Anakinra for Colchicine‐Resistant Familial Mediterranean Fever: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Ben-Zvi, Ilan; Kukuy, Olga; Giat, Eitan; Pras, Elon; Feld, Olga; Kivity, Shaye; Perski, Oleg; Bornstein, Gil; Grossman, Chagai; Harari, Gil; Lidar, Merav; Livneh, Avi

doi:10.1002/art.39995

Cited by 157 publications

(117 citation statements)

References 42 publications

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“…32 Second, familial Mediterranean fever that is refractory to colchicine prophylaxis has been successfully treated with anakinra, an IL-1 blocking agent. 33 Third, the variability in the incidence of ERMF may be accounted for, in part, by IL-1ra gene polymorphisms. Two common variants located upstream of IL1RN, the gene encoding IL-1ra, are the strongest known genetic determinants of increased soluble IL-1ra concentration.…”

Section: Discussionmentioning

confidence: 99%

Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study

Arroyo

Sanchez

Patel

et al. 2019

British Journal of Anaesthesia

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Background: Epidural-related maternal fever (ERMF) has been reported in~26% of labouring women. The underlying mechanisms remain unclear. We hypothesised that ERMF is promoted by bupivacaine disrupting cytokine production/ release from mononuclear leucocytes [mononuclear fraction (MNF)]. We examined whether bupivacaine (i) reduces caspase-1 activity and release of the anti-pyrogenic cytokine interleukin (IL)-1 receptor antagonist (IL-1ra), and (ii) is proinflammatory through mitochondrial injury/IL-1b. Methods: In labouring women, blood samples were obtained before/after epidural analgesia was implemented. Maternal temperature was recorded hourly for the first 4 h of epidural analgesia. Time-matched samples/temperatures were obtained from labouring women without epidural analgesia, pregnant non-labouring, and non-pregnant women. The primary clinical outcome was change in maternal temperature over 4 h after the onset of siting epidural catheter/enrolment. The secondary clinical outcome was development of ERMF (temperature ! 38 C). The effect of bupivacaine/saline on apoptosis, caspase-1 activity, intracellular IL-1ra, and plasma IL-1ra/IL-1b ratio was quantified in MNF from labouring women or THP-1 monocytes (using flow cytometry, respirometry, or enzyme-linked immunosorbent assay). Results: Maternal temperature increased by 0.06 C h À1 [95% confidence interval (CI): 0.03e0.09; P¼0.003; n¼38] after labour epidural placement. ERMF only occurred in women receiving epidural analgesia (five of 38; 13.2%). Bupivacaine did not alter MNF or THP-1 apoptosis compared with saline control, but reduced caspase-1 activity by 11% (95% CI: 5e17; n¼10) in MNF from women in established labour. Bupivacaine increased intracellular MNF IL-1ra by 25% (95% CI: 10e41; Obstetric Anaesthesia P<0.001; n¼10) compared with saline-control. Epidural analgesia reduced plasma IL-1ra/IL-1b ratio (mean reduction: 14; 95% CI: 7e30; n¼30) compared with women without epidural analgesia. Conclusions: Impaired release of anti-pyrogenic IL-1ra might explain ERMF mechanistically. Immunomodulation by bupivacaine during labour could promote ERMF.

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Section: Discussionmentioning

confidence: 99%

Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study

Arroyo

Sanchez

Patel

et al. 2019

British Journal of Anaesthesia

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“…8 9 For patients who are resistant or intolerant to colchicine, anti-IL-1 therapy is a safe and effective alternative. [10][11][12][13] Colchicine prevents not only FMF attacks but also disease-associated complications such as amyloid A amyloidosis, a severe manifestation with poor prognosis. 9 However, it is crucial to establish a timely and correct diagnosis of FMF before committing to daily, lifelong treatment.…”

Section: Autoinflammatory Disordersmentioning

confidence: 99%

Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever

et al. 2020

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Background and objectiveFamilial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype–phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis.MethodsPeripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1β and IL-18 levels were measured by Luminex assay.ResultsThe ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance.ConclusionThe ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.

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“…Fever attacks and chest pain were reduced during Anakinra treatment but reappeared upon discontinuation (Calligaris et al, 2008). Recent results of a double-blind, placebo-controlled, randomized study involving 14 colchicine-resistant FMF patients showed that those who received Anakinra daily at a subcutaneous dosage of 100 mg had significantly less fever attacks per month (1.7 vs. 3.5 in the placebo group) (ClinicalTrials.gov Identifier: NCT01705756) (Ben-Zvi et al, 2017). …”

Section: Skin Diseases With Il-1 Involvementmentioning

confidence: 99%

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

2017

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In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1β-induced neutrophil recruitment to the skin. IL-1β blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1α monoclonal antibody MABp1 and anti-IL-1β Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases.

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Anakinra for Colchicine‐Resistant Familial Mediterranean Fever: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Abstract: In this randomized controlled trial, anakinra appears to be an effective and safe treatment for colchicine-resistant FMF.

Cited by 157 publications

References 42 publications

Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study

Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study

Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

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