Recurrent Pericarditis A Toolkit for Health Care Professionals This activity is supported by an educational grant from Kiniksa Pharmaceuticals (UK), Ltd.
Publisher’s Note Recurrent Pericarditis: A Toolkit for Health Care Professionals is published by: Ascend Media 401 SW Ward Road, Suite 210, Lee’s Summit, MO 64081 © 2024 American Heart Association, Inc., a 501(c)(3) not-for-profit. All rights reserved. Unauthorized use prohibited. All references and data are as of August 2024.
3 A Toolkit for Health Care Professionals Recurrent Pericarditis Contents 4 Contributing Authors 6 Introduction 6 Pericardial Anatomy, Structure and Function 9 Structured History Taking for Acute Pericarditis 11 Differential Diagnosis 12 Clinical Examination 13 Initial Investigations 14 Multimodality Imaging 15 Introduction to the Immune System, Inflammation and Mechanisms of Drug Action 16 Management of Acute Pericarditis 22 Recurrent Pericarditis 25 Surgery for Refractory Disease 26 Special Topics 29 Top Takeaways Plus! Treatment and tapering of initial therapies for acute and recurrent pericarditis Page 16 Significant drug interactions with colchicine Page 17
4 Contributing Authors Cyrille Cornelio, PharmD, BCCP, is a board-certified cardiology pharmacist passionate about optimizing patient safety and outcomes, with special interests in heart failure, inflammation in cardiovascular disease, transitions of care and informatics. After receiving her doctor of pharmacy from Northeastern University, she completed a general pharmacy residency at Montefiore Medical Center in New York and a cardiology pharmacy residency at the University of Oklahoma. Dr. Cornelio is currently an assistant professor at the University of South Florida (USF) Health Taneja College of Pharmacy and an ambulatory care clinician collaborating with providers to optimize patient care within USF Health Cardiology. She is also an active member on the American Heart Association’s Clinical Pharmacology Committee and Committee on Scientific Sessions Program. Disclosures: Nothing to disclose Michael Garshick, MD, is an assistant professor of medicine and dermatology at NYU Langone Health. He graduated from Tufts University School of Medicine with Alpha Omega Alpha honors. He completed an internal medicine residency at Columbia University Medical Center and a cardiology fellowship, T32 research fellowship and a master’s program in clinical investigation at NYU Langone Health. Dr. Garshick’s s clinical and research interests include exploring mechanisms and therapeutics to treat cardiovascular disease in patients with immune-mediated inflammatory diseases. He conducts clinical trials and directs the cardio-rheumatology program at NYU Langone Health dedicated to reducing cardiovascular risk in patients with heightened systemic inflammation. Dr. Garshick has held grants from the New York Medical Society, National Psoriasis Foundation, Dermatology Foundation, American Heart Association and the NIH/NHLBI. Disclosures Employment: NYU Langone Medical Center Professional Services and Activities: Agepha, Horizon Pharma plc, Kiniksa Pharmaceuticals, Bristol Myers Squibb Tevfik F. Ismail, MBBS, PhD, is a consultant cardiologist at Guy’s and St. Thomas’ Hospital and a reader/associate professor at King’s College London, London, U.K. He is clinical lead for inflammatory myocardial and pericardial diseases and deputy clinical lead for the adult noncongenital cardiovascular magnetic resonance clinical service. He is a fellow of the Society for Cardiovascular Magnetic Resonance, the American College of Cardiology, European Society of Cardiology, the Higher Education Academy, the Royal College of Physicians and the American Heart Association. He is the cardiology editor for Clinical Medicine, the Journal of the Royal College of Physicians. His clinical and research interests include inflammatory myocardial and pericardial disease, inherited cardiac conditions, heart failure, magnetic resonance elastography, myocardial mechanics and advanced imaging methods for the assessment of non-ischemic heart muscle disease. Disclosures: Nothing to disclose Sachin Kumar, MD, is a cardiovascular fellow at Mount Sinai Morningside in New York City, with a keen interest in pericardial diseases, especially recurrent pericarditis. Driven by a passion for both patient care and education, Dr. Kumar is actively involved in research. He has contributed to the field through his publications focusing on advances in imaging and targeted therapies, which have led to a paradigm shift in managing recurrent pericarditis. He aspires to further his training with a fellowship in interventional cardiology and to advance the understanding and treatment of pericardial diseases through continued research and collaboration. Disclosures: Nothing to disclose The American Heart Association is committed to ensuring balance, independence, objectivity and scientific rigor in its certified educational activities. All faculty, planners and contributors in a position to control the content for an AHA-sponsored activity are required to disclose to the activity audience any financial relationships regardless of the amount during the prior 24 months with (1) the manufacturer(s) of any ineligible company product(s) and/or interest(s) of ineligible companies regardless of relation to the content of the activity and (2) any ineligible company supporters of the activity. When an unlabeled use of a commercial product or an investigational use not yet approved for any purpose is discussed during an educational activity, the faculty must disclose that the product is not labeled for the use under discussion or that the product is still investigational. Relationship disclosures within the past 24 months:
5 A Toolkit for Health Care Professionals Recurrent Pericarditis Janet Kloos,RN, PhD, is a clinical nurse specialist (CNS) for the critical and acute cardiology population spanning 24 years. Her CNS role centers on coordination of seamless care for complex patients, providing continuity of care of patients from the intensive care unit through discharge and beyond as lead of a post-ICU syndrome recovery clinic. Publications include acute pericarditis, cardiac tamponade, the effect of a progress journal on anxiety of families of critically ill patients, stress, anxiety and growth of nurses during the COVID-19 pandemic, ICU survivor peer-led support groups and post-ICU syndrome recovery clinics. Dr. Kloos is an active member of the Critical and Acute Illness Recovery Organization (CAIRO), an international, multidisciplinary collaborative that evolved from the THRIVE initiative of the Society of Critical Care Medicine to promote awareness of Post ICU Syndrome (PICS), increase knowledge through research, publication and practice to improve outcomes for patients and families experiencing critical illness. Her research has focused on the needs of families of critically ill patients, mood changes in cardiac tamponade, education needs and priorities of patients after MI, supporting caregivers of left ventricular assist devices and a COVID-19 nurses’ study. Disclosures: Nothing to disclose S. Allen Luis, MD, PhD, FRACP, FACC, FASE, is the co-director of the Pericardial Diseases Clinic at Mayo Clinic in Rochester, Minnesota, dean of the Mayo Clinic School of Health Sciences and associate chair for education for the department of cardiovascular diseases. He also serves as medical director for the Mayo Clinic School of Health Sciences echocardiography and advanced cardiovascular sonography programs. Dr. Luis is a member of the board of directors for the American College of Cardiology (Minnesota Chapter) and the Committee on Accreditation for Advanced Cardiovascular Sonography. Dr. Luis’ principal clinical and research interests include diagnosis and treatment across the entire spectrum of pericardial diseases, including acute, recurrent and constrictive pericarditis. His areas of interest include the treatment of inflammatory pericarditis, where he has been actively involved in clinical trials using novel treatment approaches in this disease process. Dr. Luis also has an interest in multimodality imaging, including echocardiography, cardiac MRI and cardiac CT, and its application in patients with pericardial disease. Disclosures Employment: Mayo Clinic Professional Services and Activities: Kiniksa Pharmaceuticals, Medtronic, Cardiol Therapeutics Jeannine McClinton-Adams, PharmD, received her Pharm D degree from UCSF and worked for many years as a clinical pharmacist in long-term acute care. With a passion for helping patients achieve the best possible therapeutic outcomes, she has transitioned to Medication Therapy Management (MTM). She also serves on the APha-APPM Medication Management Sig’s Clinical Committee. Disclosures: Nothing to disclose Brittany Weber, MD, PhD, FACC, is an assistant professor of medicine at Harvard Medical School and associate physician in prevention cardiology and cardiovascular imaging at Brigham and Women’s Hospital (BWH), where she is the director of the cardio-rheumatology clinic. She is a graduate of University of Pennsylvania school of medicine with a PhD in immunology and she received internal medicine training, including serving as a chief medical resident, and then cardiovascular training and cardiovascular imaging research fellowship at BWH. Her clinical interests include cardiovascular risk stratification and prevention in patients with systemic inflammatory disorders, including the use of multimodality imaging, specific antiinflammatory medications and cardiovascular effects, and pericardial disease and the use of novel anti-inflammatory treatments. Her research is broadly focused on translational research in systemic inflammatory conditions harnessing advanced cardiovascular imaging and immunology. Disclosures Employment: Brigham and Women’s Hospital Professional Services and Activities: Horizon Therapeutics, Novo Nordisk, Kiniksa Pharmaceuticals, Bristol Myers Squibb Company
6 Introduction Pericarditis is an important clinical problem and accounts for up to 5% of emergency admissions with acute chest pain. It remains the most common cause of pericardial disease worldwide.1-3 Nevertheless, dedicated pericardial clinics and acute pericardial services are few, and most patients present to and are managed by primary care physicians, emergency physicians or general cardiologists. Most patients respond to first-line treatment and experience a benign disease trajectory with eventual resolution of symptoms and no long-term sequelae. However, approximately 30% of patients can go on to develop recurrent pericarditis, which can have a dramatic deleterious effect on quality of life as well as result in increased utilization of health care resources.4,5 Although many challenges remain, the last decade has witnessed significant advances in our understanding of the pathophysiology of inflammatory pericardial disease as well as several important therapeutic advances. With timely and effective evidence-based initial care, the incidence of recurrent pericarditis can be halved,2 and for those who do go on to develop this complication, newer treatment options are now available.6 The aim of this American Heart Association (AHA) toolkit is to equip all clinicians who may encounter patients with acute pericarditis with the knowledge, skills and practical guidance to manage acute and recurrent pericarditis confidently and effectively. The Recurrent Pericarditis Toolkit has been assembled by an international and multidisciplinary team of experts. It strongly emphasizes practical guidance for issues clinicians are likely to encounter in day-to-day, clinical practice, buttressed where necessary with the theoretical basis for the guidance. Pericardial Anatomy, Structure and Function The pericardium is the outer lining of the heart consisting of an inner double-layered sac called the serous pericardium. The inner layer of the sac is the visceral layer, or epicardium, that lines the heart and proximal great vessels. The visceral layer is reflected to form the parietal pericardium, which lines the fibrous pericardium.7 The pericardial cavity exists between the two layers, which contain approximately 15-50 ml of plasma infiltrate.7 Anchoring the heart in the thorax, the pericardium acts as a mechanical protective layer for the heart against trauma and as an immunologic barrier.1 The pericardial fluid serves as a lubricant to reduce friction between the heart and its surrounding structures and eases movement during the twisting, contracting and relaxation actions. Hemodynamic effects of the pericardium occur in response to changes in intrathoracic pressure, which cause changes in pericardial and intracardiac pressure with slight increases in left ventricular (LV) stroke volume and arterial blood pressure. During inspiration, the negative intrathoracic pressure increases venous return to the right heart and slightly reduces LV filling unrelated to the normal pericardium. The toolkit is supported by a series of four vodcasts and webinars, which in turn build on an extensive library of webinars and podcasts freely available from the AHA Lifelong Learning website (https:// professional.heart.org/en/education/ recurrent-pericarditis-for-professionals). Illustration of the heart showing the pericardial layers. http://www.scientificanimations.com, CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0), via Wikimedia Commons
7 A Toolkit for Health Care Professionals Recurrent Pericarditis Acute pericarditis is caused by an inflammatory process that occurs commonly and can occur in isolation or as a consequence of an underlying autoimmune disorder. It occurs more often in males ages 20-50 years.8 Most causes of acute pericarditis are idiopathic and presumed to occur post-viral.9 In developing countries with a high prevalence, tuberculosis (TB) with or without HIV co-infection is a common cause of pericarditis. In developed countries with a low prevalence of TB, conditions causing pericarditis are systemic inflammation, cancers such as lung, breast, lymphomas and leukemia, chest irradiation, post-cardiac surgery injury syndromes, including pericarditis post-myocardial infarction, percutaneous coronary intervention and electrophysiology procedures or post-pericardiectomy.9,10 The diagnosis is made in the presence of two or more of the following: 1. Precordial chest pain that worsens with inspiration and is relieved by sitting forward 2. A pericardial friction rub on auscultation 3. Diffuse ST elevation across the precordial leads or PR-depression with reciprocal changes in aVR 4. A new or worsening pericardial effusion Diagnostic workup includes a review of past medical history, physical examination with a focus on heart auscultation, chest X-ray, electrocardiogram, echocardiography and laboratory tests for markers of inflammation [C-Reactive Protein (CRP)], troponin and thyroid levels.11 Further investigation is not recommended since most often the cause is viral or idiopathic. For patients experiencing high fever [>38º C (>100.4º F)], subacute course, development of a large pericardial effusion, cardiac tamponade or no response to non-steroidal anti-inflammatory drugs >7 days warrant more extensive diagnostic testing.12 Recurrent pericarditis may occur in approximately 20%-30% of patients as a complication of acute pericarditis after a symptom-free interval of 4 to 6 weeks or longer. Diagnostic testing is similar to that done in the acute phase. It occurs more commonly in those who were not treated with colchicine.13 The 2015 European Society of Cardiology (ESC) Guidelines recommend diagnostic testing of CRP, computed tomography (CT) and/or cardiovascular magnetic resonance (CMR) to support diagnosis in atypical cases to investigate pericardial inflammation evidenced by edema and contrast enhancement of the pericardium.1 Inflammation of the pericardium. BruceBlaus, CC BY-SA 4.0 (https://creativecommons.org/licenses/ by-sa/4.0), via Wikimedia Commons The ECG in acute pericarditis. Dr. Ihab Suliman, CC BY-SA 4.0 (https://creativecommons.org/ licenses/by-sa/4.0), via Wikimedia Commons
8 Incessant pericarditis is defined as patients with persistent symptoms lasting longer than 4 to 6 weeks (but less than 3 months) who have no clear period of remission after the acute episode. The probability of developing incessant pericarditis as reported by Cremar et al., (2016) is approximately 15%-20%.12 Chronic pericarditis refers to patients who have symptoms lasting longer than 3 months.12 Constrictive pericarditis is an uncommon complication of viral pericarditis, occurring in less than 1% of cases, but can occur in any form of pericarditis, except rarely with recurrent pericarditis.1,8,13 Development of fibrous thickening or calcification of the pericardium results in pericardial non-compliance presenting as a clinical form of heart failure.7,12,13,14 The hemodynamic alterations occurring in constrictive pericarditis are the dissociation of intrathoracicintracardiac pressures and enhanced ventricular interaction.13,14 On inspiration, the noncompliant pericardial sac impedes the transmission of pressure in the pulmonary veins to the left ventricle (LV), causing an inspiratory reduction in venous return to the LV and permitting the ventricular septum to move toward the LV. During inspiration, the right ventricle (RV) stroke volume increases, and the LV stroke volume decreases, resulting in the pulsus paradoxus, a decrease in blood pressure greater than 10 mm Hg with inspiration.7,13,14 Symptom presentation includes fatigue, peripheral edema, dyspnea and abdominal distention. Physical examination findings may include jugular venous distention, increased central venous pressure and hepatomegaly. The central venous pressure may be so high that the examiner has the patient stand up to appreciate venous pulsations.12,15 Diagnostic testing includes chest X-ray, echocardiography, CT, CMR and cardiac catheterization in determining a differential diagnosis. Laboratory findings include slight elevations in creatinine and liver enzymes (alkaline phosphatase).7,12,13,14 There are three subtypes of constrictive pericarditis as described by Adler et al. (2015):1 Transient constrictive pericarditis A temporary form of constriction due to the inflammation occurring with pericarditis, usually involving a mild effusion. It resolves once the inflammation subsides after a course of anti-inflammatory therapy. Effusive constrictive pericarditis Although pericardial fluid is typically not present in patients with constrictive pericarditis, for some a pericardial effusion further restricts cardiac filling and can cause cardiac tamponade. It is an uncommon occurrence in developed countries, usually with idiopathic pericarditis, but can be associated with radiation, neoplasm, chemotherapy, infection (especially TB and purulent forms) and post-surgical pericardial disease. Pericardiocentesis and monitoring of intracardiac pressures, such as right heart pressure and systemic arterial blood pressure, are recommended. CMR can be useful in evaluating pericardial thickness, cardiac morphology and function. Chronic constrictive pericarditis Characterized as a persistent constriction lasting longer than 3 to 6 months and may exhibit heart failure NYHA class III or IV symptoms. Laboratory findings for constrictive pericarditis include slight elevations in creatinine and liver enzymes (alkaline phosphatase).
9 A Toolkit for Health Care Professionals Recurrent Pericarditis Structured History Taking for Acute Pericarditis The goal of history taking is to: Gather data to make a diagnosis Exclude important differentials Identify features of any relevant systemic disease for which pericarditis may be a manifestation Detect comorbidities that may impact therapy Anticipate any social or occupational factors that may impinge on ongoing care. The following is not a comprehensive list, but is intended to highlight questions that are particularly relevant to identifying these features or manifestations of disorders that may accompany pericarditis or complicate its treatment. Chest pain history A comprehensive chest pain history includes onset, timing, quality, severity, radiation, associated symptoms and exacerbating and relieving factors. Typical chest pain in acute pericarditis is sharp, sudden onset and pleuritic — worse with inspiration or cough, worse laying backward and improved when sitting forward. Referred pain is also common, especially to the shoulder region. In cases of recurrent pericarditis, patients often can sense the pain coming prior to a full-blown episode. A history should also be taken to assess for complications of pericarditis, including clinical tamponade such as syncope, lightheaded/dizziness, nausea and myopericarditis such as those indicative of LV dysfunction — shortness of breath, abdominal swelling and lower extremity edema. Personal medical and surgical history Any previous episodes of acute pericarditis? { What were the circumstances in which these occurred? { Were there any complicating features (e.g., incessant course, large effusion, tamponade)? { What was the treatment given (duration, intensity)? { Did the patient adhere to the treatment? If not, why not? Was this due to side effects, medication costs, lack of knowledge? Any previous history of trauma to the chest or interventional cardiac or cardiothoracic surgical procedures? Any past history of asthma and in particular, asthma exacerbation with NSAIDs? Any past history of peptic ulcer disease/GI blood loss, significant gastroesophageal reflux disease, H pylori infection, bleeding diathesis or renal or hepatic impairment? Any history of diabetes mellitus, obesity, osteopenia/ osteoporosis/fragility fractures, vitamin D deficiency, coronary disease (which may favor use of aspirin over NSAIDs), hypertension, renal impairment or hepatic dysfunction? Any history of autoimmune rheumatic disease, inflammatory bowel disease, autoinflammatory disease or immunodeficiency (severe, prolonged, recurrent or unusual infections)? Any comorbidities that may necessitate co-prescription of potent cytochrome P450, family 3, subfamily A (CYP3A4) and/or P-glycoprotein inhibitors? Any past history of TB or exposure to this bacterial infection? Any history of abdominal surgery, particularly negative laparotomies? Any history of cancer/radiotherapy? Any psychiatric history (which may be relevant to steroid prescribing and holistic care)? Any history of claustrophobia or implants?
10 Medications and allergies Any use of anticoagulants or potent antiplatelet therapy or other drugs that may promote GI injury/ blood loss, e.g., SSRIs, bisphosphonates? Any potent CYP3A4 or P-glycoprotein inhibitors? (See “Management of Acute Pericarditis” on page 16.) Pregnancy (gestation) and breastfeeding? Any known drug allergies or relevant food/excipient allergies? Any history of adverse drug reactions to NSAIDs/ colchicine/steroids or exposure to drugs that can trigger systemic lupus erythematosus (SLE) (e.g., hydralazine, procainamide, TNFa-inhibitors)? Social history Occupational history (impact on job, financial resilience, capacity to abstain from manual work/ physical exertion, occupational injury)? Travel history, including travel to countries with high TB prevalence (Africa, S/SE Asia, China and India) or exposure to pathogens, ability to transport/store medication? Smoking history? Encourage smoking cessation, which will also reduce risks of GI ulceration with NSAIDs/steroids. Alcohol history: (relevant to reducing risks of GI upset/ ulceration and, where excessive, hepatic dysfunction, which may impact drug metabolism)? Recreational drug misuse or chronic opioid use/chronic pain/addiction? Factors that may impact care: e.g., pets, caring responsibilities, impact of illness on relationships, family, finances? Family history Any family history of autoimmune rheumatic disease, inflammatory bowel disease, periodic fever syndromes/ autoinflammatory disease. Any family history of TB or TB exposure? Review of systems General Any unexplained malaise/fatigue, anorexia, weight loss, fever/rigors, night sweats, lymphadenopathy, polyuria, polydipsia, insomnia, hypersomnolence. Respiratory Pleuritic chest pain, shortness of breath, cough, sputum, hemoptysis, wheeze. Abdominal Dysphagia, reflux, peritonitic abdominal pain (especially if recurrent), diarrhea, constipation, change in bowel habit, GI bleeding, hematemesis. Neurologic Headache, visual disturbance/diplopia, red eye/ discharge, muscle pain, paresthesia/sensory disturbance, neuropsychiatric disturbance. Musculoskeletal/Rheumatologic/Skin Arthritis (arthralgia, swelling, erythema, pattern of involvement), enthesitis, alopecia, dry eyes/ mouth, photosensitive rash, erysipelas-like rash, conjunctivitis, temperature-related rash, oral/ genital ulceration, Raynaud’s, digital ulceration.
11 A Toolkit for Health Care Professionals Recurrent Pericarditis Differential Diagnosis The differential diagnosis of those presenting with pericarditis is dependent upon signs and symptoms, prior medical history and acuity. In acute pericarditis, chest pain occurs >95% of the time.29 Myocardial ischemia (including ST-segment elevation myocardial infarction), aortic dissection, myocarditis (without a pericardial component) and pulmonary embolism should be ruled out or deemed less likely. Although the age of presentation may influence diagnostic decision-making, up to 30% of myocardial infarctions occur in those <55 years of age,30 and thus either noninvasive (e.g., computed tomography [CT]) or invasive (angiography) imaging may be required, especially if the ECG changes are not diagnostic of pericarditis. Given the inflammatory state of pericarditis (with associated leukocytosis and fever), the differential diagnosis of pericarditis often includes infections such as pneumonia. Other common non-cardiac causes of acute chest pain consist of gastrointestinal disorders, such as acid reflux, musculoskeletal complaints and fibromyalgia. These conditions can be misdiagnosed as pericarditis, particularly in those with ECGs consistent with early repolarization or left ventricular hypertrophy. In cases of suspected recurrent pericarditis, where the chest pain syndrome may be less severe, normal inflammatory biomarkers and nondiagnostic ancillary imaging should prompt a search for non-pericardial chest pain etiologies. Patients who present with a pericardial effusion without a high clinical suspicion of pericarditis may at times present a diagnostic dilemma. In a retrospective analysis of 269 patients with a pericardial effusion requiring pericardiocentesis: 26% were idiopathic 25% were malignant (including 9% as a first diagnosis of a malignancy) 20% were iatrogenic The rest of the various etiologies included heart failure, uremia, systemic disease and infection.31 The underlying causes of pericarditis can be coarsely divided into idiopathic (often assumed to be viral), infectious and noninfectious etiologies. An antecedent upper respiratory or gastrointestinal tract infection was identified in up to 40% of patients presenting with acute pericarditis without a known etiology.32 In a series of 1,162 patients with pericarditis: 55% were deemed idiopathic 9% were neoplastic 2.6% were autoimmune.33 Viruses implicated in pericarditis include coxsackievirus, adenovirus, influenza, HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In developed countries, bacterial and TB-driven pericarditis is rare; however, in developing countries with a high TB prevalence, this is a common entity. Other etiologies include radiationinduced and post-cardiac injury syndrome. Often, pericarditis and, specifically, recurrent pericarditis cases will prompt a workup for an autoimmune etiology. More common autoimmune diseases associated with pericarditis include systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis, although rarely is pericardial involvement implicated as the first clinical presentation of an autoimmune disease. Autoinflammatory disorders are an emerging cause of acute and recurrent pericarditis. Genetic data links monogenic mutations, such as Mediterranean Fever (MEFV) (implicated in Familial Mediterranean Fever) and others, including inflammasome-related mutations, to recurrent pericarditis.34 Concordant with this, a genomewide association study of almost 5,000 individuals with acute and recurrent pericarditis found an association between pericarditis and sequence variants at the interleukin 1 gene locus.35 These studies suggest that those with previously presumed idiopathic and/or viral-induced pericarditis may actually hold a genetic predisposition.
12 Clinical Examination A comprehensive clinical examination is imperative in the assessment of this patient population and should include assessment for features of: Inflammatory pericarditis Cardiac tamponade Causative etiologies Potential alternative diagnoses Inflammatory pericarditis assessment A triphasic pericardial friction rub, arising due to friction between the inflamed pericardial layers during cardiac motion, is pathognomonic of inflammatory pericarditis and is a key diagnostic characteristic of this condition. This is typically described as a grating, scratching sound that is heard best at the left sternal border and louder during inspiration. Although its specificity approaches 100%, its sensitivity is significantly less, occurring in approximately a third of patients with inflammatory pericarditis.36 Common findings also include sinus tachycardia and a lowgrade fever, although a fever >38ºC can be seen in severe inflammatory pericarditis or purulent bacterial pericarditis. Cardiac tamponade assessment Patients presenting with inflammatory pericarditis should be carefully assessed for features of cardiac tamponade complicating pericardial inflammation. It should be remembered that the diagnosis of cardiac tamponade is a clinical diagnosis, rather than one made by imaging. Examination should include assessment for: tachycardia, hypotension, pulsus paradoxus (>10mm Hg decrease in systolic blood pressure with inspiration), jugular venous distention and muffled heart sounds. Causative etiologies assessment Clinical examination should include assessment for potential causative etiologies of pericarditis based on the clinical history obtained. This should include a routine comprehensive rheumatologic examination in this patient population to carefully assess for potential autoimmune causes of pericarditis. Potential alternative diagnoses assessment Examination should include careful assessment of potential alternative diagnoses that may masquerade as pericarditis, including palpation of the anterior chest wall looking for musculoskeletal tenderness and eliciting epigastric tenderness as a marker for gastritis.
A Toolkit for Health Care Professionals Recurrent Pericarditis Initial Investigations Initial investigations in the assessment of inflammatory pericarditis include blood tests, electrocardiography and echocardiography. (See “Multimodality Imaging” on page 14.) Baseline blood tests include assessment of a complete blood count looking for neutrophilic leukocytosis, basic metabolic biochemical panel for baseline assessment of renal function and assessment of inflammatory markers, including erythrocyte sedimentation rate (ESR) and CRP. Given the inflammatory nature of recurrent pericarditis, recurrent flares of chest pain should be associated with elevated inflammatory markers. Normal inflammatory markers in the setting of chest pain should prompt evaluation for alternative non-pericarditic causes of chest pain. Troponin elevation may indicate the coexistent presence of myocardial involvement consistent with myopericarditis. Based on the history and clinical examination, consideration should be given to additional testing to determine etiology, including auto-antibody panels looking for autoimmune disease and myeloma screening. Viral serologies should not be performed typically given the ubiquitous nature of causative illnesses. ECG changes occur in approximately 60% of patients presenting with acute pericarditis and suggest coexistent epicardial inflammation. Characteristic ECG changes include widespread concave up ST-segment elevation with PR-segment depression. Typical ECG findings Stage 1, seen in the first hours to days, are characterized by widespread ST elevation (typically concave up) with reciprocal ST depression in leads aVR and V1. These ECG changes evolve with subsequent ST segments normalization with T wave flattening, followed by diffuse T-wave inversions; and, finally, ECG normalization.37 Echocardiography may identify a pericardial effusion, which is typically small, in up to 60% of patients. Additionally, it offers assessment for imaging evidence of cardiac tamponade, which may complicate this condition. CMR offers an additional useful tool in the assessment of inflammatory pericarditis by allowing assessment of pericardial thickness, pericardial delayed gadolinium enhancement and pericardial edema. It is essential that CMR is read by experts in pericardial assessment, as it is not infrequent for epicardial fat to inadvertently be misdiagnosed as delayed gadolinium enhancement of the pericardium. Additionally, it is important to note that following an index episode of acute pericarditis, pericardial delayed gadolinium enhancement is slow to resolve and may persist well beyond 12 months. Hence, the presence of delayed gadolinium enhancement of the pericardium should not be misinterpreted as representing acute pericardial inflammation in the absence of other clinical findings or elevated inflammatory markers. Echocardiography may identify a pericardial effusion, which is typically small, in up to 60% of patients. 13
14 Multimodality Imaging Echocardiography remains the primary modality for investigating patients with suspected acute pericarditis.38,39 It can be used to detect a new or worsening pericardial effusion — one of the principal clinical diagnostic features of acute pericarditis.38,40 Pericardial effusions are typically small and reported to occur in up to 60% of those patients with acute pericarditis.38 Detailed evaluation for echocardiographic features of cardiac tamponade is warranted regardless of pericardial effusion size. Echocardiographic features of cardiac tamponade include cardiac chamber compression, respirophasic ventricular interdependence, expiratory hepatic venous diastolic flow reversals, exaggerated respirophasic variation in mitral and tricuspid Doppler inflow patterns, and a dilated inferior vena cava consistent with an elevated central venous pressure. Effusive-constrictive pericardial physiology may be demonstrated by echocardiography in patients with severe pericardial inflammation with associated pericardial edema. It can also be used to help evaluate the hemodynamic effects of any effusion and can play a role in the differential diagnosis of chest pain, identifying potential alternative causes (e.g., a new regional wall motion abnormality pointing toward an acute coronary syndrome, or LV dysfunction suggesting a concomitant myocardial pathology).38 Cardiovascular magnetic resonance can play an important role in confirming the presence of acute pericarditis, particularly where the history may be atypical or if a patient with a history of pericarditis presents with chest pain but normal inflammatory markers.38,40 Where the rate of resorption of pericardial fluid matches the rate of production, an effusion may not develop, obscuring the presence of pericarditis on echocardiography.41 The healthy pericardium is a relatively avascular structure and therefore does not take up gadolinium contrast.41 However, in the setting of acute pericarditis, there is often neovascularization of the inflamed pericardium and increased pericardial water content due to capillary leak and pericardial edema. The latter can be detected on high resolution T2-weighted turbo spin echo sequences as pericardial T2 hyperintensity.41 For the same reasons, the inflamed pericardium will appear hyper-enhanced in the late phase after administration of gadolinium contrast agents. The absence of these features lowers the probability of acute pericarditis. Delayed gadolinium contrast enhancement can persist for more than 12 months following an acute episode of pericarditis despite symptomatic resolution, as pericardial vascular changes take time to resolve.42,43 Hence, the presence of mild delayed gadolinium enhancement without T2 hyperintensity may suggest prior pericardial inflammation without ongoing acute pericardial inflammation. CMR should be considered where a patient presents with a troponin rise or evidence of new contractile dysfunction on echo to identify concomitant myocardial inflammation.44 This is termed myopericarditis where the dominant pathology is pericarditis or peri-myocarditis where there is extensive myocardial inflammation or LV dysfunction, and pericardial involvement is the more peripheral process.41 In patients at risk of developing constriction, pericardial late gadolinium hyperenhancement may identify a subset of patients where this may be aborted by appropriate antiinflammatory therapy.45 Cardiovascular computed tomography may be valuable again in the differential diagnosis of chest pain in the setting of suspected pericarditis, e.g., acute aortic syndromes.38,41 Pericardial inflammation may manifest as pericardial thickening or hyperenhancement postcontrast. Cardiovascular CT should also be considered where there is a history of thoracic trauma, of if concomitant pleuropulmonary pathology or neoplastic cause for pericarditis is suspected.41 In patients with chronic pericardial constriction, cardiovascular CT may be of value in delineating areas of pericardial calcification as well as ruling out concomitant bystander coronary disease, which may require revascularization at the time of cardiothoracic surgery. Cardiovascular and wider whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging may be of value in patients with suspected systemic autoimmune rheumatic disease or where there is concern about internal malignancy as a cause for acute pericarditis.41 As well as confirming inflammation and assessing disease activity, this may also identify lymph nodes or other structures to target for biopsy where histologic data is lacking.
15 A Toolkit for Health Care Professionals Recurrent Pericarditis Introduction to the Immune System, Inflammation and Mechanisms of Drug Action The immune system plays an important role in defending the body from infectious agents/pathogens, responding to foreign/toxic material and removing abnormal potentially pre-cancerous damaged host cells (cancer surveillance).16 The immune system is divided into two main components: the adaptive immune system and the innate immune system. Each plays a crucial role in defending the body against pathogens. The adaptive immune response involves cells from the immune system recognizing specific antigens, learning to generate specific antibodies to these, or developing specific cell-mediated immunity to pathogens, damaged and infected cells.16 This adaptive process takes time to develop but provides a highly specific targeted response to antigens while minimizing injury to non-target host cells or tissues. It also requires tolerance to develop to healthy host cells and tissues.16 For an antigen the immune system has not encountered before, this process can take at least a week. This is the rationale behind vaccinations, which prime the immune system with the anticipated antigen to accelerate an anamnestic response to the antigen should it be encountered again. If this were the only component of the immune response, potential pathogens would have a significant time advantage over the host, rendering the host undefended and vulnerable to infection. Until adaptive immunity develops, the host relies on the innate immune response.17 The innate immune response refers in part to the system of proteins and phagocytic cells that are designed to recognize (using pattern recognition receptors) highly conserved molecular signatures that are unique to but common among a range of pathogens, toxins or damaged cells.17 This can include, for example, toll-like receptor proteins that recognize pathogen associated molecular patterns, such as bacterial lipopolysaccharide.18 Another group of such proteins that act within the cell to detect pathogens or cell injury are the nucleotide-binding oligomerization domain leucine-rich repeat proteins or NLR — recognizing damage/ danger-associated molecular patterns.19 When activated, one such protein, called pyrincontaining domain-3 (P3), combines with other cell proteins to form an enzyme complex called an (NLR-P3) inflammasome. This contains a cysteine proteinase called caspase-1 (also called interleukin-1 (IL-1) converting enzyme) that is activated by the inflammasome and converts inactive pro-IL-1b to its active form, interleukin-1 beta (IL-1b).19,20 The latter is a key proinflammatory cytokine that orchestrates an ongoing inflammatory response. NLR-P3 is an important inflammasome as it responds to a variety of markers of cell injury or stress, and thereby plays a key role in activating an inflammatory response.20,21 Autoimmune disease results from the inappropriate activation of the adaptive immune system by self- or autoantigens.22 In contrast, the term autoinflammation is used to describe the inappropriate activation and dysregulation of the innate immune response.22 Although acute pericarditis can occur as a complication of a systemic autoimmune disease such as SLE, most cases of idiopathic or presumed viral pericarditis are thought to have a predominantly autoinflammatory basis.23 In reality, most conditions with an immunologic basis do not have a pure autoinflammatory or autoimmune basis, but exist on a continuum with varying contributions of dysregulation of both arms of the immune system, which do not exist in isolation.24 The drugs used to treat pericarditis target different aspects of the inflammatory cascade. Colchicine is thought to inhibit the assembly of the NLR-P3 inflammasome and so indirectly reduce the production of IL-1b.25 One action of IL-1b is to stimulate the production of arachidonic acid by the enzyme lipoxygenase.26 Arachidonic acid in turn is metabolized by the enzyme cyclo oxygenase 2 to produce pro-inflammatory prostaglandins.26 Non-steroidal anti-inflammatory drugs, such as ibuprofen and aspirin, work by inhibiting cyclo-oxygenase. Corticosteroids have more pleiotropic effects, including inhibition of the transcription of pro-inflammatory genes including those for IL-1 precursors.27 Given the key role of interleukin-1b in orchestrating inflammation in acute pericarditis, recent efforts to treat pericarditis have focused on antagonizing the IL-1 receptor (anakinra, a recombinant interleukin-1 receptor antagonist) or by blocking IL-1 itself (rilonocept and goflikicept, IL-1 traps; canakinumab, a monoclonal antibody against IL-1b).23,28
First-line treatment of acute pericarditis includes off-label use of aspirin or a nonsteroidal anti-inflammatory drug (NSAID) plus colchicine for inflammation, often with a proton pump inhibitor for gastric protection. Aspirin/NSAIDs NSAIDs and aspirin inhibit cyclooxygenase and thereby prevent the production of prostaglandins via the metabolism of arachidonic acid. Relatively higher doses of aspirin/NSAIDs are necessary to mitigate symptoms attributed to pericardial inflammation.46 Aspirin may be used instead of other NSAIDs if the patient is already receiving aspirin for another condition, such as coronary or peripheral artery disease where an antiplatelet effect is required. Acute pericarditis may fail to settle or appear incessant if inadequate doses of NSAIDs are used or if these are stopped abruptly or tapered before symptoms have settled and/or inflammatory markers have normalized. Although other NSAIDs can be used, ibuprofen and aspirin have the advantage that they are inexpensive, readily available and come in tablet dose denominations that greatly facilitate tapering. NSAIDs are contraindicated when creatinine clearance is less than 30 ml/min, or there is an allergy to NSAIDs or a history of associated asthma exacerbation, recent gastrointestinal ulcer or high risk of bleeding due to concomitant use of anticoagulants. NSAIDs are also contraindicated in patients with a history of acute coronary syndromes, heart failure and in pregnancy at 20 weeks or later.1,47 Management of Acute Pericarditis Significant drug interactions with colchicine Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibitors can substantially increase serum colchicine concentrations, increasing toxicity.65 Renal and hepatic impairment further increases this risk. Awareness and risk mitigation strategies should be followed when using these drugs concomitantly. However, concomitant use of strong CYP3A4 and P-gp inhibitors should be avoided, particularly with renal or hepatic impairment. Common interactions are listed in Table 2. Visit https://link.springer.com/article/10.1007/s40264-02201265-1/tables/4 for more information. Table 1. Treatment and tapering of initial therapies for acute and recurrent pericarditis 46,48 Recommended treatment dosing Duration* Tapering recommendations Acute idiopathic pericarditis (initial episode) Recurrent pericarditis Aspirin 750-1000 mg by mouth every 8 hours 1-2 weeks Weeks to months 250-500 mg every 1 to 2 weeks Ibuprofen 600-800 mg by mouth every 8 hours 200-400 mg every 1 to 2 weeks Colchicine† 0.5-0.6 mg PO twice daily (once daily if <70 kg, age >70 years or intolerant to twice daily dosing) 3 months At least 6 months None required 16 *Duration may vary based on symptoms and time to normalization of high-sensitivity C-reactive protein (<1 mg/L). †Renal dose adjustments are required, and presence of CYP3A4/P-glycoprotein drug interactions further influences clearance and may preclude safe use of colchicine. A single loading dose of 1-2 mg may be considered before maintenance dosing, but is not necessary and may negatively impact tolerance and adherence.
A Toolkit for Health Care Professionals Recurrent Pericarditis 17 Colchicine Colchicine binds to tubulin and inhibits its polymerization into microtubules, which consequently, decreases migration and phagocytosis of leukocytes. Colchicine also blocks the NLRP3 inflammasome complex, and thereby prevents the secretion of the key pro-inflammatory cytokines interleukin1beta and interleukin-18.65 As an adjunct to an NSAID or aspirin for acute pericarditis, colchicine therapy not only increases the remission rate at 7 days, but decreases the chances of incessant or recurrent pericarditis by about 50% with a number needed to treat (NNT) of 4.48 Recurrence is one of the most important complications of acute pericarditis. The role of colchicine and the need to continue this for 3 months regardless of symptoms should be clearly explained to patients to promote adherence and reduce the risks of patients stopping treatment prematurely when they start to feel better/improve. Colchicine has a long half-life, so at the end of a course, it can be stopped abruptly without the need for tapering. It is often prescribed twice daily, but if required to promote adherence, the total dose can be given once daily, assuming patient stability and no adverse effects, e.g., 0.5-0.6 mg twice daily can be taken as 1.0-1.2 mg once daily.49 Although colchicine is safe when used and dosed appropriately, it has a narrow therapeutic index, and dose adjustment is necessary for renal and hepatic impairment to Table 2. Significant drug interactions with colchicine CYP3A4 inhibitor P-gp inhibitor Clinical considerations Cardiovascular drugs amiodarone X X Avoid if possible. If agent must be used, consider colchicine dose reduction and monitor closely. dronedarone X X Avoid if possible. If agent must be used, consider colchicine dose reduction and monitor closely. non-dihydropyridine calcium channel blockers (diltiazem, verapamil) X X Avoid if possible. If agent must be used, consider colchicine dose reduction and monitor closely. Macrolide antibiotics azithromycin X Assess risk/monitor for colchicine toxicity. clarithromycin X X Avoid combination. Azole antifungals itraconazole X X Avoid if possible. If agent must be used, consider colchicine dose reduction and monitor closely. ketoconazole X X Avoid if possible. If agent must be used, consider colchicine dose reduction and monitor closely. fluconazole X Assess risk/monitor for colchicine toxicity. voriconazole X Assess risk/monitor for colchicine toxicity. Antiretrovirals protease inhibitors (atazanavir, darunavir, ritonavir) with or without cobicistat X X Avoid combination. Calcineurin inhibitors cyclosporine X X Avoid if possible. If agent must be used, consider colchicine dose reduction and monitor closely. tacrolimus X Assess risk/monitor for colchicine toxicity. Consider colchicine dose reduction. Clinical considerations provided do NOT take into account impaired renal/hepatic function. This table does not include all possible colchicine drug interactions and is not intended to supplant clinical judgment. Recommendations also vary based on manufacturer package insert and colchicine treatment indication.
18 prevent toxicity. (See Table 1. Treatment and Tapering of Initial Therapies for Acute and Recurrent Pericarditis.) Furthermore, colchicine is metabolized by CYP3A4 and is also a substrate of P-glycoprotein, which consequently increases the risk for significant drug-drug interactions. Concomitant use of colchicine with strong CYP3A4 or P-glycoprotein inhibitors should be avoided, and close monitoring for colchicine toxicity is warranted with concomitant use of moderate CYP3A4 inhibitors. (See Table 2.)50 Particular caution should be exercised in patients receiving drugs that affect both CYP3A4 and P-glycoprotein. The most common adverse reactions of colchicine are gastrointestinal effects. Colchicine commonly causes diarrhea, and occasionally nausea and vomiting.51 If patients experience diarrhea that is likely to be attributable to colchicine, given the benefits, the dose should be halved in the first instance, rather than discontinued. Colchicine can also cause an acquired lactose intolerance that may contribute to diarrhea. Therefore, in addition to reducing the colchicine dose, a lactose-free diet should be attempted.52 Consider signposting patients to information about lactosefree diets.53 Proton pump inhibitors can also occasionally contribute to diarrhea. If these are used, consider the need for these and/or switch to a histamine type-2 receptor (H2)- antagonist. Side effects of colchicine that are less common but serious, and thus require close monitoring and possible dose reduction or discontinuation of the drug, include bone marrow suppression, renal or hepatic impairment, and neuromuscular toxicity. Extra caution is necessary in the elderly, who are at increased risk for neuromuscular toxicity and rhabdomyolysis.54 Colchicine is contraindicated in end-stage renal failure (creatinine clearance <15 mL/min), severe hepatic impairment and blood dyscrasias. Although there are varying recommendations based on different product package inserts and indications, the use of colchicine in patients with severe renal impairment is not well-studied. Patients with chronic kidney disease who are also receiving colchicine should be closely monitored for adverse effects. Colchicine is generally avoided in dialysis because it is not removed by dialysis. Avoidance with strong P-glycoprotein inhibitors or CYP3A4 inhibitors should also be strongly considered. Although colchicine crosses the placenta and is generally avoided during pregnancy, it has not been associated with increased fetal malformations when used for familial Mediterranean fever.55,56,57 Muscle toxicity and rhabdomyolysis with colchicine and HMG-CoA reductase inhibitors Both colchicine and HMG-CoA reductase inhibitors (statins) can cause myotoxicity through unique mechanisms.66 In addition to colchicine being a substrate for both CYP3A4 and P-gp, select statins are also metabolized by CYP3A4 or eliminated through P-gp, which lends to more multiple interactions between CYP3A4/P-gp inhibitors. Consequently, their coadministration poses an even greater risk for rhabdomyolysis, and data suggests this may become life-threatening. If there is an indication for concomitant statin therapy, hydrophilic statins such as pravastatin or rosuvastatin should be used to mitigate this risk. Other risk factors for myopathies should be assessed (e.g., renal/ hepatic impairment, CYP3A4/P-gp inhibitors). Consider lowering the statin dose and monitoring creatine kinase after two weeks of concomitant colchicine therapy. Visit https://www.ahajournals.org/doi/10.1161/ ATVBAHA.124.319851 for more information.46,65,66,67,68 Table 3. Inducers of CYP3A4 and P-glycoprotein CYP3A4 inducer P-gp inducer barbiturates X bosentan X carbamazepine X X phenytoin X rifabutin X rifampin X X rifapentine X Concomitant therapy with colchicine may increase rate of colchicine metabolism and decrease plasma concentrations. Avoid if possible. Corticosteroids For most patients, glucocorticoids should be avoided, if possible, as a first-line therapy for acute pericarditis. Although initially they can provide quick relief of symptoms, they may reduce the efficacy of colchicine, and they have been associated with increased rates of recurrent pericarditis. However, glucocorticoids are considered second-line treatment if a patient does not respond to effective doses of NSAIDs, and they are
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