Idiopathic Recurrent Pericarditis Research Articles

Goflikicept and Related IL-1 Inhibitors in the Treatment of Recurrent Pericarditis.

Anticytokine biologics are a promising anti-inflammatory therapy for recurrent pericarditis. Several studies have proved the efficacy and safety of interleukin-1 (IL-1) inhibitors, such as anakinra and rilonacept in patients with recurrent pericarditis. Treatment with goflikicept in a recent phase 2 and 3 trial significantly reduced the pericarditis recurrence rate compared with both the placebo and the allowed withdrawal of standard-of-care therapy. Patients with idiopathic recurrent pericarditis (IRP) achieved remission within the first 14 days of therapy. In rilonacept inhibition of interleukin-1 alpha and beta for recurrent pericarditis (phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis), rilonacept led to a significantly lower risk of pericarditis recurrence than placebo (hazard ratio, 0.04; P < 0.001) and a rapid resolution of recurrent pericarditis episodes. However, 74% of patients in the placebo group demonstrated recurrence, compared with 7% in the rilonacept group. The efficacy of anakinra was demonstrated by the AIRTRIP (anakinra-treatment of recurrent idiopathic pericarditis) trial, which showed a reduction in the incidence of recurrent pericarditis in anakinra versus placebo-treated patients (18.2% vs 90%). In patients with recurrences, the mean time to flare was 28.4 days in the placebo group versus 76.5 days in the anakinra group. IL-1 inhibitors require further research and have the potential to decrease the use of first-line drug regimens for recurrent pericarditis that are not tolerated in specific patient groups.

Pericarditis. Causes, Mechanisms of Development, Variants of Course and Therapeutic Approaches in Modern Conditions

Under physiological conditions, the pericardial cavity contains serous fluid (15-50 ml), which belongs to the plasma ultrafiltrate and is visualized during echocardiography only in systole. The thickness of the pericardium in an adult averages 2 mm (1-3 mm). Inflammatory lesions of the pericardium with or without effusion into its cavity can act as an independent disease, and as a secondary manifestation of another pathological condition. Pericarditis of infectious (14-16%) and non-infectious (15-20%) nature, primary and secondary, acute, chronic and recurrent are commonly distinguished. The prevalence of acute and idiopathic recurrent pericarditis is 27.7 per 100,000 population and 5.4-8.1 per 100,000 population, respectively. Currently, idiopathic recurrent pericarditis belongs to polygenic autoinflammatory diseases, where an important role in the initiation of the pathologic process belongs to the inflammatory cytokine — interleukin-1 (β and α). The most characteristic manifestations of acute pericarditis are chest pain, dyspnea and fever. The article summarizes the main aspects of etiology, clinical manifestations, diagnosis and therapy of pericarditis, including the peculiarities of its treatment taking into account specific conditions. A clinical case demonstrated a case of acute effusion pericarditis with recurrence, which was characterized by rapid progression of heart failure symptoms, as well as systemic manifestations (anemia, hypercytokinemia, marked muscle weakness). The results of echocardiography allowed to identify the presence of pericardial effusion. Steroid and non-steroidal anti-inflammatory, anticoagulant and antibacterial therapy led to the disappearance of pericardial effusion and normalization of the activity of inflammatory markers in serum. However, in the dynamics of observation the attempt to suspend glucocorticoid therapy again led to fluid accumulation in the pericardium, which required continuation of steroidal and non-steroidal anti-inflammatory drugs.

Novel therapeutic insights into the treatment of pericarditis: Targeting the innate immune system.

Acute pericarditis is characterized by pericardial inflammation which can be treated with anti-inflammatory drugs. A considerable percentage of patients develops recurrent pericarditis with several relapses. In developed countries, the idiopathic form is the most frequent and has a high risk of recurrences. Two pathophysiological mechanisms have been described for idiopathic recurrent pericarditis, autoimmune and autoinflammatory. The autoimmune mechanism is more frequently encountered in patients with rheumatologic disorders, especially systemic lupus erythematosus. The innate immune system plays a central role in the pathophysiology of pericarditis, especially in the autoinflammatory phenotype. Current evidence highlights the central role played by interleukin 1 (IL-1) and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) in idiopathic recurrent pericarditis. Accordingly, IL-1 blockers have been approved for the treatment of this condition. Neutrophils are likely to be important in such setting, however their role has only been partially investigated. In the present review we have collected the current knowledge on the role of innate immune system in pericarditis pathophysiology and how this can be used to provide targeted treatments for patients with recurrent pericarditis.

Anakinra in idiopathic recurrent pericarditis: acomprehensive case series and literature review.

Idiopathic recurrent pericarditis (IRP) is defined by recurring episodes of pericardial inflammation without aknown cause. This study investigates the safety and efficacy of anakinra, an interleukin‑1 inhibitor, as asuccessful therapy for IRP in cases resistant to conventional treatment. Aretrospective evaluation of patients treated at our autoinflammatory center between 2011 and 2023 was conducted. Patient files were examined for demographic, clinical, and treatment response data, including nonsteroid anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. Monogenic autoinflammatory disease screening was performed for Mediterranean Fever (MEFV), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase (MVK), nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Patients who experienced multiple episodes of pericarditis were diagnosed with recurrent pericarditis. The study evaluated anakinra treatment in IRP patients unresponsive to conventional therapy. The study included 21participants, 9(42.9%) female and 12(57.1%) male. The average age of the participants was 43.1 ± 16.5years. The MEFV mutation analysis revealed that 2(9.5%) had amutation in exon10 and4 (19.0%) had one in exon2. Out of the 16cases, 15successfully discontinued steroid treatment. Four patients (19.0%) experienced injection site reactions. C‑reactive protein (CRP) levels were measured at an average of 196 ± 67.8 mg/l before and 2.6 ± 3.15 mg/l after anakinra treatment. In conclusion, the study adds to the growing evidence for the efficacy of interleukin-1inhibitors, such as anakinra, as apromising treatment modality for IRP in cases resistant to conventional treatment.

Rilonacept use in lupus pericarditis.

Lupus pericarditis affects 22% of patients with systemic lupus erythematosus (SLE), is associated with worse outcomes, and often requires immunosuppression. Rilonacept is an interleukin-1 receptor antagonist approved for the treatment of recurrent idiopathic pericarditis, but its efficacy in lupus pericarditis is unknown. Here, we report the efficacy of rilonacept in a case series of patients with lupus pericarditis. We describe a case series of 4 patients with refractory lupus pericarditis treated with rilonacept in the Johns Hopkins Lupus Center. All patients met the 2012 SLICC criteria for SLE. Refractory lupus pericarditis was defined as recurring or persistent typical pericardial pain symptoms despite standard-of-care treatment including at least one immunosuppressant. Four patients with refractory pericarditis were included. All patients were women, age ranged 26-44 years, 2 patients reported White, 1 Black, and 1 Hispanic ethnicity. Extra-pericardial SLE manifestations were heterogeneous among patients. Only 1 of 3 patient had elevated CRP (not measured in one). Two patients were previously treated with anakinra with initial response, but pericarditis redeveloped in both. Rilonacept led to complete resolution of pericardial symptoms in 3 patients, and partial resolution (40%) in 1, within 2 weeks. Rilonacept successfully treated lupus pericarditis in this case series. Rilonacept should be considered for the treatment of lupus pericarditis.

Treatment of Idiopathic Recurrent Pericarditis With Goflikicept: Phase II/III Study Results

BackgroundIdiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disease. Interleukin (IL)-1α and IL-1β are the pivotal cytokines in the pathophysiology of acute pericarditis and its recurrence. We created a phase II/III study with a new IL-1 inhibitor—goflikicept in IRP. ObjectivesThis study sought to evaluate the efficacy and safety of goflikicept treatment in patients with IRP. MethodsWe conducted a 2-center open-label study of goflikicept in patients with IRP with and without recurrence at time of enrollment. The study consisted of 4 periods: screening, run-in (open-label treatment period), randomized withdrawal, and follow-up. Patients with clinical response to goflikicept in the run-in period were randomized (1:1) to a placebo-controlled withdrawal period, where the time to first pericarditis recurrence (primary endpoint) was evaluated. ResultsWe enrolled 22 patients, and 20 of these patients were randomized. Reduction of C-reactive protein level accompanied by reduction of chest pain and pericardial effusion compared to baseline was demonstrated during the run-in period. Recurrence of pericarditis occurred in 9 of 10 patients in the placebo group, and there were no recurrence events in goflikicept group within 24 weeks after randomization (P < 0.001). A total of 122 adverse events were reported in 21 patients (95.5%), with no deaths and no new safety signals identified for goflikicept. ConclusionsTreatment with goflikicept prevented recurrences and maintained IRP remission with a favorable risk-benefit ratio. Goflikicept reduced the risk of recurrence compared with placebo. (Study to Evaluate the Efficacy and Safety of RPH-104 Treatment in Patients With Idiopathic Recurrent Pericarditis; NCT04692766)

Acute pericarditis with pleuropulmonary involvement, fever and elevated C-reactive protein: A systemic autoinflammatory disease? A cohort study

ObjectivesThis cohort study describes a systemic phenotype of pericarditis, comparing this phenotype with other forms of pericarditis. Patients and methodsPatients in our center were enrolled in a prospectively maintained registry from 2019 to 2022. 412 patients with idiopathic recurrent pericarditis were analyzed. “Systemic inflammatory” subset was defined as the presence of all the following criteria: fever ≥38C°, CRP ≥2 times normal values, pleural effusion detected with any imaging techniques. The absence of any of the 3 criteria was defined as “isolated” subset. ResultsWe found that 211 (51.2%) of 412 patients (188 female) presented the systemic subset and the variables significantly associated with this subset in univariate analysis (p<0.001) were: higher mean age: 45.5 (±SD 17.2) vs 39.9 (±SD 16.4) years, higher mean CRP values: 128.8 vs 49.9 mg/L, higher proportion of pericardiocentesis: 19% vs 1.5%, higher mean leukocyte count: 13,143.3 vs 9910.3/mm3, higher mean neutrophils number: 10,402.5 vs 6779.8 /mm3 and lower mean lymphocyte count: 1693.9 vs 2079.3 /mm3. As results the neutrophil-to-lymphocyte ratio was higher in systemic inflammatory phenotype: 6.6 vs 3.4 (p< 0.001). Anti-IL1 therapy was started more frequently in the systemic subgroup (26%) than in the isolated subset (7.5%) (p < 0.001). On multivariate analysis neutrophil count and lymphopenia were statistically associated with the systemic subset (p < 0.001). ConclusionThis results demonstrate the relevance of the systemic inflammatory phenotype, characterized by pleural effusions, confirming its analogy with autoinflammatory diseases, thus possibly requiring an eventual escalation of therapy to IL-1 inhibitors.

Problems of immunopathology and prospects for pharmacotherapy of idiopathic recurrent pericarditis: Using an interleukin 1 inhibitor (Anakinra)

Pericarditis, a clinical syndrome characterized by inflammation and thickening of the pericardium, is one of the most common forms of inflammatory diseases of the cardiovascular system. The most common and severe complication of acute pericarditis is idiopathic recurrent pericarditis (IRP), which has a poor prognosis associated with the risk of cardiac tamponade and constrictive pericarditis. The pathogenesis of pericarditis is associated with a complex interaction of environmental factors, genetic predisposition, and pathological activation of innate and acquired immunity. Autoinflammatory mechanisms associated with hyperproduction of interleukin (IL) 1 attract particular attention. Standard therapy for pericarditis includes non-steroidal antiinflammatory drugs, colchicine, glucocorticoids, and immunosuppressive drugs. A new direction in the pharmacotherapy of pericarditis is associated with the use of Anakinra (a recombinant non-glycosylated analog of an IL-1 receptor antagonist), which blocks the signaling of IL-1β and IL-1α. The materials of numerous studies are summarized, indicating that Anakinra is an effective drug for the treatment of patients with IRI who are resistant to standard therapy. It is assumed that the wider use of Anakinra, especially in the early stages of pericarditis, will not only improve the prognosis, but also be important for the identification of the autoinflammatory phenotype of IRI and the development of personalized therapy programs.

Abstract 15397: Pericardial Delayed Hyperenhancement Predicts Outcomes in Idiopathic Recurrent Pericarditis

Introduction: Recurrent pericarditis (RP) is defined as recurrence of pericarditis after an initial documented episode of pericarditis and symptom free interval of four to six weeks. In this study, we aimed to investigate the prognostic value of the pericardial delayed hyperenhancement (DHE) in patients with idiopathic recurrent pericarditis (IRP). Hypothesis: We hypothesize that moderate to severe DHE is correlated with worse outcomes. Methods: Consecutive patients (n=223) with IRP from 2012-2019 were included. Out of 223 patients, 213 had DHE tracing. Patients were then followed for events of clinical improvement (CI), clinical remission (CR), and clinical recurrence. Results: The mean age of the 223 patients included was 45 ± 16 years, and 51% were females. DHE was divided into two groups none/mild (n=160) and moderate/severe (n=53). At baseline, median number of prior recurrences was 3 (Q1, Q3: 2,5). Furthermore, when adjusted for age, gender, prior number of recurrences, and anti-inflammatory therapy on multivariable cox-regression analysis, moderate to severe DHE was independently associated with less likelihood of having CI (HR 0.24, p&lt;0.001) and CR (HR 0.31, p=0.011), and more likelihood of having clinical recurrence (HR 1.58, p=0.02). On Kaplan Meier analysis, moderate to severe DHE was associated with more time to clinical improvement (log rank p&lt;0.0001), more time to clinical remission (log rank p&lt;0.0001), and less time to clinical recurrence (log rank p=0.0047). Conclusions: Moderate to severe DHE is independently correlated with worse outcomes in patients with IRP. DHE should be considered an important part of evaluation in patients with recurrent pericarditis and should be included in new guidelines. Our study will help clinicians utilize DHE as a prognostic marker in patients with IRP.

Abstract 14951: An Interpretable Machine Learning Model for Predicting Long-Term Clinical Outcomes in Recurrent Pericarditis

Background: Recurrent pericarditis (RP) is a complex condition associated with high morbidity. A few studies have evaluated which factors are associated with clinical remission and relapse. However currently, no models exist to predict these outcomes. Objective: We developed an explainable machine learning (ML) model that can predict long-term outcomes in patients with RP and enable identification of patients with worse outcomes. Methods: Consecutive patients with RP (n=365) from 2012-2019 included. The primary outcome was CR. The dataset was partitioned into training and evaluation sets with 5-fold cross-validation approach. The eXtreme Gradient Boosting (XGBoost) method was used to identify predictors for CR, calculate the likelihood of CR within 5 years, and stratify patients into high-risk and low-risk. The performance of the model was evaluated using the C-index. The log-rank test was utilized to assess the difference between Kaplan-Meier curves of risk groups. Finally, an explainable ML approach, SHAP, was deployed to generate both global and individual explanations of the model’s decisions. Results: The cohort was 56% female (n=205) with a mean age of 46 ± 15 years. 61% were idiopathic RP (n=223), 21% were post-cardiac injury syndrome RP (n=77), and 18% were autoimmune RP (n=65) patients. CR was achieved in 32% (n=118). XGBoost risk model included steroid dependency, total no. of recurrences, age, HR, LVEF, gender, etiology, and pericardial delayed gadolinium hyperenhancement as important parameters. The model predicted the outcome with C-index of 0.801 (95%CI, 0.74-0.86) on the validation set and exhibited significant ability in stratification of patients into low- and high-risk groups (log-rank P&lt;0.001). Conclusions: We developed a novel ML-based model for predicting CR, and stratifying patients, with high discrimination ability. The use of an explainable ML model can aid physicians in making individualized treatment decision in RP patients.

Efficacy of anakinra treatment in pediatric rheumatic diseases: Our single-center experience.

This study aims to present our experience on anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, and efficacy results in pediatric rheumatic diseases in our clinic. Between July 1st, 2016 and July 1st, 2020, a total of 33 pediatric patients (18 males, 15 females; mean age: 6±3.4 years; range 4 to 13 years) with pediatric rheumatic diseases who were treated with anakinra were retrospectively analyzed. The patients with over one-month treatment period and followed for at least one year were included. Demographic and clinical findings, outcomes, adverse events, prior and/or additional treatments were collected at baseline, at 3 and 12 months of therapy. There were 33 patients with different pediatric rheumatic diseases (11 with systemic juvenile idiopathic arthritis [sJIA] complicated by macrophage activation syndrome [MAS], six with hyperimmunoglobulin-D syndrome, five with cryopyrin-associated periodic syndrome, five with familial Mediterranean fever, four with idiopathic recurrent pericarditis, one with NLRP12-associated periodic fever syndrome and one with unclassified systemic autoinflammatory disease), in the study group. The complete response was observed 69.7% of patients, partial response in 24.2%, and no response in 6.1% at three months of treatment. Inactive disease status was achieved in 45.5% of the patients with remission-on medication and 18.2% of the patients with remission-off medication at the end of a year. Anakinra was switched to other biological treatments in 51.5% of patients (n=17). Biological switch to canakinumab and tocilizumab were observed in 70.6% and 29.4% of these patients. Except for local reactions (n=2), no adverse events were observed in any of the patients. Anakinra appears to be a promising treatment alternative owing to its rapid effect as a result of its short half-life in autoinflammatory conditions. While short-term therapy seems to be sufficient for the sJIA complicated by MAS, the patients with systemic autoinflammatory diseases maintenance a more anakinra-dependent course.

Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center.

BackgroundIdiopathic recurrent pericarditis (IRP) is an orphan disease that carries significant morbidity, partly driven by corticosteroid dependence. Innate immune modulators, colchicine and anti‐interleukin‐1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP. This study characterizes the phenotype of patients with IRP and monogenic autoinflammatory diseases, and establishes whether autoinflammatory disease genes are associated with IRP.Methods and ResultsWe retrospectively analyzed the medical records of patients with IRP (n=136) and monogenic autoinflammatory diseases (n=1910) attending a national center (London, UK) between 2000 and 2021. We examined 4 genes (MEFV, MVK, NLRP3, TNFRSF1A) by next‐generation sequencing in 128 patients with IRP and compared the frequency of rare deleterious variants to controls obtained from the Genome Aggregation Database. In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain (adjusted odds ratio 2.8 [95% CI, 1.3–6.5], P=0.012). IRP frequently manifested with systemic inflammation (raised C‐reactive protein [121/136, 89.0%] and extrapericardial effusions [68/136, 50.0%]). Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%–3.7% of cases). Rare deleterious MEFV variants were more frequent in IRP than in ancestry‐matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040).ConclusionsPericarditis is a feature of interleukin‐1 driven monogenic autoinflammatory diseases and IRP is associated with variants in MEFV, a gene involved in interleukin‐1β processing. We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain. Together these data implicate autoinflammation in IRP and support reducing reliance on corticosteroids in its management.

Recurrent Pericarditis: a Stubborn Opponent Meets New Treatments in 2022.

Purpose of ReviewOur goal in writing this review was to provide a comprehensive appraisal of current therapies for idiopathic recurrent pericarditis with a particular focus on the newest therapeutic agents. We sought to understand the role of the inflammasome in the pathophysiology of pericarditis and how it informs the use of interleukin-1 (IL-1)-directed therapies.Recent FindingsThe latest research on this topic has focused on the critical role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein) inflammasome. Very recently, components of the NLRP3 inflammasome were detected by immune staining in pericardial tissue from patients with recurrent idiopathic pericarditis. In a mouse model of pericarditis, anti-IL-1 agents anakinra and rilonacept reduced NLRP3 immunostaining. Subsequent study of these drugs in human subjects with idiopathic recurrent pericarditis demonstrated their efficacy.SummaryRecurrent idiopathic pericarditis, while relatively rare, poses a continued treatment challenge and contributes to a diminished quality of life for those patients who are afflicted. Recent developments, including an animal model of the disease and the use of IL-1-directed therapies, represent an exciting leap forward in our understanding of treatment targets. These advances offer not only new tools in our fight against this disease, but also the promise of earlier intervention and attenuation of disease morbidity. As our experience with these new agents expands, we can address questions about the ideal timing of introduction of anti-IL-1 therapy and duration of therapy and better understand the potential side effect profile. Supplementary InformationThe online version contains supplementary material available at 10.1007/s11886-022-01719-z.

Anakinra effectiveness in refractory polyserositis: An Italian multicenter study.

Polyserositis is an inflammatory condition involving different serosal membranes at the same time, specifically the pericardium, pleura, and peritoneum with exudates in the respective cavities. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and glucocorticoids may be effective in patients with polyserositis, but relapses often occur when these drugs are tapered or discontinued. The interleukin (IL)-1 receptor antagonist anakinra has shown a beneficial effect in idiopathic recurrent pericarditis, mostly in unresponsive patients who develop steroid dependence and/or colchicine resistance. To date, there are no data suggesting the best therapy for managing acute episodes and/or relapses of polyserositis. On this basis, we performed a retrospective study aimed at evaluating the effectiveness and safety profile of anakinra in treating patients with refractory polyserositis. Patients with idiopathic polyserositis or rheumatic diseases presenting inflammation of 2 or more serous membranes were included. Serositis had to be confirmed by imaging tests comprising either echocardiography, abdominal ultrasound, chest or abdomen computed tomography and/or chest x-ray scan. We included patients with polyserositis who started anakinra from January 2011 to January 2019 due to a poorly controlled disease despite treatment with NSAIDs, conventional immunosuppressant drugs, or the need to minimize oral corticosteroids intake. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and imaging tests, were recorded to monitor serositis at baseline and either at 3, 6 and 12-month follow-up. Patients with malignancies and infectious diseases were excluded from the analysis. Forty-five patients with recurrent polyserositis (23 women) (mean age 43.2±15.8 years and mean disease duration 23.1±28 years) were analysed. Polyserositis was idiopathic in 26 (57.8%) patients. Thirteen patients suffered from autoinflammatory diseases, whereas 6 were affected by autoimmune diseases. Combination treatment with colchicine and NSAIDs at anakinra baseline was administered in 38/45 (84.4%) and 37/45 (82.2%) patients, respectively. After starting anakinra, 84.5% of patients experienced a resolution of serositis with a dramatic decrease in ESR and CRP (P<0.001, for both) already at 3 months, furthermore the same beneficial effect was observed up to 12 months. No relapse was seen at 3 months, whereas the median number of relapses at 6 and 12 months was 0 (interquartile range 0-1). Glucocorticoids were discontinued in 22/45 (48.9%) patients already after 3 months (P<0.001). After 12 months 32/37 (86.5%) patients were steroid-free. Similarly, NSAIDs use significantly was decreased at 3 months (7/45 [15.6%] patients, P<0.001), whereas at 12-month follow-up no patient was on NSAIDs. Urticarial rashes at anakinra injection site occurring in 3 patients were the most common adverse events. Anakinra appeared to be a safe and useful therapeutic choice for patients refractory to optimal anti-inflammatory therapy (NSAIDs, colchicine and corticosteroids), allowing not only a dramatic reduction of recurrences but also of corticosteroids use. Anakinra was effective both in the idiopathic forms of polyserositis and in those with an underlying rheumatic disease, suggesting a common pathogenic pathway leading to serositis onset.

[Idiopathic recurrent pericarditis: review of the literature and the Geneva experience].

The notion of idiopathic recurrent pericarditis (IRP) appeared in the scientific literature in the 1930s. In 1955, W. Dressler published a case series of IRP in which treatment of cortisone and salicylates (i.e. Aspirin) was effective. About 30 years later, De La Serna et al. in 1987 and Guindo et al. in 1990, reported a beneficial effect of colchicine. In recent years, several clinical studies have helped to i mprove the management of this disease. In this present literature review of IRP, we will focus on the definition, differential diagnoses, pathophysiological hypotheses and available treatments. We will also discuss the clinical experience at the division of clinical immunology at the University Hospitals of Geneva.

Current pharmacotherapy management of children and adults with pericarditis: Prospectus for improved outcomes.

Pericarditis is the most common inflammatory pericardial disease in both children and adults. Since the 2015 European Society of Cardiology Guidelines for the diagnosis and management of pericardial disease were published, there have been significant updates to management. Pharmacotherapy has been historically reserved for idiopathic pericarditis (IP). However, there has been increasing use of pharmacotherapies, such as anti-inflammatory therapies, colchicine, and immunotherapies for other causes of pericarditis, such as post-cardiac injury syndromes (PCIS). Nevertheless, the quality of data varies depending on PCIS or idiopathic etiologies, as well as the adult and pediatric population. High-dose anti-inflammatory therapies should be used to manage symptoms associated with either etiology of pericarditis in both adults and children, but do not ameliorate the inflammatory disease process. Choice of anti-inflammatory should be guided by drug-drug/disease interactions, cost, tolerability, patient age, and should be tapered accordingly over several weeks to months. Colchicine should be added as adjuvant therapy to anti-inflammatory therapies in adults and children with IP, as it has been shown to lower the risk of recurrence, reduce pericarditis symptoms, and improve morbidity. Colchicine is also reasonable to add to adults and children with pericarditis secondary to PCIS. Systemic glucocorticoids increase risk of recurrence in adults and children with IP and are reserved for second-line treatment in acute and recurrent IP; they are generally avoided in PCIS. Immunotherapies are regarded as third-line for recurrent IP in adults and children. Limited evidence exists to support their use in patients with pericarditis from PCIS. Pharmacovigilance strategies, such as C-reactive protein and adverse drug event monitoring, are also important toward balancing efficacy and safety of the various strategies used to manage pericarditis in adults and children.

Comparative analysis of the concentrations of proinflammatory cytokines and glycosylated ferritin in patients with idiopathic recurrent pericarditis and adult-onset Still's disease

Idiopathic recurrent pericarditis (IRP) and adult-onset Still's disease (AOSD) are polygenic autoinflammatory diseases, in the pathogenesis of which pro-inflammatory cytokines from the interleukin-1 superfamily play a central role.Aim. To compare serum concentrations of proinflammatory cytokines and glycosylated ferritin (GF) in patients with IRP and AOSD during an exacerbation.Material and methods. The study included 15 patients with AOSD, 15 — IRP. The diagnosis of AOSD was established using the Yamaguchi criteria (1992). IRP was diagnosed in accordance with the 2015 European Society of Cardiology on the diagnosis and management of pericardial diseases. Blood sampling from all patients was carried out during the recurrence period prior to the anti-inflammatory therapy initiation. The serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), procalcitonin, total ferritin and GF was assessed. The results obtained were compared with levels of biochemical parameters, high-sensitivity C-reactive protein (CRP), as well as with white blood cell (WBC) and neutrophil counts.Results. The median age in the AOSD group was 28 years, and the IRP — 55 years. An increase WBC count &gt;10*109/L was detected in 10 and 9 patients in the AOSD and IRP groups, respectively. The concentration of CRP was increased in all patients and did not differ in the study groups (p=0,836).The highest values of ferritin and GF levels were found in the AOSD group (1416 ng/ml vs 408 ng/ml, p=0,008) and (12% vs 33,9%, p=0,067), respectively. In both groups, increased concentrations of IL-6 and IL-18 were determined. In the AOSD group, the concentration of IL-18 was higher than in the IRP group (2114 pg/ml vs 161,5 pg/ml, p&lt;0,001). IL-6 concentrations in the study groups did not differ (33,9 pg/ml vs 24,9 pg/ml, p=0,4). IL-1β serum concentration in all subjects corresponded to normal values.Correlation analysis in the AOSD group revealed a direct relationship between the IL-18 and ferritin concentrations (rs=0,73, p=0,03).Conclusion. The study established a similar pattern of changes in inflammatory biomarkers in patients with AOSD and IRI. The most informative marker of inflammation was IL-18.

[Anti-interleukin-1 agents: a new class of drugs for recurrent pericarditis. A practical guide for cardiologists].

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory diseases characterized by overproduction of IL-1. Idiopathic recurrent pericarditis with inflammatory phenotype (fever, leukocytosis, and elevation of C-reactive protein) has similar features and responds well to this treatment. At present, in Italy, prescription of anakinra is possible for idiopathic recurrent pericarditis with corticosteroid dependence and colchicine resistance. Anakinra is a recombinant antagonist of IL-1 receptor and blocks either IL-1α (released from pericardial cells) or IL-1β (derived for inflammatory cells, during pericarditis). Anakinra is prescribed at the dose of 2 mg/kg/day subcutaneously up to 100 mg/day subcutaneously for at least 3 to 6 months with subsequent tapering. Anakinra allows a quick control of symptoms after 1-2 doses and a fast and safe tapering and withdrawal of corticosteroids. Colchicine can be used together with anakinra. The most common side effect is represented by local skin injection site reactions after 1-2 weeks of therapy. These reactions are usually transient and can be treated by anti-histamines and topical corticosteroids. Less common side effects include elevation of transaminases (4-5%), cutaneous or respiratory infections (2-3%), and leukopenia (1-3%). Side effects are rarely responsible for permanent discontinuation of therapy. The aim of the present review is to provide a practical guide on the use of these drugs for cardiologists, who are often not familial with this new therapy for pericarditis.

Anti-interleukin-1 agents for pericarditis: a primer for cardiologists.

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor ‘trap’, binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.

Management of acute and recurrent pericarditis in pregnancy.

This review summarizes the currently available evidence on the management of acute and recurrent pericarditis during pregnancy, focusing on the safety of diagnostic procedures and treatment options for the mother and fetus. Family planning should be addressed in women with recurrent pericarditis of reproductive age and adjustment of therapy should be considered before a planned pregnancy. The treatment of pericarditis in pregnancy is similar to that for non-pregnant women but considers current knowledge on drug safety during pregnancy and lactation. The largest case series on this topic described 21 pregnancies with idiopathic recurrent pericarditis. Pregnancy should be planned in a phase of disease quiescence. Non-steroidal anti-inflammatory drugs can be used at high dosages until the 20th week of gestation (except low-dose aspirin 100 mg/die). Colchicine is allowed until gravindex positivity; after this period, administration of this drug during pregnancy and lactation should be discussed with the mother if its use is important to control recurrent pericarditis. Prednisone is safe if used at low-medium doses (2.5-10 mg/die). General outcomes of pregnancy in patients with pericarditis are good when the mothers are followed by a multidisciplinary team with experience in the field.