Advertisement

Recent advances in pericarditis

Published:September 20, 2021DOI:https://doi.org/10.1016/j.ejim.2021.09.002

      Highlights

      • Pericardial fluid composition
      • Pericardial effusions
      • Anti-IL-1
      • Pericarditis and pregnancy

      Abstract

      Pericardial diseases are an heterogeneous group of entities, ranging from acute pericarditis to asymptomatic pericardial effusions. New advances in understanding the processes underlying them have been made.
      In 2020 a prospective study defined the reference intervals of the component of normal pericardial fluid, that was found to be rich in nucleated cells, proteins, albumin and LDH, at levels compatible with the inflammatory exudates of other biological fluids such as pleural or peritoneal fluid; Light's criteria should not be used to evaluate it.
      Recently we also analyzed systematically large chronic idiopathic non-inflammatory pericardial effusions, observing that a non-invasive wait-and-see approach may be the best choice in clinical practice in oligosymptomatic cases.
      Concerning acute recurrent pericarditis (RP), an innovative interaction between cardiologists, internists and pediatric rheumatologists led to the intuition of a pivotal role of IL-1 in recurrent pericarditis characterized by an evident inflammatory recurrent phenotype, and recent data have shown the striking efficacy of anakinra and rilonacept in these patients. The proper selection of the patient is important; the ideal candidate for anti-IL-1 therapy is the patient with RP with high levels of serum C-reactive protein, high fever, neutrophil leukocitosis, pleuropulmonary involvement, frequent exacerbations and resistant to conventional therapy. On the contrary, anti-IL-1 drugs are not indicated in patients with pericardial effusion whose cause is not attributable to inflammatory phenomena.
      Finally, many patients with RP are women of childbearing age, and the possibility for these women to become pregnant must be addressed by multidisciplinary teams.

      Graphical abstract

      Keywords

      1. Introduction

      Pericardial diseases are a heterogeneous group of entities, ranging from acute pericarditis (AP) to asymptomatic pericardial effusions. Diagnosis of AP can be made when two of the following criteria are present: chest pain (85–90% of cases), typically sharp and pleuritic, improved by sitting up and leaning forward, pericardial friction rub (present in less than 33% of cases), electrocardiogram changes (up to 60% of cases), with new widespread ST elevation or PR depression in the acute phase and pericardial effusion (up to 60% of cases, generally mild) [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ]. Also, biomarkers may help, as high levels of C-reactive protein (CRP) are often found in patients with AP [
      • Bouriche F
      • Toro A
      • Negre V
      • Yvorra S.
      Acute Pericarditis: Aetiologic Diagnosis and Practical Aspect of the Management.
      ].
      After the first occurrence of AP, this pathology may be self-limiting and characterized by a complete resolution of symptoms, but a subset of patients will eventually develop one or more recurrences separated by a variable amount of time between each crisis, experiencing a recurrent pericarditis (RP). Rate of recurrences may reach 50% in patients who underwent steroid-based therapies for the first attack [
      • Bouriche F
      • Toro A
      • Negre V
      • Yvorra S.
      Acute Pericarditis: Aetiologic Diagnosis and Practical Aspect of the Management.
      ]. Recurrences are defined according the same diagnostic criteria. Other patients develop a chronic condition without symptomatic improvement: chronic incessant pericarditis.
      Tuberculosis still represent the principal etiologic cause of AP in developing countries, while so called “idiopathic” AP accounts for the majority of cases in developed countries [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ].
      In this review, we aimed to identify emerging aspects of pericardium physiology and pathology.

      2. Composition of pericardial fluid: biochemical and cellular characteristics of normal pericardial fluid

      The chemical and cytological analysis of pericardial fluid could represent an important tool for a better clinical and etiological evaluation of pericardial pathologies. Only recently a study has systematically evaluated the reference intervals of the normal pericardial fluid component according to standardized criteria in 120 patients undergoing elective cardiac surgery who did not present evidence of pericardial pathology [
      • Buoro S
      • Tombetti E
      • Ceriotti F
      • Simon C
      • Cugola D
      • Seghezzi M
      • Innocente F
      • Maestroni S
      • Del Carmen Baigorria Vaca M
      • Moioli V
      • Previtali G
      • Manenti B
      • Adler Y
      • Imazio M
      • Brucato A
      What is the normal composition of pericardial fluid?.
      ]. We observed that the pericardial fluid is rich in nucleated cells, proteins, albumin and LDH, at levels compatible with the inflammatory exudates of other biological fluids such as pleural or peritoneal fluid (Table 1).
      Table 1Biochemical and cellular characteristics of normal pericardial fluid PF = Pericardial Fluid, LDH = lactic dehydrogenase. ND not determined *Ratio: Pericardial fluid value/serum value. Gradient: Serum albumin-pericardial fluid albumin.
      Biochemistry
      Reference IntervalsMedian
      Protein content1.7-4.6 g/dl2.8 g/dl
      Albumin1.19-3.06 g/dl1.92 g/dl
      LDH141-2613 U/L357 U/L
      Glucose80-134 mg/dl95 mg/dl
      Total cholesterol12-69 mg/dl27 mg/dl
      Total protein PF/serum ratio*0.29-0.830.5
      Albumin gradient°0.18-2.37 g/dl1.4 g/dl
      Total LDH PF/serum ratio*0.4-42.991.1
      Total cholesterol PF/serum ratio*0.07-0.510.22
      PF cells, by optic microscopy
      Nucleated cells278-5608 × 106/L1977 × 106/L
      Mononucleated cells199-5219 × 106/L1919 × 106/L
      of which
      Mesothelial cells40-3790 × 106/L1283 × 106/L
      Leukocytes35-2210 × 106/L503 × 106/L
      of which
      Lymphocytes19-1634 × 106/LND
      Polymorphonucleated cells0-118 × 106/LND
      Macrophages0-214 × 106/LND
      According to the Lights criteria [
      • Light RW.
      The Light criteria: the beginning and why they are useful 40 years later.
      ], pleural fluid is defined as inflammatory when at least one of the following criteria is satisfied: fluid/serum protein ratio >0.5, fluid/serum LDH ratio >0.6, and fluid LDH >2/3 of the upper limit for serum levels. This could lead to mistakenly considering normal PF as inflammatory [
      • Imazio M
      • Biondo A
      • Ricci D
      • Boffini M
      • Pivetta E
      • Brucato A
      • Giustetto C
      • De Ferrari GM
      • Rinaldi M.
      Contemporary biochemical analisys of normal pericardial fluid.
      ,
      • Buoro S
      • Seghezzi M
      • Baigorria Vaca MDC
      • Manenti B
      • Moioli V
      • Previtali G
      • Simon C
      • Cugola D
      • Brucato A
      • Ottomano C
      • Lippi G
      Comparison between optical microscopy and automation for cytometric analysis of pericardial fluids in a cohort of adult subjects undergoing cardiac surgery.
      ]. We propose, for the future, that physicians stop interpreting pericardial fluid as an exudate or transudate based on evaluation tools that are not validated for this type of fluid, and that Light's criteria are not used to evaluate it. In fact, according to these criteria, the majority of pericardial fluids would be misinterpreted as inflammatory exudates. It could also be hypothesized that the elevated LDH levels found in physiological pericardial fluids may be caused by the release of LDH by mesothelial cells, which are particularly abundant in pericardial fluid often grouped together into bizarre aggregates (Figure 1). [
      • Imazio M
      • Biondo A
      • Ricci D
      • Boffini M
      • Pivetta E
      • Brucato A
      • Giustetto C
      • De Ferrari GM
      • Rinaldi M.
      Contemporary biochemical analisys of normal pericardial fluid.
      ,
      • Buoro S
      • Seghezzi M
      • Baigorria Vaca MDC
      • Manenti B
      • Moioli V
      • Previtali G
      • Simon C
      • Cugola D
      • Brucato A
      • Ottomano C
      • Lippi G
      Comparison between optical microscopy and automation for cytometric analysis of pericardial fluids in a cohort of adult subjects undergoing cardiac surgery.
      ].
      Figure 1
      Figure 1Aggregated mesothelial cells from pericardial fluid as observed by optic microscopy 400x magnification, cytospin stained with May-Grunwald-Giemsa reagent.

      3. New data on large, chronic pericardial effusion without increase in inflammation indices

      Acute pericarditis can occur without pericardial effusion, and pericardial effusion may not be related to pericarditis. While idiopathic pericarditis, accompanied or not by pericardial effusion, is often due to autoinflammatory phenomena, there are several other inflammatory and non-inflammatory conditions that can generate pericardial effusion. Pericardial effusion can be secondary to edema syndromes such as heart failure and renal failure, tumors, pulmonary hypertension, serositis and autoimmune diseases, hypothyroidism, infectious diseases (COVID 19 and Tuberculosis); however, the cause often remains elusive [
      • Sagristà-Sauleda J
      • Angel J
      • Permanyer-Miralda G
      • Soler-Soler J.
      Long-term follow-up of idiopathic chronic pericardial effusion.
      ,
      • Imazio M
      • Lazaros G
      • Valenti A
      • De Carlini CC
      • Maggiolini S
      • Pivetta E
      • Giustetto C
      • Tousoulis D
      • Adler Y
      • Rinaldi M
      • Brucato A.
      Outcomes of idiopathic chronic large pericardial effusion.
      ,
      • De Filippo O
      • Gatti P
      • Rettegno S
      • Iannaccone M
      • D'Ascenzo F
      • Lazaros G
      • Brucato A
      • Tousoulis D
      • Adler Y
      • Imazio M
      Is pericardial effusion a negative prognostic marker? Meta-analysis of outcomes of pericardial effusion.
      ,
      • Hoit BD.
      Pericardial Effusion and Cardiac Tamponade in the New Millennium.
      ,
      • Vakamudi S
      • Ho N
      • Cremer PC.
      Pericardial Effusions: Causes, Diagnosis, and Management.
      ,
      • Chang SA.
      Tuberculous and Infectious Pericarditis.
      ,
      • Inciardi RM
      • Lupi L
      • Zaccone G
      • Italia L
      • Raffo M
      • Tomasoni D
      • Cani DS
      • Cerini M
      • Farina D
      • Gavazzi E
      • Maroldi R
      • Adamo M
      • Ammirati E
      • Sinagra G
      • Lombardi CM
      • Metra M.
      Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19).
      ,
      • Chahine J
      • Ala CK
      • Gentry JL
      • Pantalone KM
      • Klein AL.
      Pericardial diseases in patients with hypothyroidism.
      ,
      • Ghosh AK
      • Crake T
      • Manisty C
      • Westwood M.
      Pericardial Disease in Cancer Patients.
      ,
      • Altan M
      • Toki MI
      • Gettinger SN
      • Carvajal-Hausdorf DE
      • Zugazagoitia J
      • Sinard JH
      • Herbst RS
      • Rimm DL.
      Immune Checkpoint Inhibitor-Associated Pericarditis.
      ]. The term idiopathic defines the pericardial effusion that cannot be correlated with other pathologies after the execution of non-invasive diagnostic tests such as blood chemistry tests, contrast-enhanced chest CT [
      • Fadl SA
      • Nasrullah A
      • Harris A
      • Edwards R
      • Kicska G.
      Comprehensive review of pericardial diseases using different imaging modalities.
      ] and eventually the analysis of pericardial fluid. Chronic severe idiopathic pericardial effusion in the absence of evidence of pericarditis is a poorly understood nosological entity. An old study published in 1999 included only 28 patients (46% asymptomatic at presentation). After a 7-year follow-up, 8 of these (29% of cases) developed cardiac tamponade, 24 patients underwent pericardiocentesis (86% of cases) and 20 patients underwent pericardiotomy as final therapy (71% of cases): overall the long term prognosis of this condition seemed quite poor [
      • Sagristà-Sauleda J
      • Angel J
      • Permanyer-Miralda G
      • Soler-Soler J.
      Long-term follow-up of idiopathic chronic pericardial effusion.
      ].
      Pericardial effusion is present only in 50-60% of acute pericarditis and on the other hand it may be unrelated with acute inflammation of the pericardium [
      • Imazio M
      • Lazaros G
      • Valenti A
      • De Carlini CC
      • Maggiolini S
      • Pivetta E
      • Giustetto C
      • Tousoulis D
      • Adler Y
      • Rinaldi M
      • Brucato A.
      Outcomes of idiopathic chronic large pericardial effusion.
      ] (Figure 2).
      Figure 2
      Figure 2In the study from Imazio et al.
      [
      • De Filippo O
      • Gatti P
      • Rettegno S
      • Iannaccone M
      • D'Ascenzo F
      • Lazaros G
      • Brucato A
      • Tousoulis D
      • Adler Y
      • Imazio M
      Is pericardial effusion a negative prognostic marker? Meta-analysis of outcomes of pericardial effusion.
      ]
      , only 60% of patients presenting with pericardial effusion were later diagnosed with pericarditis, while 40% of patients had a pericardial effusion related to other conditions or an idiopathic form. PE = pericardial effusion.
      Chronic effusion is defined as persistent when lasting more than 3 months, severe when it exceeds 20 mm on the semi-quantitative echocardiographic assessment of the largest end-diastolic anechoic space in the various acoustic windows, including standard and “off axis” ones [
      • Imazio M
      • Lazaros G
      • Valenti A
      • De Carlini CC
      • Maggiolini S
      • Pivetta E
      • Giustetto C
      • Tousoulis D
      • Adler Y
      • Rinaldi M
      • Brucato A.
      Outcomes of idiopathic chronic large pericardial effusion.
      ].
      In order to improve the knowledge and management of the patient with chronic severe pericardial effusion in the absence of overt pericarditis, and also to evaluate the risk of developing cardiac tamponade and the clinical outcomes of patients with this morbid condition, in 2018 we published the largest prospective study conducted so far. In this study, 3750 patients with pericardial effusion were evaluated from 2000 to 2015 in three Italian and one Greek reference centers for pericardial diseases [
      • Imazio M
      • Lazaros G
      • Valenti A
      • De Carlini CC
      • Maggiolini S
      • Pivetta E
      • Giustetto C
      • Tousoulis D
      • Adler Y
      • Rinaldi M
      • Brucato A.
      Outcomes of idiopathic chronic large pericardial effusion.
      ].
      Of these, 2250 had a subsequent diagnosis of pericarditis. Of the remaining 1500 patients with pericardial effusion, 740 had pericardial effusion secondary to other diseases in the absence of pericarditis; another 650 patients had not chronic or not large pericardial effusion and the remaining 100 had severe idiopathic chronic pericardial effusion (>20mm). Of these, 44 were asymptomatic at the time of inclusion in the study, with incidental findings on echocardiographic examination of pericardial effusion, while 56 patients were symptomatic, with reported dyspnoea in 28. Notably, 33 out of the 100 subjects had diabetes (33%). There seemed to be two phenotypes: symptomatic patients, more elderly, mainly with diabetes mellitus, arterial hypertension, atrial fibrillation, chronic obstructive pulmonary disease, and the fully asymptomatic group, younger and basically healthy. At baseline, the average extent of pericardial effusion was 25 mm and inflammatory biomarkers, in particular PCR, were normal or near-normal.
      After a follow-up of 50 months, the amount of the effusion was reduced, on average 10 mm, with a complete regression of the effusion in 39 patients, and in all cases no new pathology was detected as a cause of pericardial effusion. Adverse events were observed in 38 patients: 8 patients (8%) developed cardiac tamponade over 50 months, with the risk of cardiac tamponade being 2.2%/year. Thirty patients underwent pericardiocentesis (30%), 12 patients underwent pericardial windowing (12%), 3 patients (3%) underwent pericardiotomy.
      In this study it appears that the risk of cardiac tamponade in patients with chronic idiopathic pericardial effusion is much lower than reported in previous studies (2.2%/year), and the evolution of the effusion in these cases is often benign per se, with a reduction in the extent of effusion in most of cases. Patients undergoing invasive procedures had worse outcomes in terms of relapse or complications (including post cardiac injury syndrome) than untreated patients. The management of these patients must therefore be individualized on the basis of clinical symptoms and an echocardiographic monitoring could be performed every 3-6 months without the use of invasive techniques for the drainage of the pericardial effusion [
      • Imazio M
      • Adler Y.
      Management of pericardial effusion.
      ,
      • Vecchié A
      • Chiabrando JG
      • Dell MS
      • Bonaventura A
      • Mauro AG
      • Wohlford G
      • Van Tassell BW
      • Berrocal DH
      • Montecucco F
      • Beutler A
      • Paolini JF
      • Gal TS
      • Abbate A.
      Clinical Presentation and Outcomes of Acute Pericarditis in a Large Urban Hospital in the United States of America.
      ,
      • Klein AL
      • Abbara S
      • Agler DA
      • Appleton CP
      • Asher CR
      • Hoit B
      • Hung J
      • Garcia MJ
      • Kronzon I
      • Oh JK
      • Rodriguez ER
      • Schaff HV
      • Schoenhagen P
      • Tan CD
      • White RD.
      American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular Computed Tomography.
      ]. We propose that when dealing with chronic idiopathic large effusions, less is more [
      • Lazaros G
      • Oikonomou V
      • Oikonomou E
      • Aznaouridis K
      • Vlachopoulos C
      • Vogiatzi G
      • Lazarou E
      • Imazio M
      • Brucato A
      • Adler Y
      • Tousoulis D.
      Recurrence of Pericardial Effusion After Pericardiocentesis: Does Catheter-Induced Acute Pericardial Inflammation Play a Role?.
      ].

      4. Constrictive pericarditis

      Constrictive pericarditis is caused by inflammation, fibrosis and calcification of the pericardium with a consequent diastolic heart failure [
      • Miranda WR
      • Oh JK.
      Constrictive Pericarditis: A Practical Clinical Approach.
      ]. Prevalence of constrictive pericarditis is so far unknown, but it was reported in 0,2-0,4% of patients who underwent cardiac surgery, inflammation of pericardium due to various etiologies and pericardial trauma. Such diagnosis should be considered in all patients experiencing unexplained right heart failure especially when there is a preserved left ventricular ejection fraction. Diagnosis is usually performed by echocardiography, cardiac catheterization, cardiac CT and MRI and is based on characteristic anatomical and haemodinamic features. Diagnosis is made difficult by the fact that this pathology can generate signs and symptoms similar to cardiac tamponade and restrictive myocardial disease, thus slowing down diagnostic process. Surgical pericardiectomy represents the treatment of choice for constrictive pericarditis, possibly before severe constriction and myocardial atrophy develop. Mortality for patients who do not receive a diagnosis is about 90%, while for patients who undergo pericardiectomy the chances of survival are extremely variable, depending on the etiology and preoperative functional class [
      • Depboylu BC
      • Mootoosamy P
      • Vistarini N
      • Testuz A
      • El-Hamamsy I
      • Cikirikcioglu M.
      Surgical Treatment of Constrictive Pericarditis.
      ,
      • Liu VC
      • Fritz AV
      • Burtoft MA
      • Martin AK
      • Greason KL
      • Ramakrishna H.
      Pericardiectomy for Constrictive Pericarditis: Analysis of Outcomes.
      ].

      5. New insights on autoinflammatory processes in the pathogenesis of Recurrent Pericarditis

      RP may have a typical clinical course, characterized by recurrent attacks of pericardial inflammation accompanied by systemic symptoms and CRP elevation, followed by symptom-free periods [
      • Bouriche F
      • Toro A
      • Negre V
      • Yvorra S.
      Acute Pericarditis: Aetiologic Diagnosis and Practical Aspect of the Management.
      ].
      The observation of some clinical similarities, originally in pediatric patients, between RP and other inflammatory syndromes such as systemic-onset juvenile idiopathic arthritis (Still's disease), Familial Mediterranean Fever (FMF), cryopyrine-associated periodic syndromes (CAPS) and tumor necrosis factor receptor associated periodic syndromes (TRAPS), has led to the belief that there may be links between these pathologies also as regards the pathogenesis, and led to e very innovative interaction between cardiologists, internists and rheumatologists, particularly pediatric rheumatologists [
      • Perricone C
      • Katz D
      • Ciccacci C
      • Ceccarelli F
      • Valesini G
      • Shoenfeld Y
      • Borgiani P
      • Conti F.
      The Heart Matters: Contribution of Genetic Factors in Recurrent Pericarditis.
      ,
      • Alsarah A
      • Alsara O
      • Laird-Fick HS.
      Cardiac manifestations of Familial Mediterranean fever.
      ,
      • Hintenberger R
      • Falkinger A
      • Danninger K
      • Pieringer H.
      Cardiovascular disease in patients with autoinflammatory syndromes.
      ,
      • Erken E
      • Erken E.
      Cardiac disease in familial Mediterranean fever.
      ,
      • Perez-Brandão C
      • Trigo C
      • F Pinto F.
      Pericarditis - Clinical presentation and characteristics of a pediatric population.
      ,
      • Kilic A
      • Varkal MA
      • Durmus MS
      • Yildiz I
      • Yıldırım ZN
      • Turunc G
      • Oguz F
      • Sidal M
      • Omeroglu RE
      • Emre S
      • Yilmaz Y
      • Kelesoglu FM
      • Gencay GA
      • Temurhan S
      • Aydin F
      • Unuvar E.
      Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever.
      ,
      • Gaggiano C
      • Vitale A
      • Obici L
      • Merlini G
      • Soriano A
      • Viapiana O
      • Cattalini M
      • Maggio MC
      • Lopalco G
      • Montin D
      • Jaber MA
      • Dagna L
      • Manna R
      • Insalaco A
      • Piga M
      • La Torre F
      • Berlengiero V
      • Gelardi V
      • Ciarcia L
      • Emmi G
      • Ruscitti P
      • Caso F
      • Cimaz R
      • Hernández-Rodríguez J
      • Parronchi P
      • Sicignano LL
      • Verrecchia E
      • Iannone F
      • Sota J
      • Grosso S
      • Salvarani C
      • Frediani B
      • Giacomelli R
      • Mencarelli MA
      • Renieri A
      • Rigante D
      • Cantarini L
      Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor- Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.
      ,
      • Navallas M
      • Inarejos Clemente EJ
      • Iglesias E
      • Rebollo-Polo M
      • Zaki FM
      • Navarro OM
      Autoinflammatory diseases in childhood, part 1: monogenic syndromes.
      ,
      • Camprubí D
      • Mitjavila F
      • Arostegui JI
      • Corbella X.
      Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant.
      ,
      • Cantarini L
      • Rigante D
      • Merlini G
      • Vitale A
      • Caso F
      • Lucherini OM
      • Sfriso P
      • Frediani B
      • Punzi L
      • Galeazzi M
      • Cimaz R
      • Obici L.
      The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
      ,
      • Yang CA
      • Chiang BL.
      Inflammasomes and Childhood Autoimmune Diseases: A Review of Current Knowledge.
      ,
      • Welzel T
      • Kuemmerle-Deschner JB.
      Diagnosis and Management of the Cryopyrin- Associated Periodic Syndromes (CAPS): What Do We Know Today?.
      ,
      • Insalaco A
      • Prencipe G
      • Buonuomo PS
      • Ceccherini I
      • Bracaglia C
      • Pardeo M
      • Nicolai R
      • De Benedetti F.
      A novel mutation in the CIAS1/NLRP3 gene associated with an unexpected phenotype of cryopyrin-associated periodic syndromes.
      ,
      • Malcova H
      • Strizova Z
      • Milota T
      • Striz I
      • Sediva A
      • Cebecauerova D
      • Horvath R.
      IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives.
      ,
      • Bouomrani S
      • Masmoudi I
      • Teber SB.
      Familial Mediterranean fever: What associations to screen for?.
      ,
      • Krainer J
      • Siebenhandl S
      • Weinhäusel A.
      Systemic autoinflammatory diseases.
      ]. Moreover RP presents family aggregation in 10% of patients [
      • Brucato A
      • Brambilla G.
      Recurrent idiopathic pericarditis: familial occurrence.
      ].
      FMF is caused by a group of mutations of the MEFV gene, which encodes a pyrin that is a component of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome [
      • Perricone C
      • Katz D
      • Ciccacci C
      • Ceccarelli F
      • Valesini G
      • Shoenfeld Y
      • Borgiani P
      • Conti F.
      The Heart Matters: Contribution of Genetic Factors in Recurrent Pericarditis.
      ]. Genetic alterations of this type lead to alterations in the function of the inflammasome, which is a fundamental component in the immune and inflammatory responses generated by innate immunity and which responds to various stimuli, including PAMPs (Pathogen Associated Molecular Patterns) and DAMPs (Damage Associated Molecular Patterns) [
      • Navallas M
      • Inarejos Clemente EJ
      • Iglesias E
      • Rebollo-Polo M
      • Zaki FM
      • Navarro OM
      Autoinflammatory diseases in childhood, part 1: monogenic syndromes.
      ,
      • Camprubí D
      • Mitjavila F
      • Arostegui JI
      • Corbella X.
      Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant.
      ,
      • Cantarini L
      • Rigante D
      • Merlini G
      • Vitale A
      • Caso F
      • Lucherini OM
      • Sfriso P
      • Frediani B
      • Punzi L
      • Galeazzi M
      • Cimaz R
      • Obici L.
      The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
      ,
      • Yang CA
      • Chiang BL.
      Inflammasomes and Childhood Autoimmune Diseases: A Review of Current Knowledge.
      ,
      • Welzel T
      • Kuemmerle-Deschner JB.
      Diagnosis and Management of the Cryopyrin- Associated Periodic Syndromes (CAPS): What Do We Know Today?.
      ]. PAMPs are represented by phylogenetically conserved small molecular patterns within certain classes of microbes, which are recognized by Toll-Like-Receptors and Pattern Recognition Receptors (PRRs) and which activate the inflammasome. DAMPs, also called Alarmins, are released by damaged tissues or dead cells and are usually made up of nuclear or cytosolic proteins which, once passed into the extracellular environment, undergo molecular modifications and denaturation and consequently carry out proinflammatory activities through the interaction with the PRRs, activating the inflammasome. DAMPs and PAMPs are recognized by both cytosolic (NLRs) and membrane (TLRs) receptors and after recognition of the DAMP / PAMP these receptors are integrated into the inflammasome. Alterations, on a genetic or epigenetic basis, of the functions of the inflammasome can lead to altered inflammatory responses, with recurring characteristics [
      • Camprubí D
      • Mitjavila F
      • Arostegui JI
      • Corbella X.
      Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant.
      ]. Specifically, the inflammasome, among its various actions, is able to cleave, through Caspase 1, proIL-1 into active IL-1, a “master” cytokine. There are two types of IL-1, IL-1alpha and IL-1beta which are encoded by two different genes. While IL-1alfa is produced by several cell types, including mucosal cells, keratinocytes, mesothelial cells and endothelial cells, IL-1beta is produced by monocyto-macrophages in response to stimuli based on chemokins and bacterial products [
      • Insalaco A
      • Prencipe G
      • Buonuomo PS
      • Ceccherini I
      • Bracaglia C
      • Pardeo M
      • Nicolai R
      • De Benedetti F.
      A novel mutation in the CIAS1/NLRP3 gene associated with an unexpected phenotype of cryopyrin-associated periodic syndromes.
      ].
      All these findings might explain why some patients experience recurrent inflammatory patterns, by eventual genetic or epigenetic modifications of proteins composing inflammasome [
      • Kilic A
      • Varkal MA
      • Durmus MS
      • Yildiz I
      • Yıldırım ZN
      • Turunc G
      • Oguz F
      • Sidal M
      • Omeroglu RE
      • Emre S
      • Yilmaz Y
      • Kelesoglu FM
      • Gencay GA
      • Temurhan S
      • Aydin F
      • Unuvar E.
      Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever.
      ]. This data is fundamental, because it opens the opportunity to prepare a specific therapy against an inflammatory process of which, previously, the characteristics were not clear. The excellent action of the antiIL-1 drugs, find an even more precise rationale in the light of this proposed pathogenesis.

      6. Acute pericarditis or a systemic disease with pleuropulmonary involvement?

      Pericardial diseases may be considered either as an isolated diseases (more often managed by cardiologists) or as part of a systemic disease, often managed by internists or other specialists [
      • Lazaros G
      • Antonopoulos AS
      • Imazio M
      • Solomou E
      • Lazarou E
      • Vassilopoulos D
      • Adler Y
      • Stefanadis C
      • Tousoulis D.
      Clinical significance of pleural effusions and association with outcome in patients hospitalized with a first episode of acute pericarditis.
      ].
      In most cases of RP, characterized by periodic elevation of inflammatory indices (ESR, CRP, neutrophils), systemic involvement is present [
      • Brucato A
      • Brambilla G
      • Moreo A
      • Alberti A
      • Munforti C
      • Ghirardello A
      • Doria A
      • Shinar Y
      • Livneh A
      • Adler Y
      • Shoenfeld Y
      • Mauri F
      • Palmieri G
      • Spodick DH.
      Long-term outcomes in difficult-to-treat patients with recurrent pericarditis.
      ,
      • Navallas M
      • Inarejos Clemente EJ
      • Iglesias E
      • Rebollo-Polo M
      • Hernández JC
      • Navarro OM
      Autoinflammatory diseases in childhood, part 2: polygenic syndromes.
      ,
      • Brucato A
      • Brambilla G
      • Adler Y
      • Spodick DH
      • Canesi B.
      Therapy for recurrent acute pericarditis: a rheumatological solution?.
      ]: in 53% of cases pleuropulmonary involvement [
      • Brucato A
      • Brambilla G
      • Moreo A
      • Alberti A
      • Munforti C
      • Ghirardello A
      • Doria A
      • Shinar Y
      • Livneh A
      • Adler Y
      • Shoenfeld Y
      • Mauri F
      • Palmieri G
      • Spodick DH.
      Long-term outcomes in difficult-to-treat patients with recurrent pericarditis.
      ], in 5% of cases peritoneal involvement and in 9% of cases hepatic involvement [
      • Brucato A
      • Brambilla G
      • Adler Y
      • Spodick DH
      • Canesi B.
      Therapy for recurrent acute pericarditis: a rheumatological solution?.
      ]. This intensely inflammatory phenotype is particularly evident in children [
      • Navallas M
      • Inarejos Clemente EJ
      • Iglesias E
      • Rebollo-Polo M
      • Hernández JC
      • Navarro OM
      Autoinflammatory diseases in childhood, part 2: polygenic syndromes.
      ].
      In these patients a typical phenotype is found [
      • Lazaros G
      • Antonopoulos AS
      • Imazio M
      • Solomou E
      • Lazarou E
      • Vassilopoulos D
      • Adler Y
      • Stefanadis C
      • Tousoulis D.
      Clinical significance of pleural effusions and association with outcome in patients hospitalized with a first episode of acute pericarditis.
      ], characterized by acute onset chest pain, high fever, high CRP and neutrophilic leukocytosis. Given the severity of the presentation, the patient undergoes contrast-enhanced chest CT, to exclude pathologies affecting the aorta or an acute thromboembolic event, which shows the presence of pleural effusion, often bilateral, with concomitant areas of pulmonary atelectasis. The patient is hospitalized, often with a diagnosis of pneumonia with associated pleurisy, even if cough is typically absent, and intravenous antibiotic therapy and paracetamol as needed. Pericardial effusion may be almost absent or initially undetectable. Since the inflammatory condition is not sustained by a bacterial infection, antibiotic therapy is not able to control the painful and inflammatory symptoms: a second or third line of antibiotic therapy is started due to the persistence of fever, without benefit. A diagnostic suspicion of pericarditis is then raised and an analgesic therapy with oral medium-dose NSAIDs is undertaken (i.e. ibuprofen 600mg), without enough improvement on painful symptoms, and corticosteroid therapy is finally started, intravenously. With corticosteroids there is a rapid regression of pain, but at discharge a rapid tapering of corticosteroids is advised, and the patient returns to have a flare-up of pain and an increase in inflammation indices. A mechanism of dependence on steroid treatment is therefore created [
      • Brucato A
      • Brambilla G
      • Moreo A
      • Alberti A
      • Munforti C
      • Ghirardello A
      • Doria A
      • Shinar Y
      • Livneh A
      • Adler Y
      • Shoenfeld Y
      • Mauri F
      • Palmieri G
      • Spodick DH.
      Long-term outcomes in difficult-to-treat patients with recurrent pericarditis.
      ,
      • Brucato A
      • Brambilla G
      • Adler Y
      • Spodick DH
      • Canesi B.
      Therapy for recurrent acute pericarditis: a rheumatological solution?.
      ].

      7. New guidelines for old drugs

      NSAIDs and ASA at the maximum dose tolerated by the patient is envisaged in AP and RP until complete regression of the symptoms. The therapeutic schemes propose, for example, ibuprofen orally till 800mg every 8 hours, or ASA 500 mg-1 g every 6-8 hours or indomethacin 25-50mg every 8 hours. If the patient is hospitalized and severely ill, these drugs may be given intravenously, e.g. indomethacin 100mg intravenously over 24 hours [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ].
      Colchicine, also inhibits the inflammasome and is added to NSAIDs or ASA because it decreases relapses by 25% -50% [
      • Liantinioti G
      • Argyris AA
      Protogerou AD, Vlachoyiannopoulos P. The Role of Colchicine in the Treatment of Autoinflammatory Diseases.
      ,
      • Leung YY
      • Yao Hui LL
      • Kraus VB
      • Colchicine
      Update on mechanisms of action and therapeutic uses.
      ,
      • Vecchiè A
      • Dell M
      • Mbualungu J
      • Ho AC
      • Van Tassell B
      • Abbate A.
      Recurrent pericarditis: an update on diagnosis and management.
      ,
      • Papageorgiou N
      • Briasoulis A
      • Lazaros G
      • Imazio M
      • Tousoulis D.
      Colchicine for prevention and treatment of cardiac diseases: A meta-analysis.
      ,
      • Leung YY
      • Yao Hui LL
      • Kraus VB
      Colchicine–Update on mechanisms of action and therapeutic uses.
      ,
      • Bonaventura A
      • Montecucco F.
      Inflammation and pericarditis: Are neutrophils actors behind the scenes?.
      ,
      • Imazio M
      • Nidorf M.
      Colchicine and the heart.
      ,
      • Cacoub P
      • Marques C.
      Acute recurrent pericarditis: from pathophysiology towards new treatment strategy.
      ,
      • Lutschinger LL
      • Rigopoulos AG
      • Schlattmann P
      • Matiakis M
      • Sedding D
      • Schulze PC
      Noutsias M. Meta-analysis for the value of colchicine for the therapy of pericarditis and of postpericardiotomy syndrome.
      ]. Low-doses are recommended for at least 6 months: 0.5 mg twice daily in patients with body weight greater than 70 kg or 0.5 mg/day for patients with body weight <70 kg [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ]. In special populations, including elderly, chronic renal failure patients or patients intolerant to standard dosages, the recommended dose is no more than 0.5mg per day. Diarrhea (7% of cases), can be caused also by the concomitant use of proton-ump inhibitors and antibiotics. Colchicine may interact with clarithromycin, statins (except fluvastatin), and diltiazem [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ].
      In case of failure of response to first-line treatment (NSAIDs/ASA and colchicine) prednisone is added in triple therapy at the lowest effective doses (5-10 mg/day) [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ]. This therapy will be unavoidably chronic; consequently vitamin D and bisphosphonates should be added [
      • Hayashi R
      • Wada H
      • Ito K
      • Adcock IM.
      Effects of glucocorticoids on gene transcription.
      ].
      A very gradual tapering of the steroid is essential, lasting even months or years, with each dose reduction only after the resolution of the symptoms and normalization of the PCR. The triple therapy tapering is gradual, slow and sequential [
      • Galluzzo A
      • Imazio M.
      Advances in medical therapy for pericardial diseases.
      ]: initially it concerns the steroid, then the NSAID and then colchicine that is usually the last drug to be discontinued. In case of relapse during the triple therapy tapering it is recommended to increase the dosage of the NSAID and never to increase the dose of steroid [
      • Adler Y
      • Charron P
      • Imazio M
      • Badano L
      • Barón-Esquivias G
      • Bogaert J
      • Brucato A
      • Gueret P
      • Klingel K
      • Lionis C
      • Maisch B
      • Mayosi B
      • Pavie A
      • Ristic AD
      • Sabaté Tenas M
      • Seferovic P
      • Swedberg K
      • Tomkowski W
      ESC Scientific Document Group
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
      ].

      8. IL-1 inhibitors and new data on their use in recurrent pericarditis

      Three drugs are currently available for the inhibition of IL-1, and there are recent data regarding the efficacy and safety profiles particularly for two of these drugs in the treatment of PR: anakinra and rilonacept.
      Anakinra is a short-acting IL-1 receptor antagonist, administered daily at a dose of 100mg subcutaneously (pediatric dosage 2mg/kg per day, up to 100mg). It has received FDA approval for the treatment of Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. Anakinra dosage is not affected by the body mass index (BMI) and the patients’ gender. Similarly, although its metabolism is primarily renal, Anakinra does not need dosage adjustments in patients with GFR> 50ml/min x 1.73m2, while changes in dosage may be considered for lower glomerular filtrate values [
      • Meibohm B
      • Zhou H.
      Characterizing the impact of renal impairment on the clinical pharmacology of biologics.
      ].
      Data regarding its use in RP emerged after the publication of recent studies [
      • BB Yang
      • Baughman S
      • Sullivan JT.
      Pharmacokinetics of anakinra in subjects with different levels of renal function.
      ,
      • Lazaros G
      • Tousoulis D.
      Interleukin-1 inhibition with anakinra: a valuable ally to reverse constrictive pericarditis?.
      ,
      • Shaukat MH
      • Singh S
      • Davis K
      • Torosoff M
      • Peredo-Wende R.
      Efficacy of anakinra for idiopathic and non-idiopathic pericarditis refractory or intolerant to conventional therapy.
      ,
      • Khayata M
      • Shah NP
      • Verma BR
      • Giugni AS
      • Alkharabsheh S
      • Asher CR
      • Imazio M
      • Klein AL.
      Usefulness of Interleukin-1 Receptor Antagonists in Patients With Recurrent Pericarditis.
      ,
      • Wohlford GF
      • Buckley LF
      • Vecchié A
      • Kadariya D
      • Markley R
      • Trankle CR
      • Chiabrando JG
      • de Chazal HM
      • Van Tassell B
      • Abbate A.
      Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.
      ]. In the AIRTRIP study [
      • Brucato A
      • Imazio M
      • Gattorno M
      • Lazaros G
      • Maestroni S
      • Carraro M
      • Finetti M
      • Cumetti D
      • Carobbio A
      • Ruperto N
      • Marcolongo R
      • Lorini M
      • Rimini A
      • Valenti A
      • Erre GL
      • Sormani MP
      • Belli R
      • Gaita F
      • Martini A.
      Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial.
      ], 21 colchicine-resistant and steroid-dependent RP patients were enrolled in a randomized, double-blind, withdrawal design study to receive Anakinra or placebo. In the group of patients who continued Anakinra, 90% of patients had no relapse of RP, while in the group switched to placebo only 18% remained disease-free. Anakinra has also been shown to be effective in patients in whom the cause of RP could be traced to heart damage from surgery. In the IRAP (International Registry of Anakinra for Pericarditis) study, carried out to evaluate the efficacy of Anakinra in a real world population, Anakinra allowed a progressive tapering of the corticosteroid dose [
      • Imazio M
      • Andreis A
      • De Ferrari GM
      • Cremer PC
      • Mardigyan V
      • Maestroni S
      • Luis SA
      • Lopalco G
      • Emmi G
      • Lotan D
      • Marcolongo R
      • Lazaros G
      • De Biasio M
      • Cantarini L
      • Dagna L
      • Cercek AC
      • Pivetta E
      • Varma B
      • Berkson L
      • Tombetti E
      • Iannone F
      • Prisco D
      • Caforio ALP
      • Vassilopoulos D
      • Tousoulis D
      • De Luca G
      • Giustetto C
      • Rinaldi M
      • Oh JK
      • Klein AL
      • Brucato A
      • Adler Y.
      Anakinra for corticosteroid-dependent and colchicine-resistant pericarditis: The IRAP (International Registry of Anakinra for Pericarditis) study.
      ]. In this study, the proportion of patients requiring corticosteroids for symptom control fell from 80% (180 patients out of 224 included) to 27% (60 patients) after Anakinra (p <0.01). Anakinra is an old drug, and has shown to be safe. The most common adverse reaction was a short-lasting injection site reaction with redness, swelling and itching. This reaction is usually mild and occurs mainly in the first month of therapy, and responds well to topical therapy with ice and topical corticosteroids [
      • Kaiser C
      • Knight A
      • Nordström D
      • Pettersson T
      • Fransson J
      • Florin-Robertsson E
      • Pilström B.
      Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations.
      ]. Although this reaction is considered a mild adverse event, it is important to educate patients about the possibility of developing this reaction. During therapy with Anakinra, slight increases in transaminase levels, as well as mild leukopenia, may be observed. Anakinra has only a few contraindications. Latent tuberculosis reactivation has been reported in some patients who received Anakinra, and for this reason it is important, before starting therapy with Anakinra, that the patient is screened for tuberculosis. Furthermore, Anakinra is contraindicated in patients with known hypersensitivity to E. Coli derived proteins [
      • Goletti D
      • Petrone L
      • Ippolito G
      • Niccoli L
      • Nannini C
      • Cantini F.
      Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs.
      ].
      Rilonacept is a dimeric fusion protein, linked in-line to FC portion of human IgG1, consisting of the ligand-binding domains of IL-1 receptor protein and IL-R, that can block both activities of IL-alfa and IL-1beta [
      LiverTox
      Clinical and Research Information on Drug-Induced Liver Injury [Internet].
      ]. Similarly to Anakinra, steady state of this drug is not affected by gender of patient, nor by renal of hepatic impairment and no dose adjustment is required for such conditions [
      • Radin A
      • Marbury T
      • Osgood G
      • Belomestnov P.
      Safety and pharmacokinetics of subcutaneously administered rilonacept in patients with well-controlled end- stage renal disease (ESRD).
      ]. Moreover, Rilonacept is administered by weekly subcutaneous injections. Its efficacy in Juvenile Idiopathic Arthritis was ascertained in 2014, and FDA later approved its use also for CAPS [
      • Ilowite NT
      • Prather K
      • Lokhnygina Y
      • Schanberg LE
      • Elder M
      • Milojevic D
      • Verbsky JW
      • Spalding SJ
      • Kimura Y
      • Imundo LF
      • Punaro MG
      • Sherry DD
      • Tarvin SE
      • Zemel LS
      • Birmingham JD
      • Gottlieb BS
      • Miller ML
      • O'Neil K
      • Ruth NM
      • Wallace CA
      • Singer NG
      • Sandborg CI
      Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis.
      ,
      • Hoffman HM
      • Throne ML
      • Amar NJ
      • Sebai M
      • Kivitz AJ
      • Kavanaugh A
      • Weinstein SP
      • Belomestnov P
      • Yancopoulos GD
      • Stahl N
      • Mellis SJ.
      Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies.
      ,
      • Hoffman HM
      • Throne ML
      • Amar NJ
      • Cartwright RC
      • Kivitz AJ
      • Soo Y
      • Weinstein SP.
      Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study.
      ]. The relevance of Rilonacept in RP is recently emerging. RHAPSODY study analyzed its efficacy in patients affected by RP with elevated CRP levels [
      • Klein AL
      • Imazio M
      • Cremer P
      • Brucato A
      • Abbate A
      • Fang F
      • Insalaco A
      • LeWinter M
      • Lewis BS
      • Lin D
      • Luis SA
      • Nicholls SJ
      • Pano A
      • Wheeler A
      • Paolini JF
      RHAPSODY Investigators
      Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.
      ]. In this study, consisting in a multicenter, double-blind, event-driven, randomized withdrawal trial, 86 patients aged 12 or older, affected by RP at second or further recurrence, presenting with signs and symptoms of acute pericarditis, diagnosed according to 2015 ESC criteria for pericarditis, were enrolled. Patients were eligible independent of therapy based on NSAIDs, Colchicine, Steroids or a combination of the three. Patients received an initial dose of 320mg of Rilonacept by subcutaneous injection (or 4.4 mg per kilogram of body weight in patients <18 years of age, and then a dose of 160mg (or 2.2 mg per kilogram in patients <18 years of age) every week for a 12 weeks run in period. All other medications related to RP therapy were discontinued within 10 weeks.
      During the run-in period, the median time to resolution of pain was 5 days, and the median time to normalization of the CRP was 7 days. Patients who showed a clinical response to therapy were then randomly assigned to receive Rilonacept monotherapy or placebo. During the randomized-withdrawal period there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks.
      Only 7% of patients receiving Rilonacept experienced a recurrence in pericarditis. On the contrary, 74% of patients receiving placebo after the discontinuation of Rilonacept experienced a recurrence. Similar results were observed also in patients whose RP was ascribed to cardiac injury. The most frequently reported side effects were injection site reactions and mild to moderate upper respiratory tract infections. Only in four patients, adverse reactions led to the discontinuation of therapy. Adverse events occurred in 74 out of 86 patients and, although this number may seem high, all adverse events were rated as mild to moderate [
      • Klein AL
      • Imazio M
      • Cremer P
      • Brucato A
      • Abbate A
      • Fang F
      • Insalaco A
      • LeWinter M
      • Lewis BS
      • Lin D
      • Luis SA
      • Nicholls SJ
      • Pano A
      • Wheeler A
      • Paolini JF
      RHAPSODY Investigators
      Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.
      ]. Furthermore, any respiratory symptoms were recorded, contrary to studies on Anakinra and Canakinumab in RP, where such events were not systematically recorded.
      Canakinumab is a human monoclonal antibody directed against IL-1β. Compared with Anakinra, it has a longer half-life of ∼ 22–26 days and can be administered every 4–8 weeks at a single dose [
      • Chioato A
      • Noseda E
      • Colin L
      • Matott R
      • Skerjanec A
      • Dietz AJ
      Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: A randomized study in healthy subjects.
      ,
      • Chakraborty A
      • Tannenbaum S
      • Rordorf C
      • Lowe PJ
      • Floch D
      • Gram H
      • Roy S.
      Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1β monoclonal antibody.
      ,

      Annex I. IFLA J. 20, 338–340 (1994).

      ]. Canakinumab is approved for the treatment of FMF, TRAPS, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, CAPS, gouty arthritis, adult-onset Still's disease, and systemic juvenile idiopathic arthritis [
      • De Benedetti F
      • Gattorno M
      • Anton J
      • Ben-Chetrit E
      • Frenkel J
      • Hoffman HM
      • Koné-Paut I
      • Lachmann HJ
      • Ozen S
      • Simon A
      • Zeft A
      • Calvo Penades I
      • Moutschen M
      • Quartier P
      • Kasapcopur O
      • Shcherbina A
      • Hofer M
      • Hashkes PJ
      • Van der Hilst J
      • Hara R
      • Bujan-Rivas S
      • Constantin T
      • Gul A
      • Livneh A
      • Brogan P
      • Cattalini M
      • Obici L
      • Lheritier K
      • Speziale A
      • Junge G
      Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.
      ,
      • Sąhin A.
      • Derin M.E.
      • Albayrak F.
      • Karakaş B.
      • Karagöz Y.
      Assessment of effectiveness of anakinra and canakinumab in patients with colchicine-resistant/unresponsive familial Mediterranean fever.
      ,
      • Feist E
      • Quartier P
      • Fautrel B
      • Schneider R
      • Sfriso P
      • Efthimiou P
      • Cantarini L
      • Lheritier K
      • Leon K
      • Karyekar CS
      • Speziale A.
      Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups.
      ,
      • Landmann E.C.
      • Walker U.A
      Pharmacological treatment options for cryopyrin-associated periodic syndromes.
      ,
      • Gattorno M
      • Obici L
      • Cattalini M
      • Tormey V
      • Abrams K
      • Davis N
      • Speziale A
      • Bhansali SG
      • Martini A
      • Lachmann HJ.
      Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): An open-label, phase II study.
      ,
      • Ruperto N
      • Brunner HI
      • Quartier P
      • Constantin T
      • Wulffraat N
      • Horneff G
      • Brik R
      • McCann L
      • Kasapcopur O
      • Rutkowska-Sak L
      • Schneider R
      • Berkun Y
      • Calvo I
      • Erguven M
      • Goffin L
      • Hofer M
      • Kallinich T
      • Oliveira SK
      • Uziel Y
      • Viola S
      • Nistala K
      • Wouters C
      • Cimaz R
      • Ferrandiz MA
      • Flato B
      • Gamir ML
      • Kone-Paut I
      • Grom A
      • Magnusson B
      • Ozen S
      • Sztajnbok F
      • Lheritier K
      • Abrams K
      • Kim D
      • Martini A
      • Lovell DJ
      PRINTOPRCSG
      Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis.
      ]. Data regarding its use in RP are limited to a few case reports or case series, and its efficacy, compared to Anakinra, is controversial [
      • Çakan M.
      • Karadağ Ş.G.
      • Ayaz N.A
      Canakinumab in colchicine resistant familial mediterranean fever and other pediatric rheumatic diseases.
      ,
      • Epçaçan S.
      • Sahin S.
      • Kasapcopur O.
      Anaphylactic reaction to anakinra in a child with steroid-dependent idiopathic recurrent pericarditis and successful management with canakinumab.
      ,
      • Signa S
      • D'Alessandro M
      • Consolini R
      • Miniaci A
      • Bustaffa M
      • Longo C
      • Tosca MA
      • Bizzi M
      • Caorsi R
      • Mendonça LO
      • Pession A
      • Ravelli A
      • Gattorno M
      Failure of anti Interleukin-1 ß monoclonal antibody in the treatment of recurrent pericarditis in two children.
      ,
      • Kougkas N
      • Fanouriakis A
      • Papalopoulos I
      • Bertsias G
      • Avgoustidis N
      • Repa A
      • Sidiropoulos P.
      Canakinumab for recurrent rheumatic disease associated-pericarditis: a case series with long-term follow-up.
      ]. These data suggest that RP may be more probably regarded as a disorder where both IL-1alfa and IL-1beta have a role in the induction of the inflammatory response at the pericardial tissue level.

      9. Positioning of anti IL-1 agents

      IL-1 inhibitors must be used in selected cases [
      • Gupta M
      • Kaul S
      • Velazquez GR
      • Bandyopadhyay D
      • Fonarow GC
      • Klein A
      • Ghosh RK.
      A Brief Overview of Recurrent Pericarditis Management and the Potential of Rilonacept as a New Therapeutic Option.
      ,
      • Correia ETO
      • Dos Santos Barbetta LM
      • de Almeida JPCL
      • Mesquita ET
      Anakinra in Recurrent Pericarditis: Current Evidence on Clinical Use, Effectiveness, and Safety.
      ]. The ideal candidate for anti-IL-1 therapy is the patient with RP on an autoinflammatory basis, with high levels of serum CRP, high fever, neutrophil leukocitosis, pleuropulmonary involvement, with frequent exacerbations and resistant to conventional therapy. On the contrary, these drugs are not indicated in patients with pericardial effusion not supported by inflammatory phenomena and by a clinic suggesting pericarditis. Likewise, they are not indicated in patients with chest pain atypical for pericarditis. Their use can also be evaluated in patients in whom therapy with NSAIDs and colchicine is contraindicated for coexisting morbid conditions (Figure 3).
      Figure 3
      Figure 3Positioning of Anti-IL-1 drugs in recurrent pericarditis. The use of Anti-IL-1 drugs is suggested in patients with autoinflammatory phenotype with frequent exacerbations and resistant to conventional therapies. Their use can be considered in patients affected by recurrent pericarditis and comorbidities that prevent the use of commonly used drugs. On the contrary, their use is contraindicated in pericardial effusion with normal serum levels of CRP or in aspecific or atypical presentations of chest pain with normal serum levels of CRP. RP = Recurrent Pericarditis, CRP = C Reactive Protein.
      Anti iL-1 drugs should be administered at full dose and for long periods before beginning progressive tapering. In previous studies, there was an increased frequency of relapses in the case of premature discontinuation, i.e. before six months. Tapering is only recommended in the absence of symptoms and when CRP levels have returned to normal. Furthermore, in the tapering phase it is advisable to consider reintroducing colchicine and NSAIDs therapy [
      • Correia ETO
      • Dos Santos Barbetta LM
      • de Almeida JPCL
      • Mesquita ET
      Anakinra in Recurrent Pericarditis: Current Evidence on Clinical Use, Effectiveness, and Safety.
      ].
      Studies conducted on the efficacy and safety of Anakinra and Rilonacept in RP typically end with the request for more extensive clinical trials and with a greater number of patients included in the analysis. However, one of the first steps in planning a clinical trial is the calculation of the sample size, but these agents are expected to be so effective that the calculated sample size will always be small. For example, the per protocol calculated sample sizes were 20 patients in the AIRTRIP trial and 56 patients in the RHAPSODY trial.

      10. Recurrent Pericarditis during pregnancy and lactation

      In recent years some articles have been published on this topic, with the aim of forming a rational approach to the management of PR during pregnancy and breastfeeding. About 10% of patients with RP are women of childbearing age [
      • Serati L
      • Carnovale C
      • Maestroni S
      • Brenna M
      • Smeriglia A
      • Massafra A
      • Bizzi E
      • Picchi C
      • Tombetti E
      • Brucato A.
      Management of acute and recurrent pericarditis in pregnancy.
      ], and the possibility for these patients to become pregnant must be discussed and addressed by a multidisciplinary team. If the woman does not want to become pregnant, any type of contraceptive can be used. On the contrary, if the patient wishes to become pregnant, it is worth addressing the subject [
      • Carnovale C
      • Tombetti E
      • Battini V
      • Mazhar F
      • Radice S
      • Nivuori M
      • Negro E
      • Tamanini S
      • Brucato A.
      Inflammasome Targeted Therapy in Pregnancy: New Insights From an Analysis of Real-World. Data From the FAERS Database and a Systematic Review.
      ]. The largest case series on this topic described 21 pregnancies with idiopathic recurrent pericarditis, but a large amount of literature deals with the use of NSAIDs, corticosteroids and colchicine in pregnancy and lactation [
      • Orabona R
      • Zanardini C
      • Zatti S
      • Lojacono A
      • Procopio R
      • Vizzardi E
      • Tincani A
      • Sartori E
      • Andreoli L.
      Onset of idiopathic recurrent pericarditis during pregnancy: successful management with colchicine and intravenous immunoglobulins.
      ]. Pregnancy should be planned for a quiescent phase of the disease. NSAIDs can be used in high doses up to the 20th week of gestation, except low-dose aspirin 100 mg / day, which can be continued. Colchicine is allowed until a positive pregnancy test, after which its use can be discussed with the patient and considered for cases in which colchicine is important for the control of RP. Prednisone is also safe in pregnancy when used in low to medium dosages (2.5-10mg / day). The general outcomes of pregnancy in patients with pericarditis are good when the mothers are followed by a multidisciplinary team with experience in the field [
      • Serati L
      • Carnovale C
      • Maestroni S
      • Brenna M
      • Smeriglia A
      • Massafra A
      • Bizzi E
      • Picchi C
      • Tombetti E
      • Brucato A.
      Management of acute and recurrent pericarditis in pregnancy.
      ,
      • Carnovale C
      • Tombetti E
      • Battini V
      • Mazhar F
      • Radice S
      • Nivuori M
      • Negro E
      • Tamanini S
      • Brucato A.
      Inflammasome Targeted Therapy in Pregnancy: New Insights From an Analysis of Real-World. Data From the FAERS Database and a Systematic Review.
      ,
      • Orabona R
      • Zanardini C
      • Zatti S
      • Lojacono A
      • Procopio R
      • Vizzardi E
      • Tincani A
      • Sartori E
      • Andreoli L.
      Onset of idiopathic recurrent pericarditis during pregnancy: successful management with colchicine and intravenous immunoglobulins.
      ].
      Concerning anti -IL1 agents, no studies reporting maternal and/or fetal outcome following the use of rilonacept were found. Only a retrospective cohort study [
      • Youngstein T
      • Hoffmann P
      • Gül A
      • Lane T
      • Williams R
      • Rowczenio DM
      • Ozdogan H
      • Ugurlu S
      • Ryan J
      • Harty L
      • Riminton S
      • Headley AP
      • Roesler J
      • Blank N
      • Kuemmerle-Deschner JB
      • Simon A
      • Woolf AS
      • Hawkins PN
      • Lachmann HJ.
      International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.
      ] and a case report [
      • Egawa M
      • Imai K
      • Mori M
      • Miyasaka N
      • Kubota T.
      Placental Transfer of Canakinumab in a Patient with Muckle-Wells Syndrome.
      ] provided data on the use of canakinumab during pregnancy. Seven studies reported data on the use of anakinra in pregnant women (in total, data were available for 57 pregnancies). In a recently published article on this topic, we found no major safety issues on malformations risk of anti-IL1 therapies in pregnancy [
      • Serati L
      • Carnovale C
      • Maestroni S
      • Brenna M
      • Smeriglia A
      • Massafra A
      • Bizzi E
      • Picchi C
      • Tombetti E
      • Brucato A.
      Management of acute and recurrent pericarditis in pregnancy.
      ]. However, due to limited data, the routine use of these agents should be considered in pregnancy and breast feeding only if risk benefit ratio is favorable [
      • Carnovale C
      • Tombetti E
      • Battini V
      • Mazhar F
      • Radice S
      • Nivuori M
      • Negro E
      • Tamanini S
      • Brucato A.
      Inflammasome Targeted Therapy in Pregnancy: New Insights From an Analysis of Real-World. Data From the FAERS Database and a Systematic Review.
      ].
      Human interleukin-1 receptor antagonist is a normal component of human milk where it may play a role as an anti-inflammatory agent. Several infants have been breastfed during maternal anakinra therapy with no obvious adverse effects [
      Drugs and Lactation Database (LactMed) [Internet].
      ].

      Declaration of Competing Interest

      Antonio Brucato: Institution received funding from Kiniksa Pharmaceuticals, Ltd. as an investigative site; unrestricted research grant from SOBI and ACARPIA; travel and accommodation for advisory committee from SOBI and Kiniksa. Massimo Imazio: Institution received funding from Kiniksa Pharmaceuticals, Ltd. as an investigative site; advisory committee from SOBI and Kiniksa. Dr Emanuele Bizzi, Dr Chiara Picchi and Dr Greta Mastrangelo declare they have no conflict of interest.

      References

        • Adler Y
        • Charron P
        • Imazio M
        • Badano L
        • Barón-Esquivias G
        • Bogaert J
        • Brucato A
        • Gueret P
        • Klingel K
        • Lionis C
        • Maisch B
        • Mayosi B
        • Pavie A
        • Ristic AD
        • Sabaté Tenas M
        • Seferovic P
        • Swedberg K
        • Tomkowski W
        • ESC Scientific Document Group
        2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
        Eur Heart J. 2015; 36: 2921-2964
        • Bouriche F
        • Toro A
        • Negre V
        • Yvorra S.
        Acute Pericarditis: Aetiologic Diagnosis and Practical Aspect of the Management.
        Curr Probl Cardiol. 2021; 46 (Apr)100769
        • Buoro S
        • Tombetti E
        • Ceriotti F
        • Simon C
        • Cugola D
        • Seghezzi M
        • Innocente F
        • Maestroni S
        • Del Carmen Baigorria Vaca M
        • Moioli V
        • Previtali G
        • Manenti B
        • Adler Y
        • Imazio M
        • Brucato A
        What is the normal composition of pericardial fluid?.
        Heart. 2020; (Nov 11:heartjnl-2020-317966)
        • Light RW.
        The Light criteria: the beginning and why they are useful 40 years later.
        Clin Chest Med. 2013; 34 (Mar): 21-26
        • Imazio M
        • Biondo A
        • Ricci D
        • Boffini M
        • Pivetta E
        • Brucato A
        • Giustetto C
        • De Ferrari GM
        • Rinaldi M.
        Contemporary biochemical analisys of normal pericardial fluid.
        Heart. 2020; 106: 5414
        • Buoro S
        • Seghezzi M
        • Baigorria Vaca MDC
        • Manenti B
        • Moioli V
        • Previtali G
        • Simon C
        • Cugola D
        • Brucato A
        • Ottomano C
        • Lippi G
        Comparison between optical microscopy and automation for cytometric analysis of pericardial fluids in a cohort of adult subjects undergoing cardiac surgery.
        J Clin Pathol. 2019; 72: 493-500
        • Sagristà-Sauleda J
        • Angel J
        • Permanyer-Miralda G
        • Soler-Soler J.
        Long-term follow-up of idiopathic chronic pericardial effusion.
        N Engl J Med. 1999 Dec 30; 341: 2054-2059
        • Imazio M
        • Lazaros G
        • Valenti A
        • De Carlini CC
        • Maggiolini S
        • Pivetta E
        • Giustetto C
        • Tousoulis D
        • Adler Y
        • Rinaldi M
        • Brucato A.
        Outcomes of idiopathic chronic large pericardial effusion.
        Heart. 2019; 105 (Mar): 477-481
        • De Filippo O
        • Gatti P
        • Rettegno S
        • Iannaccone M
        • D'Ascenzo F
        • Lazaros G
        • Brucato A
        • Tousoulis D
        • Adler Y
        • Imazio M
        Is pericardial effusion a negative prognostic marker? Meta-analysis of outcomes of pericardial effusion.
        J Cardiovasc Med (Hagerstown). 2019; 20 (Jan): 39-45
        • Hoit BD.
        Pericardial Effusion and Cardiac Tamponade in the New Millennium.
        Curr Cardiol Rep. 2017; 19 (Jul): 57
        • Vakamudi S
        • Ho N
        • Cremer PC.
        Pericardial Effusions: Causes, Diagnosis, and Management.
        Prog Cardiovasc Dis. 2017; 59 (Jan-Feb): 380-388
        • Chang SA.
        Tuberculous and Infectious Pericarditis.
        Cardiol Clin. 2017; 35 (Nov): 615-622
        • Inciardi RM
        • Lupi L
        • Zaccone G
        • Italia L
        • Raffo M
        • Tomasoni D
        • Cani DS
        • Cerini M
        • Farina D
        • Gavazzi E
        • Maroldi R
        • Adamo M
        • Ammirati E
        • Sinagra G
        • Lombardi CM
        • Metra M.
        Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19).
        JAMA Cardiol. 2020 Jul 1; 5: 819-824
        • Chahine J
        • Ala CK
        • Gentry JL
        • Pantalone KM
        • Klein AL.
        Pericardial diseases in patients with hypothyroidism.
        Heart. 2019; 105 (Jul): 1027-1033
        • Ghosh AK
        • Crake T
        • Manisty C
        • Westwood M.
        Pericardial Disease in Cancer Patients.
        Curr Treat Options Cardiovasc Med. 2018 Jun 23; 20: 60
        • Altan M
        • Toki MI
        • Gettinger SN
        • Carvajal-Hausdorf DE
        • Zugazagoitia J
        • Sinard JH
        • Herbst RS
        • Rimm DL.
        Immune Checkpoint Inhibitor-Associated Pericarditis.
        J Thorac Oncol. 2019; 14 (Jun): 1102-1108
        • Fadl SA
        • Nasrullah A
        • Harris A
        • Edwards R
        • Kicska G.
        Comprehensive review of pericardial diseases using different imaging modalities.
        Int J Cardiovasc Imaging. 2020; 36 (May): 947-969
        • Imazio M
        • Adler Y.
        Management of pericardial effusion.
        Eur Heart J. 2013; 34 (Apr): 1186-1197
        • Vecchié A
        • Chiabrando JG
        • Dell MS
        • Bonaventura A
        • Mauro AG
        • Wohlford G
        • Van Tassell BW
        • Berrocal DH
        • Montecucco F
        • Beutler A
        • Paolini JF
        • Gal TS
        • Abbate A.
        Clinical Presentation and Outcomes of Acute Pericarditis in a Large Urban Hospital in the United States of America.
        Chest. 2020; 158 (Dec): 2556-2567
        • Klein AL
        • Abbara S
        • Agler DA
        • Appleton CP
        • Asher CR
        • Hoit B
        • Hung J
        • Garcia MJ
        • Kronzon I
        • Oh JK
        • Rodriguez ER
        • Schaff HV
        • Schoenhagen P
        • Tan CD
        • White RD.
        American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular Computed Tomography.
        J Am Soc Echocardiogr. 2013; 26 (Sep965-1012.e15)
        • Lazaros G
        • Oikonomou V
        • Oikonomou E
        • Aznaouridis K
        • Vlachopoulos C
        • Vogiatzi G
        • Lazarou E
        • Imazio M
        • Brucato A
        • Adler Y
        • Tousoulis D.
        Recurrence of Pericardial Effusion After Pericardiocentesis: Does Catheter-Induced Acute Pericardial Inflammation Play a Role?.
        Am J Med Sci. 2021; 361 (May): 676-678
        • Miranda WR
        • Oh JK.
        Constrictive Pericarditis: A Practical Clinical Approach.
        Prog Cardiovasc Dis. 2017; 59 (Jan-Feb): 369-379
        • Depboylu BC
        • Mootoosamy P
        • Vistarini N
        • Testuz A
        • El-Hamamsy I
        • Cikirikcioglu M.
        Surgical Treatment of Constrictive Pericarditis.
        Tex Heart Inst J. 2017 Apr 1; 44: 101-106
        • Liu VC
        • Fritz AV
        • Burtoft MA
        • Martin AK
        • Greason KL
        • Ramakrishna H.
        Pericardiectomy for Constrictive Pericarditis: Analysis of Outcomes.
        J Cardiothorac Vasc Anesth. 2021 Feb 11; (S1053-0770(21)00115-4)
        • Perricone C
        • Katz D
        • Ciccacci C
        • Ceccarelli F
        • Valesini G
        • Shoenfeld Y
        • Borgiani P
        • Conti F.
        The Heart Matters: Contribution of Genetic Factors in Recurrent Pericarditis.
        Isr Med Assoc J. 2019; 21 (Jul): 487-490
        • Alsarah A
        • Alsara O
        • Laird-Fick HS.
        Cardiac manifestations of Familial Mediterranean fever.
        Avicenna J Med. 2017; 7 (Oct-Dec): 158-163
        • Hintenberger R
        • Falkinger A
        • Danninger K
        • Pieringer H.
        Cardiovascular disease in patients with autoinflammatory syndromes.
        Rheumatol Int. 2018; 38 (Jan): 37-50
        • Erken E
        • Erken E.
        Cardiac disease in familial Mediterranean fever.
        Rheumatol Int. 2018; 38 (Jan): 51-58
        • Perez-Brandão C
        • Trigo C
        • F Pinto F.
        Pericarditis - Clinical presentation and characteristics of a pediatric population.
        Rev Port Cardiol (Engl Ed). 2019; 38 (Feb): 97-101
        • Kilic A
        • Varkal MA
        • Durmus MS
        • Yildiz I
        • Yıldırım ZN
        • Turunc G
        • Oguz F
        • Sidal M
        • Omeroglu RE
        • Emre S
        • Yilmaz Y
        • Kelesoglu FM
        • Gencay GA
        • Temurhan S
        • Aydin F
        • Unuvar E.
        Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever.
        Pediatr Rheumatol Online J. 2015 Dec 12; 13: 59
        • Gaggiano C
        • Vitale A
        • Obici L
        • Merlini G
        • Soriano A
        • Viapiana O
        • Cattalini M
        • Maggio MC
        • Lopalco G
        • Montin D
        • Jaber MA
        • Dagna L
        • Manna R
        • Insalaco A
        • Piga M
        • La Torre F
        • Berlengiero V
        • Gelardi V
        • Ciarcia L
        • Emmi G
        • Ruscitti P
        • Caso F
        • Cimaz R
        • Hernández-Rodríguez J
        • Parronchi P
        • Sicignano LL
        • Verrecchia E
        • Iannone F
        • Sota J
        • Grosso S
        • Salvarani C
        • Frediani B
        • Giacomelli R
        • Mencarelli MA
        • Renieri A
        • Rigante D
        • Cantarini L
        Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor- Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.
        Mediators Inflamm. 2020 Aug 7; 20208562485
        • Navallas M
        • Inarejos Clemente EJ
        • Iglesias E
        • Rebollo-Polo M
        • Zaki FM
        • Navarro OM
        Autoinflammatory diseases in childhood, part 1: monogenic syndromes.
        Pediatr Radiol. 2020; 50 (Mar): 415-430
        • Camprubí D
        • Mitjavila F
        • Arostegui JI
        • Corbella X.
        Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant.
        Int J Rheum Dis. 2017; 20 (Apr): 510-514
        • Cantarini L
        • Rigante D
        • Merlini G
        • Vitale A
        • Caso F
        • Lucherini OM
        • Sfriso P
        • Frediani B
        • Punzi L
        • Galeazzi M
        • Cimaz R
        • Obici L.
        The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
        Semin Arthritis Rheum. 2014; 43 (Jun): 818-823
        • Yang CA
        • Chiang BL.
        Inflammasomes and Childhood Autoimmune Diseases: A Review of Current Knowledge.
        Clin Rev Allergy Immunol. 2021; 61 (Oct): 156-170
        • Welzel T
        • Kuemmerle-Deschner JB.
        Diagnosis and Management of the Cryopyrin- Associated Periodic Syndromes (CAPS): What Do We Know Today?.
        J Clin Med. 2021 Jan 1; 10: 128
        • Insalaco A
        • Prencipe G
        • Buonuomo PS
        • Ceccherini I
        • Bracaglia C
        • Pardeo M
        • Nicolai R
        • De Benedetti F.
        A novel mutation in the CIAS1/NLRP3 gene associated with an unexpected phenotype of cryopyrin-associated periodic syndromes.
        Clin Exp Rheumatol. 2014; 32 (Jan-Feb): 123-125
        • Malcova H
        • Strizova Z
        • Milota T
        • Striz I
        • Sediva A
        • Cebecauerova D
        • Horvath R.
        IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives.
        Front Immunol. 2021 Feb 1; 11619257
        • Bouomrani S
        • Masmoudi I
        • Teber SB.
        Familial Mediterranean fever: What associations to screen for?.
        Reumatologia. 2020; 58: 150-154
        • Krainer J
        • Siebenhandl S
        • Weinhäusel A.
        Systemic autoinflammatory diseases.
        J Autoimmun. 2020; 109 (May)102421
        • Brucato A
        • Brambilla G.
        Recurrent idiopathic pericarditis: familial occurrence.
        Int J Cardiol. 2005 Jul 20; 102: 529
        • Lazaros G
        • Antonopoulos AS
        • Imazio M
        • Solomou E
        • Lazarou E
        • Vassilopoulos D
        • Adler Y
        • Stefanadis C
        • Tousoulis D.
        Clinical significance of pleural effusions and association with outcome in patients hospitalized with a first episode of acute pericarditis.
        Intern Emerg Med. 2019; 14 (Aug): 745-751
        • Brucato A
        • Brambilla G
        • Moreo A
        • Alberti A
        • Munforti C
        • Ghirardello A
        • Doria A
        • Shinar Y
        • Livneh A
        • Adler Y
        • Shoenfeld Y
        • Mauri F
        • Palmieri G
        • Spodick DH.
        Long-term outcomes in difficult-to-treat patients with recurrent pericarditis.
        Am J Cardiol. 2006 Jul 15; 98: 267-271
        • Navallas M
        • Inarejos Clemente EJ
        • Iglesias E
        • Rebollo-Polo M
        • Hernández JC
        • Navarro OM
        Autoinflammatory diseases in childhood, part 2: polygenic syndromes.
        Pediatr Radiol. 2020; 50 (Mar): 431-444
        • Brucato A
        • Brambilla G
        • Adler Y
        • Spodick DH
        • Canesi B.
        Therapy for recurrent acute pericarditis: a rheumatological solution?.
        Clin Exp Rheumatol. 2006; 24 (Jan-Feb): 45-50
        • Liantinioti G
        • Argyris AA
        Protogerou AD, Vlachoyiannopoulos P. The Role of Colchicine in the Treatment of Autoinflammatory Diseases.
        Curr Pharm Des. 2018; 24: 690-694
        • Leung YY
        • Yao Hui LL
        • Kraus VB
        • Colchicine
        Update on mechanisms of action and therapeutic uses.
        Semin Arthritis Rheum. 2015; 45 (Dec; Epub 2015 Jun 26. PMID: 26228647; PMCID: PMC4656054.): 341-350https://doi.org/10.1016/j.semarthrit.2015.06.013
        • Vecchiè A
        • Dell M
        • Mbualungu J
        • Ho AC
        • Van Tassell B
        • Abbate A.
        Recurrent pericarditis: an update on diagnosis and management.
        Panminerva Med. 2021 Feb 23;
        • Papageorgiou N
        • Briasoulis A
        • Lazaros G
        • Imazio M
        • Tousoulis D.
        Colchicine for prevention and treatment of cardiac diseases: A meta-analysis.
        Cardiovasc Ther. 2017; 35 (Feb): 10-18
        • Leung YY
        • Yao Hui LL
        • Kraus VB
        Colchicine–Update on mechanisms of action and therapeutic uses.
        Semin Arthritis Rheum. 2015; 45 (Dec): 341-350
        • Bonaventura A
        • Montecucco F.
        Inflammation and pericarditis: Are neutrophils actors behind the scenes?.
        J Cell Physiol. 2019; 234 (May): 5390-5398
        • Imazio M
        • Nidorf M.
        Colchicine and the heart.
        Eur Heart J. 2021 Jul 21; 42: 2745-2760
        • Cacoub P
        • Marques C.
        Acute recurrent pericarditis: from pathophysiology towards new treatment strategy.
        Heart. 2020; 106 (Jul): 1046-1051
        • Lutschinger LL
        • Rigopoulos AG
        • Schlattmann P
        • Matiakis M
        • Sedding D
        • Schulze PC
        Noutsias M. Meta-analysis for the value of colchicine for the therapy of pericarditis and of postpericardiotomy syndrome.
        BMC Cardiovasc Disord. 2019 Sep 2; 19: 207
        • Hayashi R
        • Wada H
        • Ito K
        • Adcock IM.
        Effects of glucocorticoids on gene transcription.
        Eur J Pharmacol. 2004 Oct 1; 500: 51-62
        • Galluzzo A
        • Imazio M.
        Advances in medical therapy for pericardial diseases.
        Expert Rev Cardiovasc Ther. 2018; 16 (Sep): 635-643
        • Meibohm B
        • Zhou H.
        Characterizing the impact of renal impairment on the clinical pharmacology of biologics.
        J Clin Pharmacol. 2012; 52 (Jan): 54S-62S
        • BB Yang
        • Baughman S
        • Sullivan JT.
        Pharmacokinetics of anakinra in subjects with different levels of renal function.
        Clin Pharmacol Ther. 2003; 74 (Jul): 85-94
        • Lazaros G
        • Tousoulis D.
        Interleukin-1 inhibition with anakinra: a valuable ally to reverse constrictive pericarditis?.
        Heart. 2020; 106 (Oct): 1540-1542
        • Shaukat MH
        • Singh S
        • Davis K
        • Torosoff M
        • Peredo-Wende R.
        Efficacy of anakinra for idiopathic and non-idiopathic pericarditis refractory or intolerant to conventional therapy.
        Eur Heart J Acute Cardiovasc Care. 2020; 9 (Dec): 888-892
        • Khayata M
        • Shah NP
        • Verma BR
        • Giugni AS
        • Alkharabsheh S
        • Asher CR
        • Imazio M
        • Klein AL.
        Usefulness of Interleukin-1 Receptor Antagonists in Patients With Recurrent Pericarditis.
        Am J Cardiol. 2020 Jul 15; 127: 184-190
        • Wohlford GF
        • Buckley LF
        • Vecchié A
        • Kadariya D
        • Markley R
        • Trankle CR
        • Chiabrando JG
        • de Chazal HM
        • Van Tassell B
        • Abbate A.
        Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.
        J Cardiovasc Pharmacol. 2020; 76 (Jul): 50-52
        • Brucato A
        • Imazio M
        • Gattorno M
        • Lazaros G
        • Maestroni S
        • Carraro M
        • Finetti M
        • Cumetti D
        • Carobbio A
        • Ruperto N
        • Marcolongo R
        • Lorini M
        • Rimini A
        • Valenti A
        • Erre GL
        • Sormani MP
        • Belli R
        • Gaita F
        • Martini A.
        Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial.
        JAMA. 2016 Nov 8; 316: 1906-1912
        • Imazio M
        • Andreis A
        • De Ferrari GM
        • Cremer PC
        • Mardigyan V
        • Maestroni S
        • Luis SA
        • Lopalco G
        • Emmi G
        • Lotan D
        • Marcolongo R
        • Lazaros G
        • De Biasio M
        • Cantarini L
        • Dagna L
        • Cercek AC
        • Pivetta E
        • Varma B
        • Berkson L
        • Tombetti E
        • Iannone F
        • Prisco D
        • Caforio ALP
        • Vassilopoulos D
        • Tousoulis D
        • De Luca G
        • Giustetto C
        • Rinaldi M
        • Oh JK
        • Klein AL
        • Brucato A
        • Adler Y.
        Anakinra for corticosteroid-dependent and colchicine-resistant pericarditis: The IRAP (International Registry of Anakinra for Pericarditis) study.
        Eur J Prev Cardiol. 2020; 27 (Jun): 956-964
        • Kaiser C
        • Knight A
        • Nordström D
        • Pettersson T
        • Fransson J
        • Florin-Robertsson E
        • Pilström B.
        Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations.
        Rheumatol Int. 2012; 32 (Feb): 295-299
        • Goletti D
        • Petrone L
        • Ippolito G
        • Niccoli L
        • Nannini C
        • Cantini F.
        Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs.
        Expert Rev Anti Infect Ther. 2018; 16 (Jun): 501-512
        • LiverTox
        Clinical and Research Information on Drug-Induced Liver Injury [Internet].
        National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD)2020 (2012–. RilonaceptApr 20. PMID: 31643801)
        • Radin A
        • Marbury T
        • Osgood G
        • Belomestnov P.
        Safety and pharmacokinetics of subcutaneously administered rilonacept in patients with well-controlled end- stage renal disease (ESRD).
        J Clin Pharmacol. 2010; 50 (Jul): 835-841
        • Ilowite NT
        • Prather K
        • Lokhnygina Y
        • Schanberg LE
        • Elder M
        • Milojevic D
        • Verbsky JW
        • Spalding SJ
        • Kimura Y
        • Imundo LF
        • Punaro MG
        • Sherry DD
        • Tarvin SE
        • Zemel LS
        • Birmingham JD
        • Gottlieb BS
        • Miller ML
        • O'Neil K
        • Ruth NM
        • Wallace CA
        • Singer NG
        • Sandborg CI
        Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis.
        Arthritis Rheumatol. 2014; 66 (Sep): 2570-2579
        • Hoffman HM
        • Throne ML
        • Amar NJ
        • Sebai M
        • Kivitz AJ
        • Kavanaugh A
        • Weinstein SP
        • Belomestnov P
        • Yancopoulos GD
        • Stahl N
        • Mellis SJ.
        Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies.
        Arthritis Rheum. 2008; 58 (Aug): 2443-2452
        • Hoffman HM
        • Throne ML
        • Amar NJ
        • Cartwright RC
        • Kivitz AJ
        • Soo Y
        • Weinstein SP.
        Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study.
        Clin Ther. 2012; 34 (Oct): 2091-2103
        • Klein AL
        • Imazio M
        • Cremer P
        • Brucato A
        • Abbate A
        • Fang F
        • Insalaco A
        • LeWinter M
        • Lewis BS
        • Lin D
        • Luis SA
        • Nicholls SJ
        • Pano A
        • Wheeler A
        • Paolini JF
        • RHAPSODY Investigators
        Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.
        N Engl J Med. 2021 Jan 7; 384 (Findings in this study represent a relevant step forward in the therapy of recurrent pericarditis, adding evidence to the importance in IL-1 in its pathogenesis and reporting on the efficacy of Rilonacept, a new therapeutic tool for its management): 31-41
        • Chioato A
        • Noseda E
        • Colin L
        • Matott R
        • Skerjanec A
        • Dietz AJ
        Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: A randomized study in healthy subjects.
        Clin. Drug Investig. 2013; 33: 801-808
        • Chakraborty A
        • Tannenbaum S
        • Rordorf C
        • Lowe PJ
        • Floch D
        • Gram H
        • Roy S.
        Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1β monoclonal antibody.
        Clin. Pharmacokinet. 2012; 51: 0-18
      1. Annex I. IFLA J. 20, 338–340 (1994).

        • De Benedetti F
        • Gattorno M
        • Anton J
        • Ben-Chetrit E
        • Frenkel J
        • Hoffman HM
        • Koné-Paut I
        • Lachmann HJ
        • Ozen S
        • Simon A
        • Zeft A
        • Calvo Penades I
        • Moutschen M
        • Quartier P
        • Kasapcopur O
        • Shcherbina A
        • Hofer M
        • Hashkes PJ
        • Van der Hilst J
        • Hara R
        • Bujan-Rivas S
        • Constantin T
        • Gul A
        • Livneh A
        • Brogan P
        • Cattalini M
        • Obici L
        • Lheritier K
        • Speziale A
        • Junge G
        Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.
        N. Engl. J. Med. 2018; 378: 1908-1919
        • Sąhin A.
        • Derin M.E.
        • Albayrak F.
        • Karakaş B.
        • Karagöz Y.
        Assessment of effectiveness of anakinra and canakinumab in patients with colchicine-resistant/unresponsive familial Mediterranean fever.
        Adv. Rheumatol. 2020; 60: 1-7
        • Feist E
        • Quartier P
        • Fautrel B
        • Schneider R
        • Sfriso P
        • Efthimiou P
        • Cantarini L
        • Lheritier K
        • Leon K
        • Karyekar CS
        • Speziale A.
        Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups.
        Clin. Exp. Rheumatol. 2018; 36: 668-675
        • Landmann E.C.
        • Walker U.A
        Pharmacological treatment options for cryopyrin-associated periodic syndromes.
        Expert Rev. Clin. Pharmacol. 2017; 10: 855-864
        • Gattorno M
        • Obici L
        • Cattalini M
        • Tormey V
        • Abrams K
        • Davis N
        • Speziale A
        • Bhansali SG
        • Martini A
        • Lachmann HJ.
        Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): An open-label, phase II study.
        Ann. Rheum. Dis. 2017; 76: 173-178
        • Ruperto N
        • Brunner HI
        • Quartier P
        • Constantin T
        • Wulffraat N
        • Horneff G
        • Brik R
        • McCann L
        • Kasapcopur O
        • Rutkowska-Sak L
        • Schneider R
        • Berkun Y
        • Calvo I
        • Erguven M
        • Goffin L
        • Hofer M
        • Kallinich T
        • Oliveira SK
        • Uziel Y
        • Viola S
        • Nistala K
        • Wouters C
        • Cimaz R
        • Ferrandiz MA
        • Flato B
        • Gamir ML
        • Kone-Paut I
        • Grom A
        • Magnusson B
        • Ozen S
        • Sztajnbok F
        • Lheritier K
        • Abrams K
        • Kim D
        • Martini A
        • Lovell DJ
        • PRINTO
        • PRCSG
        Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis.
        N. Engl. J. Med. 2012; 367: 2396-2406
        • Çakan M.
        • Karadağ Ş.G.
        • Ayaz N.A
        Canakinumab in colchicine resistant familial mediterranean fever and other pediatric rheumatic diseases.
        Turk. J. Pediatr. 2020; 62: 167-174
        • Epçaçan S.
        • Sahin S.
        • Kasapcopur O.
        Anaphylactic reaction to anakinra in a child with steroid-dependent idiopathic recurrent pericarditis and successful management with canakinumab.
        Cardiol. Young. 2019; 29: 549-551
        • Signa S
        • D'Alessandro M
        • Consolini R
        • Miniaci A
        • Bustaffa M
        • Longo C
        • Tosca MA
        • Bizzi M
        • Caorsi R
        • Mendonça LO
        • Pession A
        • Ravelli A
        • Gattorno M
        Failure of anti Interleukin-1 ß monoclonal antibody in the treatment of recurrent pericarditis in two children.
        Pediatr. Rheumatol. 2020; 18: 1-5
        • Kougkas N
        • Fanouriakis A
        • Papalopoulos I
        • Bertsias G
        • Avgoustidis N
        • Repa A
        • Sidiropoulos P.
        Canakinumab for recurrent rheumatic disease associated-pericarditis: a case series with long-term follow-up.
        Rheumatology (Oxford). 2018; 57: 1494-1495
        • Gupta M
        • Kaul S
        • Velazquez GR
        • Bandyopadhyay D
        • Fonarow GC
        • Klein A
        • Ghosh RK.
        A Brief Overview of Recurrent Pericarditis Management and the Potential of Rilonacept as a New Therapeutic Option.
        Am J Cardiovasc Drugs. 2021 May 19;
        • Correia ETO
        • Dos Santos Barbetta LM
        • de Almeida JPCL
        • Mesquita ET
        Anakinra in Recurrent Pericarditis: Current Evidence on Clinical Use, Effectiveness, and Safety.
        J Cardiovasc Pharmacol. 2020; 76 (Jul): 42-49
        • Serati L
        • Carnovale C
        • Maestroni S
        • Brenna M
        • Smeriglia A
        • Massafra A
        • Bizzi E
        • Picchi C
        • Tombetti E
        • Brucato A.
        Management of acute and recurrent pericarditis in pregnancy.
        Panminerva Med. 2021; (Mar 9)
        • Carnovale C
        • Tombetti E
        • Battini V
        • Mazhar F
        • Radice S
        • Nivuori M
        • Negro E
        • Tamanini S
        • Brucato A.
        Inflammasome Targeted Therapy in Pregnancy: New Insights From an Analysis of Real-World. Data From the FAERS Database and a Systematic Review.
        Front Pharmacol. 2021 Jan 20; 11612259
        • Orabona R
        • Zanardini C
        • Zatti S
        • Lojacono A
        • Procopio R
        • Vizzardi E
        • Tincani A
        • Sartori E
        • Andreoli L.
        Onset of idiopathic recurrent pericarditis during pregnancy: successful management with colchicine and intravenous immunoglobulins.
        J Cardiovasc Med (Hagerstown). 2020; 21 (May): 393-395
        • Youngstein T
        • Hoffmann P
        • Gül A
        • Lane T
        • Williams R
        • Rowczenio DM
        • Ozdogan H
        • Ugurlu S
        • Ryan J
        • Harty L
        • Riminton S
        • Headley AP
        • Roesler J
        • Blank N
        • Kuemmerle-Deschner JB
        • Simon A
        • Woolf AS
        • Hawkins PN
        • Lachmann HJ.
        International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.
        Rheumatology (Oxford). 2017 Dec 1; 56: 2102-2108
        • Egawa M
        • Imai K
        • Mori M
        • Miyasaka N
        • Kubota T.
        Placental Transfer of Canakinumab in a Patient with Muckle-Wells Syndrome.
        J Clin Immunol. 2017; 37 (May): 339-341
      2. Drugs and Lactation Database (LactMed) [Internet].
        National Library of Medicine (US, Bethesda (MD)2021 (2006–. AnakinraMay 17)