Background:
Amyloid A (AA) amyloidosis, previously known as secondary or reactive amyloidosis, is a long-recognized severe complication of some chronic inflammatory diseases. The pathogenesis and ...risk factors for amyloidosis in Familial Mediterranean Fever (FMF) remain partially understood (1). The development of AA amyloidosis is dependent on ethnicity and country of residence (2). In the pre-colchicine era, renal AA-amyloidosis was largely reported patients of Turkish (67%) and Sephardic Jewish ancestry (26.5%) (2,3). Currently it’s well known that the MEFV M694V variant associated with high risk of amyloidosis however, mutations on exon 2, specifically E148Q variant remained controversial.
Objectives:
To evaluate the E148Q mutation variant and concomitant AA Amyloidosis secondary to FMF after adjusted clinical-demographic characteristics.
Methods:
Patients were recruited from the renal unit at Epigenetic Health Center outpatient clinic in Turkey between September 2003 and February 2020. Patients who had biopsy confirmed FMF related AA amyloidosis were included the study. Tel-Hashomer criteria were applied in the diagnosis of FMF. The clinical characteristics of FMF patients and medication history were recorded by the physician at the time of registry entry. All patients had detailed baseline assessment of clinical features, renal functions, genetic testing, histopathological diagnosis of amyloidosis, and treatment received. We performed multiple comparisons according to the age of diagnosis, demographic features, disease phenotype, allele frequency, type of mutation and mortality. Statistical analysis was performed with Statistical Package of Social Science (SPSS) for Windows, version 15.0 (SPSS Inc, Chicago, IL).
Results:
Our registry consists of 195 patients with a diagnosis of AA amyloidosis. Complete information on 169 patients (lost to follow up, n=26) were included. The median age was 36 (19-49) years; male/female ratio was 1.6 (104/65). The median follow-up duration was 15.0 years (4-17 years). There were 101 patients diagnosed with FMF <18 years of age and 68 patients diagnosed ≥18 years of age. All participants developed renal amyloidosis before the age of 32 years. Family history of FMF was documented in 56 patients (33.1%) and family history of amyloidosis was present in 41 patients (24.3%). The three most common clinical symptoms were fever (84,6%), abdominal pain (71.6%) and arthritis (66.9%). During the follow-up, 5 patients started dialysis treatment and 9 patients had kidney transplantation. The most common allele frequency across patients was M694V (60.6%), E148Q (21.4%) and M680I (10.3%). The most frequent mutations were M694V/M694V (63.3%), M694V/E148Q (20.8%) and E148Q/E148Q (15.8%). During the follow up period, 15 patients (10 male, 5 female) died. In those that died, the mutations in 14 had M694V/M694Vand one demonstrated E148Q/E148Q.
Conclusion:
Patients with FMF related AA amyloidosis have an increased risk for mortality. This study confirmed the association between M694V and FMF-associated AA amyloidosis, which has been reported in many studies. Close clinical follow-up and further evaluation of patients with the E148Q mutation is warranted specifically if residing in FMF endemic areas. The possible relationship between E148Q and AA amyloidosis need to be confirmed in other cohorts.
References:
1Erer B, Demirkaya E, Ozen S, Kallinich T. What is the best acute phase reactant for familial Mediterranean fever follow-up and its role in the prediction of complications? A systematic review. Rheumatology international. 2016;36(4):483-7.
2Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis and rheumatism. 2007;56(5):1706-12.
3Pras M, Bronshpigel N, Zemer D, Gafni J. Variable incidence of amyloidosis in familial Mediterranean fever among different ethnic groups. Johns Hopkins Med J. 1982;150(1):22-6.
Disclosure of Interests:
None declared
Background:
Few studies have focused on Familial Mediterranean Fever (FMF)-related AA amyloidosis and cardiovascular disease event risk. Systemic inflammation stimulates the development and ...progression of atherosclerosis which is accelerated by vascular endothelial inflammation and enhanced oxidative stress. Excessive reactive oxygen species (ROS) generation has been reported in FMF, which correlated with attack severity. ROS may also be involved in amyloid formation, and in the pathogenesis of progressive renal injury.
Objectives:
In this non-randomized, 24 weeks open label interventional study, we aimed to evaluate the effect of a combination of natural products on parameters related to inflammation, endothelial dysfunction and oxidative stress in a cohort of FMF patients with AA amyloidosis.
Methods:
Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL) were given to patients with FMF related AA amyloidosis. We included patients with biopsy proven AA amyloidosis, older than 18 years who have normal estimated glomerular filtration rate (eGFR) and proteinuria >3500mg/day. Flow-mediated dilatation (FMD), asymmetric dimethylarginine (ADMA), hs-CRP, serum PTX3, Carotis intima media thickness (CIMT), malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels were studied in baseline and after 24 weeks.
Results:
67 FMF-related amyloidosis 52 male (77.6%); median recruitment age 36 years (range 21-66) were enrolled. M694V mutation was the most common mutation found (74%), with 50.7% of the patients in homozygosity. All patients were treated with colchicine, and most of them (83.6%) has been on colchicine treatment at the time of enrollment. Serum ADMA, MDA, PTX3, hsCRP, cholesterol, and proteinuria were significantly decreased compared to baseline, while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies (Table 1). The change of the inflammatory markers PTX3, and hsCRP were negatively correlated with the change in FMD and positively correlated with the change of proteinuria, ADMA, MDA, cholesterol and CIMT.
Conclusion:
24 weeks of AAL, AIC and AOL combined supplementation was significantly associated with reduction in serum inflammatory markers (PTX3 and hsCRP), improved endothelial functions (FMD, ADMA), and oxidative state (MDA). Our findings highlight the link among the three pathogenetic mechanisms including inflammation, endothelial function and oxidative status in progression of atherosclerosis and renal injury in patients with FMF related AA amyloidosis. Efficient control of these three mechanisms can have long term benefits from the cardiovascular and renal perspective of the patients with AA amyloidosis.
References:
1Romano M et al. Sci Rep, 2020
2Yilmaz M et al. Sci Rep, 2020
Table 1.
Comparison of clinical and laboratory characteristics at the baseline and after 24 weeks of AAL, AIC and AOL supplementation
Baseline
Mean (SD)
24th week
Mean (SD)
Delta
Mean (SD)
p
Total Cholesterol (mg/dl)
221.2 (60.3)
155.8 (35.4**)
-65.3 (55.5)
<0.001
eGFR (ml/min/ 1.73 m2)
110.2 (12.8)
104.1 (11.2**)
-6.1 (11.9)
<0.001
Malondialdehyde (MDA) (nmol/ml)
4.2 (1.8)
1.8 (0.5**)
-2.2 (1.8)
<0.001
CuZn-SOD (U/ml)
431.5 (154.7)
538.1 (146.4**)
159.7 (211.8)
<0.001
GSH-Px (U/ml)
47.8 (13.2)
74.1 (20.3**)
26.3 (21.1)
<0.001
ADMA (µmol/l)
4.5 (2.6)
1.3 (0.6**)
-3.2 (2.5)
<0.001
FMD (%)
5.0 (0.7)
6.4 (0.8**)
1.3 (0.9)
<0.001
CIMT (mm)
0.9 (0.2)
0.7 (0.1)
-0.2 (0.2)
<0.001
Proteinuria (mg/24h)
6855.3 (3116.9)
4079.9 (2359.6)
-2775.3 (2874.5)
<0.001
hs-CRP (mg/l)
25.5 (4.4-48.0)
3.0 (1.0-9.1)*
-20.8 (11.2)
<0.001
PTX3 (ng/ml)
13.4 (2.3-67.0)
2.3 (0.4-14.5)*
-17.5(17.5)
<0.001
Disclosure of Interests:
None declared
Neutrophil gelatinase associated lipocalin (NGAL) have been used with great success in acute renal failure and in some cases in chronic nephrotoxicity. In this work, we aimed to investigate urinary ...NGAL as an early marker of chronic renal failure (CRF).
We investigated urinary NGAL of 29 children treated with ifosfamide chemotherapy and compared them with those of 12 healthy children. Urinary β2 microglobulin, serum cystatin C, and creatinine clearance analyses were also studied.
The median age was 11 years (4-21) and median remission time was 4.3 years (1.8-14.4). The cumulative dose of ifosfamide was 36 g. Glomerular filtration rate was decreased in 41.4% and urine β2 microglobulin levels and serum cystatin C levels were elevated in 31% of the patients. As the remission time increased, serum creatinine and cystatin C levels were also increased. The sensitivity for β2 microglobulin and cystatin C in demonstrating CRF was 35.2% and 23% and specificity was 33.2% and 50% respectively. The 24-hour urine NGAL cut-off level for demonstrating CRF was found to be 1.065 ng/mL/24 hours. The sensitivity and specificity for this cut-off value were 83% and 77%, respectively.
NGAL levels were significantly higher in the study group as compared with the control group. Although ifosfamide treatment was suggested to be safe with no complication of renal failure under a dose of 80 g/m2, chronic renal failure and deficits in glomerular and tubular function could be seen when the remission time increased. Elevated NGAL levels may be a good option in determining CRF.
Secondary amyloidosis is the most important complication of FMF and endothelial function is more severely impaired. Elevated asymmetric dimethyl arginine (ADMA) may mediate the excess cardiovascular ...disease (CVD) risk of this group. We aimed to compare endothelial function characteristics, including ADMA, in patients with FMF-related amyloidosis and primary glomerulopathies and to define risk factors for a CVD event.
We undertook a cross-sectional study with prospective follow-up including consecutive patients with FMF-related amyloidosis (n = 98) or other non-diabetic glomerulopathies (n = 102). All patients had nephrotic-range proteinuria and normal glomerular filtration rate. Flow-mediated dilatation (FMD) was assessed and ADMA levels, CRP and pentraxin 3 (PTX3) were determined. Patients were followed for cardiovascular events.
Amyloidosis patients secondary to FMF showed higher levels of ADMA, CRP and PTX3 and lower FMD as compared with patients with other glomerulopathies. Cardiovascular events (n = 54) were registered during 3 years of follow-up. Increased ADMA levels and lower FMD were observed in patients with cardiovascular risk in both groups, but especially in individuals with amyloidosis.
Patients with FMF-related amyloidosis have increased CVD event risk, probably related to the high ADMA levels, elevated inflammatory markers and decreased FMD measures observed in these patients.
To analyse the demographics, main clinical and laboratory features and subtype distribution of juvenile idiopathic arthritis (JIA) in an eastern Mediterranean country, based on a multicentre ...registry.
Between March 2008 and February 2009 with this cross-sectional study, consecutive patients seen with JIA in selected centres were registered through a web-based registry. All patients were classified according to the International League of Associations for Rheumatology (ILAR) criteria.
There were 634 patients with a mean age of 11.84 ± 4.66 years and the female/male ratio was 1.2. The distributions of JIA patients according to onset of disease were as follows: systemic 92 (14.5%), oligoarticular extended 26 (4.1%), oligoarticular persistent 234 (36.9%), rheumatoid factor (RF) positive polyarthritis 20 (3.2%), RF negative polyarthritis 129 (20.3%), enthesitis-related 120 (18.9%), psoriatic 13(2.1%). The frequency of uveitis was 15.7% among all of the oligoarthritis patients. Anti-nuclear antibody (ANA) was positive mainly among the oligoarticular onset patients. Twenty-one patients also had Familial Mediterranean fever (FMF). Among systemic JIA patients, the frequency of macrophage activation syndrome (MAS) was 15.2% (n=14). At the end of the mean follow-up of 7.6 ± 4.4 years, 305 (48.1%) patients were defined to have inactive disease on medication, and 106 (16.7%) were completely free of any disease symptoms without medication.
Enthesitis related arthritis had a high frequency whereas psoriatic arthritis was very rare compared to other series. We suggest that there are certain differences in the characteristics of JIA in our eastern Mediterranean population. Thus, genetic studies need to be assessed in these populations separately and findings of genome wide association studies need to be confirmed in different populations.
BackgroundFamilial Mediterranean Fever (FMF) is the most common periodic fever syndrome, characterized by recurrent fever and serositis attacks. It has been shown that there might be an ongoing ...subclinical inflammation between attacks. Adrenomedullin (ADM) is synthesized in endothelium, and has been shown to have high levels in patients with inflammation such as FMF. Colchicine is the treatment of choice and given once or twice daily depending on expert opinion.ObjectivesIn this study, it was aimed to investigate ADM as a marker for inflammation in pediatric patients with FMF who are using colchicine in different dosage schemaMethodsPediatric patients with FMF diagnosed clinically and genetically confirmed were included in the study. The colchicine was started in one or two doses randomly. The clinical and laboratory parameters were assessed on six clinical visits made every two months. After the third visit the dosing schema was changed to twice or once depending on the schema at the beginning.ResultsA total of 37 patients (female/male ratio: 0.94) were included in the study. Mean age of patients, age at disease onset, and age at diagnosis were 7.78±2.00, 5.05±3.04, and 7.51±2.66 years, respectively. Twenty patients received colchicine in once daily dosage while 17 patients had in twice-daily dosage at the beginning of the study. There were 10 patients with heterozygote and 27 with homozygote MEFV mutations. After the treatment was started all patients demonstrated improvement in clinical and laboratory findings such as erythrocyte sedimentation rate and C-reactive protein. However, ADM levels did not show any correlation with ESR and CRP levels. Mean ADM levels in six consecutive visits were as follows, first 322.19±161.92 ng/L; second 330.50±189.63 ng/L; third 339.54±168.03 ng/L; forth 378.11±177.63 ng/L; fifth 328.91±172.30 ng/L and sixth 326.25±165.87 ng/L. ADM levels were similar in all visits (p=0.954) and did not show any difference between the first and second three visits i.e. before and after changing the dosage schema (p=0.593).ConclusionsThe results indicated that patients using colchicine in once or twice daily doses did not show any significant difference according to the clinical and laboratory findings and had similar effects in controlling disease manifestations. ADM levels did not demonstrate any alterations in all visits that may suggest the continuation of subclinical inflammation in these patients.Disclosure of InterestNone declared
BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood, affecting the joints and lasting at least 6 weeks, with the age of disease onset under 16 ...years. The classification of the childhood chronic arthritis hasn't been solved.ObjectivesWe aimed that analysing the demographics, clinical and laboratory features, disease status, and subtype distributions of JIA according to the International League of Associations for Rheumatology (ILAR) criteria in Turkey.MethodsBetween March 2010 and February 2014 with this cross-sectional study, consecutive patients seen with JIA in selected 5 major centres. All patients were classified according to the ILAR criteria. Related to the disease status assessment we evaluate acute phase reactants, physician-patient-parent global assessment of overall disease activity (PGA)(21circle VAS), pain scale (10cm VAS), disease status, and Juvenile Arthritis Damage Index (JADI). We checked the correlations between physician-patient-parent global assessment (PGA) of overall disease activity, and disease status scores.ResultsIn this study, 208 (58.1%) females and 150 (41.9%) males were evaluated (Female/Male:1.39). The mean age of patients was 11.15±4.47 years. The distributions of JIA patients according to onset of disease were as follows: systemic 50 (13.9%), oligoarticular extended 35 (9.4%), oligoarticular persistent 104 (29%), rheumatoid factor (RF) positive polyarthritis 5 (1.2%), RF negative polyarthritis 89 (24.9%), enthesitis-related 51 (13.8%), psoriatic 15 (3.8%), unclassified group 9 (2.6%). The frequency of uveitis was 21 (15.1%) among all of the oligoarticular patients and 12 (5.5%) among in the other group. ANA was positive mainly among the oligoarticular onset patients. 16 patients also had FMF. Among systemic JIA patients, the frequency of macrophage activation syndrome was 24% (n=12).Related to the disease status of the subtypes of JIA revealed that while the RF positive polyarthritis was found to have the highest, and the unclassified group has the lowest activity score via using Articular JADI. The RF (-) polyarthritis was found to has the highest, and the unclassified group has the lowest activity score according to the Extra-articular JADI. Based on the last week's parent-patient-pain score, while the unclassified group has the highest, the psoriatic arthritis has the lowest activity score.Assessment of the disease status by the PGA was resulted the fact that there was statistically significant positive correlation between parent-patient (r=0.770), moderate positive correlation between physician-parent (r=0.456) and physician-patient (r=0.512). There was also statistically positive correlation between the patient and parent pain score (r=0.857).ConclusionsWe assessed the main clinical and laboratory features, and the disease activity status of the Turkish patients with childhood chronic arthritis. We evaluated the diagnoses and the subtype distributions according to ILAR classification.Disclosure of InterestNone declared
Background There are a lot of effects of auto-inflammatory diseases (e.g. fear of attack, pain, fever, fatigue, problems at school) that are quite important to patients but have not been measured ...with the outcome instruments currently included in clinical trials of autoinflammatory diseases. Objectives The aim of this study is to develop and test a new multidimensional questionnaire for assessment of children with autoinflammatory disease (AID) in standard clinical care. Methods JAIMAR includes 16 parent or patient - centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life with disease outcome. The JAIMAR is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 7-18 years for use as a self-report. The study was conducted in children with AID and their parents in seven different paediatric rheumatology center from Turkey. To validate the JAIMAR, the Outcome Measures in Rheumatology Clinical Trials (OMERACT) filter for outcome measures in rheumatology was applied. Results Completion and scoring appeared to be quick, requiring avarage15 minutes. The analysis data set included by the parents of 250 children with FMF in 351 visits and by 179 children in 187 visits. The median age of the children was 10.64±4.38 and female to male ratio was. The JAIMAR was found to be feasible and to possess face, content, criterion and construct validity. The cronbach's alpha coefficient for internal consistency for the JAIMAR dimensions were between for parents 0.677-0.998 and for children 0.507-0.986. Parents' proxy-reported and children's self-reported data were outstandingly concordant.The JAIMAR dimensions patient self-report and parent proxy-report cronbach's alpha values were between 0.770-0.989. Conclusions The development of the JAIMAR introduces a new and multi-dimensional approach in pediatric rheumatology practice. The JAIMAR provided thorough information for the study patients about recent medical history, attack status and current health status. It is valid tool for children with autoinflammatory disease and will help enhance the quality of care of in this group of patients References Kalkan G, Demirkaya E, Acikel CH, Polat A, Peru H, Karaoglu A, Sari E, Dursun I, Gok F, Ozen S; (FAVOR). Evaluation of the current disease severity scores in paediatric FMF: is it necessary to develop a new one? Rheumatology (Oxford). 2012, 51(4):743-8. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5963
Background Childhood systemic vasculitis are a group of rare diseases with multi-organ involvement and potentially devastating consequences. The biomedical perspective does not take into account a ...patient’s own psychological perspective. Patients’ subjective experiences may represent the key domains of illness that differ from clinicians’ views. Objectives The aim of the study is to develop an multidimensional assessment instrument named “Juvenile Vasculitis Multidimensional Assessment Report” (JVAMAR) to measure all these domains. In this study it will be presented the data of “Qualitative Interviews”, one of the steps of item generation in JVAMAR. Methods Twelve children with vasculitis and their mother were enrolled to this study. Data were collected using both a demographic data form and a semi-structured interview form. Study was made on individual patient interview by face-to-face manner. Results Data analysis by grounded theory revealed four categories. These categories were (1) physical impact of disease, (2) emotional impact of disease, (3) social impact of disease and (4) complaints about treatment protocols. In the physical impact category, severe pain, hypersensitivity to cold, restriction in movement, weakness, fatigue, frequently upper respiratory tract infections, anorexia and hypertension were the prominent features. As emotional impact, the most common features were thought of death, pessimism, hopelessness, weak adaptation of social environment relevant to patients age, increased mother dependency, anxiety about treatment and future life, dissatisfaction about body image according to medical therapy and emotional hypersensitivity. In the social impact category, the patients reported that difficulty to access to health services, economic problems, decrease in academic performance, absenteeism to school, increased religious behavior and thoughts, conceal the sickness from friends. In the complaints about treatment protocols category, many patients reported improved health status after treatment but fear about having a chronic disease although the drug use regularly, they complained from life time drug use and frequency of daily drug doses. Conclusions Children with vasculitis imply that they experience several difficulties regarding physical, emotional and social aspects and treatment protocols. There is a need to develop a multidimensional instrument to measure important domains of the illness such as quality of life, the burden of disease in vasculitis, defined as the impact of permanent damage on the patient and its assessment. References Demirkaya E, Luqmani R, Ayaz N.A, Karaoglu A, Ozen S, the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR). Time to focus on outcome assessment tools for childhood vasculitis. PROJ 2011;9:29 Herlyn K, Hellmich B, Seo P, Merkel P, Patient-Reported Outcome Assessment in Vasculitis May Provide Important Data and a Unique Perspective, AC & R 2010;62:11:1639–45 Disclosure of Interest None Declared
Background Juvenile idiopathic arthritis (JIA) is the more common chronic arthritis of childhood, and can lead to significant long-term morbidity, including physical disability. Treatment of the ...disease has greatly improved short and medium-term outcomes, and its effectiveness has been often tested with trials using placebo as comparator. However, until now the real magnitude of placebo effect has not been quantified in children with JIA. Objectives To estimate the placebo effect in JIA through a meta-analysis on phase III trials which compares the active compound versus placebo using different study designs (parallel or withdrawal). Methods The systematic literature search was carried out from June to December 2012 using publications retrieved in Medline, Cochrane Controlled Trials, ClinicalTrials.gov registers. The study was developed according to the PRISMA statement. For parallel design studies the outcome was evaluated as a single one-dimensional (OD) variable or, when available, as a composite score (CS); withdrawal studies were evaluated only by CS. Results A total of 23 trials were included in the final meta-analysis. In the seven OD studies, 38% (95% CI: 32-43%) of patients responded to placebo. Considering CS parallel trials, the rate of response to placebo was high in studies enrolling different JIA categories (38%; 95% CI: 33-43%) and lower in studies with only systemic included (13%; 95% CI: 6-20%). In withdrawal design trials, the percentages of placebo patients who flared during the double blind phase in the placebo arm was lower in the studies recruiting various JIA subgroups (62%; 95% CI: 50-74%) than trials with only a population of systemic subjects (67%; 95% CI: 37-97%) with substantial evidence of heterogeneity. Conclusions A sizable number of patients seems to benefit from placebo treatment. The placebo effect is mainly influenced by the study design and the rate of systemic patients enrolled. References Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009 July 21;6(7):e1000097. Disclosure of Interest None Declared
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