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Cardiology, Cardiothoracic Department, University Hospital Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100, Udine, Italy
University of Milano, Department of biomedical and clinical sciences “Luigi Sacco”, Fatebenefratelli Hospital, Piazzale Principessa Clotilde 3, 20121, Milano, Italy
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.
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) [
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 [
]. 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 [
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 [
]. 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.
], 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 [
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). [
Comparison between optical microscopy and automation for cytometric analysis of pericardial fluids in a cohort of adult subjects undergoing cardiac surgery.
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 [
]. 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 [
] 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 [
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 [
, 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 [
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 [
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 [
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.
]. 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 [
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 [
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 [
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.
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.
The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
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 [
]. 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) [
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.
The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
]. 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 [
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 [
All these findings might explain why some patients experience recurrent inflammatory patterns, by eventual genetic or epigenetic modifications of proteins composing inflammasome [
]. 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 [
], 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 [
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 [
]. 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 [
]. 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 [
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) [
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 [
]: 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 [
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 [
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 [
]. 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 [
]. 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 [
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 [
]. 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 [
]. 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 [
Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis.
Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies.
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.
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
]. 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 [
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
]. 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 [
Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: A randomized study in healthy subjects.
]. 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 [
Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups.
]. 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.
]. 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 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 [
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 [
], 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 [
]. 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 [
]. 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 [
Concerning anti -IL1 agents, no studies reporting maternal and/or fetal outcome following the use of rilonacept were found. Only a retrospective cohort study [
] 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 [
]. 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 [
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 [
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.
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2015 ESC Guidelines for the diagnosis and management of pericardial diseases.
Comparison between optical microscopy and automation for cytometric analysis of pericardial fluids in a cohort of adult subjects undergoing cardiac surgery.
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.
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.
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.
The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up.
Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial.
Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis.
Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies.
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.
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
Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: A randomized study in healthy subjects.
Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups.
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