Repurposing Colchicine for Heart Disease.

Colchicine is one of the most ancient medications still prescribed. It is extracted from the Colchicum autumnale plant and is routinely used because of its broad anti-inflammatory properties to treat gout and familial Mediterranean fever. Colchicine has shown efficacy in various clinical settings in which inflammation is a key component, and it has become first-line therapy for acute and recurrent pericarditis. Two landmark clinical trials have recently shown that colchicine significantly improves cardiovascular outcomes on background statin and antiplatelet therapy in patients with coronary artery disease, supporting its role for the prevention of atherothrombotic events. Favorable results have also emerged in atrial fibrillation. We herein briefly review the most recent data related to the multiple cardiovascular conditions for which colchicine has been successfully repurposed.

Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.

BACKGROUND: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1ß cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis. METHODS: We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed. RESULTS: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. 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 (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. CONCLUSIONS: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).

Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1.

BACKGROUND: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs). METHODS: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment." RESULTS: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1ß, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome. CONCLUSION: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies.

Rilonacept use in lupus pericarditis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Rilonacept successfully treated lupus pericarditis in this case series. Rilonacept should be considered for the treatment of lupus pericarditis.

Purulent pericarditis caused by methicillin-sensitive Staphylococcus aureus bacteriuria.

BACKGROUND: Purulent pericarditis (PP)- a purulent infection involving the pericardial space-requires a high index of suspicion for diagnosis as it often lacks characteristic signs of pericarditis and carries a mortality rate as high as 40% even with treatment. Common risk factors include immunosuppression, diabetes mellitus, thoracic surgery, malignancy, and uremia. Most reported cases of PP occur in individuals with predisposing risk factors, such as immunosuppression, and result from more commonly observed preceding infections, such as pneumonia, osteomyelitis, and meningitis. We report a case of PP due to asymptomatic bacteriuria in a previously immunocompetent individual on a short course of high-dose steroids. CASE PRESENTATION: An 81-year-old male presented for severe epigastric pain that worsened with inspiration. He had been on high-dose prednisone for presumed inflammatory hip pain. History was notable for urinary retention requiring intermittent self-catheterization and asymptomatic bacteriuria and urinary tract infections due to methicillin-sensitive Staphylococcus aureus (MSSA). During the index admission he was found to have a moderate pericardial effusion. Pericardial fluid cultures grew MSSA that had an identical antibiogram to that of the urine cultures. A diagnosis of purulent pericarditis was made. CONCLUSION: PP requires a high index of suspicion, especially in hosts with atypical risk factors. This is the second case of PP occurring as a result of asymptomatic MSSA bacteriuria. Through reporting this case we hope to highlight the importance of early recognition of PP and the clinical implications of asymptomatic MSSA bacteriuria in the setting of urinary instrumentation and steroid use.

Interleukin-1 Blockers in Recurrent and Acute Pericarditis: State of the Art and Future Directions.

Diseases of the pericardium encompass a spectrum of conditions, including acute and recurrent pericarditis, where inflammation plays a pivotal role in the pathogenesis and clinical manifestations. Anti-inflammatory therapy indeed forms the cornerstone of treating these conditions: NSAIDs, colchicine, and corticosteroids (as a second-line treatment) are recommended by current guidelines. However, these medications come with several contraindications and are not devoid of adverse effects. In recent years, there has been an increased focus on the role of the inflammasome and potential therapeutic targets. Recurrent pericarditis also shares numerous characteristics with other autoinflammatory diseases, in which interleukin-1 antagonists have already been employed with good efficacy and safety. The objective of this review is to summarize the available studies on the use of anti-IL-1 drugs both in acute and recurrent pericarditis.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade.

OBJECTIVE: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. STUDY DESIGN: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. RESULTS: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. CONCLUSIONS: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis.

Management of acute pericarditis.

PURPOSE OF REVIEW: Provide an update on current management and most recent evidence in the treatment of pediatric pericarditis. RECENT FINDINGS: While treatment of acute pericarditis has not significantly changed over the last decade, management of recurrent acute pericarditis, with increased attention to autoinflammation as a causal mechanism, has evolved substantially. This includes clinical trial evidence that newer medications targeting interleukin-1 receptors are effective in recurrent forms of pericarditis. In addition, advanced imaging utilizing cardiac magnetic resonance has emerged as a particularly effective way to detect ongoing pericardial inflammation in support of more difficult-to-treat patients. SUMMARY: Recent advances in acute and recurrent pericarditis management have allowed for a more tailored approach to the individual patient. Yet, unresolved questions require further research.

Can the current monkeypox affect the heart? A systematic review of case series and case report.

BACKGROUND: Monkeypox is a zoonotic viral infection first reported in May 2022. Monkeypox cases present with prodromal symptoms, rash, and/or systemic complications. This study systematically reviews the monkeypox cases presented with any cardiac complications. METHODS: A systematic literature search was done to locate papers that discuss any cardiac complications associated with monkeypox; then, data were analyzed qualitatively. RESULTS: Nine articles, including the 13 cases that reported cardiac complications of the disease, were included in the review. Five cases previously had sex with men, and two cases had unprotected intercourse, which reveals the importance of the sexual route in disease transmission. All cases have a wide spectrum of cardiac complications, such as acute myocarditis, pericarditis, pericardial effusion, and myopericarditis. CONCLUSION: This study clarifies the potential for cardiac complications in monkeypox cases and provides avenues for future research to determine the underlying mechanism. Also, we found that the cases with pericarditis were treated with colchicine, and those with myocarditis were treated with supportive care or cardioprotective treatment (Bisoprolol and Ramipril). Furthermore, Tecovirimat is used as an antiviral drug for 14 days.

Viral pericarditis following ocrelizumab in a multiple sclerosis patient.

Ocrelizumab is a humanized monoclonal anti-CD20 antibody, approved for the treatment of relapsing and primary-progressive multiple sclerosis. We reported a case of pericarditis in an RRMS patient treated with ocrelizumab, who presented with chest pain, high body temperature and laboratory findings of systemic inflammation, with a favorable clinical outcome.

Paradigm Shift in Diagnosis and Targeted Therapy in Recurrent Pericarditis.

PURPOSE OF THE REVIEW: We review the pathophysiology, diagnosis, and contemporary treatment for recurrent pericarditis, with focus on interleukin-1 (IL-1) inhibitors. RECENT FINDINGS: Recurrent pericarditis occurs in about 15-30% of patients who have acute pericarditis. With increased understanding of the autoinflammatory pathophysiology of recurrent pericarditis, IL-1 inhibitors including anakinra, canakinumab, and rilonacept have been applied to this condition with great promise. In particular, the RHAPSODY trial found rilonacept significantly improves pain and inflammation, while also reducing recurrence with few adverse events. The next IL-1 inhibitor on the block for pericarditis, goflikicept, is also discussed. Understanding the role of the inflammasome via the autoinflammatory pathway in pericarditis has led to incorporation of IL-1 inhibitors in the treatment of recurrent pericarditis, with proven efficacy and safety and randomized trials. This will lead to increase uptake of this agent which demonstrated lower rates of recurrence and faster time to resolution.

Pericarditis Management in Individuals Contemplating Pregnancy, Currently Pregnant, or Breastfeeding.

PURPOSE OF REVIEW: Pericarditis complicates pregnancy planning, pregnancy, or the postpartum period, and the management approach requires special considerations. Here, we aim to summarize the latest research, diagnostic, and treatment strategies. RECENT FINDINGS: Physiologic cardiovascular (CV) adaptations occurring during pregnancy complicate diagnosis, but for most patients, an electrocardiogram (ECG) and transthoracic echocardiogram (TTE) are sufficient to diagnosis pericarditis in the appropriate clinical context. Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) can be used until 20 weeks gestation as needed. The use of colchicine is encouraged at any time point to reduce the risk of recurrence. Glucocorticoids may be used at the lowest possible dose for the least amount of time throughout pregnancy and breastfeeding. For incessant, recurrent, or refractory pericarditis, or when the above therapies are contraindicated, there may be a consideration of the use of IL-1 inhibition during pregnancy, recognizing the limited data in pregnant patients. Finally, we encourage the use of a multidisciplinary team approach including OB-GYN, cardiology, and rheumatology when available. The diagnosis and treatment of pericarditis in female patients of reproductive age require special considerations. Although highly effective treatment options are available, there is a need for greater data and larger international registries to improve treatment recommendations.

Pericarditis related to post-acute COVID infection: A case report and review of the literature.

Cardiovascular involvement has been described in acute and recovered COVID-19 patients. Here, we present a case of symptomatic pericarditis with persistent symptoms for at least six months after the acute infection and report 66 published cases of pericarditis in discharged COVID patients. Patient mean age ± SD was 49.7 ± 13.3 years, ranging from 15 to 75 years and 57.6% were female. A proportion of 89.4% patients reported at least one comorbidity, with autoimmune and allergic disorders, hypertension and dyslipidaemia, as the most frequent. Only 8.3% of patients experienced severe symptoms of acute COVID-19. The time between acute COVID and pericarditis symptoms varied from 14 to 255 days. Chest pain (90.9%), tachycardia (60.0%) and dyspnoea (38.2%) were the most frequent symptoms in post-acute pericarditis. A proportion of 45.5% and 87% of patients had an abnormal electrocardiogram and abnormal transthoracic ultrasound, respectively. Colchicine combined with non-steroidal anti-inflammatory drug (NSAID) or acetylsalicylic acid (aspirin) were prescribed to 39/54 (72%) patients. Of them, 12 were switched to corticosteroid therapy due to non-response to the first-line treatment. Only 6 patients had persisting symptoms and were considered as non-respondent to therapy.Our report highlights that pericarditis should be suspected in COVID-19 patients with persistent chest pain and dyspnoea when pulmonary function is normal. Treatment with non-steroidal anti-inflammatory and colchicine is usually effective but corticosteroids are sometimes required.

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-1ß 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-1ß (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-1ß), and canakinumab (human monoclonal anti-IL-1ß 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.

Successful treatment of two cases of acute myocarditis with colchicine.

Colchicine is an FDA-approved medicine that has been used for many years to prevent and treat gout flares as well as familial mediterranean fever. It is also used off-label to treat pericarditis, calcium pyrophosphate illness, and Behçet's syndrome. There are additional studies on the use of colchicine, which is accepted as the standard treatment for pericarditis in adults, post-pericardiotomy syndrome, post-operative and post-ablation atrial fibrillation, coronary artery disorders, prior to percutaneous coronary procedures, and myocarditis. Colchicine appears to be a promising oral cardiovascular treatment targeting the inflammatory axis, owing to its low cost and moderate side-effect profile. Our aim is to emphasise that colchicine treatment, which has a strong and effective anti-inflammatory effect profile, should be kept in mind in addition to conventional treatment in childhood myocarditis.

Colchicine in Athero-Thrombosis: Molecular Mechanisms and Clinical Evidence.

Several lines of evidence have clearly indicated that inflammation plays a pivotal role in the development of atherosclerosis and of its thrombotic complications such as acute coronary syndromes or ischemic stroke. Thus, it has been postulated that the use of anti-inflammatory agents might be extremely useful to improve cardiovascular outcome. Recently, increasing attention has been reserved to one of the oldest plant-derived drugs still in use in clinical practice, colchicine that has been used as drug to treat inflammatory diseases such gout or Mediterranean fever. To date, current guidelines of the European Society of Cardiology have included colchicine as first line choice for treatment of acute and recurrent pericarditis. Moreover, several studies have investigated its role in the clinical scenarios of cardiovascular disease including chronic and acute coronary syndromes with promising results. In this review, starting from a description of the mechanism(s) involved behind its anti-inflammatory effects, we give an overview on its potential effects in atherothrombosis and finally present an updated overview of clinical evidence on the role of this drug in cardiovascular disease.

Recurrent pericarditis. / Residiverende perikarditt.

Pericarditis is an important differential diagnosis in patients with chest pain. The two most common causes in the developed world are idiopathic pericarditis and inflammation following cardiac surgery or myocardial infarction. Recurrence of pericarditis affects up to 30 % of patients, half of whom experience multiple episodes, and approximately 10 % develop steroid-dependent and colchicine-refractory pericarditis. Recurrence is due to autoinflammatory processes in the pericardium. Advanced diagnostic imaging and treatment with colchicine and interleukin-1 inhibitors has helped reduce morbidity considerably in recent years. In this clinical review, we summarise up-to-date knowledge about the diagnostic evaluation and treatment of patients with recurrent primary pericarditis.

A retrospective analysis of colchicine in combination with NSAIDs therapy in patients with systemic form of adult-onset Still's disease with serositis.

OBJECTIVES: Adult-onset Still's disease (AOSD) is increasingly viewed as autoinflammatory disease associated with the so-called inflammasomopathy. Proinflammatory cytokines, such as IL-18 and IL-1ß, processed through the inflammasome machinery, play an important role in the pathogenesis of AOSD. AOSD is heterogenous, therefore there are two subtypes of the disease, systemic and articular, which probably imply different approaches for the treatment. Over 20% of patients with systemic AOSD have serositis. Recently, colchicine in combination with non-steroidal anti-inflammatory drugs (NSAIDs) has become the "gold standard" for recurrent pericarditis treatment. However, data on this combination therapy in AOSD are scarce. METHODS: In this retrospective case series study, we assessed the medical history of 20 patients with a systemic form of AOSD. All patients had pericarditis and received а combination of NSAIDs (in most cases ibuprofen 600-800 mg x3 daily) and colchicine (1 mg daily) for treatment. RESULTS: 13/20 (65%) of patients responded to this combination of anti-inflammatory drugs. Of note, not only pericarditis, but also other manifestations were improved such as arthritis, rash, hepatomegaly, acute phase reactants, and abnormal liver tests. CONCLUSIONS: The low cost, safety and wide availability of such therapy make this option relevant and determine the need for further study.

Rilonacept: A Newly Approved Treatment for Recurrent Pericarditis.

OBJECTIVE: To review the pharmacology, efficacy, and safety of rilonacept for the prevention and treatment of recurrent pericarditis (RP). DATA SOURCES: A MEDLINE search was conducted between January 2006 and April 2021 using the following terms: rilonacept, pharmacology, pericarditis, recurrent pericarditis, interleukin (IL) antagonist, and pharmacology; prescribing information was also used. STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing pharmacology, efficacy, and safety of IL antagonists were reviewed. DATA SYNTHESIS: Rilonacept traps IL-1α and IL-1ß. In the Phase III trial, rilonacept was associated with a lower risk of recurrence, more persistent clinical response, and higher amount of days with no or minimal pericarditis symptoms, compared with placebo. The median time to pain response was 5 days, and median time to normalization of C-reactive protein was 7 days with rilonacept. All patients receiving rilonacept during the run-in period were able to be weaned off of standard background therapy, leading to transition to rilonacept monotherapy. The most common adverse effects were upper respiratory tract infections and injection site reactions. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Rilonacept may be used for the prevention and treatment of multiple recurrences in patients receiving background therapy for RP, and reduction in risk of recurrence in adults and adolescents ≥12 years with elevated C-reactive protein. Rilonacept may be considered to wean patients from standard background therapy. CONCLUSION: Rilonacept is a safe, once weekly, subcutaneously administered IL-1 "trap," indicated for the treatment of RP, and reduction in risk of recurrent pericarditis in adults and children ≥12 years of age.

Two-dimensional transthoracic echocardiographic demonstration of reduction in fibrin content in purulent pericarditis following intrapericardial fibrinolytic agent administration.

We describe an adult patient who presented with purulent pericarditis (PP) in whom two-dimensional transthoracic echocardiography demonstrated a marked decrease in the area of the right ventricular (RV) wall together with the overlying fibrin following intrapericardial administration of a fibrinolytic agent. Documentation of this decrease by measurements performed and illustrated on two-dimensional images has not been reported previously in an adult patient with PP, to the best of our knowledge.