJECTIVEFamilial Mediterranean fever (FMF) is characterized by recurrent and self-limiting attacks with peritonitis, pleuritis, arthritis, and erysipelas-like erythema. We aimed to investigate the red cell distribution width (RDW) level as an inflammatory marker in FMF patients compared with normal subjects.DESIGN AND SETTINGSA retrospective study of FMF patients at the Department of Gastroenterology, Cumhuriyet University, between November 2011-February 2013.METHODSA total of 249 FMF patients and 131 age- and sex-matched control participants were included in the currrent study. RDW levels were also analyzed by standard methods. Each patient was given 2 mL of blood sample to obtain genomic DNA.RESULTSStatistically significant differences were observed in RDW values between the FMF patients and the control group. Also, RDW levels were higher in the FMF patients with the homozygous M94V mutation compared with those with other mutations. The receiver-operating characteristic curve analysis suggested that the optimum RDW cutoff point for the FMF patients was 13.95, with a sensitivity, specificity, negative predictive value, and positive predictive value of 70%, 64%, 68%, and 66%, respectively (area under the curve: 0.711, 95% confidence interval 0.627–0.795, P<.0001).CONCLUSIONWe suggest that RDW may show subclinical inflammation in FMF patients. RDW may be a promising marker in predicting the homozygous M694V mutation in FMF patients.

Mean Platelet Volume and Splenomegaly as Useful Markers of Subclinical Activity in Egyptian Children with Familial Mediterranean Fever: A Cross-Sectional Study.

Objective. To study whether mean platelet volume (MPV) and splenomegaly could be used as subclinical inflammatory markers in children with familial Mediterranean fever (FMF) at the attack-free period. Patients and Methods. The study included ninety-seven children with FMF. MPV was carried out within 4 hours of blood sampling according to standard laboratory practice. Splenomegaly was determined by abdominal ultrasound (USG). Results. High MPV was detected in 84.45% of our studied patients and was significantly higher in FMF patients with splenomegaly than in patients without splenomegaly. There was a statistically significant correlation between MPV and splenic span (P = 0.045). Conclusion. Elevated MPV and its significant correlation with splenic span in FMF children during the attack-free periods support the use of MPV and splenomegaly as useful markers of the subclinical inflammation in FMF patients at the attack-free period.

THU0458 MPV and RDW: Subclinical Inflammation Markers in Attack-Free Familial Mediterranean Fever (FMF) Patients

ObjectivesMean platelet volume (MPV) and red cell distribution width (RDW), as a marker of inflammation, have an important role in several chronic inflammatory disorders like familial Mediterranean fever (FMF). Many...

Trace element levels in patients with familial mediterranean Fever.

Although the genetic etiology of familial Mediterranean fever (FMF) is known, limited information is available regarding the regulation of inflammation during attack-free periods. The aim of this study was to determine the alterations in serum copper (Cu), zinc (Zn) and selenium (Se) levels that may be associated with inflammation during attack-free periods in FMF patients. This study included 33 patients with FMF and 30 healthy volunteers. Erythrocyte sedimentation rate (ESR), the serum C-reactive protein (CRP) level and serum levels of Cu, Zn and Se in FMF patients and healthy volunteers were assessed by the atomic absorption spectrophotometry method. ESR and serum CRP levels and serum Cu and Zn levels were similar between patients with FMF during an attack-free period and healthy controls (p>0.05). Serum Se levels in the patient group were significantly higher than in the control group (p<0.05). Our study shows that levels of trace elements in serum are variable in patients with FMF during attack-free periods. Serum Se concentrations may at least in part contribute to the subclinical inflammation in FMF patients during attack-free periods. However, further studies are necessary to confirm this result.

Profile of cytokines, growth factors and chemokines during attacks of FMF

Attacks of Familial Mediterranean fever (FMF) represent one of the most devastating states of inflammation. FMF is an autoinflammatory disease caused by mutations in the gene coding for pyrin. We aimed to assess the characteristics of inflammation in FMF patients during an acute attack by evaluating some growth factors, chemokines and cytokines. Six patients (median 11 years (7–16)) were sampled 12–36 hour after the onset of a typical FMF attack. All had elevated acute phase reactants. All six had homozygote mutations in the MEFV gene. Various cytokines, chemokines, growth factors and CD40 ligand were measured by a commercially available multiplex beads immunoassay based on Luminex platform. IL1Ra (median 1047 pg/ml), TNF alpha (median 3.05 pg/ml) and IL6 (median 19.14 pg/ml) levels were elevated whereas IL2, IL10, IL12, IL17 and IL13 were not detectable in any of the samples. EGF, VEGF and HGF were markedly elevated as well. Among the chemokines, MIP1b, CCL11, CXCL11 and CXCL5 were all detectable at a varying range. CD40 L was also markedly elevated. IL1Ra is induced by inflammatory stimuli with IL1 and reflects the IL1-dependent inflammatory response. Chemokines were elevated reflecting the neutrophil inflammation and recruiting in this disease. The growth factors were thought to be elevated as an inflammatory response phenomena. The CD40L induction may be serving as a link between the innate immune response and adaptive on during the attacks of FMF. The protein fingerptint of FMF will shed light on the pathogenesis of the disease and help us guide disease activity and severity.

Association between reduced levels of MEFV messenger RNA in peripheral blood leukocytes and acute inflammation

Familial Mediterranean fever (FMF) is associated with more than 70 missense mutations in the MEFV gene. The purpose of this study was to investigate the relative expression of messenger RNA (mRNA) for the MEFV gene in peripheral blood leukocytes (PBLs) obtained from patients with FMF during attacks of acute abdominal inflammation as well as during asymptomatic periods. We studied 16 patients with FMF during an attack of acute peritonitis and 17 otherwise healthy individuals who were undergoing surgery because of acute appendicitis. Blood samples were collected from both groups of patients during both acute inflammatory and asymptomatic periods. Relative levels of MEFV mRNA in PBLs were detected with real-time reverse transcriptase-polymerase chain reaction using LightCycler, with 2 sets of primers for the MEFV gene (exons 7-10 and exons 2-3) and with primers for CIAS1 and PSTPIP1 genes. Expression levels were compared with beta(2)-microglobulin as an internal control. MEFV expression was reduced in FMF patients during asymptomatic periods as compared with the non-FMF controls (P < 0.001). We observed a further decrease in MEFV expression in FMF patients during periods of inflammation (P = 0.01). Reduced levels of MEFV mRNA were also noted during the preoperative period as compared with asymptomatic periods in control patients with acute appendicitis (P = 0.01). CIAS1 expression in PBLs from patients with FMF was also found to be lower than that in the control patients. However, CIAS1 expression did not change with acute inflammation. This study confirmed that reduced expression of the MEFV gene is associated with inflammation and that it may be one of the pathogenic mechanisms of the attacks of inflammation in FMF patients, along with disease-associated variations in pyrin.