Recurrent Pericarditis A Toolkit for Health Care Professionals Kiniksa Pharmaceuticals is a proud supporter of the American Heart Association’s Addressing Recurrent Pericarditis educational content.
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 © 2026 American Heart Association, Inc., a 501(c)(3) not-for-profit. All rights reserved. Unauthorized use prohibited. All references and data are as of February 2026. Disclaimer: This toolkit incorporates therapeutic information from the 2025 European Society of Cardiology Guidelines for the management of myocarditis and pericarditis, which currently constitute the most comprehensive, evidence-based recommendations available in the absence of an American Heart Association pericarditis guideline. However, drug approvals and market availability differ across jurisdictions. While certain interleukin-1 (IL-1) inhibitors — such as anakinra and canakinumab — are authorized in both the United States and the European Union, they are not approved specifically for recurrent pericarditis. Other agents, like rilonacept (approved in the U.S.) or goflikicept (approved in Russia), may be available only in select regions. Clinicians should adhere to best practices based on current evidence and the therapeutics available in their region. The inclusion or mention of any pharmaceutical product does not constitute Heart Association endorsement.
3 A Toolkit for Health Care Professionals Recurrent Pericarditis Contents 4 Introduction 4 Pericardial Anatomy, Structure and Function 7 Structured History Taking for Acute Pericarditis 9 Differential Diagnosis 10 Clinical Examination 11 Initial Investigations 12 Multimodality Imaging 13 Introduction to the Immune System, Inflammation and Mechanisms of Drug Action 14 Management of Acute Pericarditis 26 Special Topics 29 Top Takeaways Plus! Treatment and tapering of initial therapies for acute and recurrent pericarditis Page 14 Significant drug interactions with colchicine Page 15
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. 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 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 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. The toolkit is supported by a series of four American Heart Association vodcasts and webinars, which in turn build on an extensive library of resources available on the Lifelong Learning website (https://professional. heart.org/en/education/recurrentpericarditis-for-professionals). 4
5 A Toolkit for Health Care Professionals Recurrent Pericarditis Acute pericarditis is an inflammatory pericardial syndrome with or without pericardial effusion, typically presenting within four weeks of symptom onset. It occurs more often in males aged 20–50 years,8 and most cases are idiopathic and presumed to be 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 with a clinical presentation including chest pain or infarct-like symptoms, arrhythmias, heart failure or aborted sudden cardiac death. Diagnostic criteria have evolved with the publication of the 2025 European Society of Cardiology (ESC) Guidelines, placing more emphasis on the clinical presence of classic chest pain or equivalent. 1. Clinical presentation: pleuritic/infarct-like chest pain (present in 85-90% of cases) or equivalent 2. Plus ≥1 additional finding (0 = unlikely/rejected, 1 = possible, and 2+ = definite diagnosis): a. Pericardial friction rub b. Electrocardiogram changes consisting of diffuse STsegment elevation and/or PR-segment depression c. Inflammatory biomarkers elevation (such as C-reactive protein [CRP] or sedimentation rate) d. Cardiac imaging (especially echocardiography evidence) of new or worsening pericardial effusion e. Cardiac imaging evidence of pericardial inflammation 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 nonsteroidal 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. Diagnostic testing is similar to that done in the acute phase. It occurs more commonly in those who were not treated with colchicine.13 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
6 The 2025 ESC Guidelines recommend testing for elevated markers of inflammation, such as CRP, ESR and neutrophilic leukocytosis, to provide additional diagnostic supportive criteria. CT is recommended to evaluate pericardial thickness, calcifications, masses and loculated pericardial effusions as well as concomitant pleuropulmonary diseases and chest abnormalities. CMR is recommended in patients with suspected pericarditis when a diagnosis cannot be made using clinical criteria to assess evidence of pericardial thickening, edema or LGE and to assess the persistence of disease during follow-up in selected cases.14 Incessant pericarditis is defined as patients with persistent symptoms lasting longer than four to six weeks (but less than three 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 three 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 noncompliance presenting as a clinical form of heart failure.7,12,13,15 The hemodynamic alterations occurring in constrictive pericarditis are the dissociation of intrathoracicintracardiac pressures and enhanced ventricular interaction.13,15 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.7,13,15 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.12,16 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).7,12,13,15 There are three subtypes of constrictive pericarditis as described by Adler et al. (2015):1 Transient constrictive pericarditis This is 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 antiinflammatory 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 three to six months, it may exhibit heart failure NYHA class III or IV symptoms.
7 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 treatment was 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?
8 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 14.) 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.
9 A Toolkit for Health Care Professionals Recurrent Pericarditis 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.17 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,18 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 noncardiac 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 nonpericardial 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.19 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.20 In a series of 1,162 patients with pericarditis: 55% were deemed idiopathic 9% were neoplastic 2.6% were autoimmune.21 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.22 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.23 These studies suggest that those with previously presumed idiopathic and/or viral-induced pericarditis may actually hold a genetic predisposition. Differential Diagnosis
10 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 Clinical Examination 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 one-third of patients with inflammatory pericarditis.24 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 in the assessment of inflammatory pericarditis include blood tests, electrocardiography and echocardiography. (See “Multimodality Imaging” on page 12.) 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 nonpericarditic 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 Initial Investigations 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.25 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. 11
12 Multimodality Imaging Echocardiography remains the primary modality for investigating patients with suspected acute pericarditis.26,27 It can be used to detect a new or worsening pericardial effusion — one of the principal clinical diagnostic features of acute pericarditis.26,28 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).26 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.26,28 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.29 The healthy pericardium is a relatively avascular structure and therefore does not take up gadolinium contrast.29 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.29 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.30,31 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.32 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.29 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.33 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.26,29 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.29 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.29 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.
13 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).34 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 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.35 This can include, for example, toll-like receptor proteins that recognize pathogen associated molecular patterns, such as bacterial lipopolysaccharide.36 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.37 When activated, one such protein, called pyrincontaining domain-3 (P3), combines with other cell proteins to form an enzyme complex called an (NLRP3) 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-1β to its active form, interleukin-1 beta (IL-1β).37,38 The latter is a key proinflammatory cytokine that orchestrates an ongoing inflammatory response. NLRP3 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.38,39 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.34 This adaptive process takes time to develop but provides a highly specific targeted response to antigens while minimizing injury to nontarget host cells or tissues. It also requires tolerance to develop to healthy host cells and tissues.34 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 Autoimmune disease results from the inappropriate activation of the adaptive immune system by self- or autoantigens.40 In contrast, the term autoinflammation is used to describe the inappropriate activation and dysregulation of the innate immune response.40 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.41 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.42 The drugs used to treat pericarditis target different aspects of the inflammatory cascade. Colchicine is thought to inhibit the assembly of the NLRP3 inflammasome and so indirectly reduce the production of IL-1β.43 One action of IL-1β is to stimulate the production of arachidonic acid by the enzyme lipoxygenase.44 Arachidonic acid in turn is metabolized by the enzyme cyclooxygenase 2 (COX-2) to produce pro-inflammatory prostaglandins.44 Nonsteroidal anti-inflammatory drugs, such as ibuprofen and aspirin, work by inhibiting cyclooxygenase. Corticosteroids have more pleiotropic effects, including inhibition of the transcription of pro-inflammatory genes including those for IL-1 precursors.45
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 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 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. Significant drug interactions with colchicine Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibitors can substantially increase serum colchicine concentrations, increasing toxicity.48 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 *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. 14
A Toolkit for Health Care Professionals Recurrent Pericarditis 15 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 interleukin-1β and interleukin-18.48 As an adjunct to an NSAID or aspirin for acute pericarditis, colchicine therapy not only increases the remission rate at seven days, but decreases the chances of incessant or recurrent pericarditis by about 50% with a number needed to treat (NNT) of four.49 Recurrence is one of the most important complications of acute pericarditis. The role of colchicine and the need to continue this for three 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.50 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. nondihydropyridine 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.
16 prevent toxicity. (See Table 1. Treatment and Tapering of Initial Therapies for Acute and Recurrent Pericarditis on page 14.) 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.51 (See Table 2 on page 15.) 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.52 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.53 Consider signposting patients to information about lactosefree diets.54 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.55 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.56,57,58 i Concomitant therapy with colchicine may increase rate of colchicine metabolism and decrease plasma concentrations. Avoid if possible. 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.59 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 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 may be considered if a patient does not respond to effective doses of NSAIDs, and they are used first-line when there 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
17 A Toolkit for Health Care Professionals Recurrent Pericarditis is an underlying systemic autoimmune rheumatic disease or a contraindication to NSAIDs. Where not contraindicated, colchicine should be co-prescribed with prednisone.1,55 Prednisone prescribed at a dose of 0.2-0.5 mg/kg/day for up to four weeks is required before slow tapering is begun, assuming symptoms have resolved, and inflammatory markers have normalized. Doses higher than this can increase the risks of adverse effects without any gain in efficacy. The risk of recurrence is highest when doses are tapered to below 12.5-15 mg, and therefore, tapering below this should be slow.60 Where not contraindicated, colchicine should be co-prescribed with prednisone and should be stopped only after steroids have been tapered off or at three months, whichever is longer. Patients receiving a prolonged course of oral corticosteroids should be warned about the risks of adrenal suppression and given advice on sick day rules, should they develop any intercurrent illness that prevents them taking and/or adequately absorbing their prednisone. parathyroid hormone (PTH) to ensure patients are vitamin D replete and to guide calcium/vitamin D supplementation to mitigate any impact on bone density. Use the opportunity to promote other lifestyle changes that may reduce risks, such as moderating alcohol intake and smoking cessation. In high-risk patients, consider the need for bone densitometry and formal bone protection. If a patient is exposed to prolonged courses of oral corticosteroids, once a dose of 4-5 mg is reached, it may be necessary to check adrenal reserve with a 9 a.m. cortisol (taken before 10 a.m. and before dosing with prednisone on that day). Where this is insufficient, consider the need for a Synacthen test (ACTH stimulation test) to guide further tapering.61,62,63 Table 4: Guidance on corticosteroid therapy.46 Treatment dose: prednisone 0.2-0.5 mg/kg/day* Prednisone dose Tapering based on initial treatment dose More than 50 mg 10 mg/day every 1-2 weeks 25-50 mg 5-10 mg/day every 1-2 weeks 15-25 mg 2.5 mg/day every 2-4 weeks Less than 15 mg 1.5-2.5 mg/day every 2-6 weeks *prednisone 5 mg = prednisolone 5 mg = methylprednisolone 4 mg = dexamethasone 0.75 mg = hydrocortisone 20 mg General approach to tapering Although clinical practice guidelines have defined durations of therapy for acute pericarditis, tapering should only occur if patients are asymptomatic with normalized high-sensitivity C-reactive protein (hs-CRP). Prolonged treatment courses are warranted in persistently symptomatic patients or if hs-CRP remains elevated. Persistent elevation in hs-CRP concentrations (>3 mg/L) after one week is an independent risk factor for recurrent pericarditis.64 Hs-CRP should be monitored at baseline and one week after starting therapy to ensure resolution and to help guide therapy. Once symptoms have resolved and hs-CRP has normalized (<1mg/L), tapering of aspirin/ NSAIDs and/or corticosteroids can begin. Glucocorticoids may reduce the efficacy of colchicine, and they have been associated with increased rates of recurrent pericarditis. Before initiating oral corticosteroids, consider checking a baseline hemoglobin A1c (HbA1c), vitamin D and
18 Lifestyle changes Physical activity can contribute to the pathophysiology of pericarditis through various proposed mechanisms. Exercise may worsen inflammation through increased oxidative stress and shear stress within the pericardium. Increased blood flow can also elevate the concentrations of circulating antigens.65 Patients who are not athletes should be advised to avoid exercise and strenuous activities until symptoms resolve and hs-CRP normalizes. It is recommended that patients who are athletes adhere to a more prescriptive three months of exercise restriction and refrain from all competitive sports during this time. In cases of myopericarditis, both athletes and nonathletes should limit physical activity to low-intensity or normal sedentary activities for three to six months. Reassessment of pericardial effusion should also be conducted before returning to exercise.66 Incessant pericarditis This term is used to describe pericarditis lasting more than four to six weeks but less than three months (at which point the term chronic pericarditis is used).1 It is also used if there is a symptom-free period of only less than four to six weeks, which is the interval traditionally used to define remission. The term “recurrence” is reserved for circumstances in which there is acute pericarditis after a period of remission, i.e., four to six weeks without symptoms or inflammation. The four- to six-week interval cited is arbitrary but reflects the typical duration of firstline anti-inflammatory treatment, typically with NSAIDs, including tapering. Common causes of apparently incessant or pseudo-incessant disease include: Inadequate initial control of inflammation, either through under-dosing of NSAIDs or abrupt cessation of therapy without a taper, or tapering purely based on duration of treatment rather than guided by symptoms/inflammatory markers. (See “Management of Acute Pericarditis” on page 14.) The failure to initiate colchicine or continue this for 3 months following apparent resolution may be another apparent cause. The use of colchicine can potentially halve the risk of recurrence and can also accelerate the attainment of remission when used with NSAIDs. Although often very effective at rapidly controlling inflammation and symptoms, the early use of corticosteroids in lieu of NSAIDs can also result in recrudescence of symptoms, particularly if tapering is too abrupt or rapid, often with a threshold dose at which recurrence can occur. This risk can be reduced through slow and gradual tapering, particularly at a daily dose of about 12.5-15 mg prednisone (or equivalent). Finally, another common cause of apparent recurrence may be exercise. Increased cardiac motion and friction within the pericardial sac in conjunction with heart rate and cardiac contractility in response to physical activity may promote recrudescence of inflammation. Truly incessant disease, which fails to respond to initial therapy despite adequate dosing, appropriate tapering, adjunctive use of colchicine and avoidance of additional An incessant disease trajectory has been reported to occur in up to 12% of patients presenting to a tertiary pericardial service.67
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