Endocan: A Novel Marker for Colchicine Resistance in Familial Mediterranean Fever Patients?

Introduction: Familial Mediterranean fever (FMF) patients had 5–10% colchicine resistance. Although FMF attacks are characterized by acute phase elevation, there are no biomarkers that can show colchicine resistance yet. The serum endocan levels may elevate in inflammatory and auto-inflammatory diseases.Objectives: This study aimed to evaluate serum endocan levels in FMF patients according to whether attack and colchicine resistance or not and also compare them with classical acute phase reactants.Methods: In this single-center and cross-sectional study, a total of 111 FMF patients and 60 healthy individuals were enrolled. All patients' basic demographic and clinical data were recorded and blood samples were collected.Results: A total of 46 (41.4%) FMF patients had colchicine resistance. In comparison to the FMF patients according to colchicine response, colchicine resistance patients had a significantly higher median (IQR) endocan levels than colchicine responsive patients [36.98 ng/ml (97.41) vs. 13.57 ng/ml (27.87), p = 0.007], but there were no differences between in terms of median ESR and CRP levels. Inversely, serum endocan levels were similar during an attack and attack-free period in FMF patients, although ESR and CRP levels were significantly different. Interestingly, the highest serum endocan levels were in the control group.Conclusion: In conclusion, serum endocan levels were higher in colchicine resistance than colchicine responsive patients, but attack state had no effect on serum endocan levels in our study. Unlike ESR and CRP, serum endocan may be a novel biomarker for detection of colchicine resistance and distinguish the FMF attacks.

Predictors of persistent inflammation in children with familial Mediterranean fever

ABSTRACT Objectives Persistent inflammation is an insidious feature of familial Mediterranean fever (FMF) that may cause chronic complications. This study aimed to investigate the predictors of persistent inflammation in children with FMF. Methods The medical charts of 1077 paediatric FMF patients were retrospectively collected. The patients were divided into two groups: with and without subclinical inflammation. Results A total of 133 (12%) patients had persistent inflammation. M694V homozygosity, colchicine resistance, positive family history for FMF, erysipelas-like erythema, leg pain, arthritis, chest pain, inflammatory comorbidities, early disease onset, high PRAS score, and long attack duration were established as independent predictors of persistent inflammation (P < .001, P < .001, P < .001, P < .001, P = 0.006, P < .001, P < .001, P = .014, P < .001, P < .001, and P < .001, respectively). However, gender, abdominal pain, fever, and attack frequency were not found to be independent risk factors for predicting persistent inflammation (P = .412, P = .531, P = .451, and P = .693, respectively). Conclusions M694V homozygosity, colchicine resistance, positive family history, erysipelas-like erythema, leg pain, arthritis, chest pain, inflammatory comorbidities, early disease onset, high activity score, and long attack duration may be predictors of persistent inflammation in FMF. These predictors may help clinicians suspect the occurrence of subclinical inflammation and should aid in better disease management in FMF.

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach

Objectives Colchicine is the main treatment for familial Mediterranean fever (FMF). Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities. Methods A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and pediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements. Results Consensus among the panel was achieved on 8 core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period), or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life. Conclusion Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.

Familial Mediterranean Fever (FMF) and Pregnancy: Literature Review

В обзоре обобщается текущая информация о влиянии семейной средиземноморской лихорадки (ССЛ) и ее лечения на исходы беременности, анализируется вопрос гипотетической тератогенности колхицина. В случае резистентности/непереносимости колхицина обсуждается возможность использования других лекарственных средств во время беременности, в том числе, генно-инженерных биологических препаратов, среди которых при ССЛ наиболее предпочтительны ингибиторы интерлейкина 1. Представлена эволюция взглядов на необходимость проведения пренатальной диагностики хромосомных аномалий плода пациенткам с ССЛ, получающим колхицин во время зачатия и беременности, а также в тех случаях, когда колхицинотерапия проводилась мужьям во время зачатия их женами. Акцент сделан на аспектах безопасности терапии, основные положения которых представлены в клинических рекомендациях по лечению ССЛ Европейской антиревматической лиги (EULAR,2016). Согласно этим рекомендациям, прием колхицина не должен быть прекращен во время зачатия, беременности или лактации; имеющаяся на сегодняшний день доказательная база не подтверждает необходимость выполнения амниоцентеза. The review summarizes current information on the impact of FMF and its treatment on pregnancy outcomes, and analyses the hypothetical teratogenicity of colchicine. In the case of colchicine resistance/intolerability, the possibility of using other drugs during pregnancy, including genetically engineered biological drugs, among which interleukin 1 inhibitors are preferred for FMF. An evolutionary view is presented on the need for amniocentesis in FMF patients receiving colchicine during conception and pregnancy, as well as in cases where colchicine therapy was performed to husbands during conception with their wives. Emphasis is placed on the safety aspects of therapy, the main provisions of which are presented in the clinical recommendations for the treatment of FMF of the European Anti-Rheumatic League (EULAR, 2016). According to these recommendations, colchicine should not be discontinued during conception, pregnancy or lactation; today’s evidence does not support amniocentesis.

Anakinra for constrictive pericarditis associated with incessant or recurrent pericarditis

ObjectiveFrequent flares of pericardial inflammation in recurrent or incessant pericarditis with corticosteroid dependence and colchicine resistance may represent a risk factor for constrictive pericarditis (CP). This study was aimed at the identification of CP in these patients, evaluating the efficacy and safety of anakinra, a third-line treatment based on interleukin-1 inhibition, to treat CP and prevent the need for pericardiectomy.MethodsConsecutive patients with recurrent or incessant pericarditis with corticosteroid dependence and colchicine resistance were included in a prospective cohort study from 2015 to 2018. Enrolled patients received anakinra 100 mg once daily subcutaneously. The primary end point was the occurrence of CP. A clinical and echocardiographic follow-up was performed at 1, 3, 6 months and then every 6 months.ResultsThirty-nine patients (mean age 42 years, 67% females) were assessed, with a baseline recurrence rate of 2.76 flares/patient-year and a median disease duration of 12 months (IQR 9–20). During follow-up, CP was diagnosed in 8/39 (20%) patients. After anakinra dose of 100 mg/day, 5 patients (63%) had a complete resolution of pericardial constriction within a median of 1.2 months (IQR 1–4). In other three patients (37%), CP became chronic, requiring pericardiectomy within a median of 2.8 months (IQR 2–5). CP occurred in 11 patients (28%) with incessant course, which was associated with an increased risk of CP over time (HR for CP 30.6, 95% CI 3.69 to 253.09).ConclusionsIn patients with recurrent or incessant pericarditis, anakinra may have a role in CP reversal. The risk of CP is associated with incessant rather than recurrent course.

A systematic literature review of efficacy, effectiveness and safety of biologic therapies for treatment of familial Mediterranean fever

Objectives To identify and summarize the existing evidence on the efficacy, effectiveness and safety of biologic therapies used, either as indicated or off-label, in the treatment of FMF. Methods A systematic literature review was conducted using Embase®, MEDLINE®, MEDLINE®-In Process, and Cochrane databases to identify randomized/non-randomized controlled trials (RCTs/non-RCTs) and real-world observational studies of FMF published as full-text articles (2000–September 2017) or conference abstracts (2014–September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded. Results Of the 3342 retrieved records, 67 publications, yielding 38 unique studies, were included. All studies were published after the year 2010, and the majority (21) were full-text articles. Most studies (33/38) were prospective/retrospective observational; three were double-blind, placebo-controlled RCTs (one each of anakinra, canakinumab and rilonacept); and two were non-RCTs (both canakinumab). Anakinra (26), canakinumab (21) and etanercept (6) were the most frequently used biologics across studies, whereas use of adalimumab, tocilizumab, rilonacept and infliximab was limited (1–2 studies). The available evidence suggested benefits of anakinra and canakinumab in FMF. Conclusion Anti-IL-1 therapies (i.e. anakinra and canakinumab) appear to be effective and safe options in the treatment of overall FMF, including patients with colchicine resistance and FMF-related amyloidosis. There is a need for properly designed prospective or controlled studies to conclude the superiority of one anti-IL-1 therapy over another. Evidence on the use of TNF-α and IL-6 inhibitors is limited, and further research is suggested.

OP0273 ADHERENCE TO COLCHICINE TREATMENT AND COLCHICINE RESISTANCE IN A MULTICENTRIC FMF NATIONAL COHORT

Background:Colchicine is the standard treatment for Familiar Mediterranean Fever (FMF), however about 5% of patients experience colchicine resistance. There is no standard definition of colchicine resistance. Recently a panel of experts elaborated a new definition based on a Delphi consensus approach.Objectives:We aim to describe main features of the disease and clinical outcome of a cohort of FMF patients with particular interest on the colchicine resistance and tolerability according to the definitions proposed by the recent consensus.Methods:Since November 2009, 425 Italian pediatric and adult FMF patients (pts) from 13 centers were enrolled in a national longitudinal cohort study, using the international EUROFEVER registry. Demographic, genetic and clinical data, including response to treatment, were analyzed. Supplementary information on health related quality of life and treatment adherence was also collected by a specific questionnaire.Results:Complete information were available in 341 pts (189 M and 152 F, 211 children and 120 adults). The median age at disease onset was 5.0 years (1 m-59 y); the mean diagnostic delay was 8.7 y (range 0-61 y). The median age at enrollment was 12.1 y (range 3 m - 82 y). The MEFV genotype was the following: 103 (30.2%) pts carried biallelic pathogenic variants; 59 (17.3%) one pathogenic variants and one VOUS /LB variant; 27 (7.9%) had biallelic VOUS/LB variants; 97 (28.45%) were heterozygous for pathogenic variants; 30 (8.8%) were heterozygous for VOUS/LB, 25 (7.33%) were genetically negative.Colchicine treatment was used in 280 pts; during treatment, biologic treatment (anti-IL1) in 22 pts. 61 pts received NSAID or steroid on demand.We analyzed the behavior of the pts treated with colchicine according to the statements on colchicine resistance/intolerance defined by Ozen et al (1) (Table 1).Table 1.Adherence62% displayed a total adherence (> 90% of prescription); 10.8% a good adherence (50-89% of prescriptions); 1.9% poor adherence (< 50% of prescriptions); 0.9% no adherenceDose adjustment criteria/ Recommended maximum colchicine doseMean colchicine dose:Pts <5 years: 0.57mg/de (std. dev. 0.18)5-10 year: 0.77mg/die (std. dev. 0.23)10-18 years: 1.1mg/die (std. dev. 0.39)Adults: 1.16 mg/die (std. dev. 0.37)Pts with a dose inferior to the minimum recommended dose5-10 years: 2.5%10-18 years: 15%Adults: 4%Resistance to ColchicineResistance was be defined as persistence of fever attacks, despite optimal treatment. 41.6% pts had a complete disease control32.8% Pts had < 1 episode/month for 3 months25.5% had ≥1 episode/month for 3 monthsInclusion of secondary amyloidosis in the definition of colchicine resistance5 adult pts (1.5%) displayed amyloidosisColchicine intolerance11 pts (3.2%) withdraw colchicine because of drug intolerancePatient quality of life and patient-reported outcomes20.7% of pts experience fatigue or chronic pain, 16.9% limitations in daily activities, and 16.9% have lost school/work days.Conclusion:Almost 58% of FMF pts display disease activity despite colchicine treatment. The treatment is generally under-dosed, especially in children. The adherence and the compliance to the treatment is generally good.References:[1]Ozen S et all. Recommendation on colchicine dosing and definition of colchicine resistance/intolerance in the management of FMF. Pediatric Rheumatology, 2019.Acknowledgments:This research was financial supported by Novartis AGDisclosure of Interests:Romina Gallizzi: None declared, Marta Bustaffa: None declared, Francesca Mazza: None declared, Diana Sutera: None declared, Giovanna Fabio: None declared, Laura Obici: None declared, Maria Alessio: None declared, Donato Rigante: None declared, Luca Cantarini: None declared, Antonella Insalaco: None declared, Marco Cattalini: None declared, Maria Cristina Maggio: None declared, Gabriele Simonini: None declared, Alma Nunzia Olivieri: None declared, Serena Pastore: None declared, Maddalena Lancieri: None declared, Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis

SAT0513 ASSOCIATION OF SERUM OMENTIN LEVELS WITH COLCHICINE RESISTANCE IN FAMILIAL MEDITERRANEAN FEVER

Background:Omentin is an anti-inflammatory adipokine, which plays important roles in the adjustments of glucose metabolism, cardiovascular homeostasis, atherosclerosis (1).Objectives:To investigate the omentin levels in Familial Mediterranean fever (FMF) patients and to assess the association with markers of subclinical inflammation in FMF patients such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).Methods:This cross-sectional study included 54 consecutive adult FMF patients (27 male, 27 female) and 28 healthy individuals (16 male, 12 female). The demographic and clinical features and MEFV gene mutations were recorded. The FMF patients were separated into 3 groups: 1) attack-free group, 2) active attack group and 3) colchicine-resistant group. Serum omentin levels were compared between the FMF patients and the healthy control group.Results:Serum omentin and SAA levels were higher in the study group than in the control group (108.05(19.97-343.22) vs. 199.5(42.98-339.41) p<0.05, 3.69(1.18-22.75) vs. 1.31(0.95-3.16) p<0.001) (Table 1). When the FMF patients were examined as separate groups, serum omentin values were lower in the colchicine resistant group than in the groups without resistance (Table 2). The correlation analysis showed a negative correlation between omentin and SAA levels (r = -0.240, p = 0.030).Table 1.Laboratory results of the FMF and the control groupVariablesFMF patients(n=54)Control(n=28)P valueOmentin, pg/mL108.05(19.97-343.22)199.5(42.98-339.41)0.03SAA, ng/mL3.7 (1.18-22.75)1.31(0.95-3.16)<0.001ESR, mm/h15(2-68)12(7-17)<0.001CRP, mg/L12(1-194)2.5(1-8)<0.001Variables were given as median (IQR).Calculated using Mann-Whitney U test for non-normal distribution.FMF=Familial Mediterranean fever, SAA=serum amyloid A, ESR=erythrocyte sedimentation rate, CRP=C-reactive protein, IQR=interquartile range.Table 2.Laboratory results of FMF patients with and without colchicine resistanceVariablesWith resistance(n=16)Without resistance(n=38)P valueOmentin, pg/mL76.64(19.77-224.33)186.47(28.41-343.21)0.006SAA, ng/mL3.69(1.18-22.75)3.77(1.18-21.49)0.784ESR, mm/h25.5(2-68)15(2-60)0.835CRP, mg/L11(1-67)19(1-194)0.111Variables were given as median (IQR).Calculated using Mann-Whitney U test for non-normal distribution.FMF=Familial Mediterranean fever, SAA=serum amyloid A, ESR=erythrocyte sedimentation rate, CRP=C-reactive protein, IQR=interquartile range.FOMConclusion:FMF patients with colchicine resistance are associated with decreased omentin concentrations, probably mediated by inflammation-driven mechanisms.References:[1]Yue J, Chen J, Wu Q, Liu X, Li M, Li Z, Gao Y. Serum levels of omentin-1 association with early diagnosis, lesion volume and severity of acute ischemic stroke. Cytokine. 2018;111:518–522.Disclosure of Interests:None declared