Recurrent pericarditis

INTRODUCTION — Recurrent pericarditis is a common and often vexing problem for pericardial disease specialists as well as primary care clinicians. The term refers to a syndrome in which symptoms of acute pericarditis recur after the initial episode.

Recurrent pericarditis, including its definition, proposed pathogenesis, clinical manifestations, diagnosis, and treatment, will be reviewed here. The clinical manifestations, diagnosis, and treatment of patients with an initial attack of acute pericarditis are discussed separately. (See "Acute pericarditis: Clinical presentation and diagnosis" and "Acute pericarditis: Treatment and prognosis".)

DEFINITIONS — The time course of symptoms after treatment of acute pericarditis is variable [1-8]. Although most patients experience resolution of symptoms of acute pericarditis with therapy, some patients have persistent or recurrent symptoms. The following terms are used to define these differing clinical responses to therapy.

●Acute pericarditis is a condition lasting <4 to 6 weeks. Symptoms of acute pericarditis may recur at any time following cessation of acute symptoms (table 1), typically weeks to months later [5].

●Recurrent pericarditis occurs when symptoms of acute pericarditis return after a symptom-free interval of least four to six weeks [6,9]. Four to six weeks has been established as the minimum required symptom-free interval as it represents the typical duration of antiinflammatory therapy (including taper).

The recurrence rate for acute pericarditis is not well established, but may be as high as 15 to 30 percent in patients with idiopathic acute pericarditis not treated with colchicine [2,7,10,11].

●Incessant pericarditis is defined as occurring when symptoms persist for greater than four to six weeks up to three months without a sustained remission [6]. This includes recurrence of symptoms after a symptom-free interval of less than four to six weeks after the acute episode. Such recurrences often occur during attempted drug weaning, particularly following glucocorticoid therapy, occurring less commonly following nonsteroidal antiinflammatory drug (NSAID) use. Incessant pericarditis is associated with an increased risk of developing constrictive pericarditis within six months from symptom onset [12].

●Chronic pericarditis is defined as occurring when symptoms persist for greater than three months [6].

PATHOGENESIS — Observational studies suggest that most cases of recurrent pericarditis are caused by an autoimmune disorder, but a minority of cases may be due to an infection (most likely viral, which may be chronic infection, reinfection, or new infection).

Evidence supporting an immunopathologic process includes a latent period that commonly lasts for months and similarities to other autoimmune conditions, including the presence of autoantibodies and responsiveness to glucocorticoid and other immunosuppressive therapies [13,14]. (See 'Pharmacologic therapy' below.)

It has been shown that a substantial number of cases of recurrent pericarditis display features of systemic inflammation (eg, fever and/or elevation of C-reactive protein at each episode). In such cases, recurrent pericarditis may share some features of autoinflammatory diseases, a group of disorders affecting the immune system in adults and children and often accompanied by signs of inflammation (recurrent fever, serositis, arthralgias, myalgias, elevated C-reactive protein). Indeed, in up to 10 percent of cases, a monogenic autoinflammatory diseases may be the cause of recurrences [15,16].

In some patients with recurrent pericarditis, cytokines such as interleukin (IL) 6, IL-8, and interferon gamma have been detected in the pericardial fluid but not in sera [17]. This distribution of cytokines suggests a local inflammatory process. These features of immune or inflammatory disease suggest a role for immune therapies such as IL-1 inhibitor, for patients who fail to respond to NSAIDs, glucocorticoids, and colchicine. (See "Pericardial involvement in systemic autoimmune diseases" and 'Inflammatory phenotype' below and 'Pharmacologic therapy' below.)

An infectious or systemic etiology cannot usually be identified using standard laboratory techniques. In one study of recurrent pericarditis, investigators performed extensive studies to evaluate suspected recurrent pericarditis, including pericardioscopy, multiple epicardial biopsies, and polymerase chain reaction [18]. Epicardial biopsy was performed during pericardioscopy and targeted at regions that appeared abnormal. The authors reported a higher prevalence of infection or reinfection (approximately 23 percent) than reported in other studies [7,18].

Familial factors may be important in some cases. A cluster of recurrent pericarditis has been described in five members of a family of German and Danish ancestry [19]. It was suggested that this might represent familial disease with possible autosomal dominant inheritance.

CLINICAL PRESENTATION

Key features — Recurrent pericarditis is manifested by recurrence of the symptoms and signs of acute pericarditis (table 1) after a symptom-free interval of at least four to six weeks. The presenting symptoms of recurrent pericarditis are generally similar to those for acute pericarditis, although the presenting symptoms may not be consistent for each individual patient and are frequently less intense during recurrences [20]. The predominant feature of recurrent pericarditis is usually pleuritic chest pain (often sharp, worse when lying flat, and alleviated when leaning forward), which may follow exertion. Some patients may also report dyspnea or malaise. Other clinical manifestations of acute pericarditis are often absent.

Other features and complications — Other clinical features and complications, such as pericardial rubs, pericardial effusion, and cardiac tamponade, are less common with subsequent episodes, and cardiac tamponade is a rare complication even in patients who had cardiac tamponade during the initial episode [3,9,13,21]. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Clinical features' and "Cardiac tamponade".)

Constrictive pericarditis is an uncommon complication, estimated as occurring in less than 1 percent of patients with recurrent pericarditis [6,9,13,19,22]. (See "Constrictive pericarditis: Diagnostic evaluation".)

Recurrent pericarditis is generally not associated with ventricular systolic dysfunction or heart failure [9,13].

Time course — Symptoms of recurrent pericarditis occur at a variable time after the initial attack, but usually within 18 months [11,23]. By definition, recurrent pericarditis occurs after an at least four- to six-week symptom-free interval. (See 'Definitions' above.)

Most patients with recurrent pericarditis feel well between attacks, although some patients have a more persistent or chronic course [7,8]. The number of recurrences and the intervals between them vary considerably among patients, with 40 to 50 percent of patients who experience a recurrence having only one to two recurrences, which usually occur over several months to a few years following the initial episode [9,23,24]. However, some reports have shown that the period of time prior to a recurrence, and the duration of treatment required to effectively treat recurrences, may extend for years or, in rare cases, decades [2,3,13]. Although not well documented in the literature, the clinical experience of our contributors has been that heavy exertion prior to complete resolution of pericardial inflammation may result in recurrent chest pain. (See 'Activity restriction' below.)

Predictors of recurrence — No presenting clinical feature of an initial episode of acute pericarditis reliably predicts recurrence. However, a positive response to initial aspirin or other NSAID therapy is associated with a reduced risk of recurrence, while initial therapy with a glucocorticoid is associated with a greater risk of recurrence.

An observational study of patients with presumed idiopathic acute pericarditis identified an association between lack of response to aspirin or other NSAID therapy and risk of recurrence [10]. Compared with responders, those who did not respond to aspirin or other NSAID therapy had a much higher rate of recurrent pericarditis (61 versus 10 percent) and of pericardial constriction (9.1 versus 0.5 percent). (See "Acute pericarditis: Treatment and prognosis", section on 'Nonsteroidal antiinflammatory drugs'.)

Glucocorticoid therapy as the initial treatment for acute pericarditis appears to promote recurrence, as suggested by the following studies:

●The best data come from the COPE trial of colchicine therapy in patients with a first episode of acute pericarditis in which glucocorticoids were given only when aspirin was contraindicated or not tolerated [11]. Glucocorticoid use was a significant predictor of recurrence (odds ratio [OR] 4.3, 95% CI 1.2-15.3), an effect that has been postulated to be due to promotion of viral replication [25]. The COPE trial also showed that colchicine therapy markedly reduces the rate of recurrence. (See "Acute pericarditis: Treatment and prognosis", section on 'Colchicine'.)

●Similar findings were noted in the CORE trial of colchicine therapy in patients with recurrent pericarditis by the same investigators [24]. Previous glucocorticoid use was an independent risk factor for further recurrences (OR 2.9, 95% CI 1.1-8.3).

Initial test findings — Initial testing including blood work, chest radiography, and electrocardiography can support the diagnosis, but normal findings are common and abnormal findings are often nonspecific. (See 'Diagnostic criteria' below.)

Laboratory findings — Since pericarditis is an inflammatory disease, laboratory signs of inflammation are common in patients with recurrent pericarditis. These include elevations in the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and serum C-reactive protein (CRP) concentration. While elevation in these markers supports the diagnosis and has implications for prognosis and possibly for treatment, these markers are neither sensitive nor specific for recurrent pericarditis [26,27]. Absence of elevation in WBC count, ESR, and/or CRP does not exclude the diagnosis of recurrent pericarditis.

Electrocardiogram — In recurrent pericarditis, changes on the electrocardiogram (ECG) are less specific than for acute pericarditis. Only rarely is ST elevation identified, and more common findings include nonspecific ST-segment and T-wave changes (ie, T-wave inversion or flattening). Given these observations, it is not possible to describe specific stages of ECG changes for recurrent pericarditis as in acute pericarditis.

ECG changes associated with an initial attack of acute pericarditis are discussed separately. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Electrocardiogram'.)

Chest radiograph — A chest radiograph is not required in patients with suspected recurrent pericarditis but may be performed as part of an evaluation for dyspnea. The chest radiograph is often normal in patients with recurrent pericarditis unless there is an associated pericardial effusion. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Clinical features'.)

DIAGNOSIS

Approach to diagnosis

●When to suspect recurrent pericarditis – Recurrent pericarditis should be suspected in a patient with a prior episode of acute pericarditis who develops characteristic pleuritic chest pain. Recurrent or incessant pericarditis may also be suspected in a patient with prior acute pericarditis who presents with persistent fever and pericardial effusion or new unexplained cardiomegaly.

●Initial testing – For patients with suspected recurrent pericarditis, testing should include an ECG, focused laboratory studies searching for evidence of inflammation (white blood cell [WBC] count, erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]), and an echocardiogram. Results of diagnostic testing can support a diagnosis of recurrent pericarditis, but no single test definitively makes or excludes the diagnosis. (See 'Initial test findings' above and 'Diagnostic criteria' below.)

●Echocardiogram – Transthoracic echocardiography is performed in patients with suspected recurrent pericarditis. While the echocardiogram is frequently normal, it is helpful in identifying an associated pericardial effusion (in this setting, rarely associated with cardiac tamponade) and signs of constrictive pericarditis (an uncommon complication). (See 'Other features and complications' above.)

●Advanced imaging is indicated for only selected patients when clinical evaluation and initial testing are inconclusive. For patients with recurrent chest pain after prior acute pericarditis with no signs of pericardial inflammation on initial testing, cardiovascular magnetic resonance (CMR) or computed tomography (CT) may be helpful, as noted by major society guidelines [14,28]. In such cases, the diagnosis of recurrence can rely on identification of pericardial edema and late gadolinium enhancement (LGE) on CMR [26,28,29] or detection of pericardial thickening and contrast-enhancement on CT. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Pericardial disease'.)

Imaging can also be useful to monitor disease activity and predict the outcome and probability of remission [30].

Diagnostic criteria — The following criteria are applied in identifying clinical syndromes of recurrent pericarditis (see 'Definitions' above):

●Recurrent pericarditis is diagnosed in a patient with a prior episode of acute pericarditis who develops recurrent symptoms (typically pleuritic chest pain) and at least one sign of pericardial inflammation (fever, pericardial rub, characteristic ECG changes, new or worsening pericardial effusion, elevation of an inflammatory marker [WBC count, ESR, or CRP], or evidence of pericardial inflammation on CMR or CT) after an at least four- to six-week symptom-free interval (table 1).

●Incessant pericarditis is diagnosed if diagnostic criteria for recurrent pericarditis are present, but the symptom-free interval is <4 to 6 weeks and the total duration of symptoms is three months or less.

●Chronic pericarditis is diagnosed in a patient with diagnostic criteria for recurrent pericarditis with a symptom-free interval of <4 to 6 weeks and a total duration of symptoms greater than three months.

The approach to the evaluation of the cause of recurrent pericarditis is the same as for evaluation of the cause of the initial episode of acute pericarditis, as discussed separately. (See "Acute pericarditis: Clinical presentation and diagnosis", section on 'Diagnosis'.)

Inflammatory phenotype — Patients with recurrent pericarditis may present with an inflammatory or noninflammatory phenotype. An inflammatory phenotype is characterized by the presence of one or more of signs of an inflammatory process when presenting with a recurrence: fever, elevated CRP, elevated WBC count, elevated ESR, pericardial LGE on CMR, or pericardial contrast enhancement on CT. Patients presenting without any of these signs of inflammation have a noninflammatory phenotype.

TREATMENT — The treatment of recurrent pericarditis is similar to that of the initial episode of acute pericarditis (table 2). Most patients with recurrent pericarditis can be managed effectively with medical therapy alone, and outpatient management is feasible in almost all cases [14,23,24]. Hospitalization should be limited to patients with high-risk features, as in acute pericarditis (algorithm 1) [10]. (See "Acute pericarditis: Treatment and prognosis".)

For patients with idiopathic or viral recurrent pericarditis, treatment focuses on control of symptoms as described here. For patients with recurrent pericarditis from other causes, symptomatic therapy is accompanied by specific therapy for the underlying disorder. (See "Acute pericarditis: Treatment and prognosis", section on 'Treatment'.)

General measures

Communication with the patient — Effective communication with and education of the patient is important when managing recurrent pericarditis, as the condition can be prolonged and frustrating with disabling symptoms, and management requires extended adherence to therapies. It is important to explain to the patient the nature of the disease, the likely course, and the treatment alternatives. Specific features of the disease that should be emphasized include the following:

●After successful treatment of a recurrence, further recurrences are possible, and may repeat, at variable intervals, for up to several years. (See 'Time course' above.)

●Recurrent episodes are not usually caused by reinfection, even among patients whose first illness was viral. It is reasonable to reassure patients that the disease eventually resolves in most cases, nearly always with no permanent sequelae.

●Although both are uncommon complications, the symptoms and signs of cardiac tamponade and constrictive pericarditis should be reviewed with the patient. (See "Cardiac tamponade" and "Constrictive pericarditis: Diagnostic evaluation".)

Activity restriction — Strenuous physical activity may trigger worsening of symptoms; therefore, such activity should be avoided until symptom resolution. Athletes should not participate in competitive sports until there is no longer evidence of active disease (eg, resolution of symptoms and normalization of inflammatory biomarkers). Although supporting evidence is not available, we ask patients to restrict exertion to a level necessary to perform domestic tasks and undertake sedentary work [9], as for the initial episode. (see "Acute pericarditis: Treatment and prognosis", section on 'Activity restriction')

An observational study found that improved control of heart rate with the use of beta blockers was associated with a higher rate of early resolution of symptoms [31].

Pharmacologic therapy

Our approach — The following approach is for nonpregnant patients with recurrent pericarditis. Doses are described in the table (table 2).

Management of pericarditis during pregnancy is discussed separately. (See "Management of pericardial effusion and acute pericarditis during pregnancy".)

●Initial therapy – For most patients with recurrent pericarditis, we recommend initial combination therapy with colchicine plus either an NSAID or aspirin, rather than NSAID alone. (See 'Colchicine' below and 'NSAID or aspirin' below.)

●Glucocorticoid plus colchicine – For patients with recurrent pericarditis with persistent symptoms on colchicine plus an NSAID (or aspirin) or who have a contraindications to NSAID and aspirin therapy, we suggest treatment with glucocorticoid therapy plus colchicine. (See 'Glucocorticoids' below.)

●Triple therapy – For patients with persistent symptoms on dual therapy with glucocorticoid therapy plus colchicine, we suggest addition of aspirin therapy (triple therapy).

●Fourth-line therapy – For patients with recurrent pericarditis with persistent symptoms despite third-line therapy, we treat based upon whether an inflammatory phenotype is present. In this setting the potential benefits and risks of immune therapy, and of pericardiectomy as an alternative, are considered. (See 'Role of pericardiectomy' below.)

•For patients with an inflammatory phenotype (see 'Inflammatory phenotype' above), we suggest an interleukin (IL) 1 inhibitor (rilonacept or anakinra). (See 'Interleukin 1 inhibitors' below.)

•For patients with a noninflammatory phenotype, options include intravenous immunoglobulin (IVIG; preferred for patients with an autoimmune disorder) and azathioprine (preferred for patients with no identified autoimmune disorder). (See 'Other immune therapy' below.)

NSAID or aspirin — An NSAID or aspirin is a key component of initial therapy for recurrent pericarditis (as for acute pericarditis) [14]:

●For patients without a contraindication to NSAID – For most patients with recurrent pericarditis, we use an NSAID, with the duration of therapy (typically full-dose for at least one to two weeks for symptom control followed by two or more weeks of tapered dosing) guided by the persistence of symptoms and the normalization of inflammatory biomarkers.

●For patients taking aspirin as an antiplatelet agent – For patients taking aspirin as an antiplatelet agent (including patients post-myocardial infarction) we generally avoid NSAIDs, since ibuprofen and some other NSAIDs can interfere with the antiplatelet effect of low-dose aspirin. Most patients can be effectively treated with daily aspirin doses lower than 3000 mg (table 2). Management of pericarditis associated with myocardial infarction is discussed separately. (See "Pericardial complications of myocardial infarction", section on 'Management of PIP'.)

Gastrointestinal protection should be provided during NSAID or aspirin therapy, as described separately. (See "Acute pericarditis: Treatment and prognosis", section on 'Nonsteroidal antiinflammatory drugs' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

The different NSAIDs are probably equally effective but must be given in appropriate antiinflammatory doses. Numerous NSAID regimens are available for treatment of recurrent pericarditis (table 2). Given its widespread availability, relative safety, and low cost, ibuprofen (600 to 800 mg orally three times daily) is typically the first choice for therapy. Indomethacin (50 mg three times daily) is usually reserved for more severe cases and when first-line NSAIDs fail. The patient's prior experience can provide a useful guide for deciding among agents. Many patients with recurrent pericarditis have tried a number of different NSAIDs at different times. If a patient reports that a specific drug has proven effective, it is reasonable to use that agent.

If the initial response to NSAID or aspirin therapy is not satisfactory, the dose should be increased (up to the recommended daily maximum dose), or an alternative antiinflammatory agent used, until an adequate response is achieved. The NSAID or aspirin should be administered as three doses daily to optimize symptom control until symptom resolution. This approach should be continued until it is clear that NSAIDs have failed to control the syndrome, especially the pain, or that the drugs are not tolerated. A more extensive discussion of NSAID regimens is presented separately. (See "Acute pericarditis: Treatment and prognosis", section on 'NSAID dosing'.)

Following symptom resolution, the NSAID or aspirin should be slowly tapered to reduce the subsequent recurrence rate (table 2) [10,11,23,24,32,33].

Colchicine — Colchicine is a key component of therapy for recurrent pericarditis (table 2) [14]. The use of colchicine with an NSAID can reduce or eliminate the need for glucocorticoids in patients with recurrent pericarditis. Colchicine should be prescribed in two doses daily rather than a single dose to reduce the risk of gastrointestinal intolerance and improve patient compliance [32-34].

The effectiveness of colchicine in patients with recurrent pericarditis has been evaluated in three randomized, placebo-controlled trials:

●In the CORE trial, 84 consecutive patients with a first episode of recurrent pericarditis were randomly assigned to aspirin alone or in combination with colchicine (1 to 2 mg on the first day, followed by 0.5 once or twice daily for six months) [24]. Colchicine therapy was associated with a marked and significant reduction in the primary endpoint of the rate of recurrence at 18 months (24 versus 51 percent), and a significant reduction in the secondary endpoint of symptom persistence at 72 hours (10 versus 31 percent).

●In the CORP trial, 120 consecutive patients with a first episode of recurrent pericarditis were randomly assigned to conventional antiinflammatory therapy alone (aspirin, ibuprofen, or prednisone) or in combination with colchicine (1 to 2 mg on the first day, followed by 0.5 once or twice daily for six months) [35]. Treatment with colchicine significantly reduced the primary endpoint of first recurrence at 18 months (24 versus 55 percent with placebo; absolute risk reduction [ARR] 31 percent, 95% CI 13-46), in addition to improving several secondary outcomes, including persistent symptoms at 72 hours (23 versus 53 percent with placebo; ARR 30 percent, 95% CI 13-45).

●In the CORP-2 trial, 240 patients with two or more episodes of recurrent pericarditis were randomly assigned to placebo or colchicine (six months of therapy with 0.5 mg twice daily for patients >70 kg or 0.5 mg once daily for patients ≤70 kg or who were intolerant of twice daily dosing) in addition to conventional antiinflammatory therapy (aspirin, ibuprofen, or prednisone) [36]. Compared with placebo, patients treated with colchicine experienced significantly fewer recurrences (26 [22 percent] versus 51 [43 percent] in patients receiving placebo; relative risk [RR] 0.49, 95% CI 0.24-0.65) as well as significantly fewer symptoms at 72 hours (19 versus 44 percent) and at one week (17 versus 41 percent) with no significant difference in adverse events between the two groups.

A meta-analysis identified similar efficacy in reducing the recurrence rate of pericarditis in patients with acute pericarditis (five randomized controlled trials; RR 0.46, 95% CI 0.36-0.58) and recurrent pericarditis (the three randomized trials described above; RR 0.48, 95% CI 0.36-0.63) [37]. Data from seven of these trials showed that gastrointestinal intolerance was the most commonly reported adverse effect of colchicine (RR 1.42, 95% CI 1.05-1.92).

The use of colchicine in the treatment of pericarditis and prevention of recurrence is an off-label use of the medication. Although low doses of colchicine (0.6 to 1.2 mg per day) have been safe in most patients even when given continuously over decades, there are uncommon (<1 percent) possible side effects to be considered (eg, bone marrow suppression, hepatotoxicity, and muscle toxicity) beyond the well-known gastrointestinal side effects (5 to 10 percent). Chronic kidney disease leading to increased plasma colchicine levels appears to be the major risk factor for side effects. Patient compliance may improve if a loading dose is avoided.

Glucocorticoids — Glucocorticoid therapy is generally a second- or third-line therapy for recurrent pericarditis unless there is a specific indication (systemic inflammatory disease requiring glucocorticoid therapy or pregnancy after week 20), as many patients can be successfully treated without resorting to such therapy [14]. Glucocorticoid use should be limited to selected patients given its potential adverse effects, particularly with prolonged use. Observational studies suggest that glucocorticoid therapy may increase the risk of recurrence [11,24,25,38-40], even after multiple recurrences [38]. (See "Management of pericardial effusion and acute pericarditis during pregnancy", section on 'Management'.)

Glucocorticoids are an option for the following subsets of patients:

●Patients who fail combination therapy with colchicine and NSAIDs.

●Patients with intolerance or contraindications to aspirin or NSAIDs (eg, pregnant patients at gestational week 20 or later). (See "Management of pericardial effusion and acute pericarditis during pregnancy".)

●Patients with certain systemic autoimmune disorders (eg, dermatomyositis and polymyositis) that are treated with glucocorticoids. (See "Pericardial involvement in systemic autoimmune diseases".)

Our approach to glucocorticoid use — If glucocorticoid therapy is indicated, the potential benefit and harms should be discussed with the patient. The patient should also be informed that once a glucocorticoid course has been completed, the aim is to taper the dose and finally discontinue therapy, particularly given concerns that glucocorticoids may perpetuate rather than abolish recurrences. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

For patients who require glucocorticoid therapy for recurrent pericarditis, we use moderate initial dosing (eg, 0.2 to 0.5 mg/kg/day of prednisone) followed by a slow taper (rather than high doses with a rapid taper) (table 2). We generally add colchicine during glucocorticoid therapy and continue colchicine for four weeks or more after glucocorticoid discontinuation (ie, with an overall length of treatment of three months for acute pericarditis, six months in recurrent cases). This approach is discussed in greater detail elsewhere. (See "Acute pericarditis: Treatment and prognosis", section on 'Our approach to glucocorticoid dosing'.)

There are conflicting data, mostly derived from observational studies, regarding the optimal dosing and tapering of glucocorticoid therapy when used to treat pericarditis. Although high doses of glucocorticoids (eg, prednisone 1 mg/kg/day) have been recommended in the European Society of Cardiology (ESC) guidelines, use of lower doses (eg, prednisone 0.2 to 0.5 mg/kg/day) may be equally efficacious with a reduced risk of side effects, which have been reported in up to 25 percent of patients treated with high doses [14]. Common mistakes are to use too low a dose and, more often, to taper the dose too rapidly [41].

If symptoms recur, every effort should be made not to increase or reinstitute glucocorticoids but instead control symptoms with aspirin or an NSAID. (See 'Pharmacologic therapy' above.)

Guidelines recommend osteoporosis prevention when using glucocorticoids, an issue often neglected in clinical practice. This issue is discussed in detail separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Intrapericardial glucocorticoid — Although supporting evidence is limited, for selected patients with recurrent pericarditis, intrapericardial glucocorticoid therapy is a potential option to achieve high local glucocorticoid concentrations and maintain efficacy while minimizing systemic toxicity. The 2015 ESC guidelines discuss that intrapericardial glucocorticoid therapy may be considered [14]. Such therapy may be considered as a last resort in cases with severe side effects related to systemic use. However, in our view, the utility of such an approach requires further investigation.

In a review of 84 patients with recurrent or persistent autoreactive pericarditis with effusion, pericardiocentesis with antibiotic prophylaxis was followed by intrapericardial administration of triamcinolone (300 to 600 mg/m² given in 100 mL of isotonic saline at body temperature) as a single injection and then residual pericardial fluid was drained at 24 hours; maintenance therapy consisted of colchicine (0.5 mg three times daily) for six months [7]. This regimen led to symptomatic improvement and prevented recurrence in 90 percent of patients at three months and 84 percent at one year. Most relapses were asymptomatic and only symptomatic large effusions were retreated using the higher triamcinolone dose. Transient cushingoid symptoms developed in 13 and 30 percent of patients given 300 and 600 mg/m², respectively.

There are technical considerations that may limit the usefulness of intrapericardial therapy. If the patient has a large or moderate sized pericardial effusion, intrapericardial therapy is straightforward. This is usually accomplished via intrapericardial catheter following drainage of the pericardial effusion. If the patient has a small or no pericardial effusion, pericardioscopy must be performed to utilize this form of treatment. (See "Pericardial effusion: Approach to diagnosis", section on 'Pericardial fluid analysis and biopsy'.)

Interleukin 1 inhibitors — Evidence from randomized trials and observational studies supports the use of IL-1 inhibitor (rilonacept or anakinra) for patients with recurrent pericarditis. We use these agents as fourth-line therapy in patients with an inflammatory phenotype (see 'Inflammatory phenotype' above). Use of rilonacept or anakinra may be especially helpful for glucocorticoid- or colchicine-dependent patients with an inflammatory phenotype [42-46].

Withdrawal of IL-1 inhibitor is often followed by recurrences that may require the reintroduction of the drug but are generally responsive to medical therapies without requiring the use of glucocorticoids [47]. The optimal duration of therapy is unknown, although it is probably at least six months or longer [48].

Rilonacept is a fusion protein that functions as an IL-1 alpha and IL-1 beta cytokine trap. Rilonacept promoted rapid resolution of symptoms and reduced risk of recurrence in a randomized trial enrolling 86 adults and adolescents (mean age 44.7 years) with recurrent pericarditis [49]. Pain resolution or near-resolution occurred at a median of five days and C-reactive protein (CRP) normalization at a median of seven days. Rilonacept was administered by subcutaneous injection as a loading dose of 320 mg (or 4.4 mg per kg of body weight in patients <18 years of age), followed by weekly maintenance doses of 160 mg (or 2.2 mg per kg in patients <18 years of age). After the 12-week run-in period, 61 patients were randomly assigned to weekly rilonacept or placebo. At the median time to first recurrence in the placebo group (8.6 weeks), pericarditis recurrence occurred in 23 of 31 patients (74 percent) in the placebo group compared to 2 of 30 patients (7 percent) in the rilonacept group. Four patients had adverse events leading to discontinuation of rilonacept during the run-in period. The most common adverse events were injection-site reactions and upper respiratory tract infections. The FDA approved the use of rilonacept to treat recurrent pericarditis and reduce the risk of recurrence in adults and children 12 years and older in March 2021 [50].

Anakinra is a recombinant IL-1 receptor antagonist that reduced the risk of further recurrences in patients with recurrent pericarditis in a small randomized trial and in observational studies:

●In the AIRTRIP trial, 21 patients with at least three episodes of recurrent pericarditis (who also had elevated CRP levels, colchicine resistance, and glucocorticoid dependence) were treated with anakinra (2 mg/kg up to 100 mg daily maximum) for two months [51]. After two months, and following resolution of pericarditis symptoms, patients were randomized in a double-blind fashion to continue anakinra (11 patients) or switch to placebo (10 patients) for six months or until symptoms recurred. After a median follow-up of 14 months, patients in the anakinra group had significantly fewer recurrences (18 versus 90 percent) and greater symptom-free survival compared with patients receiving placebo. However, 20 of 21 patients receiving anakinra experienced a side effect (primarily local skin reactions, although herpes zoster, elevated liver transaminases, and optic neuropathy were also reported), compared with none of the patients receiving placebo. Patients treated with anakinra were able to wean off of glucocorticoids.

●In one retrospective review of 13 patients with recurrent pericarditis refractory to traditional therapy, all 13 patients had at least partial resolution of symptoms following treatment with anakinra, with 11 of 13 patients remaining symptom-free and off of other therapies (NSAIDs, colchicine, and glucocorticoids) at median follow-up of 17 months [45].

●In an international registry of glucocorticoid-dependent and colchicine-resistant recurrent pericarditis (IRAP registry), which included 224 patients (mean age 46 years, 75 percent idiopathic, 91 percent with elevated CRP, 88 percent with pericardial effusion) with a median duration of disease of 17 months (interquartile range 9 to 33), significant reductions were seen in pericarditis recurrence (from 2.3 to 0.4 recurrences per patient per year) and glucocorticoid use (from 80 percent to 27 percent) following six months of therapy with anakinra, with no serious adverse events reported [52].

Scant evidence is available on use of canakinumab (an immunoglobulin G1 monoclonal antibody against IL-1 beta that blocks binding to the IL-1 receptor complex) for treatment of recurrent pericarditis. Case reports describe use of this treatment in patients with pericarditis with or without associated rheumatologic disorders [53,54]. Canakinumab has been generally less efficacious to control pericarditis, probably because of specific IL-1 beta blockade instead of the combined inhibition of both IL-1 alpha and beta with anakinra and rilonacept [55].

A phase II/III study with an IL-1 inhibitor, goflikicept, has shown similar efficacy to treat idiopathic recurrent pericarditis [56].

Other immune therapy — Fourth-line agents for patients with a noninflammatory phenotype include IVIG (preferred for patients with an autoimmune disorder) and azathioprine (preferred for patients with no identified autoimmune disorder). (See 'Our approach' above.).

The 2015 ESC guidelines include recommendations for azathioprine (2 mg/kg/day to be slowly uptitrated) and human IVIG (400 to 500 mg/kg/day IV for five days, with repeated cycles as needed according to the clinical response).

Limited evidence is available for these therapies. In an observational study of 46 patients with idiopathic recurrent pericarditis, patients with recurrent pericarditis treated with azathioprine had a low rate of recurrence and those that were glucocorticoid-dependent were able to taper glucocorticoid therapy [57]. However, nearly half of these patients had not received prior treatment with colchicine which is now a key component of the initial therapy for acute pericarditis. Small case series suggest that IVIG may be helpful in patients with recurrent pericarditis refractory to other therapies [58,59].

Limited evidence suggests that methotrexate and mycophenolate mofetil may be effective in patients with recurrent pericarditis not responsive to glucocorticoid therapy, glucocorticoid-dependent, or with intolerable glucocorticoid side effects [60].

Role of pericardiectomy — Pericardiectomy is an option for patients with recurrent pericarditis who have persistent symptoms after failure of medical regimens including NSAID or aspirin, colchicine, and glucocorticoid. In this setting, the potential benefits and risks of fourth-line drug regimens and of pericardiectomy (as an alternative to drug therapy) are discussed with the patient. The 2015 ESC guidelines recommend pericardiectomy as a last option in patients that are refractory to all medical therapies [14]. However, in individuals with ongoing symptoms and relapses in spite of medical therapy, pericardiectomy appears to be a safe and frequently effective treatment option which can spare months to years of immunosuppression when performed at experienced centers.

The largest reported cohort of patients with chronic recurrent pericarditis (mean six to seven relapses) included 184 patients treated at a single referral center from 1994 through 2005, with significant baseline differences noted between the two groups (patients in the surgical group had more relapses [6.9 versus 5.5 in the medical treatment group] and were more likely to have been taking colchicine or glucocorticoid) [61]. Surgery for pericardiectomy appears to be safe, with no deaths and only two major complications (one stroke, one episode of bleeding requiring reoperation) in the immediate postoperative period and no significant difference in all-cause mortality over an average follow-up of 5.5 years. Additionally, patients treated with surgical pericardiectomy had significantly fewer relapses (9 versus 29 percent in the medical treatment group).

One concern is the prospect of impaired wound healing when sternotomy is performed in patients who have had a prolonged exposure to high doses of prednisone. However, glucocorticoid use is not an absolute contraindication to proceeding with pericardiectomy. Glucocorticoids can be tapered relatively quickly after the procedure.

Recurrent pain without objective evidence of disease — A difficult management problem is presented by the patient who reports recurrence of pain, but in whom no clinical or laboratory evidence of pericarditis can be elicited. This problem is most likely to occur in more chronic cases in which numerous recurrences have been suppressed by prednisone [39]. The cause of this phenomenon is unknown, but the need to withhold prednisone is clear. The problem is further complicated by the fact that, in some patients who are having a recurrence, pain precedes objective evidence of pericarditis.

It is necessary to explain to the patient that the pain may not be a manifestation of recurrence. However, patients who have experienced frequent recurrences may be hard to convince; as a result, it is important to carefully describe the clinical dilemma and explain the need to stop prednisone or not to start a new course of glucocorticoid therapy.

Our approach is as follows:

●The pain is treated by simple analgesic remedies, and glucocorticoids are avoided for five to seven days.

●The patient is then reexamined, and ECG, chest radiograph, echocardiogram, erythrocyte sedimentation rate, CRP, and white blood cell count are obtained [3]. CMR imaging with delayed enhancement may be considered if the diagnosis remains uncertain after the above testing, as it is highly sensitive for pericardial inflammation. Signs of pericarditis that qualify for establishment of the diagnosis include pericardial rubs, ECG changes, a pericardial effusion, and pericardial inflammation shown by CMR. An otherwise unexplained elevation in serum CRP is also suggestive of recurrent pericarditis in these patients.

●If signs of pericarditis are present, another course of treatment as outlined above is begun.

●If there is no objective evidence of pericarditis, the patient is told that, although the pain is indistinguishable from that of previous episodes, pericarditis is no longer present and that it is not known why the pain has recurred. Pain management should be initiated at this point.

●Pain management begins with acetaminophen, but more potent analgesics can be given, if necessary. If the pain is still not controlled, the patient is referred to a pain clinic with periodic monitoring for pericarditis.

PROGNOSIS

General prognosis — Overall prognosis is excellent for most patients with idiopathic recurrent pericarditis, although quality of life can be severely affected in patients with recurrent, incessant, or chronic pericarditis. Severe complications are uncommon even with multiple recurrences [1-3,9,13,23,24,62].

Though symptoms associated with recurrent pericarditis can be uncomfortable and alter a patient's quality of life, the overall prognosis is generally good, and life-threatening complications (eg, cardiac tamponade, constrictive pericarditis) only rarely develop, although subclinical constrictive physiology may be evident in some patients on echocardiographic examination.

Risk of constrictive pericarditis — One of the most worrisome potential complications is evolution toward constrictive pericarditis. A common belief is that the risk of constrictive pericarditis may be related to the number of recurrences, although it has been well demonstrated that the risk is essentially related to the etiology: high risk for bacterial pericarditis (tuberculous and purulent), intermediate risk for immune-mediated and neoplastic pericarditis, low risk for viral pericarditis, and no known risk for idiopathic recurrent pericarditis [63].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pericardial disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pericarditis in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Pericarditis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Recurrent pericarditis, which occurs in up to one-third of patients following a previous attack of acute pericarditis, is characterized by return of symptoms of acute pericarditis after a symptom-free interval of at least four to six weeks. The recurrence of symptoms can be at any point following the cessation of acute pericarditis symptoms, but usually occurs weeks to months later. (See 'Definitions' above.)

●Causes – Most cases of recurrent pericarditis are likely caused by an autoimmune process, although a minority of cases may be due to viral infection. (See 'Pathogenesis' above.)

●Symptoms – The presenting symptoms of recurrent pericarditis are generally similar to those for acute pericarditis, although the presenting symptoms are frequently less intense during recurrences. The most frequent symptom of recurrent pericarditis is pleuritic chest pain. (See 'Key features' above.)

●Diagnosis – Recurrent pericarditis is diagnosed in a patient with a prior episode of acute pericarditis who develops recurrent symptoms (typically pleuritic chest pain) and at least one sign of pericardial inflammation (fever, pericardial rub, characteristic electrocardiogram changes, new or worsening pericardial effusion, elevation of an inflammatory marker, or evidence of pericardial inflammation on cardiovascular magnetic resonance or computed tomography) after an at least four- to six-week symptom-free interval (table 1). (See 'Diagnosis' above.)

●General measures – General management of recurrent pericarditis includes effective communication with and education of the patient about the expected disease course and importance of treatment adherence, including the role of activity restriction to avoid recurrence. (See 'General measures' above.)

●Pharmacologic therapy – The following approach is for nonpregnant patients with recurrent pericarditis (table 2)(see 'Our approach' above):

•Initial therapy – For most patients with recurrent pericarditis, we recommend combination therapy with colchicine plus either a nonsteroidal antiinflammatory drug (NSAID) or aspirin (table 2), rather than NSAID alone (Grade 1B). We treat most patients with ibuprofen plus colchicine, although acceptable alternatives are aspirin plus colchicine or indomethacin plus colchicine (table 2). The duration of therapy is generally at least one month and is guided by the time to resolution of symptoms and normalization of inflammatory biomarkers. (See 'NSAID or aspirin' above and 'Colchicine' above.)

•Glucocorticoid plus colchicine – For patients with recurrent pericarditis with persistent symptoms on colchicine plus NSAID (or aspirin) or who have a contraindications to NSAID and aspirin therapy, we suggest treatment with glucocorticoid therapy plus colchicine (Grade 2C). We use moderate initial dosing (eg, 0.2 to 0.5 mg/kg/day of prednisone) followed by a slow taper (rather than high doses with a rapid taper) (table 2). (See 'Glucocorticoids' above.)

•Triple therapy – For patients with persistent symptoms on dual therapy with glucocorticoid therapy plus colchicine, we suggest addition of aspirin therapy (triple therapy) (table 2) (Grade 2C).

•Fourth line therapy – For patients with recurrent pericarditis with persistent symptoms despite third-line therapy, we treat based upon whether an inflammatory phenotype is present. In this setting, the potential benefits and risks of immune therapy, and of pericardiectomy as an alternative, are discussed with the patient. (See 'Role of pericardiectomy' above.)

-For patients with an inflammatory phenotype (see 'Inflammatory phenotype' above), we suggest an interleukin 1 inhibitor (rilonacept or anakinra) (table 2) (Grade 2C). (See 'Interleukin 1 inhibitors' above.)

-For patients with a noninflammatory phenotype, options include intravenous immunoglobulin (preferred for patients with an autoimmune disorder) and azathioprine (preferred for patients with no identified autoimmune disorder) (table 2). (See 'Other immune therapy' above.)

●Role of pericardiectomy – Pericardiectomy is an option for patients with recurrent pericarditis after failure of medical regimens including NSAID (or aspirin), colchicine, and glucocorticoid. Pericardiectomy is an effective therapy which can spare months to years of immunosuppression when performed at experienced centers. (See 'Our approach' above and 'Role of pericardiectomy' above.)

●Prognosis – The overall prognosis for most patients with idiopathic recurrent pericarditis is excellent, with only a minority of patients having a recurrent, incessant, or chronic course. The risk of developing constrictive pericarditis is low for patients with viral or idiopathic recurrent pericarditis. (See 'Prognosis' above.)