POS1372 EVALUATION OF E148Q AND CONCOMITANT AA AMYLOIDOSIS SECONDARY TO FAMILIAL MEDITERRANEAN FEVER AFTER ADJUSTED CLINICAL-DEMOGRAPHIC CHARACTERISTICS

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:[1]Erer 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.[2]Touitou 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.[3]Pras 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

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Evaluation of E148Q and Concomitant AA Amyloidosis in Patients with Familial Mediterranean Fever

Journal of Clinical Medicine ◽

10.3390/jcm10163511 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3511

Author(s):

Zehra Serap Arici ◽

Micol Romano ◽

David Piskin ◽

Ferhat Guzel ◽

Sezgin Sahin ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Clinical Phenotype ◽

Clinical Manifestations ◽

Histopathological Diagnosis ◽

Close Monitoring ◽

Aa Amyloidosis ◽

Homozygous Genotype ◽

Age Of Diagnosis ◽

Mediterranean Fever

The aim of the study was to compare the clinical phenotype of patients with familial Mediterranean fever (FMF)-related AA amyloidosis, according to the age of FMF diagnosis and E148Q genotype. Patients with biopsy-confirmed FMF-related AA amyloidosis were included in the study. Tel-Hashomer criteria were applied in the diagnosis of FMF. All patients had detailed baseline assessment of clinical features, renal functions, genetic testing, histopathological diagnosis of amyloidosis, and treatment received. Multiple comparisons were performed according to the age of diagnosis, disease phenotype, mutation, and mortality. Our study included 169 patients with a diagnosis of AA amyloidosis. There were 101 patients diagnosed with FMF < 18 years of age and 68 patients diagnosed who were ≥18 years of age. The three most common clinical manifestations were fever (84.6%), abdominal pain (71.6%), and arthritis (66.9%). The most common allele among FMF patients was M694V (60.6%), followed by E148Q (21.4%), and M680I (10.3%). The most frequent genotypes were M694V/M694V (45.0%), M694V/E148Q (14.8%), and E148Q/E148Q (11.2%) among 169 patients in our cohort. During the follow-up period, 15 patients (10 male, 5 female) died, of whom 14 had M694V homozygous genotype and one was homozygous for E148Q. Clinicians should be aware of patients with homozygous E148Q genotype for close monitoring and further evaluation. The possible relationship between E148Q and AA amyloidosis needs to be confirmed in other ethnicities.

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AB1065 VISIT COMPLIANCE IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER: RESULTS FROM A GAZI UNIVERSITY FMF COHORT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4675 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1822.1-1822

Author(s):

R. Bilici Salman ◽

A. Avanoğlu Güler ◽

H. Satiş ◽

H. Karadeniz ◽

H. Babaoglu ◽

...

Keyword(s):

Logistic Regression ◽

Family History ◽

Familial Mediterranean Fever ◽

Predictive Factors ◽

Severity Score ◽

Comorbid Disease ◽

Rheumatology Clinic ◽

Mediterranean Fever ◽

One Year

Background:Follow-up in all rheumatologic patients is critical, particularly Familial Mediterranean Fever (FMF). Current recommendations for all experts by the EULAR state that patients with FMF should be evaluated 6-monthly intervals to monitore the character and frequency of the attacks and the acute phase response. Disease-related complications such as amyloidosis can beasymptomaticand need only a careful follow-up.Objectives:to quantify this phenomenon and to find predictive factors of visit compliance in patients with FMF.Methods:The study included 474 adult patients with a diagnosis of FMF who followed at the outpatient rheumatology clinic of tertiary university hospital, from January 2018 to December 2018. . Demographic, socioeconomic data, familiy history, comorbid disease, medication history, characteristics, the International Severity Score for FMF (ISSF),autoinflammatory disease damage index (ADDI) were recorded. Visit compliance was defined as the presence of two visits in the outpatient rheumatology clinic for FMF last one year for the purposes set out in EULAR suggestion.Those who had fewer than two visits in the last one year were considered noncompliant.Results:230 (48.5%) were compliant while 244 (51.5 %) patients were noncompliant with their rheumatology visit. Both compliant and noncompliant patients had similar median age and disease duration. Female sex and being married was increased the visit compliance.The results of the logistic regression model exploring factors associated with compliance indicated that presence of family history in parents, absence of family history in sibling, treatment with biologic agents, other drug using,presence of more than 2 attacks except fever and adequate medical care were important predictors of visit compliance.Conclusion:In conclusion, if FMF patients visit compliance increase, their functionality, medication adherence and quality of life will increase and flares and complication of disease can decrease. Thus, we highlight some recommendations for FMF specialist, patients and health care providers to improve outcomes.Table 2.Multivariate logistic regression analysis for predictive factors of visit compliance of the patients with FMF, n=430Adj. OR%95 CI**pFamily history in parents(positive history vs negative)1,81,0-3,10.03Family history in sibling(negative history vs positive)1,91,2-3,10.004Comorbid disease status1,30,7-2,50.32Treatment(anakinra&canakinumab vs colchicine)3,71,7-8,20.001Drug using(other drugs vs FMF drugs)2,21,1-4,40.01More than 2 attacks except fever2,31,2-4,00.004Chronic peripheral arthritis2,30,8-6,60.10Proteinuria2,20,7-6,70.14Adequate medical care1,91,2-3,10.003Number of index flare within last 12-month0,90,9-1,00.38ISSF severity score0,80,7-1,10,30Disclosure of Interests:None declared

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A Proposed Histopathologic Classification, Scoring, and Grading System for Renal Amyloidosis: Standardization of Renal Amyloid Biopsy Report

Archives of Pathology & Laboratory Medicine ◽

10.5858/134.4.532 ◽

2010 ◽

Vol 134 (4) ◽

pp. 532-544 ◽

Cited By ~ 10

Author(s):

Sait Şen ◽

Banu Sarsık

Keyword(s):

Familial Mediterranean Fever ◽

Prognostic Score ◽

Renal Amyloidosis ◽

Grading System ◽

Al Amyloidosis ◽

Pathology Report ◽

Aa Amyloidosis ◽

Microscopic Appearance ◽

Biopsy Report ◽

Mediterranean Fever

Abstract Context.—A disease associated with amyloid deposits, called amyloidosis, is associated with characteristic electron microscopic appearance, typical x-ray pattern, and specific staining. Renal involvement mainly occurs in AA amyloidosis and AL amyloidosis and usually progresses to renal failure. Objective.—The renal histopathologic changes with amyloidosis comprise a spectrum. Clear relationships between the extent of amyloid deposition and the severity of clinical manifestations have not been demonstrated. Whether there is a lack of clinicopathologic correlation is not clear, but studies have revealed the need for standardization of the renal amyloid biopsy report. With these objectives in mind, we proposed a histopathologic classification, scoring, and grading system. Renal amyloidosis was divided into 6 classes, similar to the classification of systemic lupus erythematosus. Amyloid depositions and other histopathologic lesions were scored. The sum of these scores was termed the renal amyloid prognostic score and was divided into 3 grades. Data Sources.—AA amyloidosis was detected in 90% of cases, mostly related to familial Mediterranean fever. Positive correlations between class I and grade I, class VI and grade III, and class III and grade II were observed. Also, a positive correlation was identified between severity of glomerular amyloid depositions, interstitial fibrosis, and inflammation. Because of the inadequacy of the patients' records and outcomes, different therapy regimes, and etiologies, clinical validation of this study has not been completed. Conclusions.—Standardization of the renal amyloid pathology report might be critical for patients' medication and comparison of outcome and therapeutic trials between different clinics. Because of our AA to AL amyloidosis ratio and the predisposition of familial Mediterranean fever–related AA amyloidosis, there is a need for further international collaborative studies.

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AB0055 SOLUBLE TREM-1 LEVELS IN FAMILIAL MEDITERRANEAN FEVER RELATED AA-AMYLOIDOSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3426 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1329.2-1330

Author(s):

S. Ugurlu ◽

B. H. Egeli ◽

I. M. Bolayirli ◽

H. Ozdogan

Keyword(s):

Familial Mediterranean Fever ◽

Demographic Data ◽

Enzyme Linked Immunosorbent Assay ◽

Aa Amyloidosis ◽

Control Groups ◽

Tertiary Center ◽

Healthy Control ◽

Mediterranean Fever ◽

The Mean

Background:Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is a monocyte and neutrophil receptor functioning in innate immunity. TREM-1 produces proinflammatory cytokines and serves for neutrophil degranulation. TREM-1 activity is well known in the pathogenesis of sepsis; hence it can be also present in autoinflammatory diseases such as the most common monogenic one, Familial Mediterranean Fever (FMF).Objectives:The objective of this study is to measure soluble TREM-1 (sTREM-1) activity in severe FMF cases complicated with systemic AA-Amyloidosis.Methods:The cohort of the study includes regularly followed FMF related AA-Amyloidosis patients in a tertiary center outpatient rheumatology clinic. Soluble TREM-1 levels were measured using enzyme-linked immunosorbent assay (ELISA). In addition, demographic data, renal function tests, acute phase reactants, and medical prescription history was also noted and analyzed. None of the FMF diagnosed patients had an attack during the collection of the blood samples.Results:The patients were categorized into 4 groups: FMF related AA-Amyloidosis patients (A(+) FMF(+)), FMF unrelated AA-Amyloidosis (FMF(-) A(+)), FMF patients without Amyloidosis diagnosis (FMF(+) A (-)), and healthy controls (HC). The mean ages, TREM-1, C - reactive protein (CRP), and Creatinine levels of each group are shown in Table 1. TREM-1 levels were found to be significantly higher in A(+) FMF(+) group than FMF(+) A (-), and healthy control groups (p= 0.001 and 0.002). Nevertheless, this difference was not found in between A(+) FMF(+) and FMF(-) A(+) (p= 0.447). In addition, the TREM-1 levels of FMF(+) A (-), and healthy control groups were not different (0.532). In A(+) FMF(+) group, 36 patients used colchicine with the mean dose of 1.9±0.8 mg/day, 14 patients used anakinra, and 9 patients used canakinumab. In FMF(+) A (-) group all 20 patients used colchicine with the mean dose of 2.8±0.9 mg/day, 1 patient used anakinra, and 2 patients used canakinumab.Table 1.Clinical Features of Patients and TREM-1 levelsA(+) FMF(+)(n= 42)FMF(-) A(+)(n=5)FMF(+) A(-)(n=20)HC(n=20)Age43.9±12.954.8±1935.3±9.6435.4±6.57TREM-1735.3±566.51247.1±1349.2414.3±142.3439.2±104.6CRP11.1±14.251.3±98.325.8±541.8±1.7Creatinine1.6±1.83.28±4.170.7±0.150.7±0.15Conclusion:In conclusion, TREM-1 is a proinflammatory marker found significantly high in AA-amyloidosis patients regardless of their FMF diagnosis. TREM-1 may be useful in AA-amyloidosis follow-up and early diagnosis since currently there is a deficit of an early diagnostic marker of amyloidosis. This study is a cross-sectional one so it is hard to reach a conclusion on the effectiveness of TREM-1 during regular FMF follow-up for the secondary prevention of amyloidosis. However, the sensitivity of TREM-1 as a marker cannot be denied in amyloidosis.Disclosure of Interests:None declared

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Thyroid disorders in familial Mediterranean fever: think about AA amyloidosis!

Clinical Rheumatology ◽

10.1007/s10067-021-05852-y ◽

2021 ◽

Author(s):

Hélène Vergneault ◽

Rim Bourguiba ◽

Samuel Ardois ◽

Anael Dumont ◽

Léa Savey ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Thyroid Disorders ◽

Aa Amyloidosis ◽

Mediterranean Fever

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Vitamin D status and risk of type 2 diabetes in the Norwegian HUNT cohort study: does family history or genetic predisposition modify the association?

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001948 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001948

Author(s):

Marion Denos ◽

Xiao-Mei Mai ◽

Bjørn Olav Åsvold ◽

Elin Pettersen Sørgjerd ◽

Yue Chen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Family History ◽

Genetic Predisposition ◽

Effect Modification ◽

P Value ◽

Family History Of Diabetes ◽

Increased Risk ◽

History Of

IntroductionWe sought to investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) level and the risk of type 2 diabetes mellitus (T2DM) in adults who participated in the Trøndelag Health Study (HUNT), and the possible effect modification by family history and genetic predisposition.Research design and methodsThis prospective study included 3574 diabetes-free adults at baseline who participated in the HUNT2 (1995–1997) and HUNT3 (2006–2008) surveys. Serum 25(OH)D levels were determined at baseline and classified as <50 and ≥50 nmol/L. Family history of diabetes was defined as self-reported diabetes among parents and siblings. A Polygenic Risk Score (PRS) for T2DM based on 166 single-nucleotide polymorphisms was generated. Incident T2DM was defined by self-report and/or non-fasting glucose levels greater than 11 mmol/L and serum glutamic acid decarboxylase antibody level of <0.08 antibody index at the follow-up. Multivariable logistic regression models were applied to calculate adjusted ORs with 95% CIs. Effect modification by family history or PRS was assessed by likelihood ratio test (LRT).ResultsOver 11 years of follow-up, 92 (2.6%) participants developed T2DM. A higher risk of incident T2DM was observed in participants with serum 25(OH)D level of<50 nmol/L compared with those of ≥50 nmol/L (OR 1.72, 95% CI 1.03 to 2.86). Level of 25(OH)D<50 nmol/L was associated with an increased risk of T2DM in adults without family history of diabetes (OR 3.87, 95% CI 1.62 to 9.24) but not in those with a family history (OR 0.72, 95% CI 0.32 to 1.62, p value for LRT=0.003). There was no effect modification by PRS (p value for LRT>0.23).ConclusionSerum 25(OH)D<50 nmol/L was associated with an increased risk of T2DM in Norwegian adults. The inverse association was modified by family history of diabetes but not by genetic predisposition to T2DM.

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Eculizumab discontinuation in atypical hemolytic uremic syndrome: TMA recurrence risk and renal outcomes

Clinical Kidney Journal ◽

10.1093/ckj/sfab005 ◽

2021 ◽

Author(s):

Gema Ariceta ◽

Fadi Fakhouri ◽

Lisa Sartz ◽

Benjamin Miller ◽

Vasilis Nikolaou ◽

...

Keyword(s):

Family History ◽

Hemolytic Uremic Syndrome ◽

Univariate Analysis ◽

Atypical Hemolytic Uremic Syndrome ◽

Renal Response ◽

Pathogenic Variants ◽

Increased Risk ◽

History Of ◽

Uremic Syndrome

ABSTRACT Background Eculizumab modifies the course of disease in patients with atypical hemolytic uremic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated hematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analyzed. The primary endpoint was the proportion of patients suffering thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: eGFR changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analyzed 151 patients with clinically diagnosed aHUS who had evidence of hematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants, or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; 7 (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

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